WO2025193763A1 - Method for increasing survival in patients with cancer - Google Patents

Abstract

What is described is a method of increasing survival in patients with cancer comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of a CXCR1 and/or CXCR2 antagonist or a pharmaceutically suitable solvate or salt thereof; measuring whether the patients are alive or dead; measuring whether the cancer has progressed; computing (a) a median duration from randomization or starting administering the CXCR1 and/or CXCR2 antagonist to the time of patients' death or (b) a median duration from randomization or starting administering the CXCR1 and/or CXCR2 antagonist to the time when the patients' cancer has progressed or death; wherein the CXCR1 and/or CXCR2 antagonist increases the median duration in (a) and/or (b).

Description

METHOD FOR INCREASING SURVIVAL IN PATIENTS WITH CANCER

GOVERNMENT RIGHTS

[001] This invention was made with government support under Grant Numbers CA217591 and HL142389 awarded by the National Institutes of Health. The government has certain rights in the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

[002] This application claims the benefit of U.S. Provisional Patent Application No. 63/564,132, filed March 12, 2024, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

[003] The disclosure herein relates to a method for increasing survival in patients with cancer comprising administering to a patient a therapeutically effective amount of a compound of formula SX-682, an antagonist to CXCR1 and CXCR2 receptors.

BACKGROUND

[004] In recent years, the development of new cancer treatments has focused on molecular targets, particularly proteins, implicated in cancer progression. The list of molecular targets involved in tumor growth, invasion and metastasis continues to expand, and includes proteins overexpressed by tumor cells as well as targets associated with systems supporting tumor growth such as the vasculature and immune system. The number of therapeutic or anticancer agents designed to interact with these molecular targets also continues to increase. A large number of targeted cancer medicines are now approved for clinical use with many more in the developmental pipeline. Chemokines are chemotactic proteins that have the potential to attract macrophages, T-cells, eosinophils, basophils, neutrophils, and endothelial cells to sites of inflammation and tumor growth. Chemokines are typically low molecular mass (7-9 kD) proteins that can be divided into four subfamilies: CC (or -chemokines), CXC, C (or y- chemokines) and CX3C (or 8-chemokines). The chemokines are categorized through their primary amino acid structure. The CXC subfamily is characterized by two conserved Cys residues (C) near the N- terminus and separated by an amino acid (X). The CXC-chemokines include, for example, CXCL8 (IL-8), CXCL7 (NAP-2), CXC 1 (GROa), CXCL2 (GRO ), CXCL3 (GROy), CXCL5 (ENA-78), CXCL6 (GCP-2), CXCL10 (IP- 10), CXCL9 (MIG) and CXCL4 (PF4). The CXC subfamily of chemokines is further characterized by the presence or absence of a specific amino acid sequence, glutamic acid-leucine-arginine (or ELR for short) immediately before the first Cys residue of the CXC motif. Those chemokines with the ELR motif (ELRCXC) are important for the recruitment and activation of neutrophils to sites of inflammation. CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8 are examples of ELRCXC chemokines.

[005] The ELRCXC-chemokines mediate their biological activity through interaction with the chemokine receptors CXCR1 and CXCR2. CXCR1 binds CXCL8 and CXCL6 with high affinity while CXCR2 binds all ELRCXC chemokines with high affinity.

[006] Malignant cells rely on aberrant paracrine and autocrine signaling for proliferation and survival. The chemokine receptors CXCR1 and CXCR2 are identified as potential contributors to this aberrant signaling. While not fully understood, elevated levels of ELRCXC chemokines and/or CXCR1 and/or CXCR2 receptors have been identified in samples from patients with solid tumors and with blood cancers (together cancers) such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myelofibrosis (MF), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). There is a significant need in the art to find ways to therapeutically take advantage of these changes and increase human survival in patients with cancer

SUMMARY

[007] This Summary introduces a selection of concepts in simplified form that are described further below in the Detailed Description. This Summary neither identifies key or essential features, nor limits the scope, of the claimed subject matter.

[008] A method is provided for increasing survival in patients with cancer comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of SX-682 or a pharmaceutically suitable solvate or salt thereof; measuring whether the patients are alive or dead; measuring whether the cancer has progressed; computing (a) a median duration from randomization or starting administering SX-682 to the time of patients’ death or (b) a median duration from randomization or starting administering SX-682 to the time when the patients’ cancer has progressed or death; wherein SX-682 increases the median duration in (a) and/or (b).

[009] In certain embodiments of the method, the cancer is selected from the group consisting of melanoma, lung cancer, pancreatic cancer, prostate cancer, myelodysplastic syndrome (MDS), myelofibrosis (MF), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and chronic myelomonocytic leukemia (CMML).

[0010] In one embodiment of the method, a median duration is increased by 2, 4 or months or more.

[0011] In certain embodiments, the median duration is selected from OS, PFS, DFS, RFS and EFS.

[0012] In certain embodiments, the increased median duration is statistically significant.

[0013] In one embodiment of the method, the cancer comprises a melanoma increasing in size in response to treatment with an anti-PD-1 or anti-PD-Ll blocking antibody.

[0014] In one embodiment of the method, the cancer comprises a myelodysplastic syndrome that is refractory to a hypomethylating agent.

[0015] In one embodiment of the method, the cancer comprises a melanoma that is unresectable or metastatic.

[0016] In one embodiment of the method, the cancer comprises a melanoma wherein the treatment further comprises administering an antibody selected from the group consisting of ipilimumab, abatacept, nivolumab, pembrolizumab, tremelimumab, pidilizumab, atezolizumab, durvalumab, avelumab, nivolumab, pembrolizumab, lambrolizumab, MEDI-0680, pidilizumab, AMP-224, atezolizomab, durvalumab, BMS-936559, MSB0010718C, BMS-986016, IMP-731, IMP-321, urelumab, PF-05082566, RG-7888, lucatumumab, dacetuzumab, varlilumab, enoblituzumab, G7155, and FPA-008.

[0017] In one embodiment of the method, the cancer comprises a melanoma wherein the treatment further comprises administering an antibody directed to a ligand selected from the group consisting of B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7- H4, B7-H5 (VISTA), B7-H6CD40, CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4- 1BBL, CD 137 (4- IBB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, T AILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, ED AR, XEDAR, TACI, APRIL, BCMA, LTPPR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, ED AR, EDAI, XEDAR, EDA2, TNFR1, lymphotoxin a/TNFp, TNFR2, TNFa, LTpR, lymphotoxin aip2, FAS, FASL, RELT, DR6, TROY, NGFR, IL-6, IL-10, TGF-P, VEGF, CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4

[0018] In one embodiment of the method, the cancer comprises a melanoma wherein the treatment further comprises administering an antibody that binds to a checkpoint inhibitor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4,.

[0019] In one embodiment of the method, the cancer comprises a melanoma wherein the treatment further comprises administering an antibody that binds to an agonist of a protein selected from the group consisting of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2.

[0020] In one embodiment of the method the treatment further comprises administering an IDO and/or TDO inhibitor-selected from the group consisting of indoximod, GDC-0919, F001287, GDC-0919 (NLG919), F001287, epacadostat (INCB024360), IDO-IN-1, IDO-IN-2, navoximod (IDO-IN-7).

[0021] In one embodiment of the method the treatment further comprises administering a

Janus kinase inhibitor selected from the group consisting of AT9283 (CID 135398495), AZD1480 (CID 16659841), baricitinib (CID 44205240), BMS-911543 (CID 50922691), fedratinib (CID 16722836), filgotinib (GLPG0634, CID 49831257), gandotinib (LY2784544, CID 46213929), INCB039110 (itacitinib, CID 53380437), lestaurtinib (CID 126565), momelotinib (CYT0387, CID 25062766), NS-018 (ilginatinib, CID 46866319), pacritinib (SB1518, CID 46216796), peficitinib (ASP015K, CID 57928403), ruxolitinib (CID 25126798), tofacitinib (CID 9926791), INCB052793 CID 118467751), XL019 (CID 57990869), WP1066 (CID 11210478), TG101209 (CID 16722832), NVP-BSK805 (CID 46398810), AZ960 (CID 25099184), ZM-39923 (CID 3797), ropsacitinib (CID 130339268), SAR-20347 (CID 71727668), GDC-046 (CID 49839561), deucravacitinib (CID 134821691), WHLP258 (CID 3798), brepocitinib (CID 118878093), ritlecitinib (CID 1 18115473), FM-381 (CID 122197584), oclacitinib (CID 44631938), decernotinib (CID 59422203), cerdulatinib (CID 44595079), zotiraciclib (CID 16739650), CHZ868, AJ1- 11095 and a pharmaceutically acceptable form thereof.

[0022] In one embodiment of the method the treatment further comprises administering a BCL-2 inhibitor selected from the group consisting of venetoclax (CID 49846579), navitoclax (CID 24978538), ABT-737 (CID 11228183), obatoclax (CID 11404337), AZD-4320 (CID 86661883), gossypol (3503), pelcitoclax (CID 76900653), S55746 (CID 71654876), TW-37 (CID 11455910), sabutoclax (CID 46236925), HA14-1 (CID 3549), A-385358 (CID 11556440), lisaftoclax (CID 137355972), apogossypolone (CID 135513044), BM-1197 (CID 60204010), BM-957 (CID 71456995), BCL-2-IN-4 (CID 163322037), BM-1074 (CID 56933431), BCL-2- IN-5 (CID 163322038), BCL-2-IN-6 (CID 163409068), BCL-2-IN-7 (CID 163409069), BDA- 366 (CID 91826545), BCL-2-IN-2 (CID 146681199), BCL-2-IN-8 (CID 163322290), and a pharmaceutically acceptable form thereof.

[0023] In one embodiment of the method the cancer comprises a myelodysplastic syndrome, and the treatment further comprises administering a hypomethylating agent selected from the group consisting of decitabine, decitabine with cedazuridine, and azacitidine.

[0024] In one embodiment of the method the cancer comprises multiple myeloma, and the treatment further comprises administering an anticancer therapy selected from the group consisting of daratumumab, bortezomib, carfilzomib, lenalidomide, prednisone and dexamethasone.

[0025] In one embodiment of the method, the treatment further comprises administering anti-PD-1 antibody and an anti-CTLA4 antibody.

[0026] In one embodiment of the method, the cancer comprises a prostate cancer and the treatment further comprises administering abiraterone, enzalutamide, apalutamide or darolutamide.

[0027] In another embodiment, a method is provided for increasing survival in patients with melanoma, comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of SX-682 or a pharmaceutically suitable solvate or salt thereof together with an anti-PD-1 or anti-PD-Ll blocking antibody; wherein the patient has a melanoma tumor increasing in size in response to treatment with an anti-PD-1 or anti-PD-Ll blocking antibody; measuring whether the patients are alive or dead; measuring whether the melanoma has progressed; computing (a) a median duration from randomization or starting administering SX-682 to the time of patients’ death or (b) a median duration from randomization or starting administering SX-682 to the time when the patients’ cancer has progressed or death; wherein SX-682 increases the median duration in (a) and/or (b).

[0028] In one embodiment of the method, the treatment furthering comprises administering a LAG-3 blocking antibody to the patients.

[0029] In still another embodiment, a method is provided for increasing survival in patients with myelodysplastic syndrome, comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of SX- 682 or a pharmaceutically suitable solvate or salt thereof; wherein the patients have myelodysplastic syndrome that has failed treatment with a hypomethylating agent; measuring whether the patients are alive or dead; computing a median duration from randomization or starting administering SX-682 to the time of patients’ death; wherein SX-682 increases the median duration.

[0030] In yet still another embodiment, a method is provided for treating a patient with melanoma comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of SX-682 or a pharmaceutically suitable solvate or salt thereof; wherein the melanoma is unresectable or metastatic melanoma; wherein the melanoma was increasing in size in response to treatment with an anti-PD-1 or anti-PD- l blocking antibody; administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an anti-PD-1 or anti-PD-Ll blocking antibody.

[0031] One embodiment of the method comprises further administering a pharmaceutical composition comprising a LAG-3 blocking antibody.

[0032] In one embodiment a method is provided for increasing survival in patients with cancer comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of CXCR2 antagonist or a pharmaceutically suitable solvate or salt thereof; measuring whether the patients are alive or dead; measuring whether the cancer has progressed; computing (a) a median duration from randomization or starting administering SX-682 to the time of patients’ death or (b) a median duration from randomization or starting administering SX-682 to the time when the patients’ cancer has progressed or death; wherein SX-682 increases the median duration in (a) and/or (b).

[0033] In certain embodiments of the method, the CXCR2 antagonist is selected from the group comprising a CXCR2 receptor antagonist consisting of formula I, wherein R1 and R2 are independently selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein R3 is selected from — B(R4R5), — R6 — B(R4R5), R6, — C(O) — R6, — O — R6, — S(O)y— R6 (wherein y=0, 1, or 2), — P(O)— (R4R5) and — N(R7R8); wherein R4 and R5 are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R4 and R5 together form a cyclic ester, or an acid anhydride (either mixed or symmetrical); wherein R6 is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; wherein R7 and R8 are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl and heterocyclylalkyl; R7 and R8 are both oxygen to form a nitro group; or R7 and R8 together with the nitrogen to which they are attached, form a heterocyclyl; and wherein R9 is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; or — B(R4R5), — BF3-M+, — R6— B(R4R5), — R6— BF3-M+, R6, — C(O)— R6, — O— R6, — S(O)y— R6 (wherein y=0, 1, or 2), — P(O) — (R4R5) and — N(R7R8); or an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; wherein XI is carbon or nitrogen; X2 is — S(O)y — (wherein y=0, 1, or 2), — N(R9) — , or oxygen; and n is an integer between 0 and 8; or a pharmaceutically suitable solvate or salt thereof, wherein the above R group terms are defined as provided in U.S. Patent 10,660,909.

[0034] In certain embodiments of the method, the CXCR2 antagonist is selected from the group consisting of: SX-682 [PubChem Compound ID (CID) 90467234], SX-576 (CID 46897163), SX-517 (CID 46897162), navarixin (CID 9865554), danirixin (CID 24780598), ladarixin (CID 11372270), AZD5069 (CID 56645576), DF2755A (CID 45110932), SB225002 (CID 3854666), elubrixin (CID 10479502), SRT3190 (CID 59149652), vimnerixin (CID 71209600), SCH563705 (CID 10310100), SB265610 (CID 9841667), SRT3109 (CID 44602493), SB332235 (CID 9887803), reparixin, repertaxin, LY3041658, BMS-986253, and AZD8309 (CID 12073810), and a pharmaceutically acceptable form thereof.

[0035] In another aspect, an embodiment provides a method for treating hematologic malignancies in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a CXCR2 antagonist in combination with at least one other anti -cancer therapy.

[0036] In certain embodiments of the method the hematologic malignancy is selected from myelodysplastic syndromes (MDS), myelofibrosis (MF), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myeloid leukemia (CML); chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL ), and chronic myelomonocytic leukemia (CMML).

[0037] In certain embodiments of the method the CXCR2 antagonist is selected from the group consisting of: SX-682 [PubChem Compound ID (CID) 90467234], SX-576 (CID 46897163), SX-517 (CID 46897162), navarixin (CID 9865554), danirixin (CID 24780598), ladarixin (CID 11372270), AZD5069 (CID 56645576), DF2755A (CID 45110932), SB225002 (CID 3854666), elubrixin (CID 10479502), SRT3190 (CID 59149652), vimnerixin (CID 71209600), SCH563705 (CID 10310100), SB265610 (CID 9841667), SRT3109 (CID 44602493), SB332235 (CID 9887803), reparixin, repertaxin, LY3041658, BMS-986253, and AZD8309 (CID 12073810), and a pharmaceutically acceptable form thereof. [0038] In certain embodiments of the method the anti -cancer therapy consists of one or more agents selected from BCL-2 inhibitors, hypomethylating agents (HMAs), Janus kinase inhibitors, chemotherapy, and radiation therapy.

[0039] In one embodiment of the method the CXCR2 antagonist is SX-682.

[0040] In certain embodiments of the method the BCL-2 inhibitor is selected from the group consisting of venetoclax (CID 49846579), navitoclax (CID 24978538), ABT-737 (CID 11228183), obatoclax (CID 11404337), AZD-4320 (CID 86661883), gossypol (3503), pelcitoclax (CID 76900653), S55746 (CID 71654876), TW-37 (CID 11455910), sabutoclax (CID 46236925), HA14-1 (CID 3549), A-385358 (CID 11556440), lisaftoclax (CID 137355972), apogossypolone (CID 135513044), BM-1197 (CID 60204010), BM-957 (CID 71456995), BCL-2-IN-4 (CID 163322037), BM-1074 (CID 56933431), BCL-2-IN-5 (CID 163322038), BCL-2-IN-6 (CID 163409068), BCL-2-IN-7 (CID 163409069), BDA-366 (CID 91826545), BCL-2-IN-2 (CID 146681199), BCL-2-IN-8 (CID 163322290), and a pharmaceutically acceptable form thereof.

[0041] In certain embodiments of the method the hypomethylating agent is selected from the group consisting of decitabine, decitabine with cedazuridine, and azacytidine.

[0042] In certain embodiments of the method the Janus kinase inhibitor is selected from the group consisting of AT9283 (CID 135398495), AZD1480 (CID 16659841), baricitinib (CID 44205240), BMS-911543 (CID 50922691), fedratinib (CID 16722836), filgotinib (GLPG0634, CID 49831257), gandotinib (LY2784544, CID 46213929), INCB039110 (itacitinib, CID 53380437), lestaurtinib (CID 126565), momelotinib (CYT0387, CID 25062766), NS-018 (ilginatinib, CID 46866319), pacritinib (SB1518, CID 46216796), peficitinib (ASP015K, CID 57928403), ruxolitinib (CID 25126798), tofacitinib (CID 9926791), INCB052793 CID 118467751), XL019 (CID 57990869), WP1066 (CID 11210478), TG101209 (CID 16722832), NVP-BSK805 (CID 46398810), AZ960 (CID 25099184), ZM-39923 (CID 3797), ropsacitinib (CID 130339268), SAR-20347 (CID 71727668), GDC-046 (CID 49839561), deucravacitinib (CID 134821691), WHI-P258 (CID 3798), brepocitinib (CID 118878093), ritlecitinib (CID 118115473), FM-381 (CID 122197584), oclacitinib (CID 44631938), decemotinib (CID 59422203), cerdulatinib (CID 44595079), AJ1-11095, zotiraciclib (CID 16739650), and a pharmaceutically acceptable form thereof. [0043] In certain embodiments of the method the CXCR2 inhibitor, preferably SX-682, is combined with one or more anti-cancer therapies selected from the group of hypomethylating agents (e.g., decitabine, azacytadine), BCL-2 inhibitors (e.g., venetoclax), Janus kinase inhibitors (e.g., ruxolitinib), daratumumab, bortezomib, carfilzomib, lenalidomide, prednisone and dexamethasone.

[0044] In some embodiments of the method for increasing survival in a patient with cancer, SX-682 may be replaced with another CXCR2 inhibitor.

[0045] In some embodiments of the method for increasing survival in a patient with cancer, SX-682 may be replaced with a CXCR2 inhibitor having formula I.

[0046] In some embodiments of the method for increasing survival in a patient with cancer, SX-682 may be replaced with a CXCR2 inhibitor selected from the group consisting of SX-576 (CID 46897163), SX-517 (CID 46897162), navarixin (CID 9865554), danirixin (CID 24780598), ladarixin (CID 11372270), AZD5069 (CID 56645576), DF2755A (CID 45110932), SB225002 (CID 3854666), elubrixin (CID 10479502), SRT3190 (CID 59149652), vimnerixin (CID 71209600), SCH563705 (CID 10310100), SB265610 (CID 9841667), SRT3109 (CID 44602493), SB332235 (CID 9887803), reparixin, repertaxin, AZD8309 (CID 12073810), anti- CXCR2 antibodies such as LY3041658, and anti-CXCR2 ligand antibodies such as anti-IL-8 (Interleukin-8) antibodies (e.g., BMS-986253), or a pharmaceutically acceptable form and/or solvate thereof.

[0047] In preferred embodiments of the method for increasing survival in a patient with cancer, the cancer is melanoma, lung cancer, pancreatic cancer, prostate cancer, myelodysplastic syndrome (MDS), myelofibrosis (MF), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and chronic myelomonocytic leukemia (CMML).

[0048] In certain embodiments, the patient whose survival is being increased in accordance with the methods of the invention is a newly-diagnosed AML patient who is ineligible for standard intensive chemotherapy. The subject may be a newly-diagnosed AML patient aged 75 years or older or a newly-diagnosed AML patient having a comorbidity that precludes use of standard intensive chemotherapy. [0049] In one embodiment, the patient whose survival is being increased has a cancer that is increasing in size in response to treatment with an anti-PD-1 or anti-PD-Ll blocking antibody (i.e., failing anti-PD-1 or anti-PD-Ll blocking antibody therapy).

[0050] In one embodiment, the patient whose survival is being increased has a cancer (e g., myelodysplastic syndrome) that is refractory to a hypomethylating agent (i.e., failing hypomethylating agent therapy).

[0051] In one embodiment the cancer is unresectable or metastatic melanoma.

[0052] In still other embodiments the cancer includes, but is not limited to: cancers of the colorectum, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including basal carcinoma), mesothelial lining, esophagus, breast, muscle, connective tissue, lung (including small-cell lung carcinoma and non-small-cell carcinoma), adrenal gland, thyroid, kidney, lymphoid tissue, bone marrow or bone, glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma. In some embodiments of the disclosure herein, the cancer is melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, sarcoma, ovarian cancer, head and neck cancer, cervical cancer, or myelodysplastic syndromes.

[0053] The method comprises administering SX-682 or pharmaceutical compositions thereof, either alone as monotherapy, or in combination with one or more additional agents.

[0054] In some embodiments, such additional agents comprise ipilimumab, abatacept, nivolumab, pembrolizumab, relatlimab, tremelimumab, pidilizumab, atezolizumab, durvalumab, avelumab, nivolumab, pembrolizumab, lambrolizumab, MEDI-0680, pidilizumab, AMP-224, atezolizomab, durvalumab, BMS-936559, MSB0010718C, BMS-986016 (W010/19570, WO14/08218), IMP-731, IMP-321 (W008/132601, WO09/44273), urelumab, PF-05082566, RG-7888, lucatumumab, dacetuzumab, varlilumab, enoblituzumab, G7155, and FPA-008.

[0055] In some embodiments, such additional agents comprise an antibody directed to a ligand selected from the group consisting of B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7- H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), B7-H6CD40, CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, ED AR, XEDAR, TACI, APRIL, BCM A, LT0PR, LIGHT, DcR3, HVEM, VEGI/TL1 A, TRAMP/DR3, ED AR, EDAI , XEDAR, EDA2, TNFR1, lymphotoxin a/TNFp, TNFR2, TNFa, LTpR, lymphotoxin aip2, FAS, FASL, RELT, DR6, TROY, NGFR, IL-6, IL- 10, TGF-P, VEGF, CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4.

[0056] In some embodiments, such additional agents comprise an immunomodulator selected from the group consisting of CD40L, B7, B7RP1, ant-CD40, anti-CD38, anti-ICOS, 4- IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFN-a/-P, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10.

[0057] In some embodiments, such additional agents comprise an IDO and/or TDO inhibitor-selected from the group consisting of indoximod, GDC-0919, F001287, GDC-0919 (NLG919), F001287, epacadostat (INCB024360), IDO-IN-1, IDO-IN-2, navoximod (IDO-IN-7).

[0058] In some embodiments, such additional agents comprise a Janus kinase (JAK) inhibitor selected from the group consisting of AT9283 (CID 135398495), AZD1480 (CID 16659841), baricitinib (CID 44205240), BMS-911543 (CID 50922691), fedratinib (CID 16722836), filgotinib (GLPG0634, CID 49831257), gandotinib (LY2784544, CID 46213929), INCB039110 (itacitinib, CID 53380437), lestaurtinib (CID 126565), momelotinib (CYT0387, CID 25062766), NS-018 (ilginatinib, CID 46866319), pacritinib (SB1518, CID 46216796), peficitinib (ASP015K, CID 57928403), ruxolitinib (CID 25126798), tofacitinib (CID 9926791), INCB052793 CID 118467751), XL019 (CID 57990869), WP1066 (CID 11210478), TG101209 (CID 16722832), NVP-BSK805 (CID 46398810), AZ960 (CID 25099184), ZM-39923 (CID 3797), ropsacitinib (CID 130339268), SAR-20347 (CID 71727668), GDC-046 (CID 49839561), deucravacitinib (CID 134821691), WHLP258 (CID 3798), brepocitinib (CID 118878093), ritlecitinib (CID 118115473), FM-381 (CID 122197584), oclacitinib (CID 44631938), decemotinib (CID 59422203), cerdulatinib (CID 44595079), zotiraciclib (CID 16739650), AJ1- 11095 and a pharmaceutically acceptable form thereof. For these, preferably the cancer is a hematological malignancy. A preferred embodiment is increasing the survival of a myelofibrosis (MF) patient with SX-682 and ruxolitinib.

[0059] In some embodiments, such additional agents comprise a BCL-2 inhibitor selected from the group consisting of venetoclax (CID 49846579), navitoclax (CID 24978538), ABT-737 (CID 11228183), obatoclax (CID 11404337), AZD-4320 (CID 86661883), gossypol (3503), pelcitoclax (CID 76900653), S55746 (CID 71654876), TW-37 (CID 11455910), sabutoclax (CID 46236925), HA14-1 (CID 3549), A-385358 (CID 11556440), lisaftoclax (CID 137355972), apogossypolone (CID 135513044), BM-1197 (CID 60204010), BM-957 (CID 71456995), BCL-2-IN-4 (CID 163322037), BM-1074 (CID 56933431), BCL-2-IN-5 (CID 163322038), BCL-2-IN-6 (CID 163409068), BCL-2-IN-7 (CID 163409069), BDA-366 (CID 91826545), BCL-2-IN-2 (CID 146681199), BCL-2-IN-8 (CID 163322290), and a pharmaceutically acceptable form thereof. For these, preferably the cancer is a hematologic malignancy. A preferred embodiment is increasing the survival of an acute myeloid leukemia (AML) patient with SX-682 and venetoclax.

[0060] In some embodiments, such additional agents comprise a hypomethylating agent selected from the group consisting of decitabine, decitabine with cedazuridine (or other cytidine deaminase inhibitor), and azacytidine. For these, preferably the cancer is a hematologic malignancy. A preferred embodiment is increasing the survival of a myelodysplastic syndrome (MDS) patient with SX-682 alone, or in combination with either azacytidine or decitibine.

[0061] In some embodiments, such additional agents comprise daratumumab, bortezomib, carfilzomib, lenalidomide, prednisone and dexamethasone. For these, preferably the cancer is multiple myeloma.

[0062] In some embodiments, such additional agents comprise abiraterone, enzalutamide, apalutamide or darolutamide. For these, preferably the cancer is prostate cancer.

[0063] In some embodiments, such additional agents comprise radiation (e.g., localized radiation therapy or total body radiation therapy) and/or other treatment modalities of a non- pharmacological nature, such as cell therapy or vaccination. When combination therapy is utilized, SX-682 and the one additional agent(s) may be in the form of a single composition or multiple compositions, and the treatment modalities may be administered concurrently, sequentially, or through some other regimen. By way of example, the disclosure herein contemplates a treatment regimen wherein administration of SX-682 is maintained on a daily basis, with additional anticancer treatments e.g., anti-PDl antibody, carboplatin, T-cell therapy, cancer vaccination, radiation) given intermittently during the treatment period. The combination therapy may have an additive or synergistic effect. Other survival benefits of combination therapy are described hereafter. [0064] In particular embodiments, the disclosure herein contemplates increasing patient survival with the use of SX-682 in combination with immune checkpoint inhibitors. The blockade of immune checkpoints, which results in the amplification of antigen-specific T cell responses, has been shown to be a promising approach in human cancer therapeutics. Examples of immune checkpoints (enzymes, ligands and receptors), some of which are selectively upregulated in various types of tumor cells, that are candidates for blockade include indolamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase (TDO), programmed cell death protein 1 (PD1); PD1 ligand (PDL1); B and T lymphocyte attenuator (BTLA); cytotoxic T-lymphocyte associated antigen 4 (CTLA4); T-cell membrane protein 3 (TIM3); lymphocyte activation gene 3 (LAG3); adenosine A2a receptor (A2aR); and killer inhibitory receptors. Immune checkpoint inhibitors, and combination therapy therewith, are discussed in detail elsewhere herein.

[0065] In particular embodiments, the disclosure herein contemplates increasing patient survival with the use of SX-682 in combination with cancer vaccines. Cancer vaccines are used to treat established cancers not due to viral infections, and include the use of antigen vaccines, tumor cell vaccines, dendritic vaccines, deoxyribonucleic acid vaccines, and viral vector vaccines.

[0066] In particular embodiments, the disclosure herein contemplates increasing patient survival with the use of SX-682 in combination with T-cell therapy. T-cell therapy involves the isolation, expansion, and re-introduction of a cancer patient’s tumor reactive T-cells. T-cell therapy also includes the use of genetically modified T-cells expressing chimeric antigen receptors (CARs).

[0067] In other embodiments, the disclosure herein provides methods for increasing survival in a patient with cancer, comprising administering to the subject a therapeutically effective amount of at least SX-682 and at least one chemotherapeutic agent, such agents including, but not limited to alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechl or ethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors e.g., irinotecan); platinum complexes such as cisplatin and carboplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binding agents (e.g, plicamydin); antimetabolites (e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and ribonucleotide reductase inhibitors such as hydroxyurea); tubulin interactive agents (e.g, vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives, and paclitaxel); hormonal agents (e.g., estrogens; conjugated estrogens; ethinyl estradiol; diethylstilbesterol; chlortrianisen; idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone); adrenal corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone); leutinizing hormone releasing agents or gonadotropin-releasing hormone antagonists (e.g, leuprolide acetate and goserelin acetate); and antihormonal antigens (e.g., tamoxifen, antiandrogen agents such as flutamide, darolutamide, abiraterone, enzalutamide, apalutamide or darolutamide; and antiadrenal agents such as mitotane and aminoglutethimide). The disclosure herein also contemplates the use of SX-682 in combination with other agents known in the art (e.g, arsenic tri oxide) and other chemotherapeutic agents.

[0068] In further embodiments, the disclosure herein contemplates increasing patient survival, comprising administering to the subject a therapeutically effective amount of SX-682 and at least one signal transduction inhibitor (STI). In a particular embodiment, the at least one STI is selected from the group consisting of (i) bcr/abl kinase inhibitors (e.g., GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) her-2/neu receptor inhibitors (e.g., HERCEPTIN®); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); (vi) phosphatidyl inositol kinase inhibitors; (vii) farnesyl transferase inhibitors (FTIs)

[0069] In further embodiments drawn to methods of increasing survival in a patient with cancer, the administration of a therapeutically effective amount of SX-682 in combination with at least one other anticancer therapy results in a reduction of tumor size or a slowing of tumor growth greater than reduction of the tumor size or tumor growth observed by administration of one agent alone. [0070] In certain embodiments for increasing survival in a patient with a hematologic malignancy, the methods further comprise monitoring of the patient’s blast count. The patient’s peripheral blood and/or bone marrow blast count may be reduced, for example reduced to less than 25%, for example reduced to 5%, for example reduced to less than 5%, for example reduced to minimal residual disease levels, for example reduced to undetectable levels. In certain embodiments, the bone marrow blast count is reduced to between 5% and 25% and the bone marrow blast percentage is reduced by more than 50% as compared to pretreatment.

[0071] In certain embodiments for increasing survival in a patient with a hematologic malignancy or solid tumor malignancy, the methods induce a partial response. In certain embodiments, the methods induce a complete response, optionally with platelet recovery and/or neutrophil recovery. For a hematologic malignancy, the methods may induce transfusion independence of red blood cells or platelets, or both, for 4 weeks or longer, 8 weeks or longer, 10 weeks or longer, 12 weeks or longer. In certain embodiments, the methods reduce the mortality rate after a 30-day period or after a 60-day period.

[0072] In certain embodiments for increasing survival in a patient with a hematologic malignancy, the methods further comprise a step of subjecting the subject to a bone marrow transplantation. Alternatively, or in addition, the methods may further comprise a step of administering one or more additional anti-cancer agents. The one or more additional cancer agents may be selected from any agents suitable for the treatment of myeloid malignancies, preferably AML. Preferred agents may be selected from selectin inhibitors (e.g., GML1271); FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors (e g., midostaurin); cyclin-dependent kinase inhibitors; aminopeptidase inhibitors; JAK/STAT inhibitors; cytarabine; anthracycline compounds (e.g., daunorubicin, idarubicin); doxorubicin; hydroxyurea; VYXEOS®; IDH1 or IDH2 inhibitors such as enasidenib or ivosidenib; antibodies or antigen binding fragments that bind to CD70 (e.g., cusutuzumab, SEA-CD70); Smoothened inhibitors such as glasdegib, BET bromodomain inhibitors, CD123 or CD33 targeting agents, HDAC inhibitors, LSC targeting agents, AML bone marrow niche targeting agents, and NEDD8-activating enzyme inhibitors such as pevonedistat.

[0073] The Detailed Description references the accompanying drawings which form a part this application, and which show, by way of illustration, specific example implementations. Other implementations may be made without departing from the scope of the disclosure. BRIEF DESCRIPTION OF THE FIGURES

[0074] FIG. 1 shows the study design of a phase 1, open-label, dose-escalation with expansion study of SX-682 in patients with metastatic melanoma concurrently treated with pembrolizumab who were failing anti-PD-1 or anti-PD-Ll blocking antibody therapy (“melanoma trial”).

[0075] FIG. 2 shows PD data from 43 patients pooled from the melanoma trial and other solid tumor studies; BID dose (n): 25 (6), 50 (6), 100 (13), 150 (3), 200 (11), 400 (3).

[0076] FIG. 3 shows disease control rate (DCR) as a function of dose in the melanoma trial.

[0077] FIG. 4 shows a spider plot of percent change in target lesions sum of diameters in the melanoma trial.

[0078] FIG. 5 shows PFS (n=29 evaluable) in the melanoma trial dichotomized by PD- dose relationship (200 mg vs. <100 mg, P = 0.003).

[0079] FIG. 6 shows OS (n=41 intent to treat population) in the melanoma trial dichotomized by dose-PD relationship (200 mg vs. <100 mg, P = 0.037) and historical OS (Patrinely, 2020, Cancer, 126(15): 3448-3455) after progression on anti-PDl (n=180) and nivolumab plus ipilimumab, i.e., anti-CTLA4 and anti-PDl (n=67).

[0080] FIG. 7 shows the study design of a phase 1, open-label, dose-escalation with expansion study of SX-682 monotherapy in patients with HMA refractory MDS (“MDS trial”).

[0081] FIG. 8 shows the change from baseline bone marrow blasts and response in the MDS trial. Abbreviations: marrow complete remission (mCR); hematologic improvement (HI) in erythroids (HI-E), neutrophils (HI-N) and platelets (HI-P); stable disease (SD); and progressive disease (PD).

[0082] FIG. 9 shows a swimmer plot for N=26 patients in the MDS trial treated with the 200 mg BID RP2D (escalation and expansion) showing patient ID, IPSS risk, best response and dose-holding/reduction. Abbreviations: SD, stable disease; mCR, marrow complete remission; HI-P, hematologic improvement in platelets.

[0083] FIG. 10 shows responding patient in the MDS trial on SX-682 >500 days with durable hematologic improvement in platelets (HI-P). [0084] FIG. 11 shows responding patient in the MDS trial on SX-682 >500 days with durable erythroid hematologic improvement (HI-E) and transfusion independence for over four months.

[0085] FIG. 12 shows overall survival (OS) of IPSS-R high/very high risk HMA-failure patients (n=24) in the MDS trial vs. historical OS after HMA failure (n=435) (Prebet, 2011, J Clin Oncol, 29(24): 3322-3327).

[0086] FIG. 13 shows the study design of a phase 1, open -label, dose-escalation with expansion study of SX-682 in patients with unresectable pancreatic ductal adenocarcinoma (“pancreatic cancer”) who completed a minimum of 16 weeks first-line chemotherapy without evidence of disease progression (“pancreatic cancer trial”).

[0087] FIG. 14 shows the PFS in patients in the pancreatic cancer trial treated with the combination of SX-682 and nivolumab and historical PFS in the same patient population (n = 62) not treated with the combination.

[0088] FIG. 15 shows the results of direct inhibition of tumor cell proliferation of leukemia cell lines by SX-682 in a dose-dependent fashion. The leukemia cell lines included CCRF-CEM, MOLT-4, HL-60, RPMI-8226, K-562 and SR.

[0089] FIG. 16 shows the results of direct inhibition of tumor cell proliferation of nonsmall cell lung cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The non-small cell lung cancer cell lines included A549, H226, H460, H23, H522, H322M, HOP-62, and HOP-92.

[0090] FIG. 17 shows the results of direct inhibition of tumor cell proliferation of colon cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The colon cancer cell lines included COLO 205, HCT-15, HCC-2998, KM12, HCT-116, and SW-620.

[0091] FIG. 18 shows the results of direct inhibition of tumor cell proliferation of CNS cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The CNS cancer cell lines included SF-268, SNB-19, SF-295, SNB-75, and SF-539.

[0092] FIG. 19 shows the results of direct inhibition of tumor cell proliferation (melanoma cell lines by SX-682 in a dose-dependent fashion. The melanoma cell lines included LOX IMVI, MDA-MB-435, SK-MEL-5, MALME-3M, SK-MEL-2, UACC-257, M14, SK- MEL-28, and UACC-62. [0093] FIG. 20 shows the results of direct inhibition of tumor cell proliferation of ovarian cancer cell lines by SX-682 in a dose-dependent fashion. The ovarian cancer cell lines included IBROV1, OVCAR-8, OVCAR-3, NCI/ADR-RES, OVCAR-5, and SK-OV-3.

[0094] FIG. 21 shows the results of direct inhibition of tumor cell proliferation of renal cancer cell lines by SX-682 in a dose-dependent fashion. The renal cancer cell lines included 786-0, CAK-1, TK-10, RXF 393, UO-31, ACHN, and SN12C.

[0095] FIG. 22 shows the results of direct inhibition of tumor cell proliferation of prostate cancer cell lines by SX-682 in a dose-dependent fashion. The prostate cancer cell lines included PC-3 and DU- 145.

[0096] FIG. 23 shows the results of direct inhibition of tumor cell proliferation of breast cancer cell lines by SX-682 in a dose-dependent fashion. The breast cancer cell lines included MCF7, BT-549, MDA-MB-231, T-47D, HS 578T, and MDA-MB-468.

[0097] FIG. 24 shows that SX-682 alone and in combination with immune checkpoint blockade (anti-PDl and anti-CTLA4) inhibited prostate cancer in a validated animal model. Pten^{pc /}'p5S^{pc /}'Srnad4^pc'^/' mice were administered 50 mg/kg SX-682 by oral gavage b.i.d. and 200 pg each of anti-PDl and anti-CTLA4 antibodies (immune checkpoint blockade, or “ICB”), 3x/week. Prostate weight (g) was measured after 4-6 weeks. SX-682 plus ICB was significantly better than control (P=0.0016 **), and ICB or SX682 alone (P=0.021*) (unpaired t-test). Mean + SE are shown.

DETAILED DESCRIPTION

[0098] The compound having the formula SX-682 [PubChem Compound ID (CID) 90467234] is:

SX-682

[0099] SX-682 inhibits the CXCR1 and CXCR2 receptors (U.S. Patent 8,969,365).

[00100] SX-682 inhibits tumor growth in a variety of animal cancer models (U.S. Patent

10,660,909).

[00101] The United States Food & Drug Administration (FDA) instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and fill an unmet medical need based on a surrogate endpoint, such as tumor shrinkage in cancer. A surrogate endpoint is not itself a measure of clinical benefit. In cancer, clinical benefit is an increase in progression-free survival (PFS) or overall survival (OS). Once a drug is approved under the Accelerated Approval Program, a drug company is allowed to market the drug. However, drug companies are still required to conduct studies to confirm clinical benefit (i.e., increased PFS or OS). If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place to remove the drug from the market. As of January 8, 2025, there were 106 cancer drugs approved under the Accelerated Approval Program based on tumor growth effects that were later confirmed to have clinical benefit (i.e., increased PFS or OS) and received traditional approval. However, there were 31 cancer drugs initially approved under the Accelerated Approval Program based on tumor growth effects that later studies failed to confirm clinical benefit (i.e., no increase in PFS or OS) and were withdrawn from the market. In other words, a cancer drug’s ability to increase survival (PFS or OS) in human patients cannot be predicted from its effects on tumor growth in human patients. Conversely, in some cases, a cancer drug may not shrink a tumor at all in a human patient, but still increase PFS or OS (e g., sipuleucel-T). [00102] Likewise, a cancer drug’s ability to increase survival (PFS or OS) in patients cannot be predicted from its effects on survival or tumor growth in preclinical animal models (e.g., SX-682 in preclinical models in U.S. Patent 10,660,909 and Gulhati, 2023, Nat Cancer, 4(1): 62-80). Across all indications, despite successful pre-clinical testing, 85% of clinical trials for novel drugs fail (all phases of clinical testing included); of those that survive through to phase 3, only half become approved for clinical use [Ledford, 2011, Nature, 477:526-8.]. The largest proportion of these failures occurs in trials for cancer drugs [Arrowsmith, 2011, Nat Rev Drug Discov, 10:87], For example, the Hedgehog pathway antagonist saridegib (IPL926) increased survival in mouse models with malignant solid brain tumors (Lee, 2012, Proc Natl Acad Set USA, 109:7859-64), but had no significant effect compared to placebo in patients with advanced chondrosarcoma participating in a Phase 2 randomized clinical trial (Wagner, 2013, Connective Tissue Oncology Society 18th Annual Meeting. New York, NY). Another immunomodulatory agent, TGN1412, was tested for safety in preclinical mice models and did not lead to toxicities in doses up to 100 times higher than the therapeutic dose in humans (Attarwala, 2010, J Young Pharm, 2:332-6). However, when the drug advanced to Phase 1 testing, trial participants experienced multisystem organ failure and cytokine storm even with subclinical doses (Suntharalingam, 2006, N Engl J Med, 355: 1018-28). Anti-cancer vaccines have had similar issues in translating efficacy to human clinical trials. While therapeutic vaccines have successfully raised an immune response in mice, their effects in humans have been circumvented by immunological checkpoints and immunosuppressive cytokines that are absent in mice (Yaddanapudi, 2013, Oncoimmunology, 2:e23403). Examples of failed vaccines include Stimuvax, which had failed a non-small cell lung cancer phase 3 trial (Company press release, 2012, Oncothyreon Announces that L-BLP (Stimuvax®) Did Not Meet Primary Endpoint of Improvement in Overall Survival in Pivotal Phase Trial in Patients with Non-Small Cell Lung Cancer, Oncothyreon Inc.), and Telovac, which failed in a pancreatic cancer phase 3 trial (2013. Genetic Engineering & Biotechnology News. Phase III Failure for TeloVac Pancreatic Cancer Vaccine').

[00103] One systematic review found the predictive power of animal models to predict clinical translation was less than 8% (Mak, 2014, Am J Transl Res, 6(2): 114-118). The review concluded that the overall result is that promising pre-clinical animal studies that require extensive resources both in time and money rarely translate into successful treatments. Another review found the predictive power of animal models was no different than chance alone, with a tendancy for approved drugs to actually demonstrate poorer inhibition in preclinical models than failed drugs (Pan, 2020, Front Oncol, 10:591).

[00104] In one embodiment, the disclosure herein relates to the surprising and unexpected discovery of a method for increasing survival (as defined herein) in a patient with cancer comprising, administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of SX-682 or a pharmaceutical composition thereof (e.g., a suitable solvate or salt thereof) alone or with one or more other anti -cancer agents.

[00105] Medical and Biologic Definitions

[00106] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this specification pertains.

[00107] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[00108] As used herein, and unless otherwise indicated, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[00109] The term “agonist” as used herein refers to a compound or agent having the ability to initiate or enhance a biological function of a target protein or polypeptide, such as increasing the activity or expression of the target protein or polypeptide. Accordingly, the term “agonist” is defined in the context of the biological role of the target protein or polypeptide. While some agonists herein specifically interact with (e.g., bind to) the target, compounds and/or agents that initiate or enhance a biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[00110] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound or agent having the ability to reduce or inhibit a biological function of a target protein or polypeptide, such as by reducing or inhibiting the activity or expression of the target protein or polypeptide. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein or polypeptide. An inhibitor need not completely abrogate the biological function of a target protein or polypeptide, and in some embodiments reduces the activity by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99%. While some antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein or polypeptide by interacting with other members of the signal transduction pathway of which the target protein or polypeptide are also specifically included within this definition. Non-limiting examples of biological activity inhibited by an antagonist include those associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.

[00111] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application including, but not limited to, increasing patient survival and disease treatment, as illustrated below. The therapuetically effective amount may additionally ablate targeted cells or arrest their growth, The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e g., reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. As used herein, a daily dosage can be achieved by a single administration of the targeted dosage amount or multiple administrations of smaller dosage amount(s). For example, a 150 mg daily dosage can be achieved by a single administration of 150 mg of the therapeutic agent per day, two administrations of 75 mg of the therapeutic agent per day, or three administrations of 50 mg of the therapeutic agent per day, or the like.

[00112] As used herein, the terms “treatment”, “treating”, “palliating” and “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder.

[00113] As used herein, the terms “prevention” and “preventing” are used herein to refer to an approach for obtaining beneficial or desired results including, but not limited, to prophylactic benefit. For prophylactic benefit, the pharmaceutical compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[00114] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[00115] ‘ ‘Patient” is a human.

[00116] In a controlled trial, “randomization” is the process of assigning patients to different treatment or control groups using a chance method, like a coin flip or computer program, to ensure groups are as similar as possible and reduce bias.

[00117] “ Overall survival” (“OS”) is the duration from randomization or initiation of treatment to the time of death.

[00118] ‘ ‘Progression-free survival” (“PFS”) is the duration from randomization or initiation of treatment to the time when the cancer has progressed or patient death, whichever occurs first.

[00119] ‘ ‘Disease-free survival” (“DFS”) or relapse-free survival (RFS) refers to the duration from randomization or initiation of treatment that the patient survives without any signs or symptoms of the cancer, that is, the time to the recurrence of the cancer or death due to any cause, whichever occurs first. DFS and RFS is relevant to cancers with long periods between recurrence and death (e.g., local or regionally advanced cancers of the breast, prostate, colon, and rectum). Indeed, the FDA has accepted disease-free survival as a regulatory endpoint that demonstrates clinical benefit for adjuvant therapy. Adjuvant therapy is a cancer treatment (e.g., chemotherapy) given after the initial treatment (e.g., surgical excision of the tumor) to reduce the risk of the cancer returning.

[00120] Event-free survival (EFS) refers to the time from randomization (or initiation of treatment in a trial) to the first occurrence of a defined event. Examples of events that EFS can measure include disease progression, relapse, unplanned re-treatment, treatment discontinuation for toxicity, death and symptom occurrence (e.g., pain, bone fracture as a symptomatic skeletal event as can occur in prostate cancer).

[00121] “ Survival” as used herein encompasses, but is not limited to, OS, PFS, DFS, RFS and EFS. In preferred embodiments the increase in survival is statistically significant (P<0.05), for example using the log-rank test.

[00122] A duration, OS, PFS, DFS, RFS and EFS may be expressed for an individual patient or for a group of patients, using for example, a median derived from a Kaplan-Meier survival curve known to those skilled in the art.

[00123] In preferred embodiments, the duration, OS, PFS, median OS or median PFS is increased by more than 1, 2, 3, 4, 5 or 6 months compared to the duration, OS, PFS, median OS or median PFS without administering SX-682, respectively. More than 4 months is preferable.

[00124] In preferred embodiments, DFS, RFS or EFS is increased by more than 1, 2, 3, 4, 5 or 6 months compared to the DFS, RFS or EFS without administering SX-682, respectively. More than 4 months is preferable.

[00125] The phrase “a method of treating” or its equivalent, when applied to, for example, cancer refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in an animal, or to alleviate the symptoms of a cancer. “A method of treating” cancer or another proliferative disorder does not necessarily mean that the cancer cells or other disorder will, in fact, be eliminated, that the number of cells or disorder will, in fact, be reduced, or that the symptoms of a cancer or other disorder will, in fact, be alleviated. Often, a method of treating cancer will be performed even with a low likelihood of success, but which, given the medical history and estimated survival expectancy of an animal, is nevertheless deemed an overall beneficial course of action. [00126] The term “therapeutically effective agent” means a composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[00127] As used herein, the “aggressiveness” of a tumor or cancer or malignancy refers to the rate at which the tumor is growing. Thus, a tumor is more aggressive than another tumor or cancer if it is proliferating at a higher rate. Other determinants can be used to measure the level of aggressiveness of a tumor or cancer, for example, based on the appearance of tumor or cancer cells under a microscope to determine the extent to which tumors are differentiated. A well- differentiated tumor tends to be more aggressive than a poorly-differentiated tumor or cancer.

[00128] The term “selective inhibition” or “selectively inhibit” as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target. By way of non-limiting example, the ratio of selectivity can be greater than a factor of about 1, greater than a factor of about 2, greater than a factor of about 3, greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 50, greater than a factor of about 100, greater than a factor of about 200, greater than a factor of about 400, greater than a factor of about 600, greater than a factor of about 800, greater than a factor of about 1000, greater than a factor of about 1500, greater than a factor of about 2000, greater than a factor of about 5000, greater than a factor of about 10,000, or greater than a factor of about 20,000, where selectivity can be measured by IC50. In certain embodiments, the IC50 can be measured by in vitro or in vivo assays.

[00129] “Subject” or “patient” to which administration is contemplated is limited to humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)).

[00130] The term “in vivo” refers to an event that takes place in a subject's body.

[00131] The term “in vitro” refers to an event that takes places outside of a subject's body.

For example, an in vitro assay encompasses any assay conducted outside of a subject. In vitro assays encompass cell-based assays in which cells, alive or dead, are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[00132] Combination therapy, or “in combination with” refer to the use of more than one compound or agent to treat a particular disorder or condition. For example, a CXCR2 antagonist (e g., SX-682) may be administered in combination with at least one additional therapeutic agent (e.g., a BCL-2 inhibitor). By “in combination with,” it is not intended to imply that the CXCR2 antagonist and additional therapeutic agent (e.g., the BCL-2 inhibitor) must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of this disclosure. The CXCR2 antagonist, e.g., SX-682, can be administered concurrently with, prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before), or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after), one or more other additional agents. In certain embodiments, each therapeutic agent will be administered at a dose and/or on a time schedule determined for that particular agent. The other therapeutic agent (e.g., the BCL-2 inhibitor) can be administered with the CXCR2 antagonist (e.g., SX-682) herein in a single composition or separately in a different composition. Higher combinations, e.g., triple therapy with either azacytidine or decitabine, are also contemplated herein.

[00133] The terms “co-administration of’ and “co-administering” and their grammatical equivalents, as used herein, encompass administration of two or more agents to subject so that both agents and/or their metabolites are present in the subject at the same or substantially the same time. In one embodiment, co-administration of a CXCR2 antagonist with an additional anti-cancer agent (both components referred to hereinafter as the “two active agents”) refer to any administration of the two active agents, either separately or together, where the two active agents are administered as part of an appropriate dose regimen designed to obtain the benefit of the combination therapy. Thus, the two active agents can be administered either as part of the same pharmaceutical composition or in separate pharmaceutical compositions. The additional agent can be administered prior to, at the same time as, or subsequent to administration of the CXCR2 antagonist, or in some combination thereof. Where the CXCR2 antagonist is administered to the patient at repeated intervals, e.g., during a standard course of treatment, the additional agent can be administered prior to, at the same time as, or subsequent to, each administration of the CXCR2 antagonist, or some combination thereof, or at different intervals in relation to the CXCR2 antagonist treatment, or in a single dose prior to, at any time during, or subsequent to the course of treatment with the CXCR2 antagonist. In certain embodiments, a first agent can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), essentially concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent.

[00134] As used herein, a “monotherapy” refers to the use of an agent individually (e.g., as a single compound or agent), e.g., without a second active agent to treat the same indication, e.g., cancer. For example, in this context, the term monotherapy includes the use of either the CXCR2 antagonist or the second agent individually to treat the cancer.

[00135] In certain embodiments, one or more advantageous effects of combination therapies are tested by using a CXCR2 antagonist in combination with a second therapeutic agent (e.g., BCL-2 inhibitors) as described herein.

[00136] In some embodiments, a lower dosage of one or both of the agents are needed to achieve a therapeutic effect. For example, the combination can provide a selected effect, e.g., a therapeutic effect, when at least one of the agents is administered at a lower dosage than the dose of that agent that would be required to achieve the same therapeutic effect when the agent is administered as a monotherapy. In certain embodiments, the combination of a CXCR2 antagonist (e.g., SX-682) and a second agent as described herein (e.g., a BCL-2 inhibitor as described herein) allows the CXCR2 antagonist to be administered at a lower dosage than would be required to achieve the same therapeutic effect if the CXCR2 antagonist were administered as a monotherapy. In certain embodiments, the combination of a CXCR2 antagonist (e.g., SX-682) and the BCL-2 inhibitor allows the BCL-2 inhibitor to be administered at a lower dosage than would be required to achieve the same therapeutic effect if the BCL-2 inhibitor were administered as a monotherapy.

[00137] In some embodiments, there is a reduction, prevention, delay, or decrease in the occurrence or the likelihood of occurrence of one or more side effects, toxicity, resistance, that would otherwise be associated with administration of at least one of the agents. [00138] In some embodiments, a reduction in resistance (e.g., a decrease in a measure of resistance or a decreased likelihood of developing resistance), or a delay in the development of resistance, to at least one of the agents, can occur.

[00139] In some embodiments, a reduction in MRD can occur. In certain embodiments, a combination of a CXCR2 antagonist (e.g., a CXCR2 antagonist described herein) and a second agent (e.g., a BCL-2 inhibitor) can reduce the MRD in the subject, e.g., below a level previously measured in the subject (e.g., the level measured before the combination was administered). In certain embodiments, a combination of a CXCR2 antagonist and a second agent (e.g., a BCL-2 inhibitor) can reduce the MRD in the subject below the level observed during or after treatment with a monotherapy, e.g., a monotherapy comprising either the CXCR2 antagonist or the second agent (e.g., the BCL-2 inhibitor). In certain embodiments, the MRD can be decreased below the level observed during treatment with a monotherapy comprising the CXCR2 antagonist. In certain embodiments, the MRD can be decreased below the level observed during treatment with a monotherapy comprising the second agent (e.g., the BCL-2 inhibitor). In certain embodiments, the combination can be effective to reduce the MRD below a preselected cutoff value (e.g., 1 malignant cell in 100 normal cells, 1 malignant cell in 1000 normal cells, or 1 malignant cell in 10,000 normal cells). In certain embodiments, the preselected cutoff value is 1 malignant cell in 1000 or 10,000 normal cells.

[00140] Combination index (CI) is a score of the potency shifting. Chou et al., Adv Enzyme Regul. 1984; 22: 27-55 and in U.S. Patent Publication No. 2013/0295102, the contents of which are incorporated herein by reference. A CI value of greater than 1 indicates antagonistic effect; a CI value of 1.0 is indicative of an additive effect; and a CI value of less than 1 is indicative of a synergistic effect resulting from the combination. The CI value can be determined at various percentages of inhibition or growth inhibition.

[00141] The CI can be thought of as an estimate of the fraction of the original (monotherapy) doses of each of two drugs would be needed in combination relative to the single agent doses required to achieve a chosen effect level. For example, when the combination index has a value of 0.1, only about one tenth of the total fractional amounts of the individual agents (expressed as a fraction of the amount of that agent when administered as a monotherapy to achieve a chosen effect) are needed for the combination to reach the same chosen effect level. For example, if a dose of 100 mg/kg of drug A individually or a dose of 200 mg/kg of drug B individually is needed to achieve the chosen effect, and the combination index is 0.1, then approximately 5 mg/kg of drug A and 10 mg/kg of drug B would achieve the chosen effect (one twentieth of the original doses of each of the single agents adds up to a total of one tenth). The doses of the single agents need not be reduced by the same fractional value so long as the sum of their fractional values adds up to the combination index; thus, in this example, a dose of approximately 8 mg/kg of drug A and 4 mg/kg of drug B would also achieve the chosen effect (this is 0.08 times the original dose of drug A and 0.02 times the original dose of drug B; the sum of the fractional amounts (0.08+0.02) is equal to the combination index of 0.1.)

[00142] Alternative methods for determining synergistic interaction are familiar to the skilled person. Another method for determining whether synergistic effects arise from a combination is the Chou-Talalay method (Chou, TC. Cancer Res. 2010 Jan 15;70(2):440-6, incorporated herein by reference).

[00143] As used herein, a daily dosage can be achieved by a single administration of the targeted dosage amount or multiple administrations of smaller dosage amount(s). For example, a 150 mg daily dosage can be achieved by a single administration of 150 mg of the therapeutic agent per day, two administrations of 75 mg of the therapeutic agent per day, or three administrations of 50 mg of the therapeutic agent per day, or the like.

[00144] The term “anti-cancer effect” refers to the effect a therapeutic agent has on cancer, e.g., a decrease in growth, viability, or both of a cancer cell. The IC50 of cancer cells can be used as a measure the anti -cancer effect.

[00145] IC50 refers to a measure of the effectiveness of a therapeutic agent in inhibiting cancer cells by 50%.

[00146] The term “tumor” refers to any neoplastic cell growth and proliferation, whether malignant or benign, and any pre-cancerous and cancerous cells and tissues. As used herein, the term “neoplastic” refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, “neoplastic cells” include malignant and benign cells having dysregulated or unregulated cell growth.

[00147] The term “cancer” includes, but is not limited to, solid tumors and blood born tumors. The term “cancer” refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, neck, ovaries, pancreas, prostate, testis, gastrointestinal tract (e.g, esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), bone marrow, skin, head or neck, liver, gall bladder, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g, gliomas), ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the lymphoid and hematopoietic system and the immune system (c'.g, spleen, thymus, or bone marrow). The disclosure herein also provides methods of treating or preventing other cancer-related diseases, disorders or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (c.g, epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomavirus), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically-induced cancers, metastasis, and angiogenesis. In particular embodiments, the tumor or cancer is pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer, and includes, e.g., angiogenesis and precancerous conditions such as dysplasia.

[00148] “Lymphoid” or “Lymphocytic” malignancy - As used herein, the term “lymphoid” or “lymphocytic” malignancy refers to any clonal disease of hematopoietic stem or progenitor cells. Lymphoid or lymphocytic malignancies or malignant diseases include chronic and acute conditions such as chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL).

[00149] “Myeloid malignancy” - As used herein, the term “myeloid malignancy” refers to any clonal disease of hematopoietic stem or progenitor cells. Myeloid malignancies or myeloid malignant diseases include chronic and acute conditions. Chronic conditions include myelodysplastic syndromes (MDS), myelofibrosis (MF), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML), and acute conditions include acute myeloid leukemia (AML).

[00150] “Acute myeloid malignancy” - As used herein, “acute myeloid leukemia” or “AML” refers to haematopoietic neoplasms involving myeloid cells. AML is characterised by clonal proliferation of myeloid precursors with reduced differentiation capacity. AML patients exhibit an accumulation of blast cells in the bone marrow. “Blast cells”, or simply “blasts”, as used herein refers to clonal myeloid progenitor cells exhibiting disrupted differentiation potential. Blast cells typically also accumulate in the peripheral blood of AML patients. Typically, AML is diagnosed if the patient exhibits 20% or more blast cells in the bone marrow or peripheral blood.

[00151] MDS, MF, MM, AML, MPN, CML, CLL, SLL and CMML herein each a “hematologic malignancy” and together “hematologic malignancies”.

[00152] MDS is a precursor to AML.

[00153] Myeloproliferative neoplasms (MPN) consist of myelofibrosis (high white blood cells and bone marrow and spleen fibrosis, primary or arising secondary to another MPN), polycythemia vera (increased numbers of red blood cells), essential thrombocythemia (overproduction of platelets), chronic myeloid leukemia, chronic neutrophilic leukemia (high counts of mature neutrophils), chronic eosinophilic leukemia-not otherwise specified, and MPN unclassifiable (MPN-U).

[00154] “ Standard intensive chemotherapy” - As used herein, “standard intensive chemotherapy” (also referred to herein as “intensive induction therapy” or “induction therapy”) refers to the so-called “7+3” induction chemotherapy characterized by 7 days of high dose cytarabine followed by 3 days of anthracycline administration (e.g., daunorubicin or idarubicin). Standard intensive chemotherapy can be given to eligible newly-diagnosed AML patients with the aim of inducing complete remission of AML, typically with the intention of the patient undergoing a stem cell transplant following successful chemotherapy. As explained herein, not all newly-diagnosed AML patients are eligible for this standard intensive chemotherapy.

[00155] “Leukemic stem cells” - As used herein, “leukemic stem cells” or “LSCs” are a subset of the blast cells associated with a leukemia, such as AML. LSCs are blast cells having stem cell properties such that, if transplanted into an immuno-deficient recipient, they are capable of initiating leukemic disease. LSCs can self-renew by giving rise to leukemia and also partially differentiate into non-LSC conventional blast cells that resemble the original disease but are unable to self-renew. LSCs occur with a frequency in the range of 1 in 10,000 to 1 in 1 million as a proportion of primary AML blast cells (Pollyea and Jordan (2017) Blood 129: 1627- 1635, incorporated herein by reference). LSCs may be characterized as cells that are CD34+, CD38-, optionally also CD45- and/or CD123+. LSCs may also be characterized as CD45dim, SSCIo, CD90+CD34+ cells. [00156] “Hematopoietic origin” refers to involving cells generated during hematopoiesis, a process by which cellular elements of blood, such as lymphocytes, leukocytes, platelets, erythrocytes and natural killer cells are generated. Cancers of hematopoietic origin includes lymphoma and leukemia.

[00157] “Resistant” or “refractive” refers to when a cancer that has a reduced responsiveness to a treatment, e.g., up to the point where the cancer does not respond to treatment. The cancer can be resistant at the beginning of treatment, or it may become resistant during treatment. The cancer subject may have one or more mutations that cause it to become resistant to the treatment, or the subject may have developed such mutations during treatment. The term “refractory” can refer to a cancer for which treatment (e.g., chemotherapy drugs, biological agents, and/or radiation therapy) has proven to be ineffective. A refractory cancer tumor may shrink, but not to the point where the treatment is determined to be effective. Typically, however, the tumor stays the same size as it was before treatment (stable disease), or it grows (progressive disease).

[00158] A “biomarker” or “marker” is a substance, e.g., a gene or gene product (e.g., mRNA or protein) which can be altered (e.g., having an alteration described herein), wherein said alteration is associated with, or is indicative of, a disease state, e.g., a cancer (e.g., a myeloid malignancy described herein, e.g., AML). The alteration can be in amount, structure, and/or activity of the substance (e.g., gene or gene product) in a cancer tissue or cancer cell, as compared to its amount, structure, and/or activity, in a reference sample, e g., a normal or wildtype gene or gene product, or a responder gene or gene product (e.g., a gene or gene product in a responder subject (e.g., a subject in complete or partial cancer remission). For example, a biomarker described herein which is associated with cancer or predictive of responsiveness to anti-cancer therapeutics can have an altered nucleotide sequence, amino acid sequence, chromosomal translocation, intra-chromosomal inversion, copy number, expression level, protein level, protein activity, or methylation status, in a cancer tissue or cancer cell as compared to a normal, healthy tissue or cell. Furthermore, a “biomarker” includes a molecule whose structure is altered, e.g., mutated (contains a mutation), e.g., differs from the wild type sequence at the nucleotide or amino acid level, e.g., by substitution, deletion, or insertion, when present in a tissue or cell associated with a disease state, such as cancer. In some embodiments, a biomarker can be evaluated individually, or in combinations with one or more other biomarkers. [00159] The terms “modulate”, “modulation” and the like refer to the ability of a molecule e.g., an activator or an inhibitor) to increase or decrease the function or activity of a biological target, either directly or indirectly. A modulator may act alone, or it may use a cofactor, e.g.. a protein, metal ion, or small molecule. Examples of modulators include small molecule compounds and other bioorganic molecules. Numerous libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying a modulator. The skilled artisan is able to develop one or more assays (e.g., biochemical or cell-based assays) in which such compound libraries can be screened in order to identify one or more compounds having the desired properties; thereafter, the skilled medicinal chemist is able to optimize such one or more compounds by, for example, synthesizing and evaluating analogs and derivatives thereof. Synthetic and/or molecular modeling studies can also be utilized in the identification of an Activator.

[00160] The “activity” of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor; to catalytic activity; to the ability to stimulate gene expression or cell signaling, differentiation, or maturation; to antigenic activity; to the modulation of activities of other molecules; and the like. The term “proliferative activity” encompasses an activity that promotes, that is necessary for, or that is specifically associated with, for example, normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.

[00161] ‘ ‘Anticancer therapy” means any therapeutic intervention used to treat cancer in a patient in need of such treatment. Anticancer therapy can include the use of chemotherapeutic agents, immunotherapy, radiation therapy, or surgery.

[00162] “Responsiveness,” “to respond” to treatment, a “response” from treatment, and other forms of this term, as used herein, refer to the reaction of a subject to treatment with a therapeutic, e.g., a CXCR2 antagonist, alone or in combination, e.g., monotherapy or combination therapy. In one embodiment, a response to a CXCR2 antagonist is determined. Responsiveness and “cancer progression” to a therapy, e.g., treatment with a CXCR2 antagonist alone or in combination, can be evaluated by using any of the alterations/biomarkers disclosed herein and/or comparing a subject's response to the therapy using one or more clinical criteria, such as:

[00163] IWG 2003 (for AML) described in, e.g., Cheson et al; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. doi: 10.1200/JC0.2003.04.036. Erratum in: J Clin Oncol. 2004 Feb 1;22(3):576. LoCocco, Francesco [corrected to Lo-Coco, Francesco], PMID: 14673054;

[00164] IWG 2006 (for MDS) described in Cheson et al; Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11. PMID: 16609072;

[00165] IWG 2018 (for MDS) described in Platzbecker et al; Proposals for revised IWG

2018 hematological response criteria in patients with MDS included in clinical trials. Blood.

2019 Mar 7;133(10): 1020-1030. doi: 10.1182/blood-2018-06-857102. Epub 2018 Nov 7.

[00166] IWG 2023 (for MDS) described in Zeidan et al; Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes. Blood. 2023 Apr 27;141(17):2047-2061. doi: 10.1182/blood.2022018604

[00167] IWG-MRT 2013 (for MF) described in Tefferi et al.; Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013 Aug 22; 122(8): 1395-8. doi: 10.1182/blood-2013-03-488098. Epub 2013 Jul 9. PMID: 23838352; PMCID: PMC4828070.

[00168] iRECIST (for solid tumors) described in Seymour et al.; iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol, 2017. 18(3): p. el43-el52. PMID: 28271869.

[00169] RECIST version 1.1 (for solid tumors) described in Eisenhauer et al.; New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. PMID: 19097774 DOI: 10.1016/j.ejca.2008.10.026.

[00170] These criteria provide a set of published rules that define when cancer patients improve (“respond”), stay the same (“stable”) or worsen (“progression”) during treatments.

[00171] Chemical Definitions [00172] An “antagonist of CXCR1 and/or CXCR2 receptors” or a “CXCR1 and/or CXCR2 antagonist” is a molecule that opposes the action(s) of an agonist at CXCR1 and/or CXCR2 receptors. The antagonist may oppose the action of an agonist at CXCR1 and/or CXCR2 by acting at the receptor (e.g., an allosteric small-molecule) or acting at the chemokine ligand (e.g., the HuMax-IL8 monclonal antibody that binds CXCL8). The agonist may be selected from (but not limited to) chemokine ligands CXCL1, CXCL2, CXCL3, CXCL5, and CXCL8. The activity of an agonist may include cellular processes resulting from CXCR1 and/or CXCR2 receptor activation such as intracellular calcium release, cyclic AMP generation, cellular chemotaxis, and b-arrestin recruitment. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist.

[00173] In one embodiment, the method of increasing survival in a patient with cancer in need of such treatment comprises administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist.

[00174] “ CXCR2 antagonist” is any agent, compound or molecule capable of inhibiting the activation of the CXCR2 chemokine receptor. The CXCR2 antagonist may also exhibit inhibitory activity at CXCR1 chemokine receptors, e.g., a dual CXCR1 and CXCR2 antagonist. Particular CXCR2 antagonists include but are not limited to: SX-682 [PubChem Compound ID (CID) 90467234], SX-576 (CID 46897163), SX-517 (CID 46897162), navarixin (CID 9865554), danirixin (CID 24780598), ladarixin (CID 11372270), AZD5069 (CID 56645576), DF2755A (CID 45110932), SB225002 (CID 3854666), elubrixin (CID 10479502), SRT3190 (CID 59149652), vimnerixin (CID 71209600), SCH563705 (CID 10310100), SB265610 (CID 9841667), SRT3109 (CID 44602493), SB332235 (CID 9887803), and AZD8309 (CID 12073810), or a pharmaceutically acceptable form and/or solvate thereof.

[00175] In one embodiment, the method of increasing survival in a partient with cancer in need of such treatment, comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount a CXCR1 and/or CXCR2 receptor antagonist of formula I,

wherein R¹ and R² are independently selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein R³ is selected from — B(R⁴R⁵), — R⁶ — B(R⁴R⁵), R⁶, — C(O) — R⁶, — O — R⁶, — S(O)_y — R⁶ (wherein y=0, 1, or 2), — P(O) — (R⁴R⁵) and — N(R⁷R⁸); wherein R⁴ and R⁵ are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R⁴ and R⁵ together form a cyclic ester, or an acid anhydride (either mixed or symmetrical); wherein R⁶ is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl and heterocyclylalkyl; wherein R⁷ and R⁸ are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl and heterocyclylalkyl; R⁷ and R⁸ are both oxygen to form a nitro group; or R⁷ and R⁸ together with the nitrogen to which they are attached, form a heterocyclyl; and wherein R⁹ is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; or — B(R⁴R⁵), — BF₃ M⁺, — R⁶— B(R⁴R⁵), — R⁶— BF₃’M⁺, R⁶, — C(O)— R⁶, — O— R⁶, — S(O)y— R⁶ (wherein y=0, 1, or 2), — P(O) — (R⁴R⁵) and — N(R⁷R⁸); or an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; wherein X¹ is carbon or nitrogen; X² is — S(O)_y — (wherein y=0, 1, or 2), — N(R⁹) — , or oxygen; and n is an integer between 0 and 8; or a pharmaceutically suitable solvate or salt thereof, wherein the above R group terms are defined as provided in U.S. Patent 10,660,909. [00176] In one embodiment, the method of increasing survival in a patient with cancer in need of such treatment comprises administering a therapeutically effective amount of a compound selected from the group consisting of formulas SX-517, SX-520, SX-557, SX-574, SX-577, SX-603, SX-622, SX-660, SX-662, SX-671, SX-677, SX-678, and SX-682 (structures in U.S. Patent 10,660,909).

[00177] In another embodiment, the method of increasing survival in a patient with cancer in need of such treatment comprises administering to the patient a therapeutically effective amount of at least one CXCR1 and/or CXCR2 receptor antagonist comprising the CXCL8 ligand blocking antibody HuMax-IL8.

[00178] As used herein, a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable forms, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds. In one embodiment, a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable forms, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds.

[00179] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable form. As used herein, the term “pharmaceutically acceptable form” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable forms are well known in the art. For example, Berge et al. describes pharmaceutically acceptable forms in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable forms of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable forms include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bi sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[00180] Pharmaceutically acceptable forms derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(Cl-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable forms include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[00181] In certain embodiments, the pharmaceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be of a disclosed compound or a pharmaceutically acceptable form thereof. Where the solvent is water, the solvate is a “hydrate”. Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term “compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[00182] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent compound. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, Chp 1, pp 1-12 and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[00183] The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. Other examples of prodrugs include compounds that comprise — NO, — NO2, — ONO, or — ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elsevier, N.Y., 1985).

[00184] In certain embodiments, the pharmaceutically acceptable form is an isomer.

“Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomers” include geometric double bond cis- and trans-isomers, also termed E- and Z-isomers; R- and S- enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.

[00185] “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown may be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[00186] “Enantiomeric purity” as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which can potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)- and 20% (R)-, the enantiomeric purity of the compound with respect to the (S)- isomeric form is 80%. The enantiomeric purity of a compound may be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or the Pirkle alcohol, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[00187] In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term “tautomer” is a type of isomer that includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa). “Tautomerization” includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers may be reached. Tautomerizations (i.e., the reaction providing a tautomeric pair) may be catalyzed by acid or base, or can occur without the action or presence of an external agent. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(a different) enamine tautomerizations. A specific example of keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.

[00188] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, or the replacement or enrichment of a carbon by 13C or 14C at one or more atoms in the molecule, are within the scope of this disclosure. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 13C. Tn one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 14C.

[00189] The disclosure also embraces isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ^3?S, ¹⁸F, and ³⁶C1, respectively. Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³H and/or ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can allow for ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, provided herein are compounds that can also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. All isotopic variations of the compounds as disclosed herein, whether radioactive or not, are encompassed within the scope of the present disclosure.

[00190] As used herein, and unless otherwise specified, “polymorph” may be used herein to describe a crystalline material, e.g., a crystalline form. In certain embodiments, “polymorph” as used herein are also meant to include all crystalline and amorphous forms of a compound or a salt thereof, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms of the compounds or a salt thereof, as well as mixtures thereof. [00191] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of the structure.

[00192] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[00193] “BCL-2 family” or “BCL-2 protein family” refers to the collection of pro- and anti-apoptotic proteins related to BCL-2, see Delbridge et al. (2016) Nat Rev Cancer. 16(2): 99- 109. There are at least 16 members of this family categorized into three functional groups: (i) the BCL-2 like proteins (e.g., BCL-2, BCL-XLVBCL2L1 , BCLW BCL2L2, MCL2, BFL1/BCL2A1 ); (ii) BAX and BAK; and (iii) the BH3-only proteins (e.g., BIM, PUMA, BAD, BMF, BID, NOXA, HRK, BIK). The BCL-2 family of proteins play an integral role in regulating the intrinsic apoptotic pathway with the anti-apoptotic members of the family (e.g., BCL-2, BCL-Xi) typically antagonizing the pro-apoptotic members (e.g., BAX and BIM). Deregulation of BCL-2 family members has been observed in many cancers, for example by gene translocations, amplifications, overexpression and mutations. The downstream effect of this deregulation is frequently apoptosis-resistance, which fuels cancer growth.

[00194] “BCL-2” or the “BCL-2 protein” refers to the first member of the BCL-2 protein family to be identified in humans i.e., B-cell lymphoma 2. The cDNA encoding human BCL-2 was cloned in 1986 and the key role of this protein in inhibiting apoptosis was elucidated in 1988. BCL-2 has been found to be upregulated in several different types of cancer. For example, BCL-2 is activated by the t( 14; 18) chromosomal translocation in follicular lymphoma. Amplification of the BCL-2 gene has also been reported in different cancers including leukemias (such as CLL), lymphomas (such as B-cell lymphoma) and some solid tumors (e.g., small-cell lung carcinoma). Human BCL-2 is encoded by the BCL2 gene (UniProtKB - Pl 0415) and has the amino acid sequences shown under NCBI Reference Sequences NP 000624.2 and NP 000648.2.

[00195] “BCL-2 inhibitor” refers to any agent, compound or molecule capable of specifically inhibiting the activity of BCL-2, in particular an agent, compound or molecule capable of inhibiting the anti-apoptotic activity of BCL-2. Examples of BCL-2 inhibitors suitable for use in the combinations described herein include B cell lymphoma homology 3 (BH3) mimetic compounds (Merino et al. (2018) Cancer Cell. 34(6): 879-891 ). Particular BCL-2 inhibitors include but are not limited to: venetoclax (CID 49846579), navitoclax (CID 24978538), ABT-737 (CID 11228183), obatoclax (CID 11404337), AZD-4320 (CID 86661883), gossypol (3503), pelcitoclax (CID 76900653), S55746 (CID 71654876), TW-37 (CID 11455910), sabutoclax (CID 46236925), HA14-1 (CID 3549), A-385358 (CID 11556440), lisaftoclax (CID 137355972), apogossypolone (CID 135513044), BM-1197 (CID 60204010), BM-957 (CID 71456995), BCL-2-IN-4 (CID 163322037), BM-1074 (CID 56933431), BCL-2- IN-5 (CID 163322038), BCL-2-IN-6 (CID 163409068), BCL-2-IN-7 (CID 163409069), BDA- 366 (CID 91826545), BCL-2-IN-2 (CID 146681199), and BCL-2-IN-8 (CID 163322290), or a pharmaceutically acceptable form and/or solvate thereof. Further examples of BCL-2 inhibitors are described in Ashkenazi, A et al. (2017) Nature Reviews Drug Discovery 16: 273-284, incorporated herein by reference.

[00196] “Hypomethylating agent” - DNA hypomethylating agents are a class of drugs that promote the demethylation of DNA, thereby allowing for the re-programming of cancer cells. Examples of hypomethylating agents are azacitidine and decitabine.

[00197] “Janus kinase inhibitor” or “JAK inhibitor” refers to any agent, compound or molecule capable that is a type 1 (binding to the active kinase conformation) or type 2 (binding to the inactive kinase conformation) inhibitor of JAK1 or JAK2 mediated cellular signaling. Particular JAK inhibitors include but are not limited to: AT9283 (CID 135398495), AZD1480 (CID 16659841), baricitinib (CID 44205240), BMS-911543 (CID 50922691), fedratinib (CID 16722836), filgotinib (GLPG0634, CID 49831257), gandotinib (LY2784544, CID 46213929), INCB039110 (itacitinib, CID 53380437), lestaurtinib (CID 126565), momelotinib (CYT0387, CID 25062766), NS-018 (ilginatinib, CID 46866319), pacritinib (SB1518, CID 46216796), peficitinib (ASP015K, CID 57928403), ruxolitinib (CID 25126798), tofacitinib (CID 9926791), INCB052793 CID 118467751), XL019 (CID 57990869), WP1066 (CID 11210478), TG101209 (CID 16722832), NVP-BSK805 (CID 46398810), AZ960 (CID 25099184), ZM-39923 (CID 3797), ropsacitinib (CID 130339268), SAR-20347 (CID 71727668), GDC-046 (CID 49839561), deucravacitinib (CID 134821691), WHI-P258 (CID 3798), brepocitinib (CID 118878093), ritlecitinib (CID 118115473), FM-381 (CID 122197584), oclacitinib (CID 44631938), decemotinib (CID 59422203), cerdulatinib (CID 44595079), zotiraciclib (CID 16739650), CHZ868, AJ1-11095 or a pharmaceutically acceptable form and/or solvate thereof.

[00198] “Immunotherapy” means anticancer treatments that use the patient’s immune system to attack cancer cells. Immunotherapy can include: immune checkpoint inhibitors, cancer vaccines, and T-cell therapy. Examples of these immunotherapies are given below.

[00199] “Immune checkpoint inhibitors” include inhibitors (both small molecule and biological) of programmed cell death protein 1 (PD-1), PD-L1, cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), indoleamine 2, 3 -di oxygenase (IDO), tryptophan 2,3- dioxygenase (TDO), T-cell Ig and mucin domain 3 (TIM3), lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT), B- and T-lymphocyte attenuator (BTLA), V-domain Ig suppressor of T-cell activation (VISTA), inducible T-cell COStimulator (ICOS), killer Ig-like receptors (KIRs), and CD39. Examples of biologic immune checkpoint inhibitors include ipilimumab, abatacept, nivolumab, pembrolizumab, tremelimumab, pidilizumab, atezolizumab, durvalumab, and avelumab. Examples of small molecule immune checkpoint inhibitors of IDO and/or TDO include indoximod, GDC-0919, FOO 1287, GDC-0919 (NLG919), FOO 1287, epacadostat (INCB024360), IDO-IN-1, IDO-IN-2, and navoximod (IDO-IN-7).

[00200] “Cancer vaccines” are used to treat established cancers not due to viral infections, and include the use of antigen vaccines, tumor cell vaccines, dendritic vaccines, deoxyribonucleic acid vaccines, and viral vector vaccines.

[00201] “T-cell therapy” involves the isolation, expansion, and re-introduction of a cancer patient’s tumor reactive T-cells. T-cell therapy also includes the use of genetically modified T- cells expressing chimeric antigen receptors (CARs) on their surface, wherein CARs are proteins that allow the T cells to recognize an antigen on targeted tumor cells. As used herein, such an antigen on targeted tumors cells is also referred to as a “tumor antigen”.

[00202] “Chemotherapeutic agents” include classes of compounds that can be used as in chemotherapy (antineoplastic agent) and include: alkylating agents (e.g, nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitroso ureas such as carmustine, lomustine, and streptozocin; topoisomerase 1 inhibitors (e.g., irinotecan); platinum complexes such as cisplatin and carboplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binding agents (e.g., plicamydin); antimetabolites (e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and ribonucleotide reductase inhibitors such as hydroxyurea); tubulin interactive agents (e.g., vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives, and paclitaxel); hormonal agents (e.g., estrogens; conjugated estrogens; ethinyl estradiol; diethylstilbesterol; chlortrianisen; idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone); adrenal corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone); leutinizing hormone releasing agents or gonadotropinreleasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and antihormonal antigens (e.g., tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide). As used herein, a microtubule affecting agent is a compound that interferes with cellular mitosis, i.e., having an anti-mitotic effect, by affecting microtubule formation and/or action. Such agents can be, for instance, microtubule stabilizing agents or agents that disrupt microtubule formation. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art.

[00203] Additional Anti-Cancer Agents for Combination Treatment

[00204] The disclosure herein provides methods for treating a patient and for increasing survival in a patient with cancer by administering at least one antagonist of CXCR1 and/or CXCR2 receptors and optionally further in combination with at least one additional anticancer therapy (e.g., chemotherapeutic agents, immune checkpoint inhibitors, T-cell therapy, cancer vaccines, immunomodulatory agent) or other therapeutic modalities (e.g., radiation). [00205] In preferred embodiments, survival time is increased by more than 1, 2, 3, 4, 5 or 6 months compared to the survival time without administering at least one antagonist of CXCR1 and/or CXCR2 receptors. More than 4 months is preferable.

[00206] Additional agents, such as small molecules, antibodies, adoptive cellular therapies and chimeric antigen receptor T cells (CAR-T), checkpoint inhibitors, and vaccines, that are appropriate for treating solid tumors and hematological malignancies can be administered in combination with the CXCR2 antagonists as described herein. Additional immunotherapeutic agents for hematological malignancies are described in Dong S et al, J Life Sci (Westlake Village). 2019 June; 1(1): 46-52; and Cuesta-Mateos C Et al, Front. Immunol. 8: 1936. doi: 10.3389/fimmu.2017.01936, each of which are hereby incorporated by reference in their entirety.

[00207] In such combination therapy, the various active agents frequently have different, complementary mechanisms of action. Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

[00208] As used herein, “combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (z.e., a “co-formulation”).

[00209] In certain embodiments, at least one antagonist of CXCR1 and/or CXCR2 is administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents. In other embodiments, at least one antagonist of CXCR1 and/or CXCR2 is administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). By way of example, the disclosure herein contemplates a treatment regimen wherein administration of an antagonist to CXCR1 and/or CXCR2 receptors is maintained on a daily basis, with additional anticancer treatments (e.g., anti-PDl antibody, carboplatin, cancer vaccine, T-cell therapy, radiation) given intermittently during the treatment period. Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the disclosure herein.

[00210] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more additional therapeutic agents, e.g., an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti- neoplastic agent, an anti-proliferation agent, an anti -angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (mono- and multispecific antibodies and fragments thereof in any format (e.g., including without limitation DARTs®, Duobodies®, BiTEs®, BiKEs, TriKEs, XmAbs®, TandAbs®, scFvs, Fabs, Fab derivatives)), bi-specific antibodies, non-immunoglobulin antibody mimetics (e.g., including without limitation adnectins, affibody molecules, affilins, affimers, affitins, alphabodies, anticalins, peptide aptamers, armadillo repeat proteins (ARMs), atrimers, avimers, designed ankyrin repeat proteins (DARPins®), fynomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADC), antibody-peptide conjugate), an oncolytic virus, a gene modifier or editor, a cell comprising a chimeric antigen receptor (CAR), e.g., including a T-cell immunotherapeutic agent, an NK-cell immunotherapeutic agent, or a macrophage immunotherapeutic agent, a cell comprising an engineered T-cell receptor (TCR-T), or any combination thereof.

[00211] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more additional therapeutic agents including, without limitation, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator or suppressor of a target (e.g., polypeptide or polynucleotide) including without limitation: Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such as ABL1), Acetyl-CoA carboxylase (such as ACC 1/2), activated CDC kinase (ACK, such as ACK), Adenosine deaminase, adenosine receptor (such as A2BR, A2aR, A3aR), Adenylate cyclase, ADP ribosyl cyclase- 1, adrenocorticotropic hormone receptor (ACTH), Aerolysin, AKT1 gene, Alk-5 protein kinase, Alkaline phosphatase, Alpha 1 adrenoceptor, Alpha 2 adrenoceptor, Alpha-ketoglutarate dehydrogenase (KGDH), Aminopeptidase N, AMP activated protein kinase, anaplastic lymphoma kinase (ALK, such as ALKI), Androgen receptor, Angiopoietin (such as ligand- 1, ligand-2), Angiotensinogen (AGT) gene, murine thymoma viral oncogene homolog 1 (AKT) protein kinase (such as AKT1, AKT2, AKT3), apolipoprotein A-I (AP0A1) gene, Apoptosis inducing factor, apoptosis protein (such as 1, 2), apoptosis signal-regulating kinase (ASK, such as ASK1), Arginase (I), Arginine deiminase, Aromatase, Asteroid homolog 1 (ASTE1) gene, ataxia telangiectasia and Rad 3 related (ATR) serine/threonine protein kinase, Aurora protein kinase (such as 1, 2), Axl tyrosine kinase receptor, 4-1BB ligand (CD137L), Baculoviral IAP repeat containing 5 (BIRC5) gene, Basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, Beta adrenoceptor, Beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B- lymphocyte cell adhesion molecule, B-lymphocyte stimulator ligand, Bone morphogenetic protein- 10 ligand, Bone morphogenetic protein-9 ligand modulator, Brachyury protein, Bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, Bromodomain and external domain (BET) bromodomain containing protein (such as BRD2, BRD3, BRIM), Bruton's tyrosine kinase (BTK), Calmodulin, calmodulin-dependent protein kinase (CaMK, such as CAMKII), Cancer testis antigen 2, Cancer testis antigen NY-ESO-1, cancer/testis antigen IB (CTAG1) gene, Cannabinoid receptor (such as CB1, CB2), Carbonic anhydrase, casein kinase (CK, such as CKI, CKII), Caspase (such as caspase-3, caspase-7, Caspase-9), caspase 8 apoptosis-related cysteine peptidase CASP8-FADD-like regulator, Caspase recruitment domain protein- 15, Cathepsin G, CCR5 gene, CDK-activating kinase (CAK), Checkpoint kinase (such as CHK1, CHK2), chemokine (C-C motif) receptor (such as CCR2, CCR4, CCR5, CCR8), chemokine (C-X-C motif) receptor (such as CXCR1, CXCR2, CXCR3 and CXCR4), Chemokine CC21 ligand, Cholecystokinin CCK2 receptor, Chorionic gonadotropin, c-Kit (tyrosine-protein kinase Kit or CD117), CISH (Cytokine-inducible SH2-containing protein), Claudin (such as 6, 18), cluster of differentiation (CD) such as CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e (CEACAM6), CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDwl23, CD134, CDwl37, CD158a, CD158bl, CD158b2, CD223, CD276 antigen; clusterin (CLU) gene, Clusterin, c-Met (hepatocyte growth factor receptor (HGFR)), Complement C3, Connective tissue growth factor, COP9 signalosome subunit 5, CSF-1 (colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T-lymphocyte protein 4) receptor, C-type lectin domain protein 9A (CLEC9A), Cyclin DI, Cyclin G, cyclin- dependent kinases (CDK, such as CDK1, CDK12, CDK1B, CDK2-9), cyclooxygenase (such as COXI, COX2), CYP2B1 gene, Cysteine palmitoyltransferase porcupine, Cytochrome P450 11B2, Cytochrome P450 17, cytochrome P450 17A1, Cytochrome P450 2D6, cytochrome P450 3A4, Cytochrome P450 reductase, cytokine signalling-1, cytokine signalling-3, Cytoplasmic isocitrate dehydrogenase, Cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T- lymphocyte protein-4, DDR2 gene, DEAD-box helicase 6 (DDX6), Death receptor 5 (DR5, TRAILR2), Death receptor 4 (DR4, TRAILR1), Delta-like protein ligand (such as 3, 4), Deoxyribonuclease, Deubiquitinating enzymes (DUBs), Dickkopf-1 ligand, dihydrofolate reductase (DHFR), Dihydropyrimidine dehydrogenase, Dipeptidyl peptidase IV, discoidin domain receptor (DDR, such as DDR1), Diacylglycerol kinase zeta (DGKZ), DNA binding protein (such as HU-beta), DNA dependent protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (such as alpha), DNA primase, dUTP pyrophosphatase, L- dopachrome tautomerase, E3 ubi quitin-protein ligase (such as RNF128, CBL-B), echinoderm microtubule like protein 4, EGFR tyrosine kinase receptor, Elastase, Elongation factor 1 alpha 2, Elongation factor 2, Endoglin, Endonuclease, endoplasmic reticulum aminopeptidase (ERAP, such as ERAP 1, ERAP2), Endoplasmin, Endosialin, Endostatin, endothelin (such as ET-A, ET- B), Enhancer of zeste homolog 2 (EZH2), Ephrin (EPH) tyrosine kinase (such as Epha3, Ephb4), Ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptors (EGFR), epidermal growth factor receptor (EGFR) gene, Epigen, Epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, Estradiol 17 beta dehydrogenase, Estrogen receptor (such as alpha, beta), Estrogen related receptor, Eukaryotic translation initiation factor 5 A (EIF5A) gene, Exportin 1, Extracellular signal related kinase (such as 1, 2), Extracellular signal -regulated kinases (ERK), Hypoxiainducible factor prolyl hydroxylase (HIF-PH or EGLN), Factor (such as Xa, Vila), farnesoid x receptor (FXR), Fas ligand, Fatty acid synthase (FASN), Ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4), Fibronectin, focal adhesion kinase (FAK, such as FAK2), folate hydrolase prostate-specific membrane antigen 1 (F0LH1), Folate receptor (such as alpha), Folate, Folate transporter 1, FYN tyrosine kinase, paired basic amino acid cleaving enzyme (FURIN), Beta-glucuronidase, Galactosyltransferase, Galectin-3, Ganglioside GD2, Glucocorticoid, glucocorticoid-induced TNFR-related protein GITR receptor, Glutamate carboxypeptidase II, glutaminase, Glutathione S-transferase P, glycogen synthase kinase (GSK, such as 3-beta), Glypican 3 (GPC3), gonadotropin-releasing hormone (GNRH), Granulocyte macrophage colony stimulating factor (GM-CSF) receptor, Granulocyte-colony stimulating factor (GCSF) ligand, growth factor receptor-bound protein 2 (GRB2), Grp78 (78 kDa glucose-regulated protein) calcium binding protein, molecular chaperone groEL2 gene, Heme oxygenase 1 (HOI), Heme oxygenase 2 (HO2), Heat shock protein (such as 27, 70, 90 alpha, beta), Heat shock protein gene, Heat stable enterotoxin receptor, Hedgehog protein, Heparanase, Hepatocyte growth factor, HERV-H LTR associating protein 2, Hexose kinase, Histamine H2 receptor, Histone methyltransferase (DOTIL), histone deacetylase (HD AC, such as 1, 2, 3, 6, 10, 11), Histone Hl, Histone H3, HLA class I antigen (A-2 alpha), HLA class II antigen, HLA class I antigen alpha G (HLA-G), Non-classical HLA, Homeobox protein NANOG, HSPB1 gene, Human leukocyte antigen (HLA), Human papillomavirus (such as E6, E7) protein, Hyaluronic acid, Hyaluronidase, Hypoxia inducible factor- 1 alpha (HIFla), Imprinted Maternally Expressed Transcript (Hl 9) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine-protein kinase HCK, LKappa-B kinase (IKK, such as IKKbe), IL-1 alpha, IL-1 beta, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulin (such as G, Gl, G2, K, M), Immunoglobulin Fc receptor, Immunoglobulin gamma Fc receptor (such as I, III, IIIA), indoleamine 2,3 -dioxygenase (IDO, such as IDO1 and IDO2), indoleamine pyrrole 2, 3 -dioxygenase 1 inhibitor, insulin receptor, Insulin-like growth factor (such as 1, 2), Integrin alpha-4/beta-l, integrin alpha-4/beta- 7, Integrin alpha-5/beta-l, Integrin alpha- V/beta-3, Integrin alpha- V/beta-5, Integrin alpha- V/beta-6, Intercellular adhesion molecule 1 (ICAM-1), interferon (such as alpha, alpha 2, beta, gamma), Interferon inducible protein absent in melanoma 2 (AIM2), interferon type I receptor, Interleukin 1 ligand, Interleukin 13 receptor alpha 2, interleukin 2 ligand, interleukin- 1 receptor- associated kinase 4 (IRAK4), Interleukin-2, Interleukin-29 ligand, Interleukin 35 (IL-35), isocitrate dehydrogenase (such as IDH1, IDH2), Janus kinase (JAK, such as JAK1, JAK2), Jun N terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, Killer cell Ig like receptor, Kinase insert domain receptor (KDR), Kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, Kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy- Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, Lanosterol- 14 demethylase, LDL receptor related protein- 1, Leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2), Leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT4), Leukotriene A4 hydrolase, Listeriolysin, L-Selectin, Luteinizing hormone receptor, Lyase, lymphocyte activation gene 3 protein (LAG-3), Lymphocyte antigen 75, Lymphocyte function antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), Lymphotactin, Lyn (Lck/Yes novel) tyrosine kinase, lysine demethylases (such as KDM1, KDM2, KDM4, KDM5, KDM6, A/B/C/D), Lysophosphatidate-1 receptor, lysosomal -associated membrane protein family (LAMP) gene, Lysyl oxidase homolog 2, lysyl oxidase protein (LOX), 5 -Lipoxygenase (5-LOX), Hematopoietic Progenitor Kinase 1 (HPK1), Hepatocyte growth factor receptor (MET) gene, macrophage colony-stimulating factor (MCSF) ligand, Macrophage migration inhibitory fact, MAGECI gene, MAGEC2 gene, Major vault protein, MAPK -activated protein kinase (such as MK2), Mas-related G-protein coupled receptor, matrix metalloprotease (MMP, such as MMP2, MMP9), Mcl-1 differentiation protein, Mdm2 p53-binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, Melanocyte protein Pmel 17, melanocyte stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, Melanoma associated antigen (such as 1, 2, 3, 6), Membrane copper amine oxidase, Mesothelin, MET tyrosine kinase, Metabotropic glutamate receptor 1, Metalloreductase STEAP1 (six transmembrane epithelial antigen of the prostate 1), Metastin, methionine aminopeptidase-2, Methyltransferase, Mitochondrial 3 ketoacyl CoA thiolase, mitogen-activate protein kinase (MAPK), mitogen-activated protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine/threonine kinase), mTOR complex (such as 1,2), mucin (such as 1, 5A, 16), mut T homolog (MTH, such as MTH1), Myc proto-oncogene protein, myeloid cell leukemia 1 (MCL1) gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, Neural cell adhesion molecule 1, Neurokinin 1 (NK1) receptor, Neurokinin receptor, Neuropilin 2, NF kappa B activating protein, NIMA-related kinase 9 (NEK9), Nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 A B activating NK receptor, NLRP3 (NACHT LRR PYD domain protein 3) modulators, Noradrenaline transporter, Notch (such as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), Nuclear erythroid 2-related factor 2, Nuclear Factor (NF) kappa B, Nucleolin, Nucleophosmin, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), 2 oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, Opioid receptor (such as delta), Ornithine decarboxylase, Orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, Osteocalcin, Osteoclast differentiation factor, Osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4 TNFRSF4, or CD134) receptor, P3 protein, p38 kinase, p38 MAP kinase, p53 tumor suppressor protein, Parathyroid hormone ligand, peroxisome proliferator-activated receptors (PPAR, such as alpha, delta, gamma), P- Gly coprotein (such as 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3- kinase (PI3K), phosphoinositide-3 kinase (PI3K such as alpha, delta, gamma), phosphorylase kinase (PK), PKN3 gene, placenta growth factor, platelet-derived growth factor (PDGF, such as alpha, beta), Platelet-derived growth factor (PDGF, such as alpha, beta), Pleiotropic drug resistance transporter, Plexin Bl, PLK1 gene, polo-like kinase (PLK), Polo-like kinase 1, Poly (ADP-ribose) polymerase (PARP, such as PARP1, PARP2 and PARP3, PARP7, and mono- PARPs), Preferentially expressed antigen in melanoma (PRAME) gene, Prenyl-binding protein (PrPB), Probable transcription factor PML, Progesterone receptor, Programmed cell death 1 (PD- 1), Programmed cell death ligand 1 inhibitor (PD-L1), Prosaposin (PSAP) gene, Prostanoid receptor (EP4), Prostaglandin E2 synthase, prostate specific antigen, Prostatic acid phosphatase, proteasome, Protein E7, Protein farnesyltransferase, protein kinase (PK, such as A, B, C), protein tyrosine kinase, Protein tyrosine phosphatase beta, Proto-oncogene serine/threonine-protein kinase (PIM, such as PIM-1, PIM-2, PIM-3), P-Selectin, Purine nucleoside phosphorylase, purinergic receptor P2X ligand gated ion channel 7 (P2X7), Pyruvate dehydrogenase (PDH), Pyruvate dehydrogenase kinase, Pyruvate kinase (PYK), 5 -Alpha- reductase, Raf protein kinase (such as 1, B), RAFI gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma associated protein, retinoic acid receptor (such as gamma), Retinoid X receptor, Rheb (Ras homolog enriched in brain) GTPase, Rho (Ras homolog) associated protein kinase 2, ribonuclease, Ribonucleotide reductase (such as M2 subunit), Ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron (Recepteur d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, RosI tyrosine kinase, Runt-related transcription factor 3, Gamma-secretase, SI 00 calcium binding protein A9, Sarco endoplasmic calcium ATPase, Second mitochondria-derived activator of caspases (SMAC) protein, Secreted frizzled related protein-2, Secreted phospholipase A2, Semaphorin-4D, Serine protease, serine/threonine kinase (STK), serine/threonine-protein kinase (TBK, such as TBK1), signal transduction and transcription (STAT, such as STAT-1, STAT-3, STAT-5), Signaling lymphocytic activation molecule (SLAM) family member 7, six-transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, Sodium iodide cotransporter, Sodium phosphate cotransporter 2B, Somatostatin receptor (such as 1, 2, 3, 4, 5), Sonic hedgehog protein, Son of sevenless (SOS), Specific protein 1 (Spl) transcription factor, Sphingomyelin synthase, Sphingosine kinase (such as 1, 2), Sphingosine- 1 -phosphate receptor- 1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, Stabilin-1 (STAB I), STAT3 gene, Steroid sulfatase, Stimulator of interferon genes (STING) receptor, stimulator of interferon genes protein, Stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), Superoxide dismutase, Suppressor of cytokine signaling modulators (SOCS), Survivin protein, Synapsin 3, Syndecan-1, Synuclein alpha, T cell surface glycoprotein CD28, tankbinding kinase (TBK), TATA box-binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T-cell CD3 glycoprotein zeta chain, T-cell differentiation antigen CD6, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, Telomerase reverse transcriptase (TERT) gene, Tenascin, Three prime repair exonuclease 1 (TREX1), Three prime repair exonuclease 2 (TREX2), Thrombopoietin receptor, Thymidine kinase, Thymidine phosphorylase, Thymidylate synthase, Thymosin (such as alpha 1), Thyroid hormone receptor, Thyroid stimulating hormone receptor, Tissue factor, TNF related apoptosis inducing ligand, TNFR1 associated death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSFI Igene, TNFSF9 gene, Toll-like receptor (TLR such as 1-13), topoisomerase (such as I, II, III), Transcription factor, Transferase, transferrin (TF), transforming growth factor alpha (TGFa), transforming growth factor beta (TGFB) and isoforms thereof, TGF beta 2 ligand, Transforming growth factor TGF-$ receptor kinase, Transglutaminase, Translocation associated protein, Transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast glycoprotein (TPBG) gene, Trophoblast glycoprotein, Tropomyosin receptor kinase (Trk) receptor (such as TrkA, TrkB, TrkC), tryptophan 2,3 -dioxygenase (TDO), Tryptophan 5- hydroxylase, Tubulin, Tumor necrosis factor (TNF, such as alpha, beta), Tumor necrosis factor 13C receptor, tumor progression locus 2 (TPL2), Tumor protein 53 (TP53) gene, Tumor suppressor candidate 2 (TUSC2) gene, Tumor specific neoantigens, Tyrosinase, Tyrosine hydroxylase, tyrosine kinase (TK), Tyrosine kinase receptor, Tyrosine kinase with immunoglobulin-like and EGF-like domains (TIE) receptor, Tyrosine protein kinase ABL1 inhibitor, Ubiquitin, Ubiquitin carboxyl hydrolase isozyme L5, Ubiquitin thioesterase- 14, Ubiquitin-conjugating enzyme E2I (UBE2I, UBC9), Ubiquitin-specific-processing protease 7 (USP7), Urease, Urokinase plasminogen activator, Uteroglobin, Vanilloid VR1, Vascular cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig suppressor of T-cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, Vimentin, Vitamin D3 receptor, Proto-oncogene tyrosine-protein kinase, Mer (Mer tyrosine kinase receptor modulators), YAP (Yes-associated protein modulators)es, Wee-1 protein kinase, Werner Syndrome RecQ Like Helicase (WRN), Wilms' tumor antigen 1, Wilms' tumor protein, WW domain containing transcription regulator protein 1 (TAZ), X-linked inhibitor of apoptosis protein, Zinc finger protein transcription factor or any combination thereof.

[00212] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more additional therapeutic agents that may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS- 118; Alpha 1 adrenoceptor/ Alpha 2 adrenoceptor antagonists, such as phenoxybenzamine hydrochloride (injectable, pheochromocytoma); Androgen receptor antagonists, such as nilutamide; anti-cadherin antibodies, such as HKT-288; anti-leucine-rich repeat containing 15 (LRRC15) antibodies, such as ABBV-085. ARGX-110; angiotensin receptor blockers, nitric oxide donors; antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx; anti-angiopoietin (ANG)-2 antibodies, such as MEDI3617, and LY3127804; anti-ANG-l/ANG-2 antibodies, such as AMG-780; anti-CSFIR antibodies, such as emactuzumab, LY3022855, AMG-820, FPA-008 (cabiralizumab); anti- endoglin antibodies, such as TRC105 (carotuximab); anti-ERBB antibodies, such as CDX-3379, HLX-02, seribantumab; anti-HER2 antibodies, such as HERCEPTIN® (trastuzumab), trastuzumab biosimimar, margetuximab, MEDI4276, BAT-8001, Pertuzumab (Perjeta), RG6264, ZW25 (a bispecific HER2-directed antibody targeting the extracellular domains 2 and 4; Cancer Discov. 2019 January; 9(1):8; PMID: 30504239); anti-HLA-DR antibodies, such as IMMU-114; anti-IL-3 antibodies, such as JNJ-56022473; anti-TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI Gene ID: 8784) antibodies, such as MK-4166, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; and those described, e.g., in Inti. Patent Publ. Nos. WO 2017/096179, WO 2017/096276, WO 2017/096189; and WO 2018/089628; anti-EphA3 antibodies, such as KB-004; anti-CD37 antibodies, such as otlertuzumab (TRU-016); anti-FGFR-3 antibodies, such as LY3076226, B-701 ; anti-FGFR-2 antibodies, such as GAL-F2; anti-C5 antibodies, such as ALXN-1210; anti-EpCAM antibodies, such as VB4-845; anti-CEA antibodies, such as RG-7813; anti-Carcinoembryonic-antigen- related-cell-adhesion-molecule-6 (CEACAM6, CD66C) antibodies, such as BAY-1834942, NEO-201 (CEACAM 5/6); anti-GD2 antibodies, such as APN-301; anti-interleukin- 17 (IL-17) antibodies, such as CJM-112; anti-interleukin- 1 beta antibodies, such as canakinumab (ACZ885), VPM087; anti-carbonic anhydrase 9 (CA9, CAIX) antibodies, such as TX-250; antiMucin 1 (MUC1) antibodies, such as gatipotuzumab, Mab-AR-20.5; anti-KMA antibodies, such as MDX-1097; anti-CD55 antibodies, such as PAT-SC1; anti-c-Met antibodies, such as ABBV- 399; anti-PSMA antibodies, such as ATL-101; anti-CDlOO antibodies, such as VX-15; anti- EPHA3 antibodies, such as fibatuzumab; anti-APRIL antibodies, such as BION-1301; anti- fibroblast activation protein (FAP)/IL-2R antibodies, such as RG7461; anti -fibroblast activation protein (FAP)/TRAIL-R2 antibodies, such as RG7386; anti-fucosyl-GMl antibodies, such as BMS-986012; anti-IL-8 (Interleukin-8) antibodies, such as HuMax-Inflam (BMS-986253); anti- myostatin inhibitors, such as landogrozumab; anti-delta-like protein ligand 3 (DDL3) antibodies, such as rovalpituzumab tesirine; anti-DLL4 (delta like ligand 4) antibodies, such as demcizumab; anti -clusterin antibodies, such as AB-16B5; anti-Ephrin-A4 (EFNA4) antibodies, such as PF- 06647263; anti-mesothelin antibodies, such as BMS-986148, Anti-MSLN-MMAE; anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such as lifastuzumab; anti-TGFb antibodies, such as SAR439459; anti-transforming growth factor-beta (TGF-beta) antibodies, such as ABBV-151, LY3022859, NIS793, XOMA 089; purine analogs, folate antagonists (such as pralatr exate), cladribine, pentostatin, fludarabine and related inhibitors; antiproliferative/antimitotic agents including natural products, such as vinca alkaloids (vinblastine, vincristine) and microtubule disruptors such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones, vinorelbine (NAVELBINE®), and epipodophyllotoxins (etoposide, teniposide); DNA damaging agents, such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, DEBDOX, epirubicin, iphosphamide, melphalan, merchlorethamine, mitomycin C, mitoxantrone, nitrosourea, procarbazine, taxol, Taxotere, teniposide, etoposide, and triethylenethiophosphoramide; DNA-hypomethylating agents, such as guadecitabine (SGL 110), ASTX727; antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin); enzymes such as L- asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine; DNAi oligonucleotides targeting Bcl-2, such as PNT2258; agents that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin; asparaginase stimulators, such as crisantaspase (Erwinase®) and GRASPA (ERY-001, ERY-ASP), calaspargase pegol, pegaspargase; pan-Trk, ROS1 and ALK inhibitors, such as entrectinib, TPX-0005; anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib, ceritinib, alecensa (RG7853), ALUNBRIG® (brigatinib); antiproliferative/antimitotic alkylating agents, such as nitrogen mustard cyclophosphamide and analogs (e.g., melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkyl nitrosoureas (e.g., carmustine) and analogs, streptozocin, and triazenes (e.g., dacarbazine); antiproliferative/antimitotic antimetabolites, such as folic acid analogs (methotrexate); platinum coordination complexes (e.g., cisplatin, oxiloplatinim, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide; hormones, hormone analogs (e.g., estrogen, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (e.g., letrozole and anastrozole); antiplatelet agents; anticoagulants such as heparin, synthetic heparin salts, and other inhibitors of thrombin; fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel; antimigratory agents; antisecretory agents (e.g., breveldin); immunosuppressives, such as tacrolimus, sirolimus, azathioprine, and mycophenolate; growth factor inhibitors, and vascular endothelial growth factor inhibitors; fibroblast growth factor inhibitors, such as FPA14; AMP activated protein kinase stimulators, such as metformin hydrochloride; ADP ribosyl cyclase- 1 inhibitors, such as daratumumab (DARZALEX®); Caspase recruitment domain protein- 15 stimulators, such as mifamurtide (liposomal); CCR5 chemokine antagonists, such as MK-7690 (vicriviroc); CDC17 protein kinase inhibitors, such as TAK-931; Cholesterol sidechain cleavage enzyme inhibitors, such as ODM-209; Dihydropyrimidine dehydrogenase/Orotate phosphoribosyltransferase inhibitors, such as Cefesone (tegafur+gimeracil+oteracil potassium); DNA polymerase/Ribonucleotide reductase inhibitors, such as clofarabine; DNA interference oligonucleotides, such as PNT2258, AZD-9150; Estrogen receptor modulators, such as bazedoxifene; Estrogen receptor agonists/Progesterone receptor antagonists, such as TRI- CYCLEN LO (norethindrone+ethinyl estradiol); HLA class I antigen A-2 alpha modulators, such as FH-MCVA2TCR; HLA class I antigen A-2 alpha/MART-1 melanoma antigen modulators, such as MART-1 F5 TCR engineered PBMC; Human Granulocyte Colony Stimulating Factors, such as PF-06881894; GNRH receptor agonists, such as leuprorelin acetate, leuprorelin acetate sustained release depot (ATRIGEL), triptorelin pamoate, goserelin acetate; GNRH receptor antagonists, such as elagolix, relugolix, degarelix; Endoplasmin modulators, such as anlotinib; H+K+ ATPase inhibitors, such as omeprazole, esomeprazole; ICAM-1/CD55 modulators, such as cavatak (V-937); IL-15/IL-12 modulators, such as SAR441000; Interleukin 23A inhibitors, such as guselkumab; Lysine specific histone demethylase 1 inhibitors, such as CC-90011; IL-12 Mma, such as MEDI1191; RIG-I modulators, such as RGT-100; N0D2 modulators, such as SB- 9200, and IR-103; Progesterone receptor agonists, such as levonorgestrel; Protein cereblon modulators, such as CC-92480, CC-90009; Protein cereblon modulators/DNA binding protein Ikaros inhibitors/Zinc finger binding protein Aiolos inhibitors, such as iberdomide; Retinoid X receptor modulators, such as alitretinoin, bexarotene (oral formulation); RIP-1 kinase inhibitors, such as GSK-3145095; selective oestrogen receptor degraders, such as AZD9833; SUMO inhibitors, such as TAK-981; Thrombopoietin receptor agonists, such as eltrombopag; Thyroid hormone receptor agonists, such as levothyroxine sodium; TNF agonists, such as tasonermin; Tyrosine phosphatase substrate 1 inhibitors, such as CC-95251; HER2 inhibitors, such as neratinib, tucatinib (ONT-380); EGFR/ErbB2/Ephb4 inhibitors, such as tesevatinib;

EGFR/HER2 inhibitors, such as TAK-788; EGFR family tyrosine kinase receptor inhibitors, such as DZD-9008; EGFR/ErbB-2 inhibitors, such as varlitinib; mutant selective EGFR inhibitors, such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694; epha2 inhibitors, such as MM-310; polycomb protein (EED) inhibitors, such as MAK683; DHFR inhibitor/Folate transporter 1 modulator/Folate receptor antagonist, such as pralatrexate; DHFR/GAR transformylase/Thymidylate synthase/Transf erase inhibitors, such as pemetrexed disodium; p38 MAP kinase inhibitors, such as ralimetinib; PRMT inhibitors, such as MS203, PF-06939999, GSK3368715, GSK3326595; Sphingosine kinase 2 (SK2) inhibitors, such as opaganib; Nuclear erythroid 2-related factor 2 stimulators, such as omaveloxolone (RTA-408); Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579; Mucin 1 inhibitors, such as GO-203-2C; MARCKS protein inhibitors, such as BIO-11006; Folate antagonists, such as arfolitixorin; Galectin-3 inhibitors, such as GR-MD-02; Phosphorylated P68 inhibitors, such as RX-5902; CD95/TNF modulators, such as ofranergene obadenovec; pan-PIM kinase inhibitors, such as INCB-053914; IL-12 gene stimulators, such as EGEN-001, tavokinogene telseplasmid; Heat shock protein HSP90 inhibitors, such as TAS-1 16, PEN-866; VEGF/HGF antagonists, such as MP-0250; VEGF ligand inhibitors, such as bevacizumab biosimilar; VEGF receptor antagonists/VEGF ligand inhibitors, such as ramucirumab; VEGF- 1/VEGF-2/VEGF-3 receptor antagonists; such as fruquintinib; VEGF-l/VEGF-2 receptor modulators, such as HLA-A2402/HLA-A0201 restricted epitope peptide vaccine; Placenta growth factor ligand inhibitor/VEGF-A ligand inhibitor, such as aflibercept; SYK tyrosine kinase/JAK tyrosine kinase inhibitors, such as ASN-002; Trk tyrosine kinase receptor inhibitors, such as larotrectinib sulfate; JAK3/JAK1/TBK1 kinase inhibitors, such as CS-12912; IL-24 antagonist, such as AD-IL24; NLRP3 (NACHT LRR PYD domain protein 3) modulators, such as BMS-986299; RIG-I agonists, such as RGT-100; Aerolysin stimulators, such as topsalysin; P- Glycoprotein 1 inhibitors, such as HM-30181A; CSF-1R antagonists, such as ARRY-382, BLZ- 945, RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357); CCR8 inhibitors, such as JTX-1811, 1-309, SB-649701, HG-1013, RAP-310; anti-Mesothelin antibodies, such as SEL-403; Thymidine kinase stimulators, such as aglatimagene besadenovec; Polo-like kinase 1 inhibitors, such as PCM-075, onvansertib; NAE inhibitors, such as pevonedistat (MLN-4924), TAS-4464; Pleiotropic pathway modulators, such as avadomide (CC-122); Amyloid protein binding protein-1 inhibitorS/Ubiquitin ligase modulators, such as pevonedistat; FoxMl inhibitors, such as thiostrepton; UBA1 inhibitors, such as TAK-243; Src tyrosine kinase inhibitors, such as VAL-201; VDAC/HK inhibitors, such as VDA-1102; Elf4a inhibitors, such as rohinitib, eFT226; TP53 gene stimulators, such as ad-p53; Retinoic acid receptor agonists, such as tretinoin; Retinoic acid receptor alpha (RARa) inhibitors, such as SY- 1425; SIRT3 inhibitors, such as YC8-02; Stromal cell-derived factor 1 ligand inhibitors, such as olaptesed pegol (NOX- A12); IL-4 receptor modulators, such as MDNA-55; Arginase-I stimulators, such as pegzilarginase; Topoisomerase I inhibitors, such as irinotecan hydrochloride, Onivyde: Topoisomerase I inhibitor/hypoxia inducible factor- 1 alpha inhibitors, such as PEG-SN38 (firtecan pegol); Hypoxia inducible factor-1 alpha inhibitors, such as PT-2977, PT-2385; CD122 (IL-2 receptor) agonists, such as proleukin (aldesleukin, IL-2); pegylated IL-2 (eg NKTR-214); modified variants of IL-2 (eg THOR-707); TLR7/TLR8 agonist, such as NKTR-262; TLR7 agonists, such as DS-0509, GS-9620, LHC- 165, TMX-101 (imiquimod); p53 tumor suppressor protein stimulators such as kevetrin; Mdm4/Mdm2 p53-binding protein inhibitors, such as ALRN-6924; kinesin spindle protein (KSP) inhibitors, such as filanesib (ARRY-520); CD80-fc fusion protein inhibitors, such as FPT-155; Menin and mixed lineage leukemia (MLL) inhibitors such as KO-539; Liver x receptor agonists, such as RGX-104; IL-10 agonists, such as Pegilodecakin (AM-0010); VEGFR/PDGFR inhibitors, such as vorolanib; IRAK4 inhibitors, such as CA-4948; anti-TLR-2 antibodies, such as OPN-305; Calmodulin modulators, such as CBP-501; Glucocorticoid receptor antagonists, such as relacorilant (CORT-125134); Second mitochondria-derived activator of caspases (SMAC) protein inhibitors, such as BL891065; Lactoferrin modulators, such as LTX-315; KIT proto-oncogene, receptor tyrosine kinase (KIT) inhibitors, such as PLX-9486; platelet derived growth factor receptor alpha (PDGFRA)/KIT proto-oncogene, receptor tyrosine kinase (KIT) mutant-specific antagonists/inhibitors such as BLU-285, DCC-2618; Exportin 1 inhibitors, such as eltanexor; CHST15 gene inhibitors, such as STNM-01; Somatostatin receptor antagonist, such as OPS-201; CEBPA gene stimulators, such as MTL-501; DKK3 gene modulators, such as MTG-201; Chemokine (CXCR1/CXCR2) inhibitors, such as SX-682; p70s6k inhibitors, such as MSC2363318A; methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891, APL-1202; arginine N-m ethyltransferase 5 inhibitors, such as GSK-3326595; CD71 modulators, such as CX-2029 (ABBV-2029); ATM (ataxia telangiectasia) inhibitors, such as AZD0156, AZD1390; CHK1 inhibitors, such as GDC- 0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1/2); CXCR4 antagonists, such as BL- 8040, LY2510924, burixafor (TG-0054), X4P-002, X4P-001-IO, Plerixafor; EXH2 inhibitors, such as GSK2816126; KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, GSK- 2879552; CXCR2 antagonists, such as AZD-5069; DNA dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01); protein kinase C (PKC) inhibitors, such as LXS-196, sotrastaurin; selective estrogen receptor downregulators (SERD), such as fulvestrant (Faslodex®), RG6046, RG6047, RG6171, elacestrant (RAD- 1901), SAR439859 and AZD9496; selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545; selective androgen receptor modulator (SARM), such as GTX-024, darolutamide; transforming growth factor-beta (TGF-beta) kinase antagonists, such as galunisertib, LY3200882; TGF-beta inhibitors described in WO 2019/103203; TGF beta receptor 1 inhibitors, such as PF-06952229; bispecific antibodies, such as ABT-165 (DLL4/VEGF), MM-141 (IGF- l/ErbB3), MM-111 (Erb2/Erb3), JNJ-64052781 (CD19/CD3), PRS-343 (CD- 137/HER2), AFM26 (BCMA/CD16A), JNJ-61186372 (EGFR/cMET), AMG-211 (CEA/CD3), RG7802 (CEA/CD3), ERY-974 (CD3/GPC3) vancizumab (angiopoietins/VEGF), PF-06671008 (Cadherins/CD3), AFM-13 (CD16/CD30), APV0436 (CD123/CD3), flotetuzumab (CD123/CD3), REGN-1979 (CD20/CD3), MCLA-117 (CD3/CLEC12A), MCLA-128 (HER2/HER3), JNJ-0819, JNJ-7564 (CD3/heme), AMG-757 (DLL3-CD3), MGD-013 (PD- l/LAG-3), FS-118 (LAG-3/PD-L1) MGD-019 (PD-l/CTLA-4), KN-046 (PD-l/CTLA-4), MEDI-5752 (CTLA-4/PD-1), RO-7121661 (PD-l/TIM-3), XmAb-20717 (PD-l/CTLA-4), AK- 104 (CTLA-4/PD-1), AMG-420 (BCMA/CD3), BI-836880 (VEFG/ANG2), JNJ-63709178 (CD123/CD3), MGD-007 (CD3/gpA33), MGD-009 (CD3/B7H3), AGEN1223, IMCgplOO (CD3/gpl00), AGEN-1423, ATOR-1015 (CTLA-4/OX40), LY-3415244 (TIM-3/PDL1), INHIBRX-105 (4-1BB/PDL1), faricimab (VEGF-A/ANG-2), FAP-4-IBBL (4-1BB/FAP), XmAb-13676 (CD3/CD20), TAK-252 (PD-1/OX40L), TG-1801 (CD19/CD47), XmAb-18087 (SSTR2/CD3), catumaxomab (CD3/EpCAM), SAR- 156597 (IL4/IL13), EMB-01 (EGFR/cMET), REGN-4018 (MUC16/CD3), REGN-1979 (CD20/CD3), RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), navicixizumab (DLL4/VEGF), GRB- 1302 (CD3/Erbb2), vanucizumab (VEGF-A/ANG-2), GRB-1342 (CD38/CD3), GEM-333 (CD3/CD33), IMM-0306 (CD47/CD20), RG6076, MEDI5752 (PD-l/CTLA-4), LY3164530 (MET/EGFR); Alpha-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613; XPO1 inhibitors, such as selinexor (KPT-330); Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221); IDH1 inhibitors such as AG-120, and AG-881 (IDH1 and IDH2), IDH- 305, BAY-1436032; IDH1 gene inhibitors, such as ivosidenib; interleukin-3 receptor (IL-3R) modulators, such as SL-401; Arginine deiminase stimulators, such as pegargiminase (ADI-PEG- 20); claudin-18 inhibitors, such as claudiximab; 3-catenin inhibitors, such as CWP-291; chemokine receptor 2 (CCR) inhibitors, such as PF-04136309, CCX-872, BMS-813160 (CCR2/CCR5); thymidylate synthase inhibitors, such as ONX-0801; ALK/ROS1 inhibtors, such as lorlatinib; tankyrase inhibitors, such as G007-LK; triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210), such as PY159; triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209), such as PY314; Mdm2 p53-binding protein inhibitors, such as CMG-097, HDM-201; c-PIM inhibitors, such as PIM447; sphingosine kinase- 2 (SK2) inhibitors, such as Yeliva® (ABC294640); DNA polymerase inhibitors, such as sapacitabine; Cell cycle/Microtubule inhibitors, such as eribulin mesylate; c-MET inhibitors, such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361 ; c-Met/VEGFR inhibitors, such as BMS-817378, TAS- 115; c-Met/RON inhibitors, such as BMS-777607; BCR/ABL inhibitors, such as rebastinib, asciminib, ponatinib (ICLUSIG®); MNK1/MNK2 inhibitors, such as eFT-508; Cytochrome P450 11B2/Cytochrome P450 17/AKT protein kinase inhibitors, such as LAE-201; Cytochrome P450 3A4 stimulators, such as mitotane; lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011; CSF1R/KIT and FLT3 inhibitors, such as pexidartinib (PLX3397); Flt3 tyrosine kinase/Kit tyrosine kinase inhibitor and PDGF receptor antagonists, such as quizartinib dihydrochloride; kinase inhibitors, such as vandetanib; E selectin antagonists, such as GMI-1271; differentiation inducers, such as tretinoin; epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD-9291), cetuximab; topoisomerase inhibitors, such as Adriamycin, doxorubicin, daunorubicin, dactinomycin, DaunoXome, Caelyx, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114); corticosteroids, such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone; growth factor signal transduction kinase inhibitors; nucleoside analogs, such as DFP-10917; Axl inhibitors, such as BGB-324 (bemcentinib), SLC-0211; Axl/Flt3 inhibitors, such as gilteritinib; Inhibitors of bromodomain and extraterminal motif (BET) proteins, including ABBV-744, BRD2 (NCBI Gene ID: 6046), BRD3 (NCBI Gene ID: 8019), BRD4 (NCBI Gene ID: 23476), and bromodomain testis-specific protein (BRDT; NCBI Gene ID: 676), such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, CC-95775, mivebresib, BI-894999, PLX-2853, PLX- 51107, CPI-0610, GS-5829; PARP inhibitors, such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, BGB-290, fluzolepali (SHR-3162), niraparib (JNJ-64091742), bendamustine hydrochloride; PARP/Tankyrase inhibitors such as 2X-121 (e-7499); IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, simmiparib; Proteasome inhibitors, such as ixazomib (NINLARO), carfilzomib (Kyprolis®), marizomib, bortezomib; Glutaminase inhibitors, such as CB-839 (telaglenastat), bis-2-(5-phenylacetamido-l,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); mitochondrial complex I inhibitors, such as metformin, phenformin; vaccines, such as peptide vaccine TG-01 (RAS), GALE-301, GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101 , 6MHP, OSE-2101, galinpepimut-S, SVN53-67/M57- KLH, IMU-131, peptide subunit vaccine (acute lymphoblastic leukemia, University Children's Hospital Tuebingen); bacterial vector vaccines such as CRS-207/GVAX, axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines such as nadofaragene firadenovec; autologous Gp96 vaccine; dendritic cells vaccines, such as CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, ADXS31-142, autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal/intravenous, Universitatsklinikum Erlangen); oncolytic vaccines such as, talimogene laherparepvec, pexastimogene devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-l, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, such as CV AC-301, CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax™; tumor cell vaccines, such as Vigil® (IND- 14205), Oncoquest-L vaccine; live attenuated, recombinant, serotype 1 poliovirus vaccine, such as PVS-RIPO; Adagloxad simolenin; MEDL0457; DPV-001 a tumor-derived, autophagosome enriched cancer vaccine; RNA vaccines such as, CV-9209, LV- 305; DNA vaccines, such as MEDI-0457, MVT-816, INO-5401; modified vaccinia virus Ankara vaccine expressing p53, such as MVA-p53; DPX-Survivac; BriaVax™; GI-6301; GL6207; GL 4000; 10-103; Neoantigen peptide vaccines, such as AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001 (TLR-3 agonist), GRANITE-001, NEO-PV-01; Peptide vaccines that target heat shock proteins, such as PhosphoSynVax™; Vitespen (HSPPC-96-C), NANT Colorectal Cancer Vaccine containing aldoxorubicin, autologous tumor cell vaccine+systemic CpG-B+IFN- alpha (cancer), 10-120+10-103 (PD-L1/PD-L2 vaccines), HB-201, HB-202, HB-301, TheraT®*- based vaccines; TLR-3 agonist/interferon inducers, such as Poly-ICLC (NSC-301463); STAT-3 inhibitors, such as napabucasin (BBL608); ATPase p97 inhibitors, such as CB-5083; smoothened (SMO) receptor inhibitors, such as Odomzo® (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole; interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilar (Biogenomics), ropeginterferon alfa-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon (Alfanative, Viragen), interferon alpha lb, Roferon-A (Canferon, Ro-25-3036), interferon alfa-2a follow-on biologic (Biosidus)(Inmutag, Inter 2A), interferon alfa-2b follow-on biologic (Biosidus — Bioferon, Citopheron, Ganapar, Beijing Kawin Technology — Kaferon), Alfaferone, pegylated interferon alpha-lb, peginterferon alfa-2b follow-on biologic (Amega), recombinant human interferon alpha- lb, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN alpha 2b conjugate, Dynavax (SD-101), and interferon alfa-nl (Humoferon, SM- 10500, Sumiferon); interferon gamma ligand modulators, such as interferon gamma (OH-6000, Ogamma 100); telomerase modulators, such as, tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937); DNA methyltransferases inhibitors, such as temozolomide (CCRG-81045), decitabine, guadecitabine (S-l 10, SGI-110), KRX-0402, RX-3117, RRx-001, and azacytidine (CC-486); DNA gyrase inhibitors, such as pixantrone and sobuzoxane; DNA gyrase inhibitors/Topoisimerase II inhibitors, such as amrubicin; Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), ABT-737, RG7601, and AT-101; Bcl-2/Bcl-XL inhibitors, such as novitoclax;

Notch inhibitors, such as LY3039478 (crenigacestat), tarextumab (anti-Notch2/3), BMS-906024; hyaluronidase stimulators, such as PEGPH-20; Erbb2 tyrosine kinase receptor inhibitors/Hyaluronidase stimulators, such as Herceptin Hylecta; Wnt pathway inhibitors, such as SM-04755, PRI-724, WNT-974; gamma-secretase inhibitors, such as PF-03084014, MK-0752, RO-4929097; Grb-2 (growth factor receptor bound protein-2) inhibitors, such as BP1001;

TRAIL pathway-inducing compounds, such as ONC201, ABBV-621; TRAIL modulators, such as SCB-313; Focal adhesion kinase inhibitors, such as VS-4718, defactinib, GSK2256098; hedgehog inhibitors, such as saridegib, sonidegib (LDE225), glasdegib; Aurora kinase inhibitors, such as alisertib (MLN-8237), and AZD-2811, AMG-900, barasertib, ENMD-2076; HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine, apatorsen; ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib) and VX-970; Hsp90 inhibitors, such as AUY922, onalespib (AT13387), SNX-2112, SNX5422; murine double minute (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388); CD137 agonists, such as urelumab, utomilumab (PF-05082566), AGEN2373, ADG- 106, BT-7480, QL1806; STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, GSK3745417; FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNI-42756493, LY2874455, Debio-1347; fatty acid synthase (FASN) inhibitors, such as TVB-2640; CD44 binders, such as A6; protein phosphatease 2A (PP2A) inhibitors, such as LB- 100; CYP17 inhibitors, such as seviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;

RXR agonists, such as IRX4204; hedgehog/smoothened (hh/Smo) antagonists, such as taladegib, patidegib, vismodegib; complement C3 modulators, such as Imprime PGG; IL-15 agonists, such as ALT-803, NKTR-255, interleukin- 15/Fc fusion protein, AM-0015, NIZ-985, and hetIL-15; EZH2 (enhancer of zeste homolog 2) inhibitors, such as tazemetostat, CPI-1205, GSK-2816126, PF-06821497; oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301, IMLYGIC®; D0T1L (histone methyltransferase) inhibitors, such as pinometostat (EPZ-5676); toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators; DNA plasmids, such as BC-819; PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1); WEE1 inhibitors, such as AZD-1775 (adavosertib); Rho kinase (ROCK) inhibitors, such as AT13148, KD025; Inhibition of Apoptosis Protein (IAP) inhibitors, such as ASTX660, debio-1143, birinapant, APG-1387, LCL-161; RNA polymerase inhibitors, such has lurbinectedin (PM-1183), CX-5461; Tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin), and 0X1-4503, fluorapacin (AC-0001), plinabulin, vinflunine; Toll -like receptor 4 (TLR-4) agonists, such as G100, GSK1795091, and PEPA-10; Elongation factor 1 alpha 2 inhibitors, such as plitidepsin; Elongation factor 2 inhibitors/Interleukin-2 ligands/NAD ADP ribosyltransferase stimulators, such as denileukin diftitox; CD95 inhibitors, such as APG-101, APO-OIO, asunercept; WT1 inhibitors, such as DSP-7888; splicing factor 3B subunitl (SF3B1) inhibitors, such as H3B-8800; retinoid Z receptor gamma (RORy) agonists, such as LYC-55716; and microbiome modulators, such as SER-401, EDP-1503, MRx-0518.

[00213] In some embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is co-administered with one or more additional therapeutic agents comprising an inhibitor or antagonist of: myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator (NCBI Gene ID: 4170); mitogen-activated protein kinase 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1), NCBI Gene ID: 11184); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha; NCBI Gene ID: 1606); 5 '-nucleotidase ecto (NT5E or CD73; NCBI Gene ID: 4907); ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 or CD39; NCBI Gene ID: 593); transforming growth factor beta 1 (TGFB1; NCBI Gene ID: 7040); heme oxygenase 1 (HM0X1, HO-1 or HOI; NCBI Gene ID: 3162); heme oxygenase 2 (HM0X2, HO- 2 or H02; NCBI Gene ID: 3163); vascular endothelial growth factor A (VEGFA or VEGF; NCBI Gene ID: 7422); erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2/neu or CD340; NCBI Gene ID: 2064), epidermal growth factor receptor (EGFR, ERBB, ERBB1 or HER! ; NCBI Gene ID: 1956); ALK receptor tyrosine kinase (ALK, CD246; NCBI Gene ID: 238); poly(ADP- ribose) polymerase 1 (PARP1; NCBI Gene ID: 142); poly(ADP -ribose) polymerase 2 (PARP2; NCBI Gene ID: 10038); TCDD inducible poly(ADP-ribose) polymerase (TIP ARP, PARP7; NCBI Gene ID: 25976); cyclin dependent kinase 4 (CDK4; NCBI Gene ID: 1019); cyclin dependent kinase 6 (CDK6; NCBI Gene ID: 1021); TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270; NCBI Gene ID: 8764); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP- 3; NCBI Gene ID: 331); baculoviral IAP repeat containing 2 (BIRC2, cIAPl; NCBI Gene ID: 329); baculoviral IAP repeat containing 3 (BIRC3, cIAP2; NCBI Gene ID: 330); baculoviral IAP repeat containing 5 (BIRC5, surviving; NCBI Gene ID: 332); C-C motif chemokine receptor 2 (CCR2, CD192; NCBI Gene ID: 729230); C-C motif chemokine receptor 5 (CCR5, CD195; NCBI Gene ID: 1234); C-C motif chemokine receptor 8 (CCR8, CDwl98; NCBI Gene ID: 1237); C-X-C motif chemokine receptor 3 (CXCR3, CD 182, CD 183; NCBI Gene ID: 2833); C- X-C motif chemokine receptor 4 (CXCR4, CD184; NCBI Gene ID: 7852); arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CAI (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CASA (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CAM (NCBI Gene ID: 23632)), prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5 -lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) and/or soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053); a secreted phospholipase A2 (e.g., PLA2G1B (NCBI Gene ID: 5319); PLA2G7 (NCBI Gene ID: 7941), PLA2G3 (NCBI Gene ID: 50487), PLA2G2A (NCBI Gene ID: 5320); PLA2G4A (NCBI Gene ID: 5321); PLA2G12A (NCBI Gene ID: 81579); PLA2G12B (NCBI Gene ID: 84647); PLA2G10 (NCBI Gene ID: 8399); PLA2G5 (NCBI Gene ID: 5322); PLA2G2D (NCBI Gene ID: 26279); PLA2G15 (NCBI Gene ID: 23659)); indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620); indoleamine 2,3-dioxygenase 2 (IDO2; NCBI Gene ID: 169355); hypoxia inducible factor 1 subunit alpha (HIF1 A; NCBI Gene ID: 3091); angiopoietin 1 (ANGPT1 ; NCBI Gene ID: 284); Endothelial TEK tyrosine kinase (TIE-2, TEK, CD202B; NCBI Gene ID: 7010); Janus kinase 1 (JAK1; NCBI Gene ID: 3716); catenin beta 1 (CTNNB1; NCBI Gene ID: 1499); histone deacetylase 9 (HDAC9; NCBI Gene ID: 9734), and/or 5'-3 ' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464).

[00214] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an agonist of fms related receptor tyrosine kinase 3 (FLT3); FLK2; STK1; CD135; FLK-2; NCBI Gene ID: 2322). Examples of FLT3 agonists include, but are not limited to, CDX-301 and GS-3583.

[00215] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD19 agent or antibody. Examples of anti-CD19 agents or antibodies that can be co-administered include without limitation: MOR00208, XmAb5574 (Xencor), AFM-11, Inebilizumab, MEDI 551 (Cellective Therapeutics); MDX-1342 (Medarex) and blinatumomab (Amgen).

[00216] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD20 agent or antibody. Examples of anti-CD20 agents or antibodies that can be co-administered include without limitation: IGN-002, PF-05280586; Rituximab (Rituxan/Biogen Idee), Ofatumumab (Arzerra/Genmab), Obinutuzumab (Gazyva/Roche Glycart Biotech), Alemtuzumab, Veltuzumab, IMMU-106 (Immunomedics), Ocrelizumab (Ocrevus/Biogen Idee; Genentech), Ocaratuzumab, LY2469298 (Applied Molecular Evolution) and Ublituximab, LFB-R603 (LFB Biotech.; rEVO Biologies), IGN-002, PF-05280586.

[00217] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD22 agent or antibody. Examples of anti-CD22 agents or antibodies that can be co-administered include without limitation: Epratuzumab, AMG-412, IMMU-103 (Immunomedics).

[00218] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD30 agent or antibody. Examples of anti-CD30 agents or antibodies that can be co-administered include without limitation: Brentuximab vedotin (Seattle Genetics / Pfizer).

[00219] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD33 agent or antibody. Examples of anti-CD33 agents or antibodies that can be co-administered include without limitation: CIK-CAR.CD33; CD33CART, AMG- 330 (CD33/CD3), AMG-673 (CD33/CD3), and GEM-333 (CD3/CD33), and IMGN-779.

[00220] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD37 agent or antibody. Examples of anti-CD37 agents or antibodies that can be co-administered include without limitation: BI836826 (Boehringer Ingelheim), Otlertuzumab, and TRU-016 (Trubion Pharmaceuticals).

[00221] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD38 agent or antibody. Examples of anti-CD38 agents or antibodies that can be co-administered include without limitation: CD38, such as T-007, UCART-38; Darzalex (Genmab), Daratumumab, JNJ-54767414 (Darzalex/Genmab), Isatuximab, SAR650984 (ImmunoGen), MOR202, MOR03087 (MorphoSys), TAK-079; and anti-CD38- attenukine, such as TAK573.

[00222] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD52 agent or antibody. Examples of anti-CD52 agents or antibodies that can be co-administered include without limitation: anti-CD52 antibodies, such as Alemtuzumab (Campath/University of Cambridge).

[00223] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD98 (4F2, FRP-1) agent or antibody. Examples of anti-CD98 agents or antibodies that can be co-administered include without limitation: IGN523 (Igenica).

[00224] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD157 (BST-1) agent or antibody. Examples of anti-CD157 agents or antibodies that can be co-administered include without limitation: OBT357, MENU 12 (Menarini; Oxford BioTherapeutics).

[00225] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-DKK-1 agent or antibody. Examples of anti-DKK-1 agents or antibodies that can be co-administered include without limitation: BHQ880 (MorphoSys; Novartis), and DKN-01, LY-2812176 (Eli Lilly).

[00226] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-GRP78 (BiP) agent or antibody. Examples of anti-GRP78 agents or antibodies that can be co-administered include without limitation: PAT-SM6 (OncoMab GmbH). [00227] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-NOTCHl agent or antibody. Examples of anti-NOTCHl agents or antibodies that can be co-administered include without limitation: Brontictuzumab, OMP-52M51 (OncoMed Pharmaceuticals).

[00228] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-RORl agent or antibody. Examples of anti-RORl agents or antibodies that can be co-administered include without limitation: Mapatumumab, TRM1, and HGS-1012 (Cambridge Antibody Technology).

[00229] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-SLAMF7 (CS1, CD319) agent or antibody. Examples of anti-SLAMF7 agents or antibodies that can be co-administered include without limitation: Elotuzumab, HuLuc63, BMS-901608 (Empliciti/PDL BioPharma), Mogamulizumab (KW-0761).

[00230] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-TNFRSFlOA (DR4; APO2; CD261; TRAILR1; TRAILR-1) agent or antibody. Examples of anti-TNFRSFlOA agents or antibodies that can be co-administered include without limitation: Mapatumumab, TRM1, and HGS-1012 (Cambridge Antibody Technology).

[00231] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-Transferrin Receptor (TFRC; CD71) agent or antibody. Examples of anti-Transferrin Receptor agents or antibodies that can be co-administered include without limitation: E2.3/A27.15 (University of Arizona).

[00232] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-EPHA3 agent or antibody. Examples of anti-EPHA3 agents or antibodies that can be co-administered include without limitation: Ifabotuzumab, KB004 (Ludwig Institute for Cancer Research).

[00233] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CCR4 agent or antibody. Examples of anti-CCR4 agents or antibodies that can be co-administered include without limitation: Mogamulizumab, KW-0761 (Poteligeo/Kyowa Hakko Kirin Co.)

[00234] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CXCR4 agent or antibody. Examples of anti-CXCR4 agents or antibodies that can be co-administered include without limitation: Ulocuplumab, BMS-936564, MDX-1338 (Medarex), and PF-06747143 (Pfizer).

[00235] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-BAFF agent or antibody. Examples of anti-BAFF agents or antibodies that can be co-administered include without limitation: Tabalumab, LY2127399 (Eli Lilly).

[00236] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-BAFF Receptor (BAFF-R) agent or antibody. Examples of anti-BAFF- R agents or antibodies that can be co-administered include without limitation: VAY736 (MorphoSys; Novartis).

[00237] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-RANKL agent or antibody. Examples of anti-RANKL agents or antibodies that can be co-administered include without limitation: Denosumab, AMG-162 (Prolia; Ranmark; Xgeva/ Amgen).

[00238] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-IL-6 agent or antibody. Examples of anti-IL-6 agents or antibodies that can be co-administered include without limitation: Siltuximab, CNTO-328 (Sylvant/Centocor).

[00239] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-IL-6 Receptor (IL-6R) agent or antibody. Examples of anti-IL-6R agents or antibodies that can be co-administered include without limitation: Tocilizumab, R-1569 (Actemra/Chugai Pharmaceutical; Osaka University), or AS-101 (CB-06-02, IVX-Q-101).

[00240] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-IL3RA (CD123) agent or antibody. Examples of anti-IL3RA (CD123) agents or antibodies that can be co-administered include without limitation: CSL360 (CSL), Talacotuzumab, JNJ-56022473, CSL362 (CSL); XmAb 14045 (Xencor); KHK2823 (Kyowa Hakko Kirin Co.); APV0436 (CD123/CD3); flotetuzumab (CD123/CD3); JNJ-63709178 (CD123/CD3); and XmAb-14045 (CD123/CD3) (Xencor).

[00241] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-IL2RA (CD25) agent or antibody. Examples of anti-IL2RA agents or antibodies that can be co-administered include without limitation: Basiliximab, SDZ-CHL621 (Simulect/Novartis), and Daclizumab. [00242] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-IGF-lR (CD221) agent or antibody. Examples of anti-IGF-lR agents or antibodies that can be co-administered include without limitation: Ganitumab, AMG-479 (Amgen); Ganitumab, AMG-479 (Amgen), Dalotuzumab, MK-0646 (Pierre Fabre), and AVE 1642 (ImmunoGen).

[00243] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-GM-CSF (CSF2) agent or antibody. Examples of anti-GM-CSF agents or antibodies that can be co-administered include without limitation: Lenzilumab, KB003 (KaloBios Pharmaceuticals).

[00244] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-HGF agent or antibody. Examples of anti-HGF agents or antibodies that can be co-administered include without limitation: Ficlatuzumab, AV-299 (AVEO Pharmaceuticals).

[00245] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD44 agent or antibody. Examples of anti-CD44 agents or antibodies that can be co-administered include without limitation: RG7356, RO5429083 (Chugai Biopharmaceuticals; Roche).

[00246] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-VLA-4 (CD49d) agent or antibody. Examples of anti-VLA-4 agents or antibodies that can be co-administered include without limitation: Natalizumab, BG-0002-E (Tysabri/Elan Corporation).

[00247] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-ICAM-1 (CD54) agent or antibody. Examples of anti-ICAM-1 agents or antibodies that can be co-administered include without limitation: BI-505 (Biolnvent International)

[00248] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-VEGF-A agent or antibody. Examples of anti-VEGF-A agents or antibodies that can be co-administered include without limitation: Bevacizumab (Avastin/Genentech; Hackensack University Medical Center).

[00249] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-Endosialin (CD248, TEM1) agent or antibody. Examples of anti- Endosialin agents or antibodies that can be co-administered include without limitation: Ontecizumab, MORAB-004 (Ludwig Institute for Cancer Research; Morphotek).

[00250] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-CD79 agent or antibody. Examples of anti-CD79 agents or antibodies that can be co-administered include without limitation: polatuzumab, DCDS4501A, RG7596 (Genentech).

[00251] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-isocitrate dehydrogenase (IDH) agent or antibody. Examples of anti- IDH agents or antibodies that can be co-administered include without limitation: IDH1 inhibitor ivosidenib (Tibsovo; Agios) and the IDH2 inhibitor enasidenib (Idhifa; Celgene/ Agios).

[00252] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an antibody that targets tumor associated calcium signal transducer 2 (TACSTD2) (NCBI Gene ID: 4070; EGP-1, EGP1, GA733-1, GA7331, GP50, M1S1, TROP2), such as sacituzumab.

[00253] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-major histocompatibility complex, class I, G (HLA-G; NCBI Gene ID: 3135) antibody, such as TTX-080.

[00254] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti -leukocyte immunoglobulin like receptor B2 (LILRB2, a.k.a., CD85D, ILT4; NCBI Gene ID: 10288) antibody, such as JTX-8064 or MK-4830.

[00255] TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

[00256] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (0X40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11 A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF1 IB (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

[00257] Examples of anti-TNFRSF4 (0X40) antibodies that can be co-administered include without limitation: MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628, each of which is hereby incorporated by reference in its entirety.

[00258] Examples of anti-TNF receptor superfamily member 10b (TNFRSF10B, DR5, TRAILR2) antibodies that can be co-administered include without limitation: DS-8273, CTB- 006, INBRX-109, and GEN- 1029.

[00259] Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include without limitation: selicrelumab (R07009789), mitazalimab (a.k.a., vanalimab, ADC- 1013, JNJ-64457107), RG7876, SEA-CD40, APX-005M and ABBV-428, ABBV-927, and JNJ- 64457107.

[00260] Examples of anti-TNFRSF7 (CD27) that can be co-administered include without limitation: varlilumab (CDX-1127).

[00261] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be coadministered include without limitation: urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106, BT-7480, and QL1806.

[00262] Examples of anti-TNFRSF17 (BCMA) that can be co-administered include without limitation: GSK-2857916.

[00263] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include without limitation: MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, an antibody, or fragment thereof, co-targeting TNFRSF4 (0X40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, e.g., in WO2017096179 and WO2018089628, each of which is hereby incorporated by reference in its entirety. [00264] Example of anti-TRAILRl , anti-TRAILR2, anti-TRAILR3, anti-TRAILR4 antibodies that can be co-administered include without limitation: ABBV-621.

[00265] Examples of bi-specific antibodies targeting TNFRSF family members that can be co-administered include without limitation: PRS-343 (CD-137/HER2), AFM26 (BCMA/CD16A), AFM-13 (CD16/CD30), REGN-1979 (CD20/CD3), AMG-420 (BCMA/CD3), INHIBRX-105 (4-1BB/PDL1), FAP-4-IBBL (4-1BB/FAP), XmAb-13676 (CD3/CD20), RG- 7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), and IMM-0306 (CD47/CD20), and AMG-424 (CD38.CD3).

[00266] Examples of inhibitors of PVR related immunoglobulin domain containing

(PVRIG, CD112R) that can be co-administered include without limitation: COM-701.

[00267] Examples of inhibitors of T cell immunoreceptor with Ig and ITIM domains

(TIGIT; NCBI Gene ID: 201633) that can be co-administered include without limitation: BMS- 986207, RG-6058, AGEN-1307, and COM-902, etigilimab, tiragolumab (a.k.a., MTIG-7192A; RG-6058; RO 7092284), AGEN1777, IBI-939, AB154, MG1131 and EOS884448 (EOS-448).

[00268] Examples of inhibitors of hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3,

TIM-3) that can be co-administered include without limitation: TSR-022, LY-3321367, MBG- 453, INCAGN-2390, RO-7121661 (PD-l/TIM-3), LY-3415244 (TIM-3/PDL1), and RG7769 (PD-l/TIM-3).

[00269] Examples of inhibitors of lymphocyte activating 3 (LAG-3, CD223) that can be co-administered include without limitation: relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385, TSR-033, MGD-013 (PD-l/LAG-3), and FS-118 (LAG-3/PD-L1).

[00270] Examples of anti-killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1; KIR; NCBI Gene ID: 3811) monoclonal antibodies, such as lirilumab (IPH-2102), and IPH-4102.

[00271] Examples of anti-NKG2a antibodies that can be co-administered include without limitation: monalizumab.

[00272] Examples of anti-V-set immunoregulatory receptor (VSIR, B7H5, VISTA) antibodies that can be co-administered include without limitation: HMBD-002, and CA-170 (PD- Ll/VISTA).

[00273] Examples of anti-CD70 antibodies that can be co-administered include without limitation: AMG-172. [00274] Examples of anti-ICOS antibodies that can be co-administered include without limitation: JTX-2011, GSK3359609.

[00275] Examples of ICOS agonists that can be co-administered include without limitation: ICOS-L.COMP (Gariepy, J. et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego) 2019, Abst 71.5).

[00276] Immune Checkpoint Inhibitors

[00277] In some embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more immune checkpoint inhibitors. In some embodiments, the one or more immune checkpoint inhibitors is a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.

[00278] Examples of inhibitors of CTLA4 that can be co-administered include without limitation: ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC- 392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, HBM- 4003, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD- 1/CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

[00279] Examples of inhibitors/antibodies of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include without limitation: pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMG-404, AMP-224, MED10680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GEN- 1046 (PD-L1/4-1BB), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym- 021, ABBV-181, PD1-PIK, BAT- 1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ- 053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD- 013 (PD-l/LAG-3), RO-7247669 (PD-l/LAG-3), FS-118 (LAG-3/PD-L1) MGD-019 (PD- 1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-l/TIM-3), XmAb-20717 (PD-1/CTLA4), AK-104 (CTLA4/PD-1), M7824 (PD-L1/TGFP-EC domain), CA- 170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM-3/PDL1), RG7769 (PD- l/TIM-3) and INBRX-105 (4-1BB/PDL1), GNS-1480 (PD-L1/EGFR), RG-7446 (Tecentriq, atezolizumab), ABBV-181, nivolumab (OPDIVO®, BMS-936558, MDX-1106), pembrolizumab (KEYTRUDA, MK-3477, SCH-900475, lambrolizumab, CAS Reg. No. 1374853-91-4), pidilizumab, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX- 008), CS-1003, HLX-10, MGA-012, BI-754091, REGN-2810 (cemiplimab), AGEN-2034, JS- 001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY- 3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, AK-105, PD1-PIK, BAT-1306, BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI-4736), avelumab, CK-301, (MSB0010718C), MEDI-0680, CX-072, CBT-502, PDR-001 (spartalizumab), PDR001+Tafinlar®+Mekinist®, MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC- 001), BCD-135, FAZ-053, TQB-2450, and MDX1105-01, and those described, e.g., in Inti. Patent Publ. Nos. WO2018195321, W02020014643, W2019160882, and W2018195321.

[00280] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcll/EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in WO2018183418, WO2016033486, and W02017147410.

[00281] Toll -Like Receptor (TLR) Agonists

[00282] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793). Example TLR7 agonists that can be co-administered include without limitation: DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDL9197, 3M-O51, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). An TLR7/TLR8 agonist that can be co-administered is NKTR-262. Example TLR8 agonists that can be co-administered include without limitation E-6887, IMO-4200, IMO-8400, IMO-9200, MCT- 465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-O51, 3M-052, and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Example TLR9 agonists that can be co-administered include without limitation AST-008, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO- 3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10 and PUL-042. Examples of TLR3 agonist include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND- 1.1.

[00283] Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400,

IMO-9200 and VTX-763.

[00284] Examples of TLR8 agonists include, but are not limited to, MCT-465, motolimod,

GS-9688, and VTX-1463. [00285] Examples of TLR9 inhibitors include but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042.

[00286] Examples of TLR7/TLR8 agonist, include but are not limited to, NKTR-262, IMO-4200, MEDI-9197 (telratolimod), resiquimod.

[00287] Examples of TLR agonists include without limitation: lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK- 1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.

[00288] In some embodiments, the therapeutic agent is a stimulator of interferon genes (STING) In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP), and cyclic-di-AMP.

[00289] TCR Signaling Modulators

[00290] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more agonist or antagonist of T-Cell Receptor (TCR) signaling modulators. Activation of T cells through the TCR and is essential for thymocyte development and effector T cell function. TCR activation promotes signaling cascades that ultimately determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation. Examples of TCR signaling modulators include without limitation CD2 (cluster of differentiation 2, LFA-2, T11, LFA-3 receptor), CD3 (cluster of differentiation 3), CD4 (cluster of differentiation 4), CD8 (cluster of differentiation 8), CD28 (cluster of differentiation 28), CD45 (PTPRC, B220, GP180), LAT (Linker for activation of T cells, LAT1), Lek, LFA-1 (ITGB2, CD 18, LAD, LCAMB), Src, Zap-70, SLP-76, DGKalpha, CBL-b, CISH, HPK1. Examples of agonist of cluster of differentiation 3 (CD3) that can be co-administered include without limitation MGD015.

[00291] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of cancer cells within the tumor microenvironment. Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in cancer therapeutics. In various embodiments, the immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37: 110). In various embodiments, the immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis, et al., Semin Immunol. (2017) 31 :64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[00292] Examples of immune checkpoint proteins or receptors include without limitation:

CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide- related sequence B (MICB); CD274 (PDL1, PD-L1); programmed cell death 1 (PDCD1, PD-1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG-3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD 150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); ULI 6 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAETIE; ULBP4); retinoic acid early transcript IG (RAETIG; ULBP5); retinoic acid early transcript IL (RAETIL; ULBP6); lymphocyte activating 3 (CD223); killer cell immunoglobulin like receptor (KIR); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1.

[00293] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. Illustrative T-cell inhibitory immune checkpoint proteins or receptors include without limitation: CD274 (PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T- lymphocyte associated protein 4 (CTLA4, CD 152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG-3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor (KIR); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1).

[00294] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more agonist or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. Illustrative T-cell stimulatory immune checkpoint proteins or receptors include without limitation: CD27, CD70; CD40, CD40LG; inducible T cell costimulator (TCOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSFi8 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37: 110.

[00295] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. Illustrative NK-cell inhibitory immune checkpoint proteins or receptors include without limitation: killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor DI (KLRD1, CD94).

[00296] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more agonist or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. Illustrative NK-cell stimulatory immune checkpoint proteins or receptors include without limitation: CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31 :64-75; Fang, et al., Semin Immunol. (2017) 31 :37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[00297] Adenosine Generation and Signaling

[00298] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an agonist or antagonist of AIR, A2AR, A2BR, A3R, CD73, CD39, CD26; e.g., Adenosine A3 receptor (A3R) agonists, such as namodenoson (CF102); A2aR/A2bR antagonists, such as AB928; anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006; CD73 inhibitors, such as AB-680, PSB-12379, PSB- 12441, PSB-12425, CB-708, and those described in Int Patent Publication No. WO19173692; CD39/CD73 inhibitors, such as PBF-1662; anti-CD39 antibodies, such as TTX-030; adenosine A2A receptor antagonists, such as CPI-444, AZD-4635, preladenant, PBF-509; and adenosine deaminase inhibitors, such as pentostatin, cladribine.

[00299] Bi-Specific T-Cell Engagers

[00300] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with a bi-specific T-cell engager (e.g., not having an Fc) or an anti-CD3 bi-specific antibody (e.g., having an Fc). Illustrative anti-CD3 bi-specific antibodies or BiTEs that can be co-administered include AMG-160 (PSMA/CD3), AMG-212 (PSMA/CD3), AMG-330 (CD33/CD3), AMG-420 (BCMA/CD3), AMG-427 (FLT3/CD3), AMG-562 (CD19/CD3), AMG-596 (EGFRvIII/CD3), AMG-701 (BCMA/CD3), AMG-757 (DLL3/CD3), JNJ-64052781 (CD19/CD3), AMG-211 (CEA/CD3), BLINCYTO® (CD19/CD3), RG7802 (CEA/CD3), ERY- 974 (CD3/GPC3), huGD2-BsAb (CD3/GD2), PF-06671008 (Cadherins/CD3), APVO436 (CD123/CD3), ERY974, flotetuzumab (CD123/CD3), GEM333 (CD3/CD33), GEMoab (CD3/PSCA), REGN-1979 (CD20/CD3), REGN-5678 (PSMA/CD28), MCLA-117 (CD3/CLEC12A), JNJ-0819, JNJ-7564 (CD3/heme), JNJ-63709178 (CD123/CD3), MGD-007 (CD3/gpA33), MGD-009 (CD3/B7H3), IMCgplOO (CD3/gpl00), XmAb-14045 (CD123/CD3), XmAb-13676 (CD3/CD20), XmAb-18087 (SSTR2/CD3), catumaxomab (CD3/EpCAM), REGN-4018 (MUC16/CD3), RG6026, RG6076, RG6194, RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA), GRB-1302 (CD3/Erbb2), GRB-1342 (CD38/CD3), PF-06863135 (BCMA/CD3), SAR440234 (CD3/CDwl23). As appropriate, the anti-CD3 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific T-cell engagers that can be co-administered target CD3 and a tumor-associated antigen as described herein, including, e.g., CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunologv. (2017) May 17; 6(7):el326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug. 3; 8(35):57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep. 10; 403:224-230).

[00301] Bi- and Tri-Specific Natural Killer (NK)-Cell Engagers

[00302] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (e.g., not having an Fc) or bi-specific antibody (e.g., having an Fc) against an NK cell activating receptor, e.g., CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin- like receptor (NKp65, NKp80), Fc receptor FcyR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). Illustrative anti-CD16 bi-specific antibodies, BiKEs or TriKEs that can be co-administered include AFM26 (BCMA/CD16A) and AFM-13 (CD16/CD30). As appropriate, the anti-CD16 binding bi-specific molecules may or may not have an Fc. Illustrative bi-specific NK-cell engagers that can be co-administered target CD 16 and one or more tumor-associated antigens as described herein, including, e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2/neu, HLA Class II and FOLR1. BiKEs and TriKEs are described, e.g., in Felices, et al., Methods Mol Biol. (2016) 1441 :333-346; Fang, et al., Semin Immunol. (2017) 31 :37-54.

[00303] Hematopoietic Progenitor Kinase 1 (HPK1) Inhibitors

[00304] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184). Examples of Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors include without limitation, those described in WO-2018183956, WO- 2018183964, WO-2018167147, WO-2018183964, WO-2016205942, WO-2018049214, WO- 2018049200, WO-2018049191, WO-2018102366, WO-2018049152, W02020092528, W02020092621 and WO-2016090300.

[00305] Apoptosis Signal-Regulating Kinase (ASK) Inhibitors

[00306] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of an ASK inhibitor, e.g., mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI Gene ID: 4217). Examples of ASK1 inhibitors include without limitation, those described in WO 2011/008709 (Gilead Sciences) and WO 2013/112741 (Gilead Sciences).

[00307] Bruton Tyrosine Kinase (BTK) Inhibitors

[00308] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of Bruton tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include without limitation, (S)-6-amino-9-(l-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H- purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, Calquence+AZD6738, Calquence+danvatirsen.

[00309] Cyclin-Dependent Kinase (CDK) Inhibitors

[00310] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of cyclin dependent kinase 1 (CDK1, CDC2; CDC28A;

P34CDC12; NCBI Gene ID: 983); cyclin dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin dependent kinase 3 (CDK3; NCBI Gene ID: 1018); cyclin dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI Gene ID: 1019); cyclin dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID: 1021); cyclin dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID: 1022); cyclin dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC12L4; PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK 1, 2, 3, 4, 6, 7 and/or 9, include without limitation abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, PF- 06873600, AZD4573, and TG-02.

[00311] Discoidin Domain Receptor (DDR) Inhibitors

[00312] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and/or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include without limitation, dasatinib and those disclosed in WO2014/047624 (Gilead Sciences), US 2009- 0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013/027802 (Chugai Pharmaceutical), and WO2013/034933 (Imperial Innovations).

[00313] Histone Deacetylase (HDAC) Inhibitors

[00314] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include without limitation, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat, romidepsin, tucidinostat.

[00315] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) Inhibitors

[00316] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO 1 inhibitors include without limitation, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccine, PF- 06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS- 986205, and shlDO-ST, EOS-200271, KHK-2455, LY-3381916.

[00317] Janus Kinase (JAK) Inhibitors

[00318] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor (type 1 or type 2) of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and/or Janus kinase 3 (JAK3, JAK-3, JAK3 HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include without limitation, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB 1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, CHZ868, AJ1-11095 and XL019.

[00319] Matrix Metalloprotease (MMP) Inhibitors

[00320] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of a matrix metallopeptidase (MMP), e.g., an inhibitor of MMP 1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP 12 (NCBI Gene ID: 4321), MMP 13 (NCBI Gene ID: 4322), MMP 14 (NCBI Gene ID: 4323), MMP 15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP19 (NCBI Gene ID: 4327), MMP20 (NCBI Gene ID: 9313), MMP21 (NCBI Gene ID: 118856), MMP24 (NCBI Gene ID: 10893), MMP25 (NCBI Gene ID: 64386), MMP26 (NCBI Gene ID: 56547), MMP27 (NCBI Gene ID: 64066) and/or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include without limitation, marimastat (BB-2516), cipemastat (Ro 32-3555), GS-5745 (andecaliximab) and those described in WO 2012/027721 (Gilead Biologies).

[00321] RAS and RAS Pathway Inhibitors

[00322] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of KRAS proto-oncogene, GTPase (KRAS; a.k.a., NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C— K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS proto-oncogene, GTPase (NRAS; a.k.a., NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893); HRas proto-oncogene, GTPase (HRAS; a.k.a., CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; C-H-RAS; c-K-ras; H-RASIDX; c-Ki-ras; C-BAS/HAS; C-HA- RAS1; NCBI Gene ID: 3265). The Ras inhibitors can inhibit Ras at either the polynucleotide (e g., transcriptional inhibitor) or polypeptide (e.g., GTPase enzyme inhibitor) level. In some embodiments, the inhibitors target one or more proteins in the Ras pathway, e.g., inhibit one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT and mTOR.

[00323] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of KRAS. Examples of KRAS inhibitors include AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (G12C) and K-Ras (G12D)-selective inhibitory peptides.

[00324] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of KRAS mRNA. Illustrative KRAS mRNA inhibitors include anti-KRAS U1 adaptor, AZD-4785, siG12D-LODER™, and siG12D exosomes.

[00325] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of MEK. Illustrative MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and selumetinib.

[00326] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of AKT. Illustrative AKT inhibitors that can be co-administered include RG7440, MK-2206, ipatasertib, afuresertib, AZD5363, and ARQ-092, capivasertib, triciribine, ABTL-0812 (PI3K/Akt/mTOR). [00327] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of Raf. Illustrative Raf inhibitors that can be co-administered BGB-283 (Raf/EGFR), HM-95573, LXH-254, LY-3009120, RG7304, TAK-580, dabrafenib, vemurafenib, encorafenib (LGX818), PLX8394. RAF-265 (Raf/VEGFR), ASN-003 (Raf/PI3K).

[00328] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of ERK. Illustrative ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, GDC-0994, and ulixertinib.

[00329] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of PI3K. Illustrative PI3K inhibitors that can be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pictilisib, eganelisib (IPI-549). Illustrative PI3K/mT0R inhibitors that can be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, RG6114.

[00330] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of mTOR. Illustrative mTOR inhibitors that can be coadministered include: sapanisertib, vistusertib (AZD2014), ME-344, sirolimus (oral nano- amorphous formulation, cancer), TYME-88 (mTOR/cytochrome P450 3A4).

[00331] In certain embodiments, Ras-driven cancers (e.g., NSCLC) having CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib. See, e g., Zhou, et al., Cancer Lett. 2017 Nov. 1; 408: 130-137. Also, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB 1/2/4 inhibitor neratinib. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb. 1; 19(2): 132-137.

[00332] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of RAS. Examples of RAS inhibitors include NEO-100, rigosertib.

[00333] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an antagonist of EGFR, such as AMG-595, necitumumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomuzotuximab, ABT-806, vectibix, modotuximab, RM- 1929.

[00334] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI Gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB- 3068, RMC-4630, SAR442720 and those described in WO2018172984 and WO2017211303.

[00335] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinonol, binimetinib, CK-127, cobimetinib (GDC- 0973, XL-518), MT- 144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib+trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040, RG7421.

[00336] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, pl 10-alpha; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kgamma, PIK3, pllOgamma, pl20-PI3K; Gene ID: 5494); and/or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, PIODELTA, PI3K, pl 10D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor. Examples of PI3K inhibitors include without limitation, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 1082439, BEZ235, bimiralisib (PQR309), buparlisib (BKM120), BYL719 (alpelisib), carboxyamidotriazole orotate (CTO), CH5132799, CLR-457, CLR-1401, copanlisib (BAY SO- 6946), DS-7423, dactolisib, duvelisib (IPI-145), fimepinostat (CUDC-907), gedatolisib (PF- 05212384), GDC-0032, GDC-0084 (RG7666), GDC-0077, pictilisib (GDC-0941), GDC-0980, GSK2636771, GSK2269577, GSK2141795, idelalisib (Zydelig®), INCB040093, INCB50465, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, NERLYNX® (neratinib), nemiralisib (GSK2269557), omipalisib (GSK2126458, GSK458), 0XY111A, panulisib (P7170, AK151761), PA799, perifosine (KRX-0401), Pilaralisib (SAR245408; XL147), puquitinib mesylate (XC-302), SAR260301, seletalisib (UCB-5857), serabelisib (INK-1117, MLN-1117, TAK-117), SF1126, sonolisib (PX-866), RG6114, RG7604, rigosertib sodium (ON-01910 sodium), RP5090, tenalisib (RP6530), RV-1729, SRX3177, taselisib, TG100115, umbralisib (TGR-1202), TGX221, voxtalisib (SAR245409), VS-5584, WX-037, X-339, X-414, XL499, XL756, wortmannin, ZSTK474, and the compounds described in WO 2005/113556 (ICOS), WO 2013/052699 (Gilead Calistoga), WO 2013/116562 (Gilead Calistoga), WO 2014/100765 (Gilead Calistoga), WO 2014/100767 (Gilead Calistoga), and WO 2014/201409 (Gilead Sciences).

[00337] Spleen Tyrosine Kinase (SYK) Inhibitors

[00338] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of spleen associated tyrosine kinase (SYK, p72-Syk, Gene ID: 6850). Examples of SYK inhibitors include without limitation, 6-(lH-indazol-6-yl)-N-(4- morpholinophenyl)imidazo[l,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and those described in U.S. Pat. No. 8,450,321 (Gilead Conn.) and those described in U.S. 2015/0175616.

[00339] Tyrosine-kinase Inhibitors (TKIs)

[00340] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with a tyrosine kinase inhibitor (TKI). TKIs may target epidermal growth factor receptors (EGFRs) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include without limitation:, axitinib, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E- 6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, olmutinib, osimertinib (AZD-9291), pazopanib, ponatinib, poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012), sunitinib, famitinib L-malate, (MAC-4), tivoanib, TH-4000, tivoanib, and MEDI-575 (anti-PDGFR antibody), TAK-659, Cabozantinib.

[00341] Chemotherapeutic Agents

[00342] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with a chemotherapeutic agent or anti -neoplastic agent.

[00343] As used herein, the term “chemotherapeutic agent” or “chemotherapeutic” (or “chemotherapy” in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (e.g., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include but not limited to: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemylolomelamine; acetogenins, e.g., bullatacin and bullatacinone; a camptothecin, including synthetic analog topotecan; bryostatin, callystatin; CC-1065, including its adozelesin, carzelesin, and bizelesin synthetic analogs; cryptophycins, particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin, including the synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5- azacytidine; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin phill), dynemicin including dynemicin A, bisphosphonates such as clodronate, an esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores, aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6- mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; folic acid replinishers such as frolinic acid; radiotherapeutic agents such as Radium-223, 177-Lu- PSMA-617; trichothecenes, especially T-2 toxin, verracurin A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel; platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; trabectedin, triaziquone; 2,2',2"-trichlorotriemylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids such as retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5 -fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5 -fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5 -fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5 -fluorouracil, irinotecan, oxaliplatin), and pharmaceutically acceptable forms, acids, or derivatives of any of the above. Such agents can be conjugated onto an antibody or any targeting agent described herein to create an antibody-drug conjugate (ADC) or targeted drug conjugate.

[00344] Also included in the definition of “chemotherapeutic agent” are anti-hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, anti-androgens, and pharmaceutically acceptable forms, acids or derivatives of any of the above that act to regulate or inhibit hormone action on tumors. Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON®). Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMTDEX®). Examples of anti-androgens include apalutamide, abiraterone, darolutamide, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204. An example progesterone receptor antagonist includes onapristone.

[00345] Anti-Angiogenic Agents

[00346] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-angiogenic agent. Anti-angiogenic agents that can be co-administered include, but are not limited to: retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN, regorafenib, necuparanib, suramin, squalamine, tissue inhibitor of metalloproteinase- 1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor- 1, plasminogen activator inbibitor-2, cartilage-derived inhibitor, paclitaxel (nab- paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs such as l-azetidine-2- carboxylic acid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline, a,a'-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, beta- 1 -anticollagenase-serum, alpha-2- antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”, thalidomide, angiostatic steroid, carboxy aminoimidazole, metalloproteinase inhibitors such as BB-94, inhibitors of S100A9 such as tasquinimod. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF, and Ang- l/Ang-2.

[00347] Anti-Fibrotic Agents

[00348] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-fibrotic agent. Anti-fibrotic agents that can be co-administered include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No. 4,965,288 relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen and U.S. Pat. No. 4,997,854 relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593 relating to compounds such as 2- isobutyl-3-fluoro-, chloro-, or bromo-allylamine, U.S. Pat. Nos. 5,021,456, 5,059,714, 5,120,764, 5,182,297, 5,252,608 relating to 2-(l-naphthyloxymemyl)-3 -fluoroallylamine, and US 2004- 0248871, which are herein incorporated by reference.

[00349] Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines such as 2-bromo-ethylamine, 2-chloroethylamine, 2- trifluoroethylamine, 3 -bromopropylamine, and p-halobenzylamines; and selenohomocysteine lactone.

[00350] Other anti-fibrotic agents are copper chelating agents penetrating or not penetrating the cells. Exemplary compounds include indirect inhibitors which block the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases. Examples include the thiolamines, particularly D-penicillamine, and its analogs such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2- acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p- 1 -dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2- acetamidoethanethiol sulphanate, and sodium-4-mercaptobutanesulphinate trihydrate.

[00351] Anti-Inflammatory Agents

[00352] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an anti-inflammatory agent. Example anti-inflammatory agents include without limitation inhibitors of one or more of: arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CAI (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CAI 1 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA 14 (NCBI Gene ID: 23632)), prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1 ; NCBT Gene ID: 5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5- lipoxygenase (AL0X5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) and/or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, e.g., a dual inhibitor of COX-2/COX-1, COX-2/SEH, COX-2/CA, COX-2/5-LOX.

[00353] Examples of inhibitors of prostaglandin-endoperoxide synthase 1 (PTGS1, COX- 1; NCBI Gene ID: 5742) that can be co-administered include without limitation: mofezolac, GLY-230, and TRK-700.

[00354] Examples of inhibitors of prostaglandin-endoperoxide synthase 2 (PTGS2, COX- 2; NCBI Gene ID: 5743) that can be co-administered include without limitation: diclofenac, mel oxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, meisuoshuli, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, Anitrazafen, Apricoxib, Cimicoxib, Deracoxib, Flumizole, Firocoxib, Mavacoxib, NS-398, Pamicogrel, Parecoxib, Robenacoxib, Rofecoxib, Rutecarpine, Tilmacoxib, and Zaltoprofen. Examples of dual COX1/COX2 inhibitors that can be co-administered include without limitation, HP-5000, lomoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, HP-5000. Examples of dual COX-2/carbonic anhydrase (CA) inhibitors that can be co-administered include without limitation polmacoxib and imrecoxib.

[00355] Examples of inhibitors of secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include without limitation: LY3023703, GRC 27864, and compounds described in WO2015158204, WO2013024898, W02006063466, W02007059610, WO2007124589, W02010100249, W02010034796, W02010034797, WO2012022793, WO2012076673, WO2012076672, W02010034798, W02010034799, WO2012022792, W02009103778, WO2011048004, WO2012087771, WO2012161965, WO2013118071, WO2013072825, WO2014167444, WO2009138376, WO2011023812, WO2012110860, WO2013153535, W02009130242, WO2009146696, WO2013186692, WO2015059618, WO2016069376, WO2016069374, W02009117985, W02009064250, W02009064251 , W02009082347, W02009117987, and W02008071173. Metformin has further been found to repress the COX2/PGE2/STAT3 axis, and can be co- administered. See, e.g., Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[00356] Examples of inhibitors of carbonic anhydrase (e.g., one or more of CAI (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CAI 1 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CAB (NCBI Gene ID: 377677), CAM (NCBI Gene ID: 23632)) that can be co-administered include without limitation: acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide and dichlorphenamide. A dual COX-2/CA1/CA2 inhibitor that can be co-administered includes CG100649.

[00357] Examples of inhibitors of arachidonate 5 -lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240) that can be co-administered include without limitation: meclofenamate sodium, zileuton.

[00358] Examples of inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) that can be co-administered include without limitation compounds described in WO2015148954. Dual inhibitors of COX-2/SEH that can be co-administered include compounds described in WO2012082647. Dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) that can be co-administered include compounds described in WO2017160861.

[00359] Examples of inhibitors of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression loci-2, TPL2; NCBI Gene ID: 1326) that can be co-administered include without limitation: GS-4875, GS-5290, BHM-078 and those described, e.g., in WO2006124944, WO2006124692, WO2014064215, W02018005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9): 1015-35; Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila, et al., Bioorg Med Chem. (2007) 15(19):6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758- 61.

[00360] Tumor Oxygenation Agents

[00361] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an agent that promotes or increases tumor oxygenation or reoxygenation, or prevents or reduces tumor hypoxia. Illustrative agents that can be co-administered include, e.g., Hypoxia inducible factor-1 alpha (HIF-la) inhibitors, such as PT-2977, PT-2385; VEGF inhibitors, such as bevasizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and/or an oxygen carrier protein (e.g., a heme nitric oxide and/or oxygen binding protein (HNOX)), such as OMX-302 and HNOX proteins described in WO 2007/137767, WO 2007/139791, WO 2014/107171, and WO 2016/149562.

[00362] Immunotherapeutic Agents

[00363] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an immunotherapeutic agent. Example immunotherapeutic agents that can be co-administered include without limitation: abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab biosimilar, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab, detumomab, dinutuximab, drozitumab, duligotumab, dusigitumab, ecromeximab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, figitumumab, flanvotumab, futuximab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY, MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, moxetumomab pasudotox, naptumomab, narnatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, trastuzumab biosimilar, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, and 3F8. Rituximab can be used for treating indolent B-cell cancers, including marginal-zone lymphoma, WM, CLL and small lymphocytic lymphoma. A combination of Rituximab and chemotherapy agents can be especially effective. [00364] The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle such as indium- 111, yttrium-90 (90Y-clivatuzumab), or iodine- 131.

[00365] In some embodiments, the immunotherapeutic agent is an antibody-drug conjugate (ADC). Illustrative ADCs that can be co-administered include without limitation drug- conjugated antibodies, fragments thereof, or antibody mimetics targeting the proteins or antigens listed above. Example ADCs that can be co-administered include without limitation: gemtuzumab, brentuximab, trastuzumab, inotuzumab, glembatumumab, anetumab, mirvetuximab, depatuxizumab, rovalpituzumab, vadastuximab, labetuzumab, sacituzumab, lifastuzumab, indusatumab, polatzumab, pinatuzumab, coltuximab, indatuximab, milatuzumab, rovalpituzumab, ABBV-011, ABBV-2029, ABBV-321, ABBV-647, MLN0264 (anti-GCC, guanylyl cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla); SYD985 (anti-HER2, Duocarmycin), milatuzumab-doxorubicin (hCD74-DOX), DCDT2980S, belantamab mafodotin (GSK2857916), polatuzumab vedotin (RG-7596), SGN-CD70A, SGN-CD19A, inotuzumab ozogamicin (CMC-544), lorvotuzumab mertansine, SAR3419, isactuzumab govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8201 ((trastuzumab deruxtecan), 225 Ac- lintuzumab, U3-1402, 177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetumab ravtansine, CX- 2009, SAR-566658, W-0101, ABBV-085, gemtuzumab ozogamicin, ABT-414, glembatumumab vedotin (CDX-011), labetuzumab govitecan (IMMU-130), sacituzumab govitecan (IMMU-132), lifastuzumab vedotin, (RG-7599), milatuzumab-doxorubicin (IMMU-110), indatuximab ravtansine (BT-062), pinatuzumab vedotin (RG-7593), SGN-LIV1A, SGN-CD33A, SAR566658, MLN2704, SAR408701, rovalpituzumab tesirine, ABBV-399, AGS-16C3F, ASG- 22ME, AGS67E, AMG 172, AMG 595, AGS-15E, BAY1129980, BAY1187982, BAY94-934 (anetumab ravtansine), GSK2857916, Humax-TF-ADC (tisotumab vedotin), IMGN289, IMGN529; IMGN853 (mirvetuximab soravtansine), LOP628, PCA062, MDX-1203, MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, PF-06688992, PF-06804103, RG7450, RG7458, RG7598, SAR566658, SGN-CD33A, DS-1602 and DS-7300, DS-6157, DS- 6000, TAK-164, MEDI2228, MEDI7247, AMG575, ADCs that can be co-administered are described, e.g., in Lambert, et al., Adv Ther (2017) 34: 1015-1035 and in de Goeij, Current Opinion in Immunology (2016) 40: 14-23.

[00366] Illustrative therapeutic agents (e.g., anticancer or antineoplastic agents) that can be conjugated to the drug-conjugated antibodies, fragments thereof, or antibody mimetics include without limitation: monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), a calicheamicin, ansamitocin, maytansine or an analog thereof (e.g., mertansine/emtansine (DM1), ravtansine/soravtansine (DM4)), an anthracyline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA crosslinking agent SC-DR002 (D6.5), duocarmycin, a microtubule inhibitors (MTI) (e.g., a taxane, a vinca alkaloid, an epothilone), a pyrrolobenzodiazepine (PBD) or dimer thereof, a duocarmycin (A, Bl, B2, Cl, C2, D, SA, CC-1065), and other anticancer or anti -neoplastic agents described herein.

[00367] Cancer Gene Therapy and Cell Therapy

[00368] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with a cancer gene therapy and cell therapy. Cancer gene therapies and cell therapies include the insertion of a normal gene into cancer cells to replace a mutated or altered gene; genetic modification to silence a mutated gene; genetic approaches to directly kill the cancer cells; including the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to cancer cells, or activate the patient's own immune system (T cells or Natural Killer cells) to kill cancer cells, or find and kill the cancer cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against cancer.

[00369] Cellular Therapies

[00370] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with one or more cellular therapies. Illustrative cellular therapies include without limitation co-admini strati on of one or more of a population of immune cells. In some embodiments, the immune cells are natural killer (NK) cells, NK-T cells, T cells, gamma delta T cells, B-cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TILs) a granulocyte, an innate lymphoid cell, a megakaryocyte, a monocyte, a macrophage, a platelet, a thymocyte, a myeloid cell, and/or dendritic cells (DCs). In some embodiments, the cellular therapy entails a T cell therapy, e.g., co-admini stering a population of alpha/beta TCR T cells, gamma/delta TCR T cells, regulatory T (Treg) cells and/or TRuC™ T cells. In some embodiments, the cellular therapy entails a NK cell therapy, e.g., co-admini stering NK-92 cells. As appropriate, a cellular therapy can entail the co-administration of cells that are autologous, syngeneic or allogeneic to the subject. [00371] In some embodiments, the cellular therapy entails co-administering immune cells engineered to express chimeric antigen receptors (CARs) or T cell receptors (TCRs) TCRs. In particular embodiments, a population of immune cells is engineered to express a CAR, wherein the CAR comprises a tumor antigen-binding domain. In other embodiments, a population of immune cells is engineered to express T cell receptors (TCRs) engineered to target tumor derived peptides presented on the surface of tumor cells. In one embodiment, the immune cell engineered to express chimeric antigen receptors (CARs) or T cell receptors (TCRs) TCRs is a T cell. In another embodiment, the immune cell engineered to express chimeric antigen receptors (CARs) or T cell receptors (TCRs) TCRs is an NK cell.

[00372] With respect to the structure of a CAR, in some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both of a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain comprises a functional signaling domain of one or more proteins selected from the group consisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcR beta (Fc Epsilon Rib), CD79a, CD79b, Fcgamma Rlla, DAP10, and DAP12 4-1BB/CD137, activating NK cell receptors, an Immunoglobulin protein, B7-H3, BAFFR, BLAME (SLAMF8), BTLA, CD 100 (SEMA4D), CD103, CD160 (BY55), CD18, CD19, CD19a, CD2, CD247, CD27, CD276 (B7-H3), CD28, CD29, CD3 delta, CD3 epsilon, CD3 gamma, CD30, CD4, CD40, CD49a, CD49D, CD49f, CD69, CD7, CD84, CD8alpha, CD8beta, CD96 (Tactile), CDl la, CDl lb, CDl lc, CDl ld, CDS, CEACAMI, CRT AM, cytokine receptor, DAP-10, DNAM1 (CD226), Fc gamma receptor, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, ICAM-1, Ig alpha (CD79a), IL-2R beta, IL-2R gamma, IL-7R alpha, inducible T cell costimulator (ICOS), integrins, ITGA4, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB2, ITGB7, ITGB1, KIRDS2, LAT, LFA-1, LFA-1, ligand that binds with CD83, LIGHT, LIGHT, LTBR, Ly9 (CD229), Lyl08), lymphocyte function-associated antigen- 1 (LFA-1; CD1-Ia/CD18), MHC class 1 molecule, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80 (KLRF1), OX-40, PAG/Cbp, programmed death-1 (PD-1), PSGL1, SELPLG (CD162), Signaling Lymphocytic Activation Molecules (SLAM proteins), SLAM (SLAMF1; CD 150; IPO-3), SLAMF4 (CD244; 2B4), SLAMF6 (NTB- A, SLAMF7, SLP-76, TNF receptor proteins, TNFR2, TNFSFi4, a Toll ligand receptor, TRANCE/RANKL, VLA1, or VLA-6, or a fragment, truncation, or a combination thereof.

[00373] In some embodiments, the costimulatory domain comprises a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-lBB(CD137), 0X40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, lymphocyte function-associated antigen-1 (LFA-1), MYD88, B7-H3, a ligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD 19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD 103, ITGAL, CD1A (NCBI Gene ID: 909), CD IB (NCBI Gene ID: 910), CD1C (NCBI Gene ID: 911), CDID (NCBI Gene ID: 912), CDE (NCBI Gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD 18, LFA-1), ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAMI, CRT AM, Ly9 (CD229), CD 160 (BY55), PSGL1, CD 100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46, and NKG2D.

[00374] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD3 delta, CD3 gamma, CD45, CD4, CD5, CD7, CD8 alpha, CD8 beta, CD9, CDl la, CDl lb, CDl lc, CDl ld, CD16, CD18, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, 0X40, CD2, CD27, ICOS (CD278), 4-lBB(CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF), CD19, CD19a, IL2R beta, IL2R gamma, IL7R alpha, ITGAi, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CDID, CD1E, ITGAE, CD 103, ITGAL, ITGAM, ITGAX, ITGB1, ITGB2, ITGB7, CD29, ITGB2 (LFA-1, CD 18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAMI, CRT AM, Ly9 (CD229), CD 160 (BY55), PSGL1, CD 100 (SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C activating NK cell receptors, an Immunoglobulin protein, BTLA, CD247, CD276 (B7-H3), CD30, CD84, CDS, cytokine receptor, Fc gamma receptor, GADS, ICAM-1, Ig alpha (CD79a), integrins, LAT, a ligand that binds with CD83, LIGHT, MHC class 1 molecule, PAG/Cbp, TNFSFi4, a Toll ligand receptor, TRANCE/RANKL, or a fragment, truncation, or a combination thereof.

[00375] In some embodiments, the CAR comprises a hinge domain. A hinge domain may be derived from a protein selected from the group consisting of the CD2, CD3 delta, CD3 epsilon, CD3 gamma, CD4, CD7, CD8.alpha„ CD8.beta., CDIa (ITGAL), CDIb (ITGAM), CDIIc (ITGAX), CDIId (ITGAD), CD 18 (ITGB2), CD 19 (B4), CD27 (TNFRSF7), CD28, CD28T, CD29 (ITGB1), CD30 (TNFRSF8), CD40 (TNFRSF5), CD48 (SLAMF2), CD49a (ITGAI), CD49d (ITGA4), CD49f (ITGA6), CD66a (CEACAMI), CD66b (CEACAM8), CD66c (CEACAM6), CD66d (CEACAM3), CD66e (CEACAM5), CD69 (CLEC2), CD79A (B-cell antigen receptor complex-associated alpha chain), CD79B (B-cell antigen receptor complex- associated beta chain), CD84 (SLAMF5), CD96 (Tactile), CD 100 (SEMA4D), CD 103 (ITGAE), CD134 (0X40), CD137 (4-1BB), CD150 (SLAMF1), CD158A (KIR2DL1), CD158B1 (KIR2DL2), CD158B2 (KIR2DL3), CD158C (KIR3DP1), CD158D (KIRDL4), CD158F1 (KIR2DL5A), CD158F2 (KIR2DL5B), CD158K (KIR3DL2), CD160 (BY55), CD162 (SELPLG), CD226 (DNAM1), CD229 (SLAMF3), CD244 (SLAMF4), CD247 (CD3-zeta), CD258 (LIGHT), CD268 (BAFFR), CD270 (TNFSFi4), CD272 (BTLA), CD276 (B7-H3), CD279 (PD-1), CD314 (NKG2D), CD319 (SLAMF7), CD335 (NK-p46), CD336 (NK-p44), CD337 (NK-p30), CD352 (SLAMF6), CD353 (SLAMF8), CD355 (CRTAM), CD357 (TNFRSF18), inducible T cell co-stimulator (ICOS), LFA-1 (CD1 la/CD18), NKG2C, DAP-10, ICAM-1, NKp80 (KLRF1), IL-2R beta, IL-2R gamma, IL-7R alpha, LFA-1, SLAMF9, LAT, GADS (GrpL), SLP-76 (LCP2), PAG1/CBP, a CD83 ligand, Fc gamma receptor, MHC class 1 molecule, MHC class 2 molecule, a TNF receptor protein, an immunoglobulin protein, a cytokine receptor, an integrin, activating NK cell receptors, or Toll ligand receptor, IgGl, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM or fragment or combination thereof.

[00376] In some embodiments, the TCR or CAR antigen binding domain or the immunotherapeutic agent described herein (e.g., monospecific or multi-specific antibody or antigen-binding fragment thereof or antibody mimetic) binds a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (aNeuSAc(2-8)aNeuSAc(2-3)PDGaip(l -4)bDGIcp(l-l)Cer); ganglioside GM3 (aNeuSAc(2-3)PDGalp(I-4)PDGlcp(l-l)Cer); GM-CSF receptor; TNF receptor superfamily member 17 (TNFRSF17, BCMA); B-lymphocyte cell adhesion molecule; Tn antigen ((Tn Ag) or (GalNAcu-Ser/Thr)); prostate-specific membrane antigen (PSMA); Receptor tyrosine kinase-like orphan receptor 1 (R0R1); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin- 13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha (IL-1 IRa); prostate stem cell antigen (PSCA); Protease Serine 21 (Testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); HLA class I antigen A-2 alpha; HLA antigen; Lewis(Y)antigen; CD24; Platelet-derived growth factor receptor beta (PDGFR-beta); Stage-specific embryonic antigen-4 (SSEA-4); CD20; delta like 3 (DLL3); Folate receptor alpha; Folate receptor beta, GDNF alpha 4 receptor, Receptor tyrosineprotein kinase, ERBB2 (Her2/neu); Mucin 1, cell surface associated (MUC1); APRIL receptor; ADP ribosyl cyclase- 1; Ephb4 tyrosine kinase receptor, DCAMKL1 serine threonine kinase, Aspartate beta-hydroxylase, epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); Prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF -I receptor), carbonic anhydrase IX (CAIX); Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2); glycoprotein 100 (gplOO); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type-A receptor 2 (EphA2); ephrin type-A receptor 3 (EphA3), Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight-melanomaassociatedantigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); Folate receptor beta; tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of the prostate I (STEAP1); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); IL- 15 receptor (IL- 15); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); Polysialic acid; placentaspecific 1 (PLAC1); hexasaccharide portion of globoH glycoceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCR Gamma Alternate Reading Frame Protein (TARP); Wilms tumor protein (WT1); Cancer/testis antigen 1 (NY-ESO-1); Cancer/testis antigen 2 (LAGE-la); Melanoma associated antigen 1 (MAGE-A1); Melanoma associated antigen 3 (MAGE-A3); Melanoma associated antigen 4 (MAGE-A4); T cell receptor beta 2 chain C; ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X Antigen Family, Member A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53, (p53); p53 mutant; prostein; survivin; telomerase; prostate carcinoma tumor antigen-

1 (PCTA-1 or Galectin 8), melanoma antigen recognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant; human Telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine

2 (TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl-transferase V (NA17); paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin-Al; Cyclin B; v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN); Ras Homolog Family Member C (RhoC); Tyrosinase-related protein 2 (TRP-2); Cytochrome P450 1B1(CYP IBI); CCCTC- Binding Factor (Zinc Finger Protein)-Like (BORIS or Brother of the Regulator of Imprinted Sites), Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3); Paired box protein Pax-5 (PAX5); proacrosin binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); Peptidoglycan recognition protein, synovial sarcoma, X breakpoint 2 (SSX2); Receptor for Advanced Glycation Endproducts (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 moleculelike family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-2 (GPC2); Glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of the tumor associated antigen presented in an MHC.

[00377] In some embodiments, the tumor antigen is selected from CD 150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 in combination, HER2-HER3 in combination, HERV — K, HIV-1 envelope glycoprotein gpl20, HIV-1 envelope glycoprotein gp41, HLA-DR, HLA class I antigen alpha G, HM1.24, K-Ras GTPase, HMW-MAA, Her2, Her2/neu, IGF-1R, IL-l lRalpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, la, li, Ll-CAM, Ll-cell adhesion molecule, Lewis Y, LI- CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligands, NKG2D Ligands, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, a G-protein coupled receptor, alphafetoprotein (AFP), an angiogenesis factor, an exogenous cognate binding molecule (ExoCBM), oncogene product, anti-folate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D 1), ephrinB2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate binding protein, gplOO, hepatitis B surface antigen, Epstein-Barr nuclear antigen 1, Latent membrane protein 1, Secreted protein BARF1, P2X7 purinoceptor, Syndecan-1, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutated p53, mutated ras, necrosis antigens, oncofetal antigen, ROR2, progesterone receptor, prostate specific antigen, tEGFR, tenascin, P2-Microglobulin, Fc Receptor-like 5 (FcRL5).

[00378] Examples of cell therapies include without limitation: AMG-119, Algenpantucel- L, ALOFISEL®, Sipuleucel-T, (BPX-501) rivogenlecleucel U.S. Pat. No. 9,089,520, W02016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109- AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19- ARTEMIS, ProHema, FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells, SNK-01, NEXI-001, CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22 cells, EGFRt/19-28z/4-lBBL CAR T cells, autologous 4H1 l-28z/flL-12/EFGRt T cell, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL- 12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005, LAAP T-cell therapy, PD-1 knockout T cell therapy (esophageal cancer/NSCLC), anti-MUCl CAR T-cell therapy (esophageal cancer/NSCLC), anti- MUC1 CAR T-cell therapy+PD-1 knockout T cell therapy (esophageal cancer/NSCLC), anti- KRAS G12D mTCR PBL, anti-CD123 CAR T-cell therapy, anti-mutated neoantigen TCR T-cell therapy, tumor lysate/MUCl/survivin PepTivator-loaded dendritic cell vaccine, autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal/intravenous), anti-LeY-scFv- CD28-zeta CAR T-cells, PRGN-3005, iC9-GD2-CAR-IL-15 T-cells, HSC-100, ATL-DC-101, MIDRIX4-LUNG, MIDRIXNEO, FCR-001, PLX stem cell therapy, MDR-101, GeniusVac- Mel4, ilixadencel, allogeneic mesenchymal stem cell therapy, romyelocel L, CYNK-001, ProTrans, ECT-100, MSCTRAIL, dilanubicel, FT-516, ASTVAC-2, E-CEL UVEC, CK-0801, allogenic alpha/beta CD3+ T cell and CD 19+B cell depleted stem cells (hematologic diseases, TBX-1400, HLCN-061, umbilical cord derived Hu-PHEC cells (hematological malignancies/aplastic anemia), AP-011, apceth-201, apceth-301, SENTI-101, stem cell therapy (pancreatic cancer), ICOVIRiS-cBiTE, CD33HSC/CD33 CAR-T, PLX-Immune, SUBCUVAX, CRISPR allogeneic gamma-delta T-cell based gene therapy (cancer), ex vivo CRISPR allogeneic healthy donor NK-cell based gene therapy (cancer), ex-vivo allogeneic induced pluripotent stem cell-derived NK-cell based gene therapy (solid tumor), and anti-CD20 CAR T-cell therapy (nonHodgkin's lymphoma).

[00379] Additional Agents for Targeting Tumors

[00380] Additional agents for targeting tumors include without limitation: Alphafetoprotein modulators, such as ET-1402, and AFP-TCR; Anthrax toxin receptor 1 modulator, such as anti-TEM8 CAR T-cell therapy; TNF receptor superfamily member 17 (TNFRSF17, BCMA), such as bb-2121 (ide-cel), bb-21217, JCARH125, UCART-BCMA, ET-140, MCM- 998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR), JNJ-68284528; Anti-CLL-1 antibodies, (see, for example, PCT/US2017/025573); Anti-PD-L-CAR tank cell therapy, such as KD-045; Anti-PD-Ll t-haNK, such as PD-L1 t-haNK; anti-CD45 antibodies, such as 131I-BC8 (lomab-B); anti-HER3 antibodies, such as LJM716, GSK2849330; APRIL receptor modulator, such as anti-BCMA CAR T-cell therapy, Descartes-011; ADP ribosyl cyclase-1 /APRIL recepor modulator, such as dual anti-BCMA/anti-CD38 CAR T-cell therapy; CART-ddBCMA; B7 homolog 6, such as CAR-NKp30 and CAR-B7H6; B-lymphocyte antigen CD19, such as TBI-1501, CTL-119 huCART-19 T cells, iso-cell, JCAR-015 U.S. Pat. No. 7,446,190, JCAR-014, JCAR-017, (WO2016196388, W02016033570, WO2015157386), axicabtagene ciloleucel (KTE-C19, Yescarta®), KTE-X19, U.S. Pat. Nos. 7,741,465, 6,319,494, UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019), W02012079000, WO2017049166, CD19CAR-CD28-CD3zeta- EGFRt-expressing T cells, CD19/4-1BBL armored CAR T cell therapy, C-CAR-011, CIK- CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110; anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia); anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia/Non- Hodgkin's lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silenced IL-6 expression, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB- CART2019.1 (CD19/CD20), GC-197 (CD19/CD7), CLIC-1901, ET-019003, anti-CD19-STAR- T cells, AVA-001, BCMA-CD19 cCAR (CD19/APRIL), ICG-134, ICG-132 (CD19/CD20), CTA-101, WZTL-002, dual anti-CD19/anti-CD20 CAR T-cells (chronic lymphocytic leukemia/B-cell lymphomas), HY-001, ET-019002, YTB-323, GC-012 (CD19Z APRIL), GC-022 (CD19/CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem; UCAR-011, ICTCAR- 014, GC-007F, PTG-01, CC-97540; allogeneic anti-CD19 CART cells, such as GC-007G;

APRIL receptor modulator; SLAM family member 7 modulator, BCMA-CS1 cCAR; autologous dendritic cell tumor antigen (ADCTA), such as ADCTA-SSLG; B-lymphocyte antigen CD20, such as ACTR707 ATTCK-20, PBCAR-20A; allogenic T cells expressing CD20 CAR, such as LB-1905; B-lymphocyte antigen CD 19/B -lymphocyte antigen 22, such as TC-310; B- lymphocyte antigen 22 cell adhesion, such as UCART-22, JCAR-018 W02016090190; NY- ESO-1 modulators, such as GSK-3377794, TBI-1301, GSK3537142; Carbonic anhydrase, such as DC-Ad-GMCAIX; Caspase 9 suicide gene, such as CaspaCIDe DLI, BPX-501; CCR5, such as SB-728; CCR5 gene inhibitor/TAT gene/TRIM5 gene stimulator, such as lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy -transduced autologous CD34-positive hematopoietic progenitor cells; CDwl23, such as MB-102, IM-23, JEZ-567, UCART-123; CD4, such as ICG- 122; CD5 modulators, such as CD5.28z CART cells; Anti-CD22, such as anti-CD22 CART; Anti-CD30, such as TT-11; Dual anti-CD33/anti-CLLl, such as LB-1910; CD40 ligand, such as BPX-201 , MEDI5083; CD56, such as allogeneic CD56-positive CD3-negative natural killer cells (myeloid malignancies); CD19/CD7 modulator, such as GC-197; T-cell antigen CD7 modulator, such as anti-CD7 CAR T-cell therapy (CD7-positive hematological malignancies); CD123 modulator, such as UniCAR02-T-CD123; Anti-CD276, such as anti-CD276 CART; CEACAM protein 5 modulators, such as MG7-CART; Claudin 6, such as CSG-002; Claudin 18.2, such as LB- 1904; Chlorotoxin, such as CLTX-CART; EBV targeted, such as CMD-003; MUC16EGFR, such as autologous 4H1 l-28z/f!L-12/EFGRt T cell; Endonuclease, such as PGN-514, PGN-201; Epstein-Barr virus specific T-lymphocytes, such as TT-10; Epstein-Barr nuclear antigen 1/Latent membrane protein 1/Secreted protein BARF1 modulator, such as TT-10X; Erbb2, such as CST- 102, CIDeCAR; Ganglioside (GD2), such as 4SCAR-GD2; Gamma delta T cells, such as ICS- 200; folate hydrolase 1 (FOLH1, Glutamate carboxypeptidase II, PSMA; NCBI Gene ID: 2346), such as CIK-CAR.PSMA, CART-PSMA-TGFORDN, P-PSMA-101; Glypican-3(GPC3), such as TT-16, GLYCAR; Hemoglobin, such as PGN-236; Hepatocyte growth factor receptor, such as anti-cMet RNA CAR T; HLA class I antigen A-2 alpha modulator, such as FH-MCVA2TCR; HLA class I antigen A-2 alpha/Melanoma associated antigen 4 modulator, such as ADP- A2M4CD8; HLA antigen modulator, such as FIT-001, NeoTCR-Pl; Human papillomavirus E7 protein, such as KITE-439 (see, for example, PCT/US2015/033129); ICAM-1 modulator, such as AIC-100; Immunoglobulin gamma Fc receptor III, such as ACTR087; IL-12, such as DC- RTS-IL-12; IL-12 agonist/mucin 16, such as JCAR-020; IL-13 alpha 2, such as MB-101; IL-15 receptor agonist, such as PRGN-3006, ALT-803; interleukin- 15/Fc fusion protein (e.g., XmAb24306); recombinant interleukin- 15 (e.g., AM0015, NIZ-985); pegylated IL-15 (e.g., NKTR-255); IL-2, such as CST-101; Interferon alpha ligand, such as autologous tumor cell vaccine+systemic CpG-B+IFN-alpha (cancer); K-Ras GTPase, such as anti-KRAS G12V mTCR cell therapy; Neural cell adhesion molecule LI LCAM (CD171), such as ICAR-023; Latent membrane protein 1/Latent membrane protein 2, such as Ad5f35-LMPdl-2-transduced autologous dendritic cells; MART-1 melanoma antigen modulator, such as MART-1 F5 TCR engineered PBMC; Melanoma associated antigen 10, such as MAGE-A10C796T MAGE-A10 TCR; Melanoma associated antigen 3/Melanoma associated antigen 6 (MAGE A3/A6) such as KITE-718 (see, for example, PCT/US2013/059608); Mesothelin, such as CSG-MESO, TC-210; Mucin 1 modulator, such as ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053; Anti- MICA/MICB, such as CYAD-02; NKG2D, such as NKR-2; Ntrkrl tyrosine kinase receptor, such as JCAR-024; PRAMET cell receptor, such as BPX-701 ; Prostate stem cell antigen modulator, such as MB-105; Roundabout homolog 1 modulator, such as ATCG-427;

Peptidoglycan recognition protein modulator, such as Tag-7 gene modified autologous tumor cell vaccine; PSMA, such as PSMA-CAR T-cell therapy (lentiviral vector, castrate-resistant prostate cancer); SLAM family member 7 modulator, such as IC9-Luc90-CD828Z; TGF beta receptor modulator, such as DNR.NPC T-cells; T-lymphocyte, such as TT-12; T-lymphocyte stimulator, such as ATL-001; TSH receptor modulator, such as ICTCAR-051; Tumor infiltrating lymphocytes, such as LN- 144, LN- 145; and/or Wilms tumor protein, such as JTCR-016, WT1- CTL, ASP-7517.

[00381] MCL1 Apoptosis Regulator, BCL2 Family Member (MCL1) Inhibitors

[00382] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcll/EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in WO2018183418, WO2016033486, WO2019222112 and W02017147410.

[00383] Cytokine Inducible SH2 Containing Protein (CISH) Inhibitors

[00384] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with an inhibitor of cytokine inducible SH2 containing protein (CISH; CIS; G18; SOCS; CIS-1; BACTS2; NCBI Gene ID: 1154). Examples of CISH inhibitors include those described in W02017100861, WO2018075664 and W2019213610.

[00385] Gene Editors

[00386] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with gene editor. Illustrative gene editing system that can be co-administered include without limitation a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system (e.g., an ARCUS), and a homing meganuclease system.

[00387] Others Drugs with Unspecified Targets

[00388] In various embodiments, a CXCR2 antagonist (e.g., SX-682) as described herein, is combined with human immunoglobulin (10% liquid formulation), Cuvitru (human immunoglobulin (20% solution), levofolinate disodium, IMSA-101, BMS-986288, IMUNO BGC Moreau RJ, R-OKY-034F, GP-2250, AR-23, calcium levofolinate, porfimer sodium, RG6160, ABBV-155, CC-99282, polifeprosan 20 with carmustine, Veregen, gadoxetate disodium, gadobutrol, gadoterate meglumine, gadoteridol, 99mTc-sestamibi, pomalidomide, pacibanil, and/or valrubicin.

[00389] Exemplified Combination Therapies

[00390] Lymphoma or Leukemia Combination Therapy

[00391] Some chemotherapy agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, anti -thymocyte globulin, arsenic tri oxide, Bcl-2 family protein inhibitor ABT-263, beta alethine, BMS-345541bortezomib (VELCADE®, PS-341), bryostatin 1, bulsulfan, campath- 1H, carboplatin, carfilzomib (Kyprolis®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17 AAG), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), ICE (iphosphamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013), pomalidomide (POMALYST®/IMNOVID®) lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, obatoclax (GX15- 070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride, perifosin, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alfa, recombinant interleukin-11, recombinant interleukin- 12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulphones, tacrolimus, tanespimycin, temsirolimus (CC1-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf®), venetoclax (ABT- 199).

[00392] One modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium- 111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

[00393] The abovementioned therapies can be supplemented or combined with stem cell transplantation or treatment. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

[00394] Non-Hodgkin's Lymphomas Combination Therapy

[00395] Treatment of non-Hodgkin's lymphomas (NHL), especially those of B cell origin, includes using monoclonal antibodies, standard chemotherapy approaches (e g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (Mitoxantrone, Chlorambucil, Prednisolone), all optionally including rituximab (R) and the like), radioimmunotherapy, and combinations thereof, especially integration of an antibody therapy with chemotherapy.

[00396] Examples of unconjugated monoclonal antibodies for the treatment of NHL/B- cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti -TNF -related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[00397] Examples of experimental antibody agents used in treatment of NHL/B-cell cancers include ofatumumab, ha20, PRO ! 31921, alemtuzumab, galiximab, SGN-40, CHIR- 12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab. [00398] Examples of standard regimens of chemotherapy for NHL/B-cell cancers include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R MCP.

[00399] Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

[00400] Mantle Cell Lymphoma Combination Therapy

[00401] Therapeutic treatments for mantle cell lymphoma (MCL) include combination chemotherapies such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the abovementioned therapies may be combined with stem cell transplantation or ICE in order to treat MCL.

[00402] An alternative approach to treating MCL is immunotherapy. One immunotherapy uses monoclonal antibodies like rituximab. Another uses cancer vaccines, such as GTOP-99, which are based on the genetic makeup of an individual patient's tumor.

[00403] A modified approach to treat MCL is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN). In another example, BEXXAR® is used in sequential treatment with CHOP.

[00404] Other approaches to treating MCL include autologous stem cell transplantation coupled with high-dose chemotherapy, administering proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administering antiangiogenesis agents such as thalidomide, especially in combination with rituximab.

[00405] Another treatment approach is administering drugs that lead to the degradation of Bcl-2 protein and increase cancer cell sensitivity to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agents.

[00406] A further treatment approach includes administering mTOR inhibitors, which can lead to inhibition of cell growth and even cell death. Non-limiting examples are sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus in combination with RITUXAN®, VELCADE®, or other chemotherapeutic agents. [00407] Other recent therapies for MCL have been disclosed. Such examples include flavopiridol, palbociclib (PD0332991), R-roscovitine (selicicilib, CYC202), styryl sulphones, obatoclax (GX15-070), TRAIL, Anti-TRAIL death receptors DR4 and DR5 antibodies, temsirolimus (TORISEL®, CC1-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG).

[00408] Waldenstrom's Macroglobulinemia Combination Therapy

[00409] Therapeutic agents used to treat Waldenstrom's Macroglobulinemia (WM) include aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, anti neopl aston A10, antineoplaston AS2-1, anti -thymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, beta alethine, bortezomib (VELCADE®), bryostatin 1, busulfan, campath- 1H, carboplatin, carmustine, caspofungin acetate, CC- 103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-i l l monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (such as tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alfa, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, ulocuplumab, veltuzumab, vincristine sulfate, vinorelbine ditartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[00410] Examples of therapeutic procedures used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro- treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

[00411] Diffuse Large B-cell Lymphoma Combination Therapy

[00412] Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and RICE.

[00413] Chronic Lymphocytic Leukemia Combination Therapy

[00414] Examples of therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

[00415] Myelofibrosis Combination Therapy

[00416] Myelofibrosis inhibiting agents include, but are not limited to, hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors (e.g., JAK inhibitors ruxolitinib, fedratinib, momelotinib and pacritinib). Non-limiting examples of hedgehog inhibitors are saridegib and vismodegib. Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat. Non-limiting examples of tyrosine kinase inhibitors are lestaurtinib, bosutinib, imatinib, radotinib, and cabozantinib.

[00417] Multiple Myeloma Therapy

[00418] Multiple myeloma inhibiting agents include, but are not limited to, daratumumab, bortezomib, carfilzomib, lenalidomide, melphalan, prednisone and dexamethasone.

[00419] Hyperproliferative Disorder Combination Therapy

[00420] Gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel may be used with a JAK inhibitor and/or PI3K6 inhibitor to treat hyperproliferative disorders.

[00421] Hypomethylating Agents [00422] The methods described herein include administration of a hypomethylating agent. Hypomethylating agents include, but are not limited to, azacitidine (Vidaza, also known as azacytidine) and decitabine (Dacogen). In some embodiments, the hypomethylating agent is azacitidine or decitabine. In some embodiments, the hypomethylating agent is azacitidine.

[00423] Azacitidine (5-azacytidine) is a chemical analogue of cytidine and is approved by the U.S. FDA for use in the treatment of myelodysplastic syndrome (MDS). Azacitidine removes methyl groups on DNA and also inhibits DNA methyltransferase, causing hypomethylation of DNA. At higher concentrations, azacitidine incorporates into DNA and RNA, resulting in direct cytotoxicity of abnormal hematopoietic cells in the bone marrow.

[00424] Decitabine (5-aza-2'deoxycitidine) is a chemical analogue of cytidine and is approved by the U.S. FDA for use in the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Similar to azacitidine, decitabine inhibits DNA methyltransferase, causing hypomethylation of DNA. However, decitabine is only integrated into DNA strands. Once integrated into DNA, decitabine binds irreversibly to DNA methyltransferases (DNMTs) and inhibits disengagement of the DNMTs from the DNA strand, resulting in inhibition of methylation of the DNA.

[00425] Composition and methods

[00426] The methods described herein include administration of a therapeutically effective dose of compositions to a patient, e.g., a therapeutically effective dose of a CXCR2 antagonist and an anti -cancer agent for the treatment of solid tumors and myeloid malignancies. The methods described herein surprisingly increase patient survival.

[00427] Compositions are administered to a patient in an amount sufficient to increase survival, substantially ablate targeted cells or arrest targeted cell growth, as described above. Single or multiple administrations of the compositions may be administered depending on the dosage and frequency as needed and tolerated by the patient. The particular dose used for a treatment will depend upon the medical condition and history of the patient, as well as other factors such as age, weight, gender, administration route, efficiency, etc.

[00428] Effective doses of the combined agents of the present invention for the treatment of cancer vary depending upon many different factors, including means of administration, target site, physiological state of the patient, other medications administered, and whether treatment is prophylactic or therapeutic. Nonhuman mammals may also be treated, e g., companion animals such as dogs, cats, horses, etc., laboratory mammals such as rabbits, mice, rats, etc., and the like. Treatment dosages can be titrated to optimize safety and efficacy.

[00429] In some embodiments, the CXCR2 antagonist is administered at a dose of about 50-1000 mg (e.g., about 50-400 mg, 50-300 mg, 50-200 mg, 50-100 mg, 150-900 mg, 150-600 mg, 200-800 mg, 300-600 mg, 400-500 mg, 300-500 mg, 200-500 mg, 100-500 mg, 100-400 mg, 200-300 mg, 100-200 mg, 250-350 mg, or about 75 mg, 150 mg, 200 mg, 300 mg, 400 mg, 450 mg, or 600 mg). In some embodiments, the CXCR2 antagonist is administered daily, e.g., once daily or twice daily. In some embodiments, the CXCR2 antagonist is administered for 1 week (e.g., 7 days) in a 4-week cycle (e.g., 28-day cycle). In some embodiments, the CXCR2 antagonist is administered for two weeks (e.g., 14 days) in a 4-week cycle (e.g., 28-day cycle). In some embodiments, the CXCR2 antagonist is administered for 3 weeks (e.g., 21 days) in a 4- week cycle. In some embodiments, the CXCR2 antagonist is administered daily, e g., once daily or twice daily at a total dose of about 50-1000 mg (e.g., about 50-400 mg, 50-300 mg, 50-200 mg, 50-100 mg, 100-200 mg, 150-900 mg, 150-600 mg, 200-400 mg, 200-800 mg, 300-600 mg, 400-500 mg, 300-500 mg, 200-500 mg, 100-500 mg, 100-400 mg, 200-300 mg, 100-200 mg, 250-350 mg, or about 75 mg, 150 mg, 300 mg, 450 mg, or 600 mg). In some embodiments, the CXCR2 is administered once daily. In other embodiments, the CXCR2 antagonist is administered twice daily. In some embodiments, the CXCR2 antagonist is administered twice daily and each dose, e g., the first and second dose, comprises about 25-400 mg (e g., 25-100 mg, 50-200 mg, 75-150, or 100-400 mg) of the CXCR2 antagonist. In some embodiments, the CXCR2 antagonist is administered once daily and the dose comprises about 50-600 mg (e.g., 50- 150 mg, 100-400 mg, 200-300, or 300-500 mg) of the CXCR2 antagonist. In some embodiments, the CXCR2 antagonist is administered orally. In some embodiments, the CXCR2 antagonist is administered orally twice daily for a total daily dose of 200 mg in a 4-week cycle (e.g., 28-day cycle). In some embodiments, the CXCR2 antagonist is administered orally twice daily for a total daily dose of 400 mg in a 4-week cycle (e.g., 28-day cycle). In some embodiments, the CXCR2 antagonist is administered orally twice daily for a total daily dose of 800 mg in a 4 week cycle (e.g., 28 day cycle).

[00430] In some embodiments, the CXCR2 antagonist is administered twice daily, e.g., about 12 hours apart. In some embodiments, the CXCR2 antagonist is administered on an empty stomach at least e g., 0.5, 1, 1.5, or 2 hours before a meal. In some embodiments, the CXCR2 antagonist is administered at the same time daily. In some embodiments, if a subject misses a dose of the CXCR2 antagonist, the subject will be administered the missed dose of the CXCR2 antagonist within, e.g., 1, 2, 3 or 4 hours of the missed dose.

[00431] Without wishing to be bound by theory, it is believed that in some embodiments, blockade of CXCR2 receptors by a CXCR2 antagonist (e.g., SX-682) inhibits neutrophil egress from the bone marrow into systemic circulation. This results in a neutropenia that is readily monitored by complete blood count (CBC) analysis. In some embodiments, the dose of the CXCR2 antagonist (e.g., SX-682) results in a >10% suppression of circulating neutrophils. In other embodiments, the dose of the CXCR2 antagonist (e.g., SX-682) results in a >50% suppression of circulating neutrophils. In other embodiments, the dose of the CXCR2 antagonist (e.g., SX-682) results in a >75% suppression of circulating neutrophils. In some embodiments, maximum suppression of circulating neutrophils will occur after 1 - 7 days of continuous dosing of the CXCR2 antagonist.

[00432] Anti-apoptotic members of the BCL-2 family, including BCL-2, have been reported as overexpressed in primary AML samples (Bogenberger et al. (2014) Leukemia 28(2); 1657-65). BCL-2 overexpression has also been reported in leukemic stem cells (LSCs) obtained from AML patients (Lagadinou et al. (2013) Cell Stem Cell 12(3); 329-341 ). Inhibition of BCL- 2 in ex vivo LSC populations led to selective eradication of quiescent LSCs (Lagadinou et al. (2013) Cell Stem Cell 12(3); 329-341 ).

[00433] Without wishing to be bound by theory, the combination of the present invention is considered to be particularly effective for the treatment of AML and MDS due to the combined therapeutic effect of the CXCR2 antagonist and the BCL-2 inhibitor, particularly the combined effect at the level of the LSCs. The self-renewal capacity of LSCs means that the persistence of these cells is a major factor contributing to disease relapse.

[00434] The increased efficacy of the combinations of the invention translated into potent inhibition of primary LSC cells from AML and MDS patients. The combination therapy of the present invention thus targets both the blast cells and the LSC compartment thereby improving the likelihood of disease remission whilst reducing the risk of relapse.

[00435] In certain preferred embodiments of the combinations of the invention, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable form thereof. Venetoclax is a smallmolecule inhibitor of BCL-2, described in US2010/0305122 (incorporated herein by reference). [00436] By inhibiting BCL-2, venetoclax inhibits the anti-apoptotic or pro-survival activity of this protein. Venetoclax induces apoptosis rapidly in the majority of CLL cells and BCL-2-overexpressing lymphoma cell lines.

[00437] Early studies indicated that venetoclax may be useful as a therapy for AML (Konopleva et al. (2016) Cancer Discov. 6(10); 1 106-17). However, it was found to have limited activity as a monotherapy. Subsequent studies investigated the efficacy of venetoclax in combination with hypomethylating agents, namely azacitidine and decitadine, and these combinations were found to be particularly efficacious (Bogenberger et al. (2015) Leuk Lymphoma 56(1 ): 226-229). Clinical trials have been carried out to test the combination of venetoclax with either azacitidine, decitabine, or low-dose cytarabine (Dinardo et al. (2018) Lancet Oncol. 19(2): 216-228; Dinardo et al. (2019) Blood 133(1 ); 7-17). The results of these trials have led to FDA approval for use of venetoclax in combination with azacitidine, decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.

[00438] Formulation of the combination

[00439] The agents of the combinations described herein may be combined or formulated in any manner allowing the combination therapy to be administered to an animal or patient in need thereof, preferably a patient in need thereof. The combination may be formulated for single dose administration or for multiple dose administration.

[00440] In certain embodiments, the agents of the combinations may be co-formulated i.e., formulated as a single pharmaceutical composition. For embodiments wherein the agents are coformulated, the combination or composition is suitable for simultaneous administration of the agents.

[00441] In preferred embodiments, the agents of the combinations described herein are formulated as separate compositions or pharmaceutical compositions. For embodiments wherein the agents are formulated separately, the possibility exists for simultaneous or separate administration of the different agents or compositions. If the different compositions are administered separately, there may be sequential administration of the agents in any preferred order. The interval between administration of the agents may be any suitable time interval. The administration of the different compositions may be carried out once (for a single dose administration) or repeatedly (for a multiple dose administration).

[00442] The CXCR2 antagonist (preferably SX-682 or a pharmaceutically acceptable form thereof) may be formulated using any suitable pharmaceutical carriers, adjuvants and/or excipients (e.g., see U.S. Patent 10,660,909 for SX-682 and CXCR2 antagonists of Formula I). Suitable agents include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.

[00443] In certain embodiments, the compositions are formulated for administration to a subject via any suitable route of administration including but not limited to intramuscular, intravenous, intradermal, intraperitoneal injection, subcutaneous, epidural, nasal, oral, rectal, topical, inhalational, buccal ( e.g., sublingual), and transdermal administration. In certain embodiments, the compositions are formulated as aqueous solutions, tablets, capsules, powders or any other suitable dosage form.

[00444] Excipients for preparation of compositions comprising a CXCR2 antagonist (e.g., SX-682) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3 -butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, com starch, corn oil, cottonseed oil, crosspovidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof. Excipients for preparation of compositions comprising a CXCR2 antagonist (e.g., SX-682) to be administered orally in liquid dosage forms include, for example, 1 ,3 -butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparation of compositions comprising a CXCR2 antagonist (e.g., SX-682) to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water, and mixtures thereof. Excipients for preparation of compositions comprising a CXCR2 antagonist (e.g., SX-682) to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.

[00445] For embodiments wherein the agents of the combination are formulated separately i.e., as separate compositions, the separate compositions may be formulated for the same route of administration. For embodiments wherein the agents of the combination are formulated separately i.e., as separate compositions, the separate compositions may be formulated for different routes of administration. For example, the anti-cancer agent may be formulated for intravenous administration and the CXCR2 antagonist (e.g., SX-682) may be formulated for oral administration.

[00446] As noted above, the combination therapies of the present invention may comprise a venetoclax product marketed and sold by Abb Vie Inc. and Genentech. Tablets for oral administration are available as pale yellow or beige tablets that contain 10, 50, or 100 mg venetoclax as the active ingredient. Each tablet also contains the following inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium stearyl fumarate, and calcium phosphate dibasic. In addition, the 10 mg and 100 mg coated tablets include the following: iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide. The 50 mg coated tablets also include the following: iron oxide yellow, iron oxide red, iron oxide black, polyvinyl alcohol, talc, polyethylene glycol and titanium dioxide.

[00447] For combinations of the invention comprising or consisting of agents in addition to the CXCR2 antagonist (e.g., SX-682) and a BCL-2 inhibitor (preferably venetoclax), the one or more additional agents may be formulated for administration via the same route or via a different route as compared with the other agents. For example, in preferred embodiments wherein the combination includes (i) a CXCR2 antagonist (e.g., SX-682); (ii) venetoclax or a pharmaceutically acceptable form thereof; and (iii) azacytidine, the CXCR2 antagonist (e.g., SX- 682) and venetoclax or pharmaceutically acceptable forms thereof may be administered orally whilst the azacytidine may be administered subcutaneously via injection. In preferred embodiments wherein the combination includes (i) a CXCR2 antagonist (e g., SX-682); (ii) venetoclax or a pharmaceutically acceptable thereof; and (iii) decitabine, the CXCR2 antagonist (e.g., SX-682) and venetoclax or pharmaceutically acceptable forms thereof may be administered orally whilst the decitabine may be administered subcutaneously via injection.

[00448] Methods of treatment

[00449] The combination therapies described in accordance with the invention can be used in methods of increasing survival of a patient with a solid tumor or hematologic malignancy, particularly a myeloid malignancy.

[00450] The present invention provides a CXCR2 antagonist (e/g/, SX-682) for use in increasing survival of patient with a solid tumor or hematologic malignancy, particularly a myeloid malignancy, and potentially additionally causing a tumor, blast or hematologic response, wherein the CXCR2 antagonist (e g., SX-682) is administered alone, or in combination with at least one more anticancer agent. The FDA approved label of each anticancer agent referenced herein is incorporated by reference.

[00451] The present invention further provides a combination in for use in the treatment of a malignancy, particularly melanoma, pancreatic cancer, prostate cancer and the hematologic malignancies consisting of myelodysplastic syndrome (MDS), myelofibrosis (MF), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myeloid leukemia (CML); chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and chronic myelomonocytic leukemia (CMML), in a human subject.

[00452] In a yet further aspect, the present invention provides a method for treating a malignancy, particularly a myeloid malignancy, in a human subject, said method comprising administering to the patient a CXCR2 antagonist. The invention also provides a method for treating a malignancy, particularly a myeloid malignancy, in a human subject, said method comprising the steps of (i) administering to the subject a CXCR2 antagonist; and (ii) administering to the subject a BCL-2 inhibitor, preferably venetoclax or a pharmaceutically acceptable form thereof. Steps (i) and (ii) of the method may be performed in either order.

[00453] The term “malignancy” encompasses diseases in which abnormal cells proliferate in an uncontrolled manner and invade the surrounding tissues. Malignant cells that have entered the body’s blood and lymph systems are capable of travelling to distal sites in the body and seeding at secondary locations. [00454] In particular embodiments, the methods described herein are for treating myeloid malignancies, wherein a myeloid malignancy refers to any clonal disease of hematopoietic stem or progenitor cells. The myeloid malignancy treated in accordance with the methods of the invention may be a newly-diagnosed myeloid malignancy or a relapsed/refractory myeloid malignancy.

[00455] In certain embodiments, the myeloid malignancy is selected from: acute myeloid leukemia (AML); myelodysplastic syndromes (MDS); myelofibrosis (MF); myeloproliferative neoplasms (MPN); multiple myeloma (MM); chronic myeloid leukemia (CML); and chronic myelomonocytic leukemias (CMML). In preferred embodiments, the myeloid malignancy is acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myelofibrosis (MF).

[00456] Myeloid malignancies can be categorized and diagnosed according to the WHO 2008 classification, taken in combination with the 2016 update to this classification, see in particular Arber et al. (2016) Blood 127(20) :2391 -2405, incorporated herein by reference.

[00457] Acute myeloid leukemia (AML) refers to hematopoietic neoplasms involving myeloid cells. AML is characterized by clonal proliferation of myeloid precursors with reduced differentiation capacity. AML patients exhibit an accumulation of blast cells in the bone marrow. Blast cells also accumulate in the peripheral blood of AML patients. Typically, AML is diagnosed if the patient exhibits 20% or more blast cells in the bone marrow or peripheral blood.

[00458] According to the WHO classification, AML in general encompasses the following subtypes: AML with recurrent genetic abnormalities; AML with myelodysplasia-related changes; therapy-related myeloid neoplasms; myeloid sarcoma; myeloid proliferations related to Down syndrome; blastic plasmacytoid dendritic cell neoplasm; and AML not otherwise categorized (e.g., acute megakaryoblastic leukemia, acute basophilic leukemia).

[00459] AML can also be categorized according to the French-American-British (FAB) classification, encompassing the subtypes: MO (acute myeloblastic leukemia, minimally differentiated); Ml (acute myeloblastic leukemia, without maturation); M2 (acute myeloblastic leukemia, with granulocytic maturation); M3 (promyelocytic, or acute promyelocytic leukemia (APL)); M4 (acute myelomonocytic leukemia); M4eo (myelomonocytic together with bone marrow eosinophilia); M5 (acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b)); M6 (acute erythroid leukemias, including erythroleukemia (M6a) and very rare pure erythroid leukemia (M6b)); or M7 (acute megakaryoblastic leukemia). [00460] As used herein, “AML” refers to any of the conditions encompassed by the WHO and/or FAB classifications, unless specified otherwise. Certain AML subtypes are considered to be of more favorable prognosis, some of intermediate prognosis and some of poor prognosis. The skilled person is aware of which subtypes would fall into which risk category.

[00461] As used herein, “MDS” refers to any of the conditions encompassed by the WHO and/or FAB classifications, unless specified otherwise. For both AML and MDS, the WHO categorization is preferred herein. Myelodysplastic syndrome (MDS) is characterized by dysplasia, cytopenia and/or abnormal changes in bone marrow cellularity and/or myeloid differentiation, for example increased blast cell infiltration. MDS is a precursor to AML. According to the WHO classification, MDS in general encompasses the following subtypes: MDS with single lineage dysplasia (previously called "refractory cytopenia with unilineage dysplasia”, which includes refractory anemia, refractory neutropenia, and refractory thrombocytopenia); MDS with ring sideroblasts, which includes subgroups with single lineage dysplasia and multilineage dysplasia (previously called "refractory anemia with ring sideroblasts”); MDS with multilineage dysplasia (previously called "refractory cytopenia with multilineage dysplasia"); MDS with excess blasts (MDS-EB, previously called "refractory anemia with excess blasts"), which can be further subclassified into MDS-EB- 1 and MDS-EB-2 based on blast percentages; MDS with isolated del(5q); and MDS, unclassified.

[00462] MDS can also be categorized according to the French-American-British (FAB) classification, encompassing the subtypes: M9980/3 (refractory anemia (RA)); M9982/3 (refractory anemia with ring sideroblasts (RARS)); M9983/3 (refractory anemia with excess blasts (RAEB)); M9984/3 (refractory anemia with excess blasts in transformation (RAEB-T)); and M9945/3 (chronic myelomonocytic leukemia (CMML)).

[00463] Myeloproliferative neoplasms (MPN) are clonal neoplasms similar to MDS but according to the WHO classification, MPN in general encompasses the following subtypes: chronic myeloid leukemia (CML); chronic neutrophilic leukemia (CNL); polycythemia vera (PV); primary myelofibrosis (PMF); essential thrombocythemia (ET); chronic eosinophilic leukemia, not otherwise specified; and MPN unclassifiable.

[00464] Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) fall within the category of MDS/MPN disorders according to the WHO classification, for the reason that they represent myeloid neoplasms with clinical, laboratory and morphologic features that overlap between MDS and MPN.

[00465] Patient characteristics

[00466] The patients treated in accordance with the methods described herein may have newly-diagnosed disease (e.g., AML), relapsed disease or primary refractory disease (together “refractory”) to a anticancer agent. In one embodiment, the patient has a cancer that is increasing in size, i.e., refractory, in response to treatment with an anti-PD-1 or anti-PD-Ll blocking antibody (i.e., failing anti-PD-1 or anti-PD-Ll blocking antibody therapy). In another embodiment, the patient has a cancer (e.g., myelodysplastic syndrome or AML) that is refractory to a hypomethylating agent (i.e., failing hypomethylating agent therapy). In another embodiment, the patient has a cancer (e.g., prostate cancer) that is refractory to anti -androgens including apalutamide, abiraterone, darolutamide and/or enzalutamide.

[00467] A standard approach to treatment for newly-diagnosed AML patients is the “standard 7+3 intensive chemotherapy” approach characterized by 7 days of high dose cytarabine followed by 3 days of anthracycline administration (e.g., daunorubicin or idarubicin). Intensive chemotherapy is given with the aim of inducing complete remission of AML, typically with the intention of the patient undergoing a stem cell transplant following successful chemotherapy.

[00468] Standard intensive chemotherapy is associated with significant toxicity and sideeffects, meaning it is not suitable for patients unable to tolerate these effects. These patients are termed “ineligible for standard intensive chemotherapy”. A patient may be ineligible for standard intensive chemotherapy because, for example, they exhibit one or more comorbidities indicating they would not tolerate the toxicity, or the prognostic factors characterizing their disease indicate an unfavorable outcome of standard intensive chemotherapy. Determination of an individual patient’s eligibility for standard intensive chemotherapy would be performed by a clinician taking into account the individual patient’s medical history and clinical guidelines (e.g., the National Comprehensive Cancer Network (NCCN) guidelines, incorporated herein by reference). AML patients over the age of 60 are often assessed as ineligible for standard intensive chemotherapy, with other factors to be considered including the cytogenetics and/or molecular abnormalities of the AML being treated. [00469] A patient ineligible for standard intensive chemotherapy may instead receive chemotherapy of reduced intensity, such as low dose cytarabine (LDAC). Patients who are ineligible for standard intensive chemotherapy and for whom LDAC are not appropriate can receive best supportive care (BSC), including hydroxyurea (HU) and transfusion support.

[00470] Patients or subjects treated in accordance with the methods described herein may be those classified as “ineligible for standard intensive chemotherapy”. The combinations of the invention comprise targeted therapies that may be predicted to have fewer side-effects. As such, patients deemed ineligible for standard intensive chemotherapy, for any of the reasons identified above, may be treated with the combinations according to the present invention.

[00471] As discussed above, venetoclax is authorized in the US for use in combination with azacytidine, decitabine or low-dose cytarabine for the treatment of newly-diagnosed AML in adults who are aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy. Thus, in certain embodiments, particularly embodiments wherein the BCL-inhibitor is venetoclax or a pharmaceutically acceptable form thereof, patients or subjects treated in accordance with the methods described herein are newly-diagnosed AML patients aged 75 years or older. In further embodiments, patients or subjects treated in accordance with the methods described herein are newly-diagnosed AML patients having comorbidities that preclude use of intensive induction therapy. Patients having a comorbidity precluding use of intensive induction chemotherapy may be classified as such based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, or creatinine clearance <45 ml/min. Such embodiments are particularly preferred when the BCL-2 inhibitor in the combination according to the invention is venetoclax or a pharmaceutically acceptable form thereof.

[00472] Patients or subjects treated in accordance with the methods described herein may be eligible for other treatments, for example standard intensive chemotherapy, but may receive the combination therapies described herein as an alternative treatment option. For example, patients or subjects treated in accordance with the methods described herein may be newly- diagnosed AML patients otherwise eligible for standard intensive chemotherapy or anti-PDl refractory melanoma patients eligible for treatment with relatlimab.

[00473] The BCL-2 inhibitor, preferably venetoclax or pharmaceutically acceptable form thereof, of the combination may be dosed according to any regimen determined to be effective for the compound. The FDA prescribing information for use of venetoclax in treating AML proposes a dosing schedule having a ramp-up phase followed by a maintenance phase. In situations where venetoclax is prescribed in combination with azacytidine or decitabine, a dosing schedule is recommended consisting of: 100 mg venetoclax on day 1; 200 mg venetoclax on day 2; 400 mg venetoclax on day 3; and 400 mg venetoclax in combination with 75 mg/m² azacytidine or 20 mg/m² decitabine daily thereafter until disease progression or unacceptable toxicity is observed. In situations where venetoclax is prescribed in combination with low-dose cytarabine, a dosing schedule is recommended consisting of: 100 mg venetoclax on day 1; 200 mg venetoclax on day 2; 400 mg venetoclax on day 3; and 600 mg venetoclax in combination with 20 mg/m² daily thereafter until disease progression or unacceptable toxicity is observed.

[00474] In certain embodiments, each dose, for example oral dose, of the venetoclax or pharmaceutically acceptable form thereof is in the range from 100-600 mg. In certain embodiments, the venetoclax or pharmaceutically acceptable form thereof is dosed daily at 400mg. In certain embodiments, the venetoclax or pharmaceutically acceptable form thereof is dosed daily at 600mg. As described above, the daily fixed-dosing of venetoclax may be preceded by a ramp-up period, for example 3 days, wherein increasing doses of venetoclax are administered to the patient until the maintenance daily dose is reached.

[00475] For embodiments of the invention wherein the combination comprises a nucleoside metabolic inhibitor or the method comprises administering a nucleoside metabolic inhibitor, the nucleoside metabolic inhibitor may be administered at a dose in the range of 20- 100 mg/m² per day. As already noted, ranges described herein include the end points of the range unless indicated otherwise - for example, administration at a dose in the range of 20-100 mg/m² per day includes administration at a dose of 20 mg/m² per day and administration at a dose of 100 mg/m² per day, as well as all doses between the two end points.

[00476] In certain embodiments, the nucleoside metabolic inhibitor is azacytidine and is administered at a dose in the range of 70-80 mg/m² per day. In certain preferred embodiments the nucleoside metabolic inhibitor is azacytidine and is administered at a dose of 75 mg/m² per day.

[00477] In certain embodiments, the nucleoside metabolic inhibitor is decitabine and is administered at a dose in the range of 15-25 mg/m² per day. In certain preferred embodiments the nucleoside metabolic inhibitor is decitabine and is administered at a dose of 20 mg/m² per day.

[00478] For embodiments wherein the combination of the invention includes a nucleoside metabolic inhibitor, or the method involves administration of a nucleoside metabolic inhibitor, the nucleoside metabolic inhibitor may be administered over a dosing period of a daily dose for 5-10 days. That is, a dose of the nucleoside inhibitor is administered every day for a period or 5, 6, 7, 8, 9, or 10 days in length. In certain preferred embodiments the nucleoside metabolic inhibitor is administered over a dosing period of a daily dose for 7 days. The preferred nucleoside metabolic inhibitor is azacytidine.

[00479] In certain embodiments, the nucleoside metabolic inhibitor is administered according to a dosage regimen of repeated dosing periods, wherein the end of one dosing period and the start of the next dosing period are separated by 18-25 days. That is, the dosage regimen includes at least 2 dosing periods in which a dose of the nucleoside inhibitor is administered every day (for example for a period 5, 6, 7, 8, 9 or 10 days in length), wherein the end of the one dosing period and the start of the next dosing period are separated by 18, 19, 20, 21 , 22, 23, 24, or 25 days. In certain embodiments the end of one dosing period and the start of the next dosing period are separated by 21 days.

[00480] In certain embodiments, each dosing period is of the same length (e.g., 7 days). In certain embodiments, the end of each dosing period and the start of the next dosing period are separated by the same number of days (e.g., 21 days).

[00481] In certain embodiments, the first dose of nucleoside metabolic inhibitor is administered 0-7 or 7-21 days after the first dose of the CXCR2 antagonist. In certain embodiments the first dose of nucleoside metabolic inhibitor is administered 10-17 days after the first dose of the CXCR2 antagonist. In certain embodiments the first dose of nucleoside metabolic inhibitor is administered 14 days after the first dose of the CXCR2 antagonist.

[00482] In certain embodiments, one patient treatment cycle consists of 28 days and the nucleoside metabolic inhibitor, preferably azacytidine or decitabine, is administered every day for a period of 5, 6, 7, 8, 9 or 10 days beginning on day 1 of the cycle. The methods of treatment described herein may comprise multiple treatment cycles. Each treatment cycle may replicate the preceding treatment cycle. In certain embodiments, a patient treated with a CXCR2 antagonist, a BCL-2 inhibitor (preferably venetoclax or a pharmaceutically acceptable form thereof) and azacytidine is treated according to a cycle consisting of 28 days wherein azacytidine is administered daily on the first 7 days of the 28-day cycle. In certain embodiments, a patient treated with a CXCR2 antagonist, a BCL-2 inhibitor (preferably venetoclax or a pharmaceutically acceptable form thereof) and decitabine is treated according to a cycle consisting of 28 days wherein decitabine is administered daily on the first 5 days of the 28-day cycle. For embodiments wherein the patient is treated according to a 28-day cycle with a CXCR2 antagonist, a BCL-2 inhibitor ((preferably venetoclax or a pharmaceutically acceptable form thereof) and a nucleoside metabolic inhibitor (preferably azacytidine or decitabine), the CXCR2 antagonist may be administered every day of the 28-day cycle. In preferred embodiments, the CXCR2 antagonist is SX-682. In further preferred embodiments, the CXCR2 antagonist (e.g., SX-682) is administered twice daily for a total daily dose of 400 mg.

[00483] It is a further advantage of the invention that following an initial period of combination therapy, the administration of a nucleoside metabolic inhibitor (NMI) (e.g., azacytidine) can be tapered or stopped. There is the potential for accumulated toxicity arising from prolonged periods of NMI treatment, for example cytopenia arising from the effect of NMIs on non-blast cell types. Therefore, by tapering or stopping the dose of NMI after an initial period, the risk of such toxicity can be reduced and non-blast cell types can recover. In certain embodiments, treatment according to the invention comprises administering to the patient a CXCR2 antagonist, a BCL-2 inhibitor (for example venetoclax) and a NMI as a combination therapy according to any of the embodiments described above in a first stage (induction therapy), and in a subsequent second stage administering to the patient a CXCR2 antagonist, a BCL-2 inhibitor (for example venetoclax) and a NMI as a combination therapy but wherein the dose of the NMI in the second stage (maintenance therapy) is lower than the dose of NMI administered in the first stage. The dose of the NMI in the second stage may be zero.

[00484] In such embodiments, the dose of CXCR2 antagonist administered in the second stage (i.e., maintenance therapy) is any dose according to the embodiments already described. That is, in some embodiments, the CXCR2 antagonist is administered at a dose of about 50-1000 mg (e.g., about 50-400 mg, 50-300 mg, 50-200 mg, 50-100 mg, 150-900 mg, 150-600 mg, 200- 800 mg, 300-600 mg, 400-500 mg, 300-500 mg, 200-500 mg, 100-500 mg, 100-400 mg, 200- 300 mg, 100-200 mg, 250-350 mg, or about 75 mg, 150 mg, 200 mg, 300 mg, 400 mg, 450 mg, or 600 mg). In some embodiments, the CXCR2 antagonist is administered daily, e.g., once daily or twice daily. In some embodiments, the CXCR2 antagonist is administered for 1 week (e.g., 7 days) in a 4-week cycle (e.g., 28-day cycle). In some embodiments, the CXCR2 antagonist is administered for two weeks (e.g., 14 days) in a 4-week cycle (e.g., 28-day cycle). In some embodiments, the CXCR2 antagonist is administered for 3 weeks (e.g., 21 days) in a 4-week cycle. In some embodiments, the CXCR2 antagonist is administered daily, e.g., once daily or twice daily at a total dose of about 50-1000 mg (e.g., about 50-400 mg, 50-300 mg, 50-200 mg, 50-100 mg, 100-200 mg, 150-900 mg, 150-600 mg, 200-400 mg, 200-800 mg, 300-600 mg, 400- 500 mg, 300-500 mg, 200-500 mg, 100-500 mg, 100-400 mg, 200-300 mg, 100-200 mg, 250- 350 mg, or about 75 mg, 150 mg, 300 mg, 450 mg, or 600 mg). In some embodiments, the CXCR2 is administered once daily or every other day. In other embodiments, the CXCR2 antagonist is administered twice daily. In some embodiments, the CXCR2 antagonist is administered twice daily and each dose, e.g., the first and second dose, comprises about 25-400 mg (e g., 25-100 mg, 50-200 mg, 75-150, or 100-400 mg) of the CXCR2 antagonist. In some embodiments, the CXCR2 antagonist is administered once daily and the dose comprises about 50-600 mg (e.g., 50-150 mg, 100-400 mg, 200-300, or 300-500 mg) of the CXCR2 antagonist. In some embodiments, the CXCR2 antagonist is administered orally. In some embodiments, the CXCR2 antagonist is administered orally twice daily for a total daily dose of 200 mg in a 4-week cycle (e.g., 28-day cycle). In some embodiments, the CXCR2 antagonist is administered orally twice daily for a total daily dose of 400 mg in a 4-week cycle (e.g., 28-day cycle). In some embodiments, the CXCR2 antagonist is administered orally twice daily for a total daily dose of 800 mg in a 4 week cycle (e.g., 28 day cycle). The duration of the first stage (i.e., induction therapy), the timing of the transition to the second stage (i.e. maintenance therapy) and the extent to which the dose of NMI is tapered or stopped entirely are factors that will be tailored to the individual patient and determined by their clinician according to the individual patient’s response to therapy and their medical history. Therefore, the following embodiments are provided by way of non-limiting examples.

[00485] In certain embodiments the induction therapy is administered to the patient until their bone marrow and/or peripheral blood blast percentage is less than 10%, preferably less than 5%.

[00486] In certain embodiments, the induction therapy is administered for at least 5 NMI dosing periods, optionally at least 6, 7, 8, 9, or at least 10 NMI dosing periods. [00487] In certain embodiments, the dose of the NMI in the maintenance period is no more than 50 mg/m² per day, optionally no more than 40 mg/m² per day, optionally no more than 30 mg/m² per day, optionally no more than 20 mg/m² per day. In certain embodiments, the dose of the NMI in the maintenance period is zero.

[00488] As explained elsewhere herein, the agents of the combinations may be formulated for administration by any suitable routes of administration. Thus, the administration of the agents in accordance with the methods of the invention can be via any suitable routes and need not be via the same route for individual agents. For example, the CXCR2 antagonist and the BCL-2 inhibitor (e.g., venetoclax) may be administered orally, whilst a hypomethylating agent such as azacytidine or decitabine may be administered intravenously or subcutaneously via injection.

[00489] For dosing methods of other anticancer agents referenced herein, their FDA approved label should be consulted, and each approved label is incorporated herein by reference.

[00490] Treatment Outcomes

[00491] In certain emodiments, the methods described herein involve monitoring patient PFS by measuring whether the patient is alive or dead; measuring whether the cancer has progressed; and computing PFS as the duration from starting administering a CXCR2 antagonist (e.g., SX-682) to the time when the cancer has progressed or patient death, whichever occurs first.

[00492] In certain emodiments, the methods described herein involve monitoring patient OS by measuring whether the patient is alive or dead; measuring whether the cancer has progressed; and computing OS as the duration from starting administering a CXCR2 antagonist (e.g., SX-682) to the time of patient death.

[00493] In certain emodiments, the methods described herein involve monitoring patient tumor size using clinical visual observation, computed tomography (CT) imaging, magnetic resonance (MRI) imaging, positron emission tomography (PET) or radionuclide scintigraphy, and then further optionally determining response by iRECIST or RECIST version 1.1.

[00494] In certain embodiments, the methods described herein involve monitoring the patient’s blast count i.e., the number of blast cells. As used herein, “blast cells” or “blasts” refer to myeloblasts or myeloid blasts which are the myeloid progenitor cells within the bone marrow. In healthy individuals, blasts are not found in the peripheral blood circulation and there should be less than 5% blast cells in the bone marrow. In subjects with myeloid malignancies, particularly AML and MDS, there is increased production of abnormal blasts with disrupted differentiation potential, and the overproduction of these abnormal blasts can be detected by monitoring the patient’s blast count in the peripheral blood circulation or the bone marrow or both.

[00495] The proportion of blast cells in the bone marrow or peripheral blood can be assessed by methods known in the art, for example flow cytometric or cell morphologic assessment of cells obtained from a bone marrow biopsy of the subject, or a peripheral blood smear. The proportion of blasts is determined versus total cells in the sample. For example, flow cytometry can be used to determine the proportion of blast cells using the number of CD45^dim, SSC^low cells relative to total cell number. By way of further example, cell morphological assessment can be used to determine the number of morphologically identified blasts relative to the total number of cells in the field of view being examined.

[00496] In certain embodiments are provided methods for reducing the proportion of blasts cells in the bone marrow to less than 25%, less than 20%, for example less than 10%. In certain embodiments are provided methods for reducing the proportion of blasts cells in the bone marrow to less than 5%. In certain embodiments are provided methods for reducing the proportion of blast cells in the bone marrow to between about 5% and about 25%, wherein the bone marrow blast cell percentage is also reduced by more than 50% as compared with the bone marrow blast cell percentage prior to performing the method (or pretreatment).

[00497] In certain embodiments are provided methods for reducing the proportion of blasts cells in the peripheral blood to less than 25%, less than 20%, for example less than 10%. In certain embodiments are provided methods for reducing the proportion of blasts cells in the peripheral blood to less than 5%. In certain embodiments are provided methods for reducing the proportion of blast cells in the peripheral blood to between about 5% and about 25%, wherein the peripheral blood blast cell percentage is also reduced by more than 50% as compared with the peripheral blast cell percentage prior to performing the method (or pretreatment).

[00498] For clinical determination of blast cell percentage, typically cell morphological (also known as cytomorphology) assessment is preferred.

[00499] Optionally, a response in AML is determined by IWG 2003; a response in MDS is determined by IWG 2006, IWG 2018 or IWG 2023; and a response in MF is determined by IWG-MRT 2013. [00500] In particular embodiments, the methods described herein induce a complete response. In the context of AML treatment, a complete response or “complete remission” is defined as: bone marrow blasts < 5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC > 1.0 x 10⁹/L (1000/pL); platelet count > 100 x 10⁹/L (100,000/pL), see Dohner et al. (2017) Blood 129(4): 424-447.

[00501] The methods may achieve a complete response with platelet recovery i.e., a response wherein the platelet count is > 100 x 10⁹/L (100,000/pL). The methods may achieve a complete response with neutrophil recovery i.e. a response wherein the neutrophil count is > 1.0 x 10⁹/L (1000/pL). Alternatively, or in addition, the methods may induce a transfusion independence of red blood cells or platelets, or both, for 8 weeks or longer, 10 weeks or longer, 12 weeks or longer.

[00502] In particular embodiments, the methods described herein induce a minimal or measurable residual disease (or MRD) status that is negative, see Schuurhuis et al. (2018) Blood. 131 (12): 1275-1291 .

[00503] In certain embodiments, the methods described herein induce a complete response without minimal residual disease (CRMRD), see Dohner et al. ibid.

[00504] The method may achieve a partial response or induce partial remission. In the context of AML treatment, a partial response or partial remission includes a decrease of the bone marrow blast percentage of 5% to 25% and a decrease of pretreatment bone marrow blast percentage by at least 50%, see Dohner et al. ibid.

[00505] The methods described herein increase survival. The methods described herein increase survival as compared with the gold-standard treatment for the particular disease or condition to be treated. The gold-standard treatment may also be identified as the best practice, the standard of care (some settings have no standard of care as the gold-standard), the standard medical care or standard therapy. For any given disease, there may be one or more gold-standard treatments depending on differing clinical practice, for example in different countries, and are known to those skilled in the art. The treatments already available for myeloid malignancies are varied and include chemotherapy, radiation therapy, stem cell transplant and certain targeted therapies. Furthermore, clinical guidelines in both the US and Europe govern the standard treatment of myeloid malignancies, for example AML, see O’Donnell et al. (2017) Journal of the National Comprehensive Cancer Network 15(7):926-957 and Dohner et al. (2017) Blood 129(4):424-447, both incorporated by reference.

[00506] The methods of the present invention may increase or improve survival relative to patients undergoing any of the standard treatments for myeloid malignancy.

[00507] The methods described herein may include a further step of subjecting the patient or subject to a bone marrow transplant. The methods described herein may also be used to prepare a patient having a myeloid malignancy for a bone marrow transplantation. As described above, the methods of the present invention may be carried out so as to reduce the absolute or relative numbers of blast cells in the bone marrow or peripheral blood. In certain embodiments, the methods are carried out so as to reduce the blast cell count in the bone marrow and/or peripheral blood prior to transplant. The methods may be used to reduce the blast cell count to less than 5% to prepare the patient or subject for a bone marrow transplant.

[00508] Kits

[00509] The combinations of the invention described herein may be provided in the form of a kit packaged so as to include instructions for use.

[00510] Incorporation bv Reference

[00511] Various publications are cited in the foregoing description and throughout the following examples, each of which is incorporated by reference herein in its entirety.

[00512] Example 1: A Phase 1, Open-Label, Dose-Escalation with Expansion Study of SX-682 in Subjects with Metastatic Melanoma Concurrently Treated with Pembrolizumab

[00513] Human melanoma is exemplary of human solid tumor cancers, and in particular is exemplary of solid tumors that include lung cancer, pancreatic cancer and prostate cancer.

[00514] A phase 1 dose-escalation with expansion trial (NCT03161431) was performed that evaluated treating patients with histologically confirmed unresectable Stage III or Stage IV melanoma (i.e., unresectable or metastatic) as per the AJCC staging system with pembrolizumab and escalating doses of twice-daily (BID) SX-682 (25 - 400 mg) in a 21 -day cycle (FIG. 1). Patients must have had prior disease progression on anti-PDl therapy (i.e., anti-PDl or anti-PD- Ll, including prior adjuvant). Mucosal melanoma and asymptomatic brain metastases were allowed. Escalation cohorts had a 21 -day SX-682 monotherapy (MONO) run-in. Response assessment by RECIST version 1.1 was every 2 cycles during combination (COMBO) treatment. The primary endpoint was safety: adverse events (AEs), dose-limiting toxicity (DLT) and maximally-tolerated dose (MTD). Secondary endpoints included objective response rate by RECIST 1.1 (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival (PFS) and overall survival (OS).

[00515] There were 51 patients enrolled and treated; median age of 65 (range 24-91), 55% male, 61% elevated lactate dehydrogenase (LDH) tumor marker, 39% BRAF mutated, and with significant disease burden consisting of a median 7.5 cm sum of largest target lesion diameters (Table 1)

Table 1. Patient demographics and baseline characteristics. *Sum of reference diameters of target lesions.

[00516] All patients received prior anti-PD-1, 37 (73%) received combined anti-PD-1 and anti-CTLA-4, and 23 (45%) had > 3 prior therapies. That is, all patients had a cancer that was increasing in size in response to treatment with an anti-PD-1 or anti-PD-Ll blocking antibody (i.e., failing anti-PD-1 or anti-PD-Ll blocking antibody therapy) and 73% further had failed combined anti-CTLA4 and anti-PDl blocking antibody therapy.

[00517] Apart from direct tumor effects, CXCR2 mediates bone marrow neutrophil release (trafficking) and thus absolute neutrophil count (ANC) is a facile pharmacodynamic (PD) marker of peripheral CXCR1/2 inhibition. The fitted ED50 was 97 mg BID and doses >150 mg BID were on the pharmacodynamic (PD)-dose curve plateau (FIG. 2). That is, <100 mg BID gave incomplete CXCR1/2 inhibition, and >200 mg BID gave complete inhibition. No MONO DLT or MTD was identified. The 200 mg dose cohort was expanded in COMBO based on safety and PD: mg BID dose (n) = 25 (3), 50 (3), 100 (6), 150 (8), 200 (31). Any grade and grade 3/4 treatment-related AEs (TRAEs) occurred in 75% and 43%, respectively, and drug discontinuation (DD) due to TRAEs in 20%. There was no infectious or febrile neutropenia signal. Excluding uncomplicated neutropenia (PD effect permitted in trial), grade 3/4 TRAEs were seen in 25% and DD in 12% (rash, transaminitis).

[00518] Consistent with the dose-PD relationship (i.e., incomplete vs. complete CXCR1/2 inhibition), DCR depended significantly on SX-682 dose (P vs. <100 mg): 0% (0/9) at <100 mg, 50% (3/6) at 150 mg (P = 0.0440) and 63% (12/19) at 200 mg (P = 0.0028) (FIG. 3). At the 200 mg BID dose the ORR was 21% with 1 patient have a CR and 3 patients have PR. Kinetics of change in tumor burden also correlated with dose (FIG. 4).

[00519] Consistent with the dose-PD relationship (i.e., incomplete vs. complete CXCR1/2 inhibition), the 200 mg dose gave a significantly longer PFS than doses <100 mg (P = 0.003) (FIG. 5). Again, consistent with the dose-PD relationship (i.e., incomplete vs. complete CXCR1/2 inhibition), the 200 mg dose more than doubled survival compared to doses <100 mg (i.e., 15.2 months at effective dosing vs. 7.4 months at ineffective dosing, P = 0.037) (FIG. 6). The latter 7.4 month value was consistent with the historical 7.2 month survival (n=180) after progression on anti-PDl monotherapy (i.e., failing anti-PD-1 or anti-PD-Ll blocking antibody therapy) and 5.6 month survival (n=67) after progression on nivolumab plus ipilimumab, i.e., failing combined anti-CTLA4 and anti-PDl blocking antibody therapy) (Patrinely, 2020, Cancer, 126(15): 3448-3455). Thus, pembrolizumab combined with SX-682 at doses providing complete CXCR1/2 inhibition (therapeutically effective) significantly increased patient survival, in particular significantly increased OS and PFS, compared to SX-682 doses providing incomplete CXCR1/2 inhibition (therapeutically ineffective) and compared to the same historical patient populations as in the melanoma trial that failed anti-PD-1 or anti-PD-Ll blocking antibody therapy and failed combined anti-CTLA4 and anti-PDl blocking antibody therapy.

[00520] Example 2: A Phase 1, Open-Label, Dose-Escalation with Expansion Study of SX-682 Monotherapy in Subjects with Hypomethylating Agent (HMA) Refractory Myelodysplastic Syndrome

[00521] MDS is a heterogeneous pre-leukemic syndrome to AML that arises from a small pool of initiating mutant leukemic cells in hematopoietic stem cell (HSC) compartments. Multistep processes involving recurrently mutated genes and cytogenetic aberrations lead to clonal expansion of mutant HSC, increased blasts, dysplastic hematopoiesis and cytopenias. MDS is an exemplary hematologic malignancy, and particularly an exemplary myeloid malignancy of the group comprising AML, MF, MPN and CMML.

[00522] A phase 1 dose-escalation with expansion trial (NCT04245397) was performed that evaluated treating patients with HMA refractory MDS with escalating doses of twice-daily (BID) SX-682 (25 - 400 mg). SX-682 was administered orally twice-daily (BID) in six continuous 28-day cycles with treatment continuing past the end of cycle 6 in patients responding by IWG 2006 response criteria (FIG. 7). Response was assessed at the end of cycles 1, 3 and 6 and every third cycle thereafter. Dose-escalation followed a 3+3 design. Eligible patients failed at least 4 cycles of HMA and if patient with deletion of the long arm of chromosome 5 [del(5q)] additionally must have failed at least 4 cycles of lenalidomide. Patients could have any IPSS MDS risk. A total of 17 patients were enrolled in escalation. Responses were first observed beginning with the 50 mg dose cohort (FIG. 8). The pooled response rate (ORR) in the 50, 100 and 200 mg BID dose escalation cohorts (n = 12) was 50% (6/12; 95% confidence interval (CI), 25 - 75%) with patients treated for a median of 5.1 cycles.

[00523] The 200 mg dose yielded the most rapid reduction in blasts with 2 of 6 patients (33%) achieving a marrow complete remission (mCR) in keeping with this dose providing maximum receptor inhibition and was selected as the recommended phase 2 dose (RP2D). Twenty-six patients were treated with the RP2D. Across all doses 50 to 200 mg BID, 10 of 32 (31%) patients had a response: 5 mCR (16%) and 5 HI (16%) (FIG. 9).

[00524] One patient (FIG. 10) had a durable near-CR (on SX-682 >500 days) consisting of platelet hematologic improvement (HI-P, >100,000/pL, FIG. 10) and erythroid hematologic improvement (HI-E, hemoglobin > 10 g/dL) and transfusion independence for over four months (FIG. 11). The patient required 16 red blood cell transfusions in the seven weeks before starting SX-682 therapy.

[00525] SX-682 provided a clear increase in survival, nearly tripling OS in IPSS-R high and very high risk patients (n=24) compared to historical OS after HMA failure (n=435) (14.9 vs. 5.6 months) (Prebet, 2011, J Clin Oncol, 29(24): 3322-3327) (FIG. 12).

[00526] Example 3: An Open-label Phase 1 Study to Evaluate the Safety and Efficacy of SX-682 in Combination with Nivolumab as Maintenance Therapy in Patients with Unresectable Pancreatic Ductal Adenocarcinoma

[00527] A phase 1, open-label, dose-escalation with expansion trial (NCT04477343) was performed that evaluated treating patients with unresectable pancreatic ductal adenocarcinoma (“pancreatic cancer”) who completed a minimum of 16 weeks first-line chemotherapy without evidence of disease progression with escalating doses of twice-daily (BID) SX-682 (50 - 400 mg) in combination with nivolumab (FIG. 13).

[00528] As of April 7, 2023 (data cutoff), there were 8 evaluable patients. Each of 7 patients (88%) had progression free survival (PFS) longer than the median 3.8-month PFS in the historical control (i.e. the placebo arm in the Phase 3 olaparib POLO trial, n = 62; Golan, 2019, N Engl J Med, 381(4): 317-327) (FIG. 14). The interim median PFS for all patients is 6.2 months versus 3.8 months in the historical control, and one patient continues on study without disease progression for 25 months as of the data cutoff. Nivolumab monotherapy is known not to increase PFS in this patient setting. Thus, the combination of SX-682 with nivolumab increased patient survival, in particular increased PFS, compared to PFS in the same historical patient population not treated with the combination.

[00529] Example 4: A Open-Label Phase 2, Single-Arm Study of the CXCR1/2 Inhibitor SX-682 Plus Enzalutamide in Men with Abiraterone-Resistant Metastatic Castration Resistant Prostate Cancer

[00530] This is a phase 2 one-arm, open-label trial (NCT06228053) of SX-682 with enzalutamide in patients with metastatic castrate-resistant prostate cancer (mCRPC) failing abiraterone. The trial will enroll 53 evaluable patients with mCRPC diagnosis with (a) any histology, (b) not previously treated with enzalutamide, and (c) prior abiraterone with prednisone (or with dexamethasone) and with rising PSA (a rising PSA requires at least 3 measurements obtained at least 1 week apart showing increase from nadir with the last level above 2 ng/mL by local testing) or progression of lesions by CT, MRI or bone scan.

[00531] Patients will receive enzalutamide 160 mg orally once daily plus SX-682200 mg twice daily in continuous 21 -day cycles. Patients will be treated until progressive disease by iRECIST or PCWG3 bone scan criteria (or optionally through progression), death or unacceptable toxicity.

[00532] The primary endpoint is clinical benefit (CB), wherein CB is a composite endpoint defined as 1) iRECIST iCR or iPR, 2) PSA50 or 3) stable disease by iRECIST and PCWG3 bone scan criteria for at least 6 months. PSA response (PSA50) is a categorical efficacy variable defined as a > 50% decline from baseline and confirmed >3 weeks later.

[00533] Secondary endpoints include, but are not limited to, (a) PF SI (time from the date study treatment starts to the earliest progression event from iRECIST (i .e., iPFS), PCWG3 bone scan criteria, or death) and PFS2 (same as PF SI but using RECIST 1.1 instead of iRECIST), (b) overall survival (the time from the start of study treatment until death due to any cause), (c) RECIST 1.1, (d) PSA50, (e) PSA PFS, (f) ASOM (percent change in sum of measures taking the baseline sum of measures as reference), (g) symptomatic skeletal events (SSEs) and (h) duration of response (DOR).

[00534] SX-682 and enzalutamide will provide a greater rate of CB and increased PFS and

OS compared to enzalutamide alone without SX-682.

[00535] Example 5: In vitro evaluation of combination therapy in AML model

[00536] The BCL-2 antagonist, venetoclax, targets and eliminates leukemic stem cells (LSCs) by suppression of oxidative phosphorylation and demonstrated very promising activity in older AML patients in clinical phase I and II studies in combination with standard of care (Pollyea et al., Nature Medicine (2018) 24; 1859-1866). However, even with novel agents such as venetoclax, there are still patients that become refractory or relapse. It was hypothesized that combining venetoclax, decitabine, and CXCR2 antagonist SX-682 with distinct but complementary mechanisms of action could successfully eliminate LSCs.

[00537] To test this hypothesis, a drug-combination study will be carried out according to the Chou-Talalay method (Chou TC, Cancer Research (2010) 70(2); 440-6) in leukemic cell lines. These cell lines may be patient derived, or cells that are commercially available, such as HL-60, Kasumi-6, MOLM-13, NB-4, and N0M0-1 cells. [00538] Initially, leukemic cells will be treated with decitabine, SX-682 or venetoclax alone to determine the IC50 for each treatment. Leukemic cells will be treated with a concentration range of SX-682 (0.1 - 20 mM), venetoclax (0.5 and 200 nM), decitabine (0.01 -1 mM) or vehicle. The assay will be performed in triplicate.

[00539] To determine synergy, a constant combination ratio experiment will be carried out at equipotency ratio (IC50dru_gi/IC50dru_g2, or IC50dru_gi/IC50dm_g2/IC50dru_g3) so that each drug contributed equally to cell killing. Combination drug dose responses will be assessed in two technical replicates for every dose/dose combination as previously described (Riether et al., Sci Transl Med (2015) 7(298); 298ral l9).

[00540] Leukemic cells will be treated with vehicle, decitabine, SX-682 or venetoclax alone, a double combination of venetoclax and decitabine, decitabine and SX-682, or venetoclax and SX-682, or a triple combination of decitabine, SX-682 and venetoclax (or azacitidine in place of decitabine for the indicated combinations). All combinations will be tested at three high and three low concentrations (above and below the identified IC50s) and in a constant ratio. Viable leukemic cell numbers will be assessed 72 hours later by Annexin V staining or other suitable measure of cell viability, and the effect of drug treatment will be calculated as the ratio of surviving cells to vehicle-treated cells.

[00541] The Combination Index (CI) will be calculated and plotted against Fraction affected (Fa) using CompuSyn or other suitable software.

[00542] Fa values of 0, 0.5, and 1 correspond to 0, 50, and 100% killed cells. A Cl of <1 , 1 , >1 represents synergism, additivity, and antagonism, respectively. IC50s indicates Fa values reached for the combination of respective IC50 concentrations. The principles and advantages of the Fa-CI plot method of assessing synergism are provided in, for example, Chou TC, Cancer Research (2010) 70(2); 440-6 and Zhao et al. Front Biosci (Elite Ed). (2010) 2; 241 -249 (each of which is incorporated herein by reference in its entirety).

[00543] SX-682 used in combination with venetoclax and/or decitabine or azacitidine are tested for elimination of leukemic cell lines in vitro.

[00544] Example 6: In vivo evaluation of combination therapy in MF model

[00545] Approximately 10 - 14 days post-transplant, hMPLW515L transplanted mice that exhibit disease will be assigned to four separate treatment arms: vehicle, Janus kinase inhibitor ruxolitinib (60 mg/kg orally BID), CXCR1/2 antagonist SX-682 (200 mg/kg/day) or combination therapy (ruxolitinib + SX-682). Following 21 days of treatment, automated peripheral blood counts will be performed using a ProCyte Dx (or similar instrument) on samples collected by submandibular bleeding. Timed sacrifice studies will be completed at 7 - 8 weeks posttransplant. At the time of sacrifice, bone marrow will be harvested and spleens and livers will be removed and weighed, and single-cell suspensions will be prepared for cell staining and fractionation, flow cytometry, Western blot analysis, and histopathological analysis.

[00546] SX-682 in combination with ruxolitinib are tested in normalizing peripheral blood levels, and in decreasing fibrosis development in the bone marrow and spleen in treated mice.

[00547] SX-682 in combination with type II JAK inhibitors (e.g., CHZ868, AJ1-11095) is tested as described above and will increase survival.

[00548] Example 7: A Phase 1/2 Open-Label Study of SX-682 in Combination with Venetoclax (VEN) and Azacytidine (AZA) in Untreated and Relapsed/Refractory Subjects with Acute Myeloid Leukemia (AML)

[00549] The primary objectives of this clinical study are to determine: (1) the tolerated SX-682 dose in combination with VEN and AZA in patients with AML, (2) the adverse event profile, and (3) the overall response rate (ORR) = complete remission (CR) + incomplete count recovery (CRi) + partial remission (PR).

[00550] The secondary endpoints of this study are to determine: (1) other efficacy endpoints [CR, CR + CRi, time to CR + CRi, measurable residual disease (MRD) by flow cytometry, event free survival (EFS), PFS, overall survival (OS)], and (2) number of patients proceeding to hematological stem cell transplant (HSCT).

[00551] The target patient population will include: (1) a newly diagnosed cohort with subjects confirmed to have AML by World Health Organization (WHO) criteria and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or comorbidities; and (2) a relapsed/refractory cohort with subjects confirmed to have AML by WHO criteria and relapsed after, or was refractory to, a prior VEN-containing treatment.

[00552] In the dose escalation phase of the trial, patients will receive AZA 75 mg/m2 subcutaneous (SC) or IV for 7-days, SX-682 (50, 100 or 200 mg BID po) and VEN 400 mg po daily with 3 -day VEN ramp up only on Cycle 1 beginning with 100 mg on Day 1, 200 mg on Day 2 and 400 mg thereafter (or VEN equivalent with azoles). Subjects will be hospitalized during the VEN ramp-up period during Cycle 1 (e.g., Days -1 through Day 4). One Cycle will be for 28 days.

[00553] Subjects will continue their treatment until documented disease progression per Investigator assessment, unacceptable toxicity, withdrawal of consent, or the subject meets other protocol criteria for discontinuation (whichever occurs first). All subjects will have a Final Visit performed when treatment is discontinued unless the subject has withdrawn consent to participate in the study. Baseline laboratory assessments will be obtained at Cycle 1 Day 1 prior to first dose of study treatment. Disease assessments by IWG criteria will be performed at the end of Cycle 1 (± 3 days) and every 3 cycles starting on Cycle 2 Day 1 and continuing until disease progression per IWG criteria, or the subject withdraws consent. Safety will be assessed by serial physical exams, vital signs, hematology, and chemistry laboratories and AEs. Reporting of AEs and laboratory data will be based on grading per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

[00554] The Phase 1 safety run-in will be performed to establish the tolerated SX-682 dose in the drug triplet combination with VEN + AZA. A dose level of SX-682 is considered tolerated in the triplet if it contains 0 or 1 DLTs in the 6 patients treated at that dose level. The recommended Phase 2 dose (RP2D) for SX-682 in Phase 2 will be selected based on the totality of PD, activity, safety, and efficacy from three Phase 1 run-in safety cohorts of 6 patients each: 50, 100 and 200 mg BID. Subjects will be assigned to a dose level in the order of study entry with at least a 3-day stagger in enrollment between individual subjects. Doses are not escalated, and no further subjects enrolled unless all patients receiving the highest current dose have been observed for at least Cycle 1. A subject who withdraws from Cycle 1 of the study for reasons other than a DLT will be replaced. The Phase 1 may optionally explore intermediate doses and alternative duration and sequencing (e.g., less than 28 days or SX-682 dosing that does not overlap with VEN or AZA).

[00555] In Phase 2, further subjects will be enrolled at the SX-682 RP2D for the triplet. Together with the Phase 1 and Phase 2 enrollment, 60 AML patients total are intended to be treated with the triplet in two treatment cohorts: (a) newly diagnosed and untreated subjects who are ineligible for standard induction therapy (n=40), and (b) subjects who relapsed after, or were refractory to, a prior VEN-containing treatment (n=20). [00556] SX-682 and VEN/ AZA will be efficacious in newly diagnosed and/or VEN refractory/relapsed AML patients, resulting in greater responses and increased PFS and OS.

[00557] Example 8: A Phase 2 Open-Label Study of SX-682 in Combination with Decitabine in Hypomethylating Agent Relapsed/Refractory (HMA-RR) Subjects with Myelodysplastic Syndrome (MDS)

[00558] The trial in Example 2 was amended to further include the combination of SX- 682 with decitabine in HMA relapsed/refractory MDS. The primary objectives of this study are to determine: (1) the tolerated SX-682 dose in combination with intravenous or oral decitabine (i.e., decitabine with the cytidine deaminase inhibitor cedazuridine) in patients with MDS, (2) the adverse event profile of the combination therapy, and (3) evidence of improved overall response rate [(ORR) = complete remission (CR) + incomplete count recovery (CRi) + partial remission (PR)] of the combination therapy over treatment with SX-682 alone.

[00559] The secondary endpoints of this study are to determine: (1) Proportion of subjects achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by IWG 2006 criteria; (2) Duration of response defined as the time between achieving response and progression of disease; (3) AML transformation according to WHO criteria; (4) Overall survival (OS); (5) Single- and multi-dose PK parameters.

[00560] The target patient population will include patients diagnosed with MDS according to WHO criteria stratified into the following IPSS risk categories: (1) low and intermediate- 1 and have failed prior treatment; and (2) intermediate-2 and high risk. All patients will have relapsed or are refractory to standard therapy, or for whom standard treatments are contraindicated.

[00561] In this trial, patients will receive SX-682 200 mg BID po daily with decitabine given orally once daily on days 1 through 5 of each cycle. One cycle will be for 28 days.

[00562] Subjects will continue their treatment until documented disease progression per Investigator assessment, unacceptable toxicity, withdrawal of consent, or the subject meets other protocol criteria for discontinuation (whichever occurs first). All subjects will have a Final Visit performed when treatment is discontinued unless the subject has withdrawn consent to participate in the study. Baseline laboratory assessments will be obtained at Cycle 1 Day 1 prior to first dose of study treatment. Disease assessments by IWG criteria will be performed at the end of Cycle 1 (± 3 days) and every 3 cycles starting on Cycle 2 Day 1 and continuing until disease progression per IWG criteria, or the subject withdraws consent. Safety will be assessed by serial physical exams, vital signs, hematology, and chemistry laboratories and AEs. Reporting of AEs and laboratory data will be based on grading per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

[00563] SX-682 and decitabine will be efficacious in HMA relapsed/refractor MDS patients, resulting in greater responses and increased PFS and OS, as compared to either SX-682 or decitabine as monotherapy.

[00564] Example 9: In vivo evaluation of combination therapy in newly diagnosed MM model

[00565] VK*MYC MM cells (1 x 10⁶) will be intravenously administered to each mouse model (Chesi M et al. Blood. 2012;120(2):376-85). Tumor growth will be monitored by plasma clonal IgG accumulation measured by serum protein electrophoresis (SPE). When the IgG monoclonal protein (M-spike) to albumin ratio surpasses about 0.28 (corresponding to ~10 g/dL in a MM patient), therapy with different treatment regimens will be started. CXCR2 blockade with SX-682 will significantly increase overall survival and its effects will synergize with bortezomib and dexamethasone.

[00566] Example 10: In vivo evaluation of combination therapy in newly diagnosed MM model

[00567] VK*MYC MM cells ( 1 N O⁶) will be intravenously administered to each mouse model. When the IgG M-spike to albumin ratio reaches about 0.28, the mice will be lethally irradiated for initial MM treatment, followed by syngeneic (autologous) transplantation with bone marrow and T cells. Plasma IgG levels will be monitored until tumor recurrence (relapse). When the M-spike reaches about 0.28, the mice will be treated with SX-682. SX-682 as a single agent will significantly decrease tumor burden and increase overall survival.

[00568] Example 11: Inhibition of Tumor Cell Proliferation by SX-682

[00569] SX-682 was evaluated against the human tumor cell line panel at five concentration levels (0.01, 0.1, 1, 10, 100 pM) as performed by the Developmental Therapeutics Program at the National Cancer Institute (Shoemaker, 2006, Nat Rev Cancer, 6:813-23).

[00570] The human tumor cell lines of the cancer screening panel were grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. Cells were inoculated into 96 well microtiter plates in 100 pL at plating densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of individual cell lines. After cell inoculation, the microtiter plates were incubated at 37°C, 5% CO2, 95% air and 100% relative humidity for 24 h prior to addition of SX-682.

[00571] After 24 h, two plates of each cell line are fixed in situ with TCA, to represent a measurement of the cell population for each cell line at the time of drug addition (Tz). SX-682 was solubilized in dimethyl sulfoxide at 400-fold the desired final maximum test concentration and stored frozen prior to use. At the time of SX-682 addition, an aliquot of frozen concentrate was thawed and diluted to twice the desired final maximum test concentration with complete medium containing 50 pg/ml gentamicin. Additional four, 10-fold or ’A log serial dilutions are made to provide a total of five drug concentrations plus control. Aliquots of 100 pl of these different drug dilutions were added to the appropriate microtiter wells already containing 100 pl of medium, resulting in the required final drug concentrations.

[00572] Following drug addition, the plates were incubated for an additional 48 h at 37°C, 5% CO2, 95 % air, and 100 % relative humidity. For adherent cells, the assay was terminated by the addition of cold TCA. Cells were fixed in situ by the gentle addition of 50 pl of cold 50% (w/v) TCA (final concentration, 10% TCA) and incubated for 60 minutes at 4°C. The supernatant was discarded, and the plates were washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (100 pl) at 0.4% (w/v) in 1% acetic acid was added to each well, and plates were incubated for 10 minutes at room temperature. After staining, unbound dye was removed by washing five times with 1% acetic acid and the plates were air dried. Bound stain was subsequently solubilized with 10 mM TRIS, and the absorbance was read on an automated plate reader at a wavelength of 515 nm. For suspension cells, the methodology is the same except that the assay was terminated by fixing settled cells at the bottom of the wells by gently adding 50 pl of 80% TCA (final concentration, 16% TCA). Using the seven absorbance measurements (time zero, (Tz), control growth, (C), and test growth in the presence of drug at the five concentration levels (Ti)), the percentage growth was calculated at each of the drug concentrations levels. Percentage growth inhibition was calculated as:

(Ti-Tz)Z(C-Tz) x 100 for concentrations for which Ti>/=Tz

(Ti-Tz)ZTz x 100 for concentrations for which Ti<Tz

[00573] Three dose response parameters were calculated for each experimental agent. Growth inhibition of 50% (GI50) is calculated from [(Ti-Tz)/(C-Tz)] x 100 = 50, which was the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation. The drug concentration resulting in total growth inhibition (TGI) is calculated from Ti = Tz. The LC50 (concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared to that at the beginning) indicating a net loss of cells following treatment is calculated from (Ti-Tz)/Tz x 100 = -50. Values are calculated for each of these three parameters if the level of activity is reached; however, if the effect is not reached or is exceeded, the value for that parameter is expressed as greater or less than the maximum or minimum concentration tested.

[00574] FIG. 15 shows the results of direct inhibition of tumor cell proliferation of leukemia cell lines by SX-682 in a dose-dependent fashion. The leukemia cell lines included CCRF-CEM, MOLT-4, HL-60, RPML8226, K-562 and SR.

[00575] FIG. 16 shows the results of direct inhibition of tumor cell proliferation of nonsmall cell lung cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The non-small cell lung cancer cell lines included A549, H226, H460, H23, H522, H322M, HOP-62, and HOP-92.

[00576] FIG. 17 shows the results of direct inhibition of tumor cell proliferation of colon cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The colon cancer cell lines included COLO 205, HCT-15, HCC-2998, KM12, HCT-116, and SW-620.

[00577] FIG. 18 shows the results of direct inhibition of tumor cell proliferation of CNS cancer cell lines by SX-682 in a dose-dependent fashion as measured in FIG. 3A. The CNS cancer cell lines included SF-268, SNB-19, SF-295, SNB-75, and SF-539.

[00578] FIG. 19 shows the results of direct inhibition of tumor cell proliferation (melanoma cell lines by SX-682 in a dose-dependent fashion. The melanoma cell lines included LOX IMVI, MDA-MB-435, SK-MEL-5, MALME-3M, SK-MEL-2, UACC-257, M14, SK- MEL-28, and UACC-62.

[00579] FIG. 20 shows the results of direct inhibition of tumor cell proliferation of ovarian cancer cell lines by SX-682 in a dose-dependent fashion. The ovarian cancer cell lines included IBROV1, OVCAR-8, OVCAR-3, NCI/ADR-RES, OVCAR-5, and SK-OV-3.

[00580] FIG. 21 shows the results of direct inhibition of tumor cell proliferation of renal cancer cell lines by SX-682 in a dose-dependent fashion. The renal cancer cell lines included 786-0, CAK-1, TK-10, RXF 393, UO-31, ACHN, and SN12C. [00581] FIG. 22 shows the results of direct inhibition of tumor cell proliferation of prostate cancer cell lines by SX-682 in a dose-dependent fashion. The prostate cancer cell lines included PC-3 and DU- 145.

[00582] FIG. 23 shows the results of direct inhibition of tumor cell proliferation of breast cancer cell lines by SX-682 in a dose-dependent fashion. The breast cancer cell lines included MCF7, BT-549, MDA-MB-231, T-47D, HS 578T, and MDA-MB-468.

[00583] FIG. 24 shows that SX-682 alone and in combination with immune checkpoint blockade (anti-PDl and anti-CTLA4) inhibited prostate cancer in a validated animal model.

Pterf^,c'^/p53^{pc ,}'Smad4^pc'^/' mice were administered 50 mg/kg SX-682 by oral gavage b.i.d. and 200 pg each of anti-PDl and anti-CTLA4 antibodies (ICB), 3x/week. Prostate weight (g) was measured after 4-6 weeks. SX-682 plus ICB was significantly better than control (P=0.0016 **), and ICB or SX682 alone (P=0.021 *) (unpaired t-test). Mean + SE are shown.

[00584] It should be understood that the subject matter defined in the appended claims is not necessarily limited to the specific implementations described above. The specific implementations described above are disclosed as examples only.

Claims

We claim:

1. A method of increasing survival in patients with cancer comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of SX-682 or a pharmaceutically suitable solvate or salt thereof; measuring whether the patients are alive or dead; measuring whether the cancer has progressed; computing (a) a median duration from randomization or starting administering SX-682 to the time of patients’ death or (b) a median duration from randomization or starting administering SX-682 to the time when the patients’ cancer has progressed or death; wherein SX-682 increases the median duration in (a) and/or (b).

2. The method of claim 1, wherein the cancer is selected from the group consisting of melanoma, lung cancer, pancreatic cancer, prostate cancer, myelodysplastic syndrome (MDS), myelofibrosis (MF), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and chronic myelomonocytic leukemia (CMML)

3. The method of claim 1, wherein a median duration is increased by 2 months or more.

4. The method of claim 1, wherein a median duration is increased by 4 months or more.

5. The method of claim 1, wherein a median duration is increased by 6 months or more.

6. The method of claim 1, wherein a median duration is selected from OS, PFS, DFS,

RFS and EFS.

7. The method of claim 1, wherein the increased median duration is statistically significant.

8. The method of claim 1, wherein the cancer comprises a melanoma increasing in size in response to treatment with an anti-PD-1 or anti-PD-Ll blocking antibody.

9. The method of claim 1, wherein the cancer comprises a myelodysplastic syndrome that is refractory to a hypomethylating agent.

10. The method of claim 1, wherein the cancer comprises a melanoma that is unresectable or metastatic.

11. The method of claim 1, wherein the cancer comprises a melanoma, and wherein the treatment further comprises administering an antibody selected from the group consisting of ipilimumab, abatacept, nivolumab, pembrolizumab, tremelimumab, pidilizumab, atezolizumab, durvalumab, avelumab, nivolumab, pembrolizumab, lambrolizumab, MEDL0680, pidilizumab, AMP-224, atezolizomab, durvalumab, BMS-936559, MSB0010718C, BMS-986016, IMP-731, IMP-321, urelumab, PF-05082566, RG-7888, lucatumumab, dacetuzumab, varlilumab, enoblituzumab, G7155, and FPA-008.

12. The method of claim 1, wherein the cancer comprises a melanoma., and wherein the treatment further comprises administering an antibody directed to a ligand selected from the group consisting of B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7- H4, B7-H5 (VISTA), B7-H6CD40, CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4- 1BBL, CD 137 (4- IBB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, ED AR, XEDAR, TACI, APRIL, BCMA, LT0PR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, ED AR, EDAI, XEDAR, EDA2, TNFR1, lymphotoxin a/TNFp, TNFR2, TNFa, LTpR, lymphotoxin aip2, FAS, FASL, RELT, DR6, TROY, NGFR, IL-6, IL- 10, TGF-P, VEGF, CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4

13. The method of claim 1, wherein the cancer comprises a melanoma, and wherein the treatment further comprises administering an antibody that binds to a checkpoint inhibitor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4,.

14. The method of claim 1, wherein the cancer comprises a melanoma, and wherein the treatment further comprises administering an antibody that binds to an agonist of a protein selected from the group consisting of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2.

15. The method of claim 1, wherein the treatment further comprises administering an IDO and/or TDO inhibitor-selected from the group consisting of indoximod, GDC-0919, F001287, GDC-0919 (NLG919), F001287, epacadostat (INCB024360), IDO-IN-1, IDO-IN-2, navoximod (IDO-IN-7).

16. The method of claim 1, wherein the treatment further comprises administering a Janus kinase inhibitor selected from the group consisting of AT9283 (CID 135398495), AZDI 480 (CID 16659841), baricitinib (CID 44205240), BMS-91 1543 (CID 50922691), fedratinib (CID 16722836), filgotinib (GLPG0634, CID 49831257), gandotinib (LY2784544, CID 46213929), INCB039110 (itacitinib, CID 53380437), lestaurtinib (CID 126565), momelotinib (CYT0387, CID 25062766), NS-018 (ilginatinib, CID 46866319), pacritinib (SB1518, CID 46216796), peficitinib (ASP015K, CID 57928403), ruxolitinib (CID 25126798), tofacitinib (CID 9926791), INCB052793 CID 118467751), XL019 (CID 57990869), WP1066 (CID 11210478), TG101209 (CID 16722832), NVP-BSK805 (CID 46398810), AZ960 (CID 25099184), ZM-39923 (CID 3797), ropsacitinib (CID 130339268), SAR-20347 (CID 71727668), GDC-046 (CID 49839561), deucravacitinib (CID 134821691), WHI-P258 (CID 3798), brepocitinib (CID 118878093), ritlecitinib (CID 118115473), FM-381 (CID 122197584), oclacitinib (CID 44631938), decernotinib (CID 59422203), cerdulatinib (CID 44595079), zotiraciclib (CID 16739650), CHZ868, AJ1-11095 and a pharmaceutically acceptable form thereof.

17. The method of claim 1, wherein the treatment further comprises administering a BCL-2 inhibitor selected from the group consisting of venetoclax (CID 49846579), navitoclax (CID 24978538), ABT-737 (CID 11228183), obatoclax (CID 11404337), AZD-4320 (CID 86661883), gossypol (3503), pelcitoclax (CID 76900653), S55746 (CID 71654876), TW-37 (CID 11455910), sabutoclax (CID 46236925), HA14-1 (CID 3549), A-385358 (CID 11556440), lisaftoclax (CID 137355972), apogossypolone (CID 135513044), BM-1197 (CID 60204010), BM-957 (CID 71456995), BCL-2-IN-4 (CID 163322037), BM-1074 (CID 56933431), BCL-2- IN-5 (CID 163322038), BCL-2-IN-6 (CID 163409068), BCL-2-IN-7 (CID 163409069), BDA- 366 (CID 91826545), BCL-2-IN-2 (CID 146681199), BCL-2-IN-8 (CID 163322290), and a pharmaceutically acceptable form thereof.

18. The method of claim 1, wherein the cancer comprises a myelodysplastic syndrome, and wherein the treatment further comprises administering a hypomethylating agent selected from the group consisting of decitabine, decitabine with cedazuridine, and azacitidine.

19. The method of claim 1, wherein the cancer comprises multiple myeloma and wherein the treatment further comprises administering an anti cancer therapy selected from the group consisting of daratumumab, bortezomib, carfilzomib, lenalidomide, prednisone and dexamethasone.

20. The method of claim 1, wherein the treatment further comprises administering anti- PD-1 antibody and an anti-CTLA4 antibody.

21. The method of claim 1, wherein the cancer comprises a prostate cancer, and wherein the treatment further comprises administering abiraterone, enzalutamide, apalutamide or darolutamide.

22. A method of increasing survival in patients with melanoma, comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of SX-682 or a pharmaceutically suitable solvate or salt thereof together with an anti-PD-1 or anti-PD-Ll blocking antibody; wherein the patient has a melanoma tumor increasing in size in response to treatment with an anti-PD-1 or anti-PD-Ll blocking antibody; measuring whether the patients are alive or dead; measuring whether the melanoma has progressed; computing (a) a median duration from randomization or starting administering SX-682 to the time of patients’ death or (b) a median duration from randomization or starting administering SX-682 to the time when the patients’ cancer has progressed or death; wherein SX-682 increases the median duration in (a) and/or (b).

23. The method of claim 22, wherein the treatment furthering comprises administering a LAG-3 blocking antibody to the patients.

24. A method of increasing survival in patients with myelodysplastic syndrome, comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of SX-682 or a pharmaceutically suitable solvate or salt thereof; wherein the patients have myelodysplastic syndrome that has failed treatment with a hypomethylating agent; measuring whether the patients are alive or dead; computing a median duration from randomization or starting administering SX-682 to the time of patients’ death; wherein SX-682 increases the median duration.

25. A method of treating a patient with melanoma comprising, administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of SX-682 or a pharmaceutically suitable solvate or salt thereof; wherein the melanoma is unresectable or metastatic melanoma; wherein the melanoma was increasing in size in response to treatment with an anti-PD-1 or anti-PD-Ll blocking antibody; administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an anti-PD-1 or anti-PD-Ll blocking antibody.

26. The method of claim 25, furthering comprising administering a pharmaceutical composition comprising a LAG-3 blocking antibody.

27. A method of increasing survival in patients with cancer comprising, administering to the patients a treatment comprising a pharmaceutical composition comprising a therapeutically effective amount of a CXCR1 and/or CXCR2 antagonist or a pharmaceutically suitable solvate or salt thereof; measuring whether the patients are alive or dead; measuring whether the cancer has progressed; computing (a) a median duration from randomization or starting administering the CXCR1 and/or CXCR2 antagonist to the time of patients’ death or (b) a median duration from randomization or starting administering the CXCR1 and/or CXCR2 antagonist to the time when the patients’ cancer has progressed or death; wherein the CXCR1 and/or CXCR2 antagonist increases the median duration in (a) and/or (b).

28. The method of claim 27, where the CXCR1 and/or CXCR2 antagonist is selected from the group consisting of formula I, wherein R¹ and R² are independently selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein R³ is selected from — B(R⁴R³), — R⁶ — B(R⁴R⁵), R⁶, — C(O) — R⁶, — O — R⁶, — S(O)_y — R⁶ (wherein y=0, 1, or 2), — P(O) — (R⁴R⁵) and — N(R⁷R⁸); wherein R⁴ and R⁵ are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R⁴ and R³ together form a cyclic ester, or an acid anhydride (either mixed or symmetrical); wherein R⁶ is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; wherein R⁷ and R⁸ are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl and heterocyclylalkyl; R⁷ and R⁸ are both oxygen to form a nitro group; or R⁷ and R⁸ together with the nitrogen to which they are attached, form a heterocyclyl; and wherein R⁹ is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; or — B(R⁴R⁵), — BFs‘M⁺, — R⁶— B(R⁴R⁵), — R⁶— BF₃’M⁺, R⁶, — C(O)— R⁶, — O— R⁶, — S(O)_y— R⁶ (wherein y=0, 1, or 2), — P(O) — (R⁴R⁵) and — N(R⁷R⁸); or an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; wherein X¹ is carbon or nitrogen; X² is — S(O)_y — (wherein y=0, 1, or 2), — N(R⁹) — , or oxygen; and n is an integer between 0 and 8; or a pharmaceutically suitable solvate or salt thereof.

29. The method of Claim 27, wherein the CXCR1 and/or CXCR2 antagonist is selected from the group consisting of: SX-682 [PubChem Compound ID (CID) 90467234], SX-576 (CID 46897163), SX-517 (CID 46897162), navarixin (CID 9865554), danirixin (CID 24780598), ladarixin (CID 11372270), AZD5069 (CID 56645576), DF2755A (CID 45110932), SB225002 (CID 3854666), elubrixin (CID 10479502), SRT3190 (CID 59149652), vimnerixin (CID 71209600), SCH563705 (CID 10310100), SB265610 (CID 9841667), SRT3109 (CID 44602493), SB332235 (CID 9887803), reparixin, repertaxin, LY3041658, BMS-986253, and AZD8309 (CID 12073810), and a pharmaceutically acceptable form thereof.

30. A method for treating hematologic malignancies in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a CXCR1 and/or CXCR2 antagonist in combination with at least one other anti-cancer therapy.

31. The method of Claim 30, wherein the hematologic malignancy is selected from myelodysplastic syndromes (MDS), myelofibrosis (MF), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myeloid leukemia (CML); chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL ), and chronic myelomonocytic leukemia (CMML).

32. The method of Claim 30, wherein the CXCR1 and/or CXCR2 antagonist is selected from the group consisting of SX-682 [PubChem Compound ID (CID) 90467234], SX-576 (CID 46897163), SX-517 (CID 46897162), navarixin (CID 9865554), danirixin (CID 24780598), ladarixin (CID 11372270), AZD5069 (CID 56645576), DF2755A (CID 45110932), SB225002 (CID 3854666), elubrixin (CID 10479502), SRT3190 (CID 59149652), vimnerixin (CID 71209600), SCH563705 (CID 10310100), SB265610 (CID 9841667), SRT3109 (CID 44602493), SB332235 (CID 9887803), reparixin, repertaxin, LY3041658, BMS-986253, and AZD8309 (CID 12073810), and a pharmaceutically acceptable form thereof.

33. The method of Claim 30, wherein the anti-cancer therapy consists of one or more agents selected from BCL-2 inhibitors, hypomethylating agents (HMAs), Janus kinase inhibitors, chemotherapy, and radiation therapy.

34. The method of Claim 30, wherein the CXCR1 and/or CXCR2 antagonist is SX-682.

35. The method of Claim 33, wherein the BCL-2 inhibitor is selected from the group consisting of venetoclax (CID 49846579), navitoclax (CID 24978538), ABT-737 (CID 11228183), obatoclax (CID 11404337), AZD-4320 (CID 86661883), gossypol (3503), pelcitoclax (CID 76900653), S55746 (CID 71654876), TW-37 (CID 11455910), sabutoclax (CID 46236925), HA14-1 (CID 3549), A-385358 (CID 11556440), lisaftoclax (CID 137355972), apogossypolone (CID 135513044), BM-1197 (CID 60204010), BM-957 (CID 71456995), BCL-2-IN-4 (CID 163322037), BM-1074 (CID 56933431), BCL-2-IN-5 (CID 163322038), BCL-2-IN-6 (CID 163409068), BCL-2-IN-7 (CID 163409069), BDA-366 (CID 91826545), BCL-2-IN-2 (CID 146681 199), BCL-2-TN-8 (CID 163322290), and a pharmaceutically acceptable form thereof.

36. The method of Claim 33, wherein the hypomethylating agent is selected from the group consisting of decitabine, decitabine with cedazuridine, and azacytidine.

37. The method of Claim 33, wherein the Janus kinase inhibitor is selected from the group consisting of AT9283 (CID 135398495), AZD1480 (CID 16659841), baricitinib (CID 44205240), BMS-911543 (CID 50922691), fedratinib (CID 16722836), fdgotinib (GLPG0634, CID 49831257), gandotinib (LY2784544, CID 46213929), INCB039110 (itacitinib, CID 53380437), lestaurtinib (CID 126565), momelotinib (CYT0387, CID 25062766), NS-018 (ilginatinib, CID 46866319), pacritinib (SB1518, CID 46216796), peficitinib (ASP015K, CID 57928403), ruxolitinib (CID 25126798), tofacitinib (CID 9926791), INCB052793 CID 118467751), XL019 (CID 57990869), WP1066 (CID 11210478), TG101209 (CID 16722832), NVP-BSK805 (CID 46398810), AZ960 (CID 25099184), ZM-39923 (CID 3797), ropsacitinib (CID 130339268), SAR-20347 (CID 71727668), GDC-046 (CID 49839561), deucravacitinib (CID 134821691), WHI-P258 (CID 3798), brepocitinib (CID 118878093), ritlecitinib (CID 118115473), FM-381 (CID 122197584), oclacitinib (CID 44631938), decernotinib (CID 59422203), cerdulatinib (CID 44595079), AJ1-11095, zotiraciclib (CID 16739650), and a pharmaceutically acceptable form thereof.

38. The method of Claim 31, wherein the hematologic malignancy is MDS.

39. The method of Claim 31, wherein the hematologic malignancy is AML.

40. The method of Claim 31, wherein the hematologic malignancy is myelofibrosis.

41. The method of Claim 34, wherein the anti-cancer therapy is a hypomethylating agent.

42. The method of Claim 41, further comprising administering a BCL-2 inhibitor.

43. The method of Claim 34, wherein the anti-cancer therapy is a Janus kinase inhibitor.

44. The method of Claim 39, wherein the CXCR1 and/or CXCR2 antagonist is SX-682.

45. The method of Claim 44, wherein the anti-cancer therapy is a hypomethylating agent.

46. The method of Claim 44, further comprising administering a BCL2 inhibitor.

47. The method of Claim 46, wherein the BCL2 inhibitor is venetoclax.

48. The method of Claim 40, wherein the CXCR1 and/or CXCR2 antagonist is SX-682.

49. The method of Claim 48, wherein the anti-cancer therapy is a Janus kinase inhibitor.

50. The method of Claim 49, wherein the Janus kinase inhibitor is ruxolitinib.

51. The method of Claim 34, wherein the hematologic malignancy is multiple myeloma and the anti -cancer therapy is selected from the group consisting of daratumumab, bortezomib, carfilzomib, lenalidomide, prednisone and dexamethasone.