EP4637769A1 - Methods of treating advanced solid tumors - Google Patents

Abstract

Provided herein are methods of using a compound of Formula (I), or a pharmaceutically acceptable form thereof, for treating advanced solid tumors, including in combination with an VEGFR inhibitor.

Description

METHODS OF TREATING ADVANCED SOLID TUMORS

1. CROSS-REFERENCE

[0001] This application claims the benefit of priority from U.S. Provisional Application Nos. 63/476,604, filed December 21, 2022, 63/501,108, filed May 9, 2023, and 63/582,448, filed September 13, 2023, each of which is incorporated by reference in its entirety.

2. FIELD

[0002] Provided herein are methods of using a famesyltransferase inhibitor that is a compound of Formula (I):

Formula (I) or a pharmaceutically acceptable form thereof, in combination with a vascular endothelial growth factor receptor (VEGFR) inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzalintinib, or a pharmaceutically acceptable form thereof, for treating, preventing, or managing advanced solid tumors. Further provided herein are methods of using the compound of Formula (I), or a pharmaceutically acceptable form thereof, for mitigating, slowing the progression of, or overcoming tyrosine kinase inhibitor (TKI) resistance in a subject with an advanced solid tumor currently being treated with or previously treated with a TKI. Further provided herein are methods of using the compound of Formula (I), or a pharmaceutically acceptable form thereof, for preventing or delaying emergence of TKI resistance in a TKI-naive subject with an advanced solid tumor.

[0003] Also provided herein are methods of using the compound of Formula (I), or a pharmaceutically acceptable form thereof, for treating an advanced solid tumor with an HRAS amplification and/or HRAS overexpression, optionally in combination with an HRAS mutation. Also provided herein are methods of using the compound of Formula (I), or a pharmaceutically acceptable form thereof, for treating, preventing, or managing an advanced solid tumor with squamous histology and an HRAS amplification and/or HRA S overexpression, optionally in combination with an HRAS mutation. Also provided herein are methods of using the compound of Formula (I), or a pharmaceutically acceptable form thereof, for treating, preventing, or managing an advanced solid tumor with NRAS amplification and/or NRAS overexpression, optionally in combination with an NRAS mutation. In some aspects, the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with an NRAS or HRAS amplification.

3. BACKGROUND

[0004] Angiogenesis plays an important role in tumor progression as new blood vessels support tumor growth, supply oxygen and nutrients to proliferating tumor cells, and promote metastasis formation. Notable angiogenesis inhibitors target the vascular endothelial growth factor (VEGF) signaling pathway, and include inhibitors of the VEGF receptor (VEGF), primarily VEGFR-2. Receptor tyrosine kinases and VEGFRs mediate an array of signaling pathways in endothelial cells, such as the Ras/Raf, MEK/MAPK, phosphatidylinositol 3 ’-kinase (PI3K), Akt/PKB, and mTOR pathways, which are involved in both normal cellular function and pathologic processes such as oncogenesis, proliferation, migration, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

[0005] Inhibitors in this category have shown clinical efficacy in diverse tumor types, including renal cell cancer, thyroid cancer, hepatocellular cancer, and gastro-intestinal stromal tumors (GISTs). Several VEGFR inhibitor small molecule therapeutics have been approved for such cancers, and include cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzalintinib. VEGFR inhibitors can exhibit inhibitory activity against one or more VEGFR isoforms, and can be multi-targeted kinase inhibitors with activity against additional receptor tyrosine kinases, such as FGFR-1, -2, -3, or -4, PDGFR-a or -|3, KIT, RET, MET, AXL, ROS1, TYRO3, MER, TRKB, FLT-3, TIE-2, DDR2, TRKA, EPH2A, RAF-1, BRAF, BRAE V600E, SAPK2, PTK5, ABL, FGFR-1 or -3, Itk, Lek, c- Fms, or CSF-1R, or a combination thereof. The platelet-derived growth factor (PDGF) family is also involved in tumor angiogenesis. Certain anti -angiogenic kinase inhibitors are inhibitors of both VEGFR and PDGFR signaling. VEGFR inhibitors can be Type 1 kinase inhibitors, which recognize the active conformation of a kinase, for example, sunitinib, Type II inhibitors, which recognize the inactive conformation of a kinase, such as sorafenib, or covalent inhibitors, such as vandetanib.

[0006] Although anti -angiogenic VEGFR inhibitors have demonstrated clinical utility, preclinical and clinical studies have revealed resistance to these agents. Modulation of downstream signaling pathways by VEGFR inhibitors can induce resistance by driving development of other pathways for stimulating angiogenesis, such as AXL, MET, and PDGF/PDGFR, allowing for escape of cancer cells from VEGF/VEGFR blockade. In some examples, initial clinical response is followed by tumor progression due to acquired drug resistance, and in other examples, tumors have intrinsic resistance to the inhibitors. In addition, treatment with anti-angiogenics can lead to significant toxicities, including severe bleeding, disturbed wound healing, gastro-intestinal perforation, hypertension, fatigue, and QT prolongation.

[0007] Renal cell carcinoma (RCC) is the most common type of renal cancer, diagnosed in around 400,000 patients worldwide each year, and caused more than 180,000 deaths in 2020. Nearly a third of new diagnoses are in patients having unresectable, advanced, or metastatic disease at the time of diagnosis, and 20 to 30% of patients with localized tumors will eventually relapse after nephrectomy. The 5-year survival rate for patients with advanced RCC is 12%. The majority of RCC diagnoses (approx. 80% are in the category of clear cell renal cell carcinoma (ccRCC), which is a highly vascularized tumor type, most commonly due to inactivation of the Von Hippel-Lindau (VHL) gene. Deletion of VHL stabilizes hypoxiainducible factor alpha protein (HIFa) to drive the hypoxic transcriptional response, including induction of VEGF and PDGF2 that mediate tumor angiogenesis.

[0008] Anti-angiogenic TKIs such as sunitinib (which mainly targets the VEGFR and PDGFR) and axitinib (a specific VEGFR- 1, -2, and -3 inhibitor) demonstrated therapeutic benefit in patients with ccRCC by exploiting the dependency of ccRCC tumors on the vasculature for oxygen, nutrients, and growth factors. Sunitinib is the most commonly used TKI, but only 20 to 30% of patients response to initial treatment and almost all initial responders develop resistance within two years. The anti -angiogenic TKI strategy has also been applied successfully to other tumor types, such as thyroid cancer, hepatocellular carcinoma, and neuroendocrine tumors. However, as noted above, resistance to TKIs commonly develops, leading to disease progression. [0009] Anti -angiogenic VEGFR inhibitors have been approved for clinical use in a range of advanced solid tumors. Cabozantinib is an inhibitor of MET, VEGFR-1, -2, and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2, and has been approved for treatment of thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. Lenvantinib is an inhibitor of VEGFR-1, -2, and -3, as well as FGFR-1, -2, -3, and -4, PDGFR-a, KIT, and RET, and has been approved for treatment of certain types of thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, and endometrial carcinoma. Axitinib is an inhibitor of VEGFR-1, -2, and -3, and has been approved for treatment of renal cell carcinoma. Regorafenib is an inhibitor of VEGFR-1, -2, and -3, RET, KIT, PDGFR-a, PDGFR-P, FGFR-1 and -2, TIE-2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl, and CSF-1R, and has been approved for treatment of colorectal cancer, hepatocellular carcinoma, and GIST. Vandetanib is an inhibitor of VEGFR and EGFR family members, RET, BRK, TIE-2, and members of the EPH receptor and Src kinase families, and has been approved for treatment of thyroid cancer.

Pazopanib is an inhibitor of VEGFR-1, -2, and -3, PDGFR-a and -P, FGFR-1 and -3, Kit, Itk, Lek, and c-Fms, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Sunitinib is an inhibitor of VEGFR-1, -2, and -3, PDGFR-a and - , KIT, FLT3, CSF- 1R, and RET, and has been approved for treatment of renal cell carcinoma, GIST, and pancreatic neuroendocrine tumors. Sorafenib is an inhibitor of VEGFR-1, -2, and -3, PDGFR-P, c-CRAF, BRAF, mutant BRAF, KIT, FLT-3, RET, and RET/PTC, and has been approved for treatment of renal cell carcinoma, hepatocellular carcinoma, and thyroid carcinoma. Tivozanib is an inhibitor of VEGFR-1, -2, and -3, PDGFR-P, and c-kit, and has been approved for treatment of renal cell carcinoma. Zanzalintinib (e.g., zanzalintinib fumarate) is an inhibitor of tyrosine kinases such as MET, VEGFR, AXL, and MER. Fruquintinib (e.g., fruquintinib free base) is an inhibitor of VEGFR-1, -2, and -3, and has been approved for treatment of colorectal cancer, in particular, metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.

[0010] Farnesylation is important for the function of more than 140 proteins; however, the blockade of farnesylation does not always significantly affect protein function owing to compensatory mechanisms including prenylation by type 1 geranylgeranyl transferase as for Kirsten rat sarcoma virus oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS). Harvey rat sarcoma virus gene homolog (HRAS), however, cannot be geranylgeranylated, and its membrane localization and cellular function (e.g., oncogenic signaling) were suppressed by the selective nonpeptide famesyltransferase inhibitor (FTI), tipifamib, in in vitro and in vivo studies. HRAS-dependent tumors were shown to be highly sensitive to FTI treatment in PDX models of head and neck squamous cell carcinoma (HNSCC). In addition, tipifamib has shown a high response rate and favorable long-term outcome in patients with // M /-mutant HNSCC. In addition, tumor cell lines and mouse models with AT A-dependent tumors have been shown to be responsive to tipifamib with inhibition of angiogenesis as well as inhibition of cell and tumor growth and induction of apoptosis that correlates with inhibitions of famesylated targets, including NRAS (End et al., Cancer Res. 2001, 61, 131-137).

[0011] While mutations are important drivers of tumor biology, there are other factors, including overexpression of non-mutated oncogenic signaling proteins and the influence of the tumor microenvironment, that may regulate tumor growth and survival. For instance, approximately 30% of human tumors express an alteration in HRAS, KRAS, and/or NRAS. The Cancer Genome Atlas (TCGA) shows the overexpression of HRAS in 25% to 30% of HNSCC patients, indicating a potential dependence on HRAS that may be analogous to HRAS as a driver oncogene to a broader population of HNSCCs (‘cBioPortal for Cancer Genomics’ (2020), https://www.cbioportal.org/). A higher prevalence of oncogenic HRAS mutations and high levels of HRAS RNA and protein (e g., overexpression) were observed in multiple tumor types with squamous histology independent of tumor origination site (e.g., esophageal, head and neck, lung, and others), but such alterations occur in non-squamous tumor types as well. NRAS alterations are observed in a range of solid tumor types, such as melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, small cell lung carcinoma), breast cancer, ovarian cancer, pancreatic cancer (e.g., carcinoma or ductal adenocarcinoma), glioma, HNSCC, and thyroid cancer, and other tumor types such as leukemia and lymphoma.

[0012] There remains a need in the art for therapies and regimens to treat advanced solid tumors, including metastatic, relapsed, or refractory forms thereof. Similarly, there remains a need to reduce, avoid, delay, or overcome to the extent possible, drug resistance associated with existing therapies, including in the treatment of advanced solid tumors. The methods provided herein address one or more of the above-noted issues associated with treatments of advanced solid tumors.

4. SUMMARY

[0013] In one aspect is a method of treating an advanced solid tumor in a subject comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), and a VEGFR inhibitor.

[0014] In another aspect is a method of mitigating, slowing the progression of, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), and a VEGFR inhibitor.

[0015] In another aspect is a method of preventing or delaying emergence of TKI drug resistance in an advanced solid tumor in an TKI-naive subject, comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), and a VEGFR inhibitor.

[0016] In another aspect is a pharmaceutical composition comprising (a) the compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor.

[0017] In another aspect is a pharmaceutical kit comprising (a) the compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor.

[0018] In another aspect, provided herein is a pharmaceutical packaging comprising: (1) (a) the compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor; or (2) (a) a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent, and (b) a pharmaceutical composition comprising a VEGFR inhibitor, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0019] In another aspect is a method of treating an advanced solid tumor with an HRAS amplification and/or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same). In another aspect is a method of treating an advanced solid tumor with squamous histology and an HRAS amplification and/or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same).

[0020] In another aspect is a method of treating an advanced solid tumor with NRAS amplification and/or NRAS overexpression, optionally in combination with an NRAS mutation, in a subject comprising administered to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same).

[0021] In another aspect is a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable form thereof, for use in the methods described herein.

5. BRIEF DESCRIPTION OF THE FIGURES

[0022] FIG. 1 : Plot of tumor volume over time for treatment of A498 RCC CDX with the compound of Formula (I), axitinib, or the combination.

[0023] FIG. 2: Plot of tumor volume over time for treatment of KI- 12-0073 RCC PDX with the compound of Formula (I), axitinib, or the combination.

[0024] FIGS. 3A-3B: Combination treatment of the compound of Formula (I) and cabozantinib inhibited tumor growth in RCC CDX models. FIG. 3A: 786-0 CDX treated with the compound of Formula (I) (20 mg/kg, BID) and cabozantinib (20 mg/kg, QD) (lane 3) compared to treatment with the compound of Formula (I) (lane 1) or cabozantinib (lane 2) alone; FIG. 3B: A498 CDX treated with the compound of Formula (I) and cabozantinib (8 or 20 mg/kg, QD) (lanes 4 and 5, respectively) compared to treatment with the compound of Formula (I) alone (lane 1) or cabozantinib alone (lanes 2 and 3).

[0025] FIGS. 4A-4F: Combination of the compound of Formula (I) and cabozantinib inhibited tumor growth in RCC PDX and CDX models for the compound of Formula (I), cabozantinib, and the combination. Plot of tumor volume over time (FIG. 4A) and plot of % tumor volume change (FIG. 4B) in a KI- 12-0073 VHL-mutant ccRCC PDX model; plot of tumor volume over time (FIG. 4C) and plot of % tumor volume change (FIG. 4D) in a 786-0 CDX model; and plot of tumor volume over time (FIG. 4E) and plot of % tumor volume change (FIG. 4F) in a KI-0326 VHL-mutant ccRCC PDX model.

[0026] FIG. 5 : Plot of % tumor volume change at day 28 relative to day 0 for mice with 786-0 VHL-mutant CDX treated with the compound of Formula (I) (20 mg/kg, BID) and cabozantinib (4, 8, 10, or 12 mg/kg, QD), alone or in combination.

[0027] FIG. 6 : Plot of tumor volume over time for 786-0 CDX mice treated with cabozantinib, the compound of Formula (I), lenvatinib, lenvatinib plus everolimus, the compound of Formula (I) plus cabozantinib, and the compound of Formula (I) with lenvatinib. [0028] FIG. 7: Plot of tumor volume over time for 786-0 CDX mice treated with the compound of Formula (I), cabozantinib, axitinib, or the combination of the compound of Formula (I) and cabozantinib.

[0029] FIG. 8 : Immunoblot of cell signaling markers from 786-0 CDX cells following treatment with cabozantinib, the combination of Formula (I), or the combination.

[0030] FIGS. 9A-9C: Plots of % cell viability of HUVEC cells treated with varying concentrations of the compound of Formula (I) and varying concentrations of cabozantinib (FIG. 9A), axitinib (FIG. 9B), or lenvantinib (FIG. 9C).

[0031] FIGS. 10A-10F: Tube formation in HUVEC cells was inhibited by the combination of the compound of Formula (I) and axitinib or cabozantinib. FIG. 10A: vehicle; FIG. 10B: axitinib; FIG. IOC: cabozantinib; FIG. 10D: compound of Formula (I); FIG. 10E: axitinib and compound of Formula (I); FIG. 10F: cabozantinib and compound of Formula (I).

[0032] FIGS. 11A-11B: GFP imaging (FIG. 11A) and plots of number of master segments and total master segments length (FIG. 11B) of the effect on tube formation in GFP-labeled HUVEC cells treated with vehicle, the compound of Formula (I), cabozantinib, or the combination.

[0033] FIG. 12: Plot of cell death, as percentage normalized to baseline, over time, in HUVEC cells treated with the compound of Formula (I), cabozantinib, or the combination (with staurosporine as control).

[0034] FIG. 13: Immunoblot of HRAS levels in SCC9 and HSC3 cells following GTP pulldown.

[0035] FIG. 14: Plot of tumor volume over time for vehicle and compound of Formula (I) in an HN2594 (HRAS^WT'^hlgh) patient-derived xenograft model.

[0036] FIG. 15: Plot of tumor volume over time for vehicle and the compound of Formula (I) at varying doses in an HN2576 (HRAS^WT'^hlgh) HNSCC patient-derived xenograft model.

[0037] FIG. 16: Plot of tumor volume over time for vehicle and the compound of Formula (I) at varying doses in an HN2594 (HRAS^WT'^hlgh) HNSCC patient-derived xenograft model. 6. DETAILED DESCRIPTION

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0039] As used herein, and in the specification and the accompanying claims, the indefinite articles “a” and “an” and the definite article “the” include plural as well as single referents unless the context clearly indicates otherwise.

[0040] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percentages of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified dose, amount, or weight percent.

[0041] As used herein, a “pharmaceutically acceptable form” of compounds disclosed herein includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative), of compounds disclosed herein, which includes combinations thereof (e.g., a solvate of a pharmaceutically acceptable salt, or an isomer and/or isotopologue of a compound or of a solvate, salt, or solvate of salt of such compound). In some embodiments, a “pharmaceutically acceptable form” includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer (e.g., tautomer or stereoisomer), and isotopologue (i.e., isotopically labeled derivative) of a compound of Formula (I) as disclosed herein.

[0042] The term “isomer” as used herein comprises a stereoisomer or tautomer as defined herein. As used herein, the term “stereoisomers” is understood to mean 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 Zraws-isomers, also termed E- and Z- isomers; R- and S-enantiomers; diastereomers, (t/)-isomers and (/)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.

[0043] As used herein and unless otherwise indicated, the term “stereoisomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. In some embodiments is the stereoisomerically pure compound of Formula (I) (i.e., ( )-3-amino-3-(l-methyl-l/7-imidazol-5- yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-2²,4⁴-dicarbonitrile), substantially free of a compound of Formula (II) (i.e., (J?)-3-amino-3-(l-methyl-l//-imidazol-5-yl)-6-oxa- 2(4, 6)-quinolina- 1,4(1, 3)-dibenzenacy cl ohexaphane-2²,4⁴-dicarbonitrile). A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments provided herein, including mixtures thereof.

[0044] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (.S') configuration, or may be a mixture thereof. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0045] Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on a chiral stationary phase.

[0046] The use of stereoisomerically pure forms of such compounds, as well as the use of mixtures of those forms, are encompassed by the embodiments provided herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions provided herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag gmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0047] In certain embodiments, the pharmaceutically acceptable form is an atropisomer. Atropisomers are stereoisomers resulting from hindered rotation about a single bond axis where the rotational barrier is sufficient to allow for isolation of the rotational isomers.

[0048] 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 protonshift 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 can be reached. Tautomerizations (i.e., the reaction providing a tautomeric pair) can be catalyzed by acid or base, or can occur without the action or presence of an external agent. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamineimine; and enamine-(a different) enamine tautomerizations. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0049] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of a compound are within the scope of the compound as provided herein.

[0050] In certain embodiments, a compound described herein is in the form of a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” 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 salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail (see J. Pharm. Sci. (1977) 66:1-19). Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases, such as suitable inorganic and organic addition acids and bases.

[0051] In certain embodiments, the pharmaceutically acceptable form of a compound disclosed herein is exclusive of a salt form (/.<?., is not a salt), sometimes referred to as a free form or free base form, of a compound disclosed herein. In some embodiments are solvates of such free base forms.

[0052] In certain embodiments, a compound as described herein is in the form of a solvate (e.g., a hydrate). As used herein, the term “solvate” refers to a compound that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate.” In some embodiments, the solvate is a hydrate. Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 0.1, 0.25, 0.50, 0.75, or 1 solvent or water molecules, or 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 (or a pharmaceutically acceptable salt thereof) and solvates of the compound or of pharmaceutically acceptable salts thereof, as well as mixtures thereof.

[0053] The term “isotopologue” refers to isotopically-enriched compounds that are identical to those recited herein, but for the fact 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. 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. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, iSQ 32p 33p 33g, 34g, 35g, 36g, 18p, 35Q 36Q, _an(| 37 , _reSp_eCtf _veJy , each of which is alSO within the scope of this description. 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, 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. When the compounds are enriched with deuterium, the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds the naturally occurring deuterium- to-hydrogen ratio. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium. 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 compounds disclosed herein can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Isotopically- enriched compounds can generally be prepared using procedures known to persons of ordinary skill in the art by substituting an appropriate isotopically-enriched reagent for a non-isotopically- enriched reagent. An embodiment described herein may include an isotopologue form wherein the isotopologue is substituted on one or more atom members of said compound with one or more deuterium atoms in place of one or more hydrogen atoms. An embodiment described herein may include a compound wherein a carbon atom may have from 1 to 3 hydrogen atoms optionally replaced with deuterium.

[0054] As used herein, compounds disclosed herein include, but are not limited to, free base forms or pharmaceutically acceptable salts thereof, and solvates or hydrates thereof, and isotopologues (i.e., isotopically labeled derivative) of such compounds. In some embodiments are contemplated a free base or pharmaceutically acceptable salt of a compound of Formula (I), or a hydrate or solvate and/or isotopologue (i.e., isotopically labeled derivative) or analogous forms of a VEGFR inhibitor. [0055] It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.

[0056] As used herein, the term “pharmaceutically acceptable carrier, excipient, or diluent” means a carrier, excipient, or diluent approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a specific carrier for intravenously administered pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutically acceptable carrier, excipient or diluent 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. Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.

[0057] As used herein, the term “VEGFR inhibitor” means a small molecule compound that inhibits one or more VEGFR isoforms (e.g., VEGFR-1, VEGFR-2, VEGFR-3) with an ICso value of less than or equal to 500 nM in a biochemical or cellular assay. In some embodiments, the ICso is less than or equal to 250 nM, or 150 nM, or 100 nM, or 50 nM, or 30 nM, or 20 nM, or 10 nM, or 5 nM, or 1 nM. A VEGFR inhibitor includes pharmaceutically acceptable forms thereof. A VEGFR inhibitor may inhibit one or more VEGFR isoforms and also other targets besides the VEGF receptor, such as FGFR-1, -2, -3, or -4, PDGFR-a or - , KIT, RET, MET, AXL, ROS1, TYRO3, MER, TRKB, FLT-3, TIE-2, DDR2, TRKA, EPH2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, ABL, or CSF-1R, or a combination thereof. In some embodiments, a VEGFR inhibitor inhibits at least one VEGFR isoform and at least one of PDGFR-a and PDGFR-p. In some embodiments, a VEGFR inhibitor is a Type 1 kinase inhibitor, or a Type II inhibitor, or a covalent inhibitor. VEGFR inhibitors can be Type 1 kinase inhibitors, which recognize the active conformation of a kinase, for example, sunitinib, Type II inhibitors, which recognize the inactive conformation of a kinase, such as sorafenib, or covalent inhibitors, such as vandetanib. In some embodiments, the VEGFR inhibitor is approved by the U.S. Food and Drug Administration (FDA) or an analogous regulatory authority in another jurisdiction for treatment of renal cell carcinoma, thyroid cancer, hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor, soft tissue sarcoma, pancreatic neuroendocrine tumor, or endometrial carcinoma. In some embodiments, the advanced solid tumor is a squamous cell carcinoma, large cell carcinoma, or adenocarcinoma. Exemplary VEGFR inhibitors include, but are not limited to, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzalintinib. In some embodiments, the VEGFR inhibitor is cabozantinib, lenvantinib, axitinib, pazopanib, sunitinib, sorafenib, or tivozanib. In some embodiments, the VEGFR inhibitor is zanzalintinib. In some embodiments, the VEGFR inhibitor is fruquintinib. In some embodiments, the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib. In some embodiments the VEGFR inhibitor is cabozantinib. Herein, reference to a VEGFR inhibitor or common name thereof includes reference to pharmaceutically acceptable forms thereof. In some embodiments, the pharmaceutically acceptable form of the VEGFR inhibitor is cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzalintinib fumarate.

[0058] As used herein, the term “advanced solid tumor” has its general meaning in the art and refers to an abnormal mass of tissue that does not contain cysts or liquid areas, particularly a disease in tissues involving uncontrolled cell growth, which, in some cases, leads to metastasis. The advanced solid tumor can be benign or malignant, and can develop in muscles, bone, or organs of the body. In some embodiments, the advanced solid tumor is renal cell carcinoma (RCC) (such as clear cell RCC, papillary RCC, chromophobe RCC, advanced RCC, or unclassified RCC, and relapsed or refractory RCC, and RCC post-nephrectomy), thyroid cancer (such as medullary thyroid cancer, differentiated thyroid cancer, including locally advanced, metastatic, symptomatic, progressive, and/or radioactive iodine-refractory forms), hepatocellular carcinoma (including unresectable forms), colorectal cancer (such as metastatic colorectal cancer), gastrointestinal stromal tumor (GIST; including locally advanced, unresectable, or metastatic GIST, and progressive/intolerant to imatinib, e.g., imatinib mesylate), soft tissue sarcoma (including advanced soft tissue sarcoma), pancreatic neuroendocrine tumor (including progressive, differentiated, locally advanced, and metastatic forms), or endometrial carcinoma. In some embodiments, the advanced solid tumor is a squamous cell carcinoma, large cell carcinoma, or adenocarcinoma. In some embodiments, the advanced solid tumor is thyroid cancer, thyroid carcinoma, head and neck cancer, head and neck squamous cell carcinoma, urothelial cancer, salivary gland cancer, bladder cancer, breast cancer, ovarian cancer, endometrial carcinoma, brain cancer, gastric cancer, prostate cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, colorectal carcinoma, skin cancer, melanoma, liver cancer, pancreatic cancer, or pancreatic ductal cell carcinoma. In some embodiments, the advanced solid tumor is melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, small cell lung carcinoma), breast cancer, ovarian cancer, pancreatic cancer (e.g., carcinoma or ductal adenocarcinoma), glioma, HNSCC, or thyroid cancer.

[0059] In some embodiments, the advanced solid tumor with HRAS amplification and/or HRAS overexpression, optionally in combination with an HRAS mutation, is HNSCC. In some embodiments, the advanced solid tumor has an HRAS amplification. In some embodiments, the advanced solid tumor overexpresses HRAS. In some embodiments, the advanced solid tumor has squamous histology. In some embodiments, the advanced solid tumor has NRAS amplification and/or NRAS overexpression. In some aspects, the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with an NRAS or HRAS amplification. In some embodiments, the advanced solid tumor is metastatic, advanced, relapsed, unresectable, recurrent, or refractory, or a combination thereof.

[0060] As used herein, the term “HNSCC” refers to head and neck squamous cell carcinoma (HNSCC). Head and neck squamous cell carcinoma (HNSCC) is the seventh most common invasive carcinoma worldwide, with about 830,000 new diagnoses annually worldwide and 200,000 deaths per year worldwide, and about 54,000 new cases per year in the US. It is also the most common cancer in central Asia. HNSCC has 2 different etiologies and corresponding tumor types. The first subtype is associated with tobacco smoking and alcohol consumption, and unrelated to Human papillomavirus (HPV- or HPV negative). The second subtype is associated with infection with high-risk HPV (HPV+ or HPV positive). The second subtype is largely limited to oropharyngeal cancers. HPV+ tumors are distinct entity with better prognosis and may require differential treatments. Significant proportion of HNSCC, particularly oropharyngeal cancers, are caused by HPV infection. High-risk HPV subtype 16 accounts for 85% of all HPV+ tumors in HNSCC. P16 can be used as surrogate marker of HPV infection in HNSCC, particularly in the oropharynx. More accurate HPV testing is available and based on E6/E7 detection (Liang C, et al. Cancer Res. 2012;72:5004-5013).

[0061] As used herein and unless otherwise indicated, the terms “dysregulated HRAS" or "HRAS dysregulation,” refer to tumors that are dependent upon HRAS due to an oncogenic alteration in the RAS pathway, including, but not limited to, oncogenic HRAS mutations, oncogenic amplification of the HRAS gene, and oncogenic copy gain of the HRAS gene, or combinations thereof.

[0062] As used herein and unless otherwise indicated, the term “HRAS alteration” refers to tumors that are dependent upon a modified HRAS gene, such as a mutated HRAS gene or an amplified HRAS gene.

[0063] As used herein, the term “overexpression” refers to tumors that produce an elevated number of copies of a protein relative to a reference level. In some embodiments, the overexpressed protein is a wild-type protein. In some embodiments, the overexpressed protein is a mutant protein.

[0064] As used herein, the term “amplification” refers to an increase in the number of copies of a gene relative to a reference level. In some embodiments, the amplified gene is a wild-type gene. In some embodiments, the amplified gene is a mutant gene.

[0065] As used herein and unless otherwise indicated, the term “copy gain” refers to amplification of a gene between diploid (n=2) and the designated cutoff for “amplification” of the particular gene (for example, n = 4, 5, or 6). For example, the designated cutoff for amplified HRAS or NRAS gene may be n = 4 or 5 or 6, and thus copy gain of the HRAS or NRAS gene would cover n = 2 up to n = 4 or 5 or 6, respectively.

[0066] The terms “HRAS mutation” or “H-Ras mutation” as used herein refer to an activation mutation in an HRAS gene or H-Ras protein. An H-Ras mutation can refer to either a genetic alternation in the DNA sequence of the HRAS gene that results in activation of the corresponding H-Ras protein, or the alteration in the amino acid sequence of an H-Ras protein that results in its activation. Thus, the terms “HRAS mutation” or “H-Ras mutation” as used herein do not include an alternation in a HRAS gene that does not result in the activation of the H-Ras protein, or an alternation of an H-Ras protein sequence that does not lead to its activation. Accordingly, a sample or a subject that does not have any “H-Ras mutation” as used herein can still have a mutation in the HRAS gene that does not affect the activity of the H-Ras protein or a mutation that impairs the activity of the H-Ras protein, or have a mutation in an H-Ras protein that does not affect its activity or a mutation that impairs its activity. A sample or a subject can have multiple copies of the HRAS gene. A sample or a subject can also have both wild type and mutant H-Ras proteins. As used herein, a sample or a subject having an H-Ras mutation can also have a copy of wild type HRAS gene and/or the wild type H-Ras protein. A sample or a subject that is determined to “have wild type H-Ras,” as used herein, refers to the sample or subject that only has the wild type HRAS gene and the wild type H-Ras protein, and no H-Ras mutation. In some embodiments, the mutant HRAS gene encodes a mutant H-Ras protein, wherein the HRAS gene mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from a group consisting of G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes an amino acid substitution at a position of G12 in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is at a codon that encodes a G12R substitution in the mutant H-Ras protein. The HRAS gene mutation can be a mutation at a codon that encodes a G12C, G12D, G12A, G12V, G12S, G12F, G12R, or G12N, substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes a G12V substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes an amino acid substitution at a position of G13 in the mutant H-Ras protein. The HRAS gene mutation can be a mutation at a codon that encodes a G13A, G13C, G13V, G13D, GI 3R, G13S, G13N, or G13V, substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes a GI 3C substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes a GI 3R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes an amino acid substitution at a position of Q61 in the mutant H-Ras protein. The HRAS gene mutation can be a mutation at a codon that encodes a Q61E, Q61K, Q61H, Q61L, Q61P, or Q61R, substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes a Q61L substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes a Q61R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes an amino acid substitution at a position of Q22 in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes a Q22K or Q22T substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes an amino acid substitution at a position of KI 17 in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes a KI 17N or KI 17L substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes an amino acid substitution at a position of A146 in the mutant H-Ras protein. The HRAS gene mutation can be a mutation at a codon that encodes an A146V, A146T, or A146P substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation at a codon that encodes an A146P substitution in the mutant H-Ras protein. In some embodiments, the mutation can be a mutation at another codon that results in activation of H-Ras protein.

[0067] As used herein and unless otherwise indicated, the terms “dysregulated NRASR or “NRAS dysregulation,” refer to tumors that are dependent upon NRAS due to an oncogenic alteration in the RAS pathway, including, but not limited to, oncogenic NRAS mutations, oncogenic amplification of the NRAS gene, and oncogenic copy gain of the NRAS gene, or combinations thereof.

[0068] As used herein and unless otherwise indicated, the term “NRAS alteration” refers to tumors that are dependent upon a modified NRAS gene, such as a mutated NRAS gene or an amplified NRAS gene.

[0069] The terms “NRAS mutation” or “N-Ras mutation” as used herein refer to an activation mutation in an NRAS gene or N-Ras protein, respectively. An N-Ras mutation can refer to either a genetic alternation in the DNA sequence of the NRAS gene that results in activation of the corresponding N-Ras protein, or the alteration in the amino acid sequence of an N-Ras protein that results in its activation. Thus, the terms “NRAS mutation” or “N-Ras mutation” as used herein do not include an alternation in a NRAS gene that does not result in the activation of the N-Ras protein, or an alternation of an N-Ras protein sequence that does not lead to its activation. Accordingly, a sample or a subject that does not have any “N-Ras mutation” as used herein can still have a mutation in the NRAS gene that does not affect the activity of the N-Ras protein or a mutation that impairs the activity of the N-Ras protein, or have a mutation in an N-Ras protein that does not affect its activity or a mutation that impairs its activity. A sample or a subject can have multiple copies of the NRAS gene. A sample or a subject can also have both wild type and mutant N-Ras proteins. As used herein, a sample or a subject having an N-Ras mutation can also have a copy of wild type NRAS gene and/or the wild type N-Ras protein. A sample or a subject that is determined to “have wild type N-Ras,” as used herein, refers to the sample or subject that only has the wild type NRAS gene and the wild type N-Ras protein, and no N-Ras mutation. In some embodiments, the mutant NRAS gene encodes a mutant N-Ras protein, wherein the NRAS gene mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from a group consisting of G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant N-Ras protein. In some embodiments, the modification is a G12C, G12D, G12S, G12V, G12R, Q61H, Q61K, Q61L, Q61R, or A146T substitution.

[0070] Advanced solid tumors may be categorized using the tumor-node metastasis (TNM) staging system. See Spira, J. & Ettinger, D.S., N. Engl. J. Med., 350:382-(2004); Greene et al (eds). AJCC Cancer Staging Manual. 6^th edition. New York: Springer-Verlag, 2002:167-77; Sobin, L.H. & C.H. Wittekind (eds). International Union Against Cancer. TNM classification of malignant tumors. 6^th edition. New York: Wiley-Liss (2002). Accordingly, in some embodiments, the advanced solid tumor may be stratified into stages (e.g., occult, stage 0, stage I A, stage IB, stage II A, stage IIB, stage III A, stage IIIB, or stage IV).

[0071] As used herein and unless otherwise indicated, the terms “relapsed” or “recurrent” refer to a disorder, disease, or condition that responded to treatment (e.g., achieved a partial or complete response) then had progression. The treatment can include one or more lines of therapy. For example, “relapsed” HNSCC or “recurrent” HNSCC may refer to HNSCC that has been previously treated with one or more lines of therapy. In one embodiment, the relapsed HNSCC (or recurrent HNSCC) is HNSCC that has been previously treated with one, two, three or four lines of therapy. Tn one embodiment, the relapsed HNSCC (or recurrent HNSCC) is HNSCC that has been previously treated with two or more lines of treatment. In another example, the advanced solid tumor may have been treated with one or more TKIs prior to treatment. For example, the disorder, disease, or condition is RCC. In some embodiments, the RCC has been treated previously with one TKI, two TKIs, or three TKIs, or at least one TKI. [0072] As used herein and unless otherwise indicated, the term “refractory” refers to a disorder, disease, or condition that has not responded to prior treatment that can include one or more lines of therapy. In some embodiments, the disorder, disease, or condition has been previously treated one, two, three or four lines of therapy. In some embodiments, the disorder, disease, or condition has been previously treated with two or more lines of treatment, and has less than a complete response (CR) to most recent systemic therapy containing regimen. For example, the disorder, disease, or condition is HNSCC. For example, the disorder, disease, or condition is RCC. In some embodiments, the RCC has been treated previously with one TKI, two TKIs, or three TKIs, or at least one TKI.

[0073] As used herein, the terms “prevention” and “preventing” refer to obtaining beneficial or desired results including, but not limited, to prophylactic benefit. For prophylactic benefit, the compounds and pharmaceutical compositions disclosed herein can be administered according to the methods of treating as provided herein to a patient at risk of developing an advanced solid tumor, to a patient reporting one or more of the physiological symptoms of an advanced solid tumor, even though a diagnosis of the advanced solid tumor may not have been made, or to a patient in remission from an advanced solid tumor. In some instances, the prophylactic benefit can be reducing the risk of recurrence of the solid tumor after prior therapy, e.g., the risk of recurrent RCC following nephrectomy.

[0074] As used herein and unless otherwise indicated, the term “effective amount” in connection with a compound means an amount capable of treating, preventing, or managing a disorder, disease or condition, or symptoms thereof. In some embodiments, an effective amount of the compound of Formula (I) or a pharmaceutically acceptable form thereof, an effective amount of a VEGFR inhibitor, and/or an effective amount in the context of a combination thereof, can provide one or more benefits according to the methods of treating provided herein. For example, the effective amount of the compound of Formula (I) or a pharmaceutically acceptable form thereof, the effective amount of a VEGFR inhibitor, and/or the effective amount in the context of a combination thereof, can prevent, treat, and/or ameliorate one or more symptoms associated with an advanced solid tumor; can prevent or delay emergence of drug resistance in an advanced solid tumor; can mitigate, slow the progression of, or overcome drug resistance in an advanced solid tumor; can inhibit disease progression or tumor growth, reduce (in size, volume, or extent of metastasis) a primary tumor, relieve tumor-related symptoms, inhibit tumor-secreted factors, delay appearance of primary or secondary tumors, delay time to emergence of drug resistance, slow development of primary or secondary tumors, decrease occurrence of primary or secondary tumors, slow or decrease severity of secondary effects of disease, arrest tumor growth, produce regression of tumors, increase Time to Progression (TTP), increase Progression-Free Survival (PFS), increase Overall Survival (OS), increase overall response rate (ORR, e.g., complete response (CR) and partial response (PR) as determined by patient’s best tumor response), increase in CR rate, increase duration of response (DoR), or decrease time to response (TTR), or any combination thereof. CR, PR, DoR, and PFS may be assessed according to RECIST v. 1. 1 guidelines. In some instances, drug resistance is TKI resistance or VEGFR inhibitor resistance, or resistance to one or more specific VEGFR inhibitors.

[0075] In some embodiments, where a dose amount, a per day dose amount, or an amount in a pharmaceutical composition, pharmaceutical kit, or pharmaceutical packaging is described for a compound that is in a pharmaceutically acceptable salt and/or solvate form, the amount is expressed as the mass of the compound in its free form (e.g., free base) equivalent amount (i.e., the form of the compound exclusive of the salt and unsolvated). The amount is referred to as “free form equivalent” or “free base equivalent.”

[0076] As used herein, the terms “continuous dosing” and “continuous dosing schedule,” or “continuous” and “continuously” in the context of administering, refer to daily administration, such as once daily (QD), twice daily (BID), three times daily (TID), or four times a day (QID), of the compound of Formula (I) or a pharmaceutically acceptable form thereof, or of the VEGFR inhibitor, or a combination thereof, as disclosed herein.

[0077] As used herein, the terms “concurrently” or “concurrent,” in the context of an administration, refer to a co-admini strati on of two or more agents, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof and the VEGFR inhibitor, to a subject during a single day and conducted in close proximity in time of one another during that day. For example, in certain embodiments, the concurrent administration of two or more agents to a subject is conducted within 3 hours, 2 hours, 1 hour, 30 minutes, or simultaneously, during a single day.

[0078] As used herein, the terms “sequentially” or “sequential,” in the context of an administration, refer to a co-admini strati on of two or more agents, such as a compound of Formula (I), or pharmaceutically acceptable form thereof, and a VEGFR inhibitor, in a particular order, such as in a scheduled order, to a subject during a single day. For example, in certain embodiments, the concurrent administration of two agents to a subject, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof and the VEGFR inhibitor, is conducted such that one agent is first administered to the subject followed by administration of the second agent to the subject on the same day, with no specific time limit unless otherwise specified, during the same day.

[0079] As used herein, the terms “interval dosing” and “interval dosing schedule” refer to a schedule of administering an agent on certain days and not administering the agent on other days during the course of a treatment cycle, such as during a 28-day treatment cycle. For example, interval dosing of an agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof and the VEGFR inhibitor, includes scheduled periods of dosing of an agent followed by scheduled periods of a drug holiday of the agent during the course of a treatment cycle, such as during a 28-day treatment cycle. For example, interval dosing of an agent includes, but is not limited to, administering the agent only every other day, administering the agent continuously only every other week (e.g., one week on and one week off, or vice versa, such as continuously on days 1-7 and 15-21 of a 28-day treatment cycle, or days 8-14 and 22-28 of a 28-day treatment cycle), administering the agent continuously only for two consecutive weeks (e.g., two weeks on and two weeks off, or vice versa, such as continuously on days 1-14 of a 28-day treatment cycle, days 7-21 of a 28-day treatment cycle, or days 15-28 of a 28-day treatment cycle), or administering the agent continuously only for three consecutive weeks (e.g., three weeks on and one week off, or vice versa, such as continuously on days 1-21 of a 28-day treatment cycle, or days 7-28 of a 28-day treatment cycle), during a treatment cycle, such as during a 28-day treatment cycle, or for example administering the agent continuously for four consecutive weeks of a six-week treatment cycle. For example, in certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable form thereof and/or the VEGFR inhibitor, as disclosed herein, may each be administered independently only every other day, continuously only every other week, or continuously only for week 1, weeks 2, or weeks 3, during the course of a treatment cycle, such as during a 28-day treatment cycle.

[0080] A “treatment cycle” as understood herein is a given period of time during which one or more treatments are administered to a subject in need thereof. In some embodiments, a treatment cycle is a 28-day treatment cycle.

[0081] As used herein, the terms “delayed dosing,” “delayed dosing period,” and “delayed dosing schedule” refer to a period of time between administering an initial dose of a VEGFR inhibitor according to the methods described herein and subsequently administering an initial dose of the compound of Formula (I) or a pharmaceutically acceptable form thereof to the subject. In some embodiments, the subject is a VEGFR inhibitor-naive subject. In some embodiments, the subject has a relapsed or refractory advanced solid tumor. In some embodiments, the subject has a relapsed or refractory advanced solid tumor and was previously treated with a VEGFR inhibitor that was terminated prior to administration of the initial dose of the VEGFR inhibitor. For example, a delayed dosing period can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1.25 years, about 1.5 years, about 1.75 years, about 2 years, about 2.25 years, about 2.5 years, about 2.75 years, or about 3 years. For example, in certain embodiments, a delayed dosing period is no longer than about 12 months, about 9 months, about 6 months, about 3 months, about 2 months, about 8 weeks, about 6 weeks, about 5 weeks, about 1 month, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week. In some embodiments, the delayed dosing schedule comprises administering the compound of Formula (I) or a pharmaceutically acceptable form thereof on an interval dosing schedule after the delayed dosing period.

[0082] As used herein, the terms “dose escalation,” “dose escalation interval,” “escalation dosing,” “escalation dosing period,” and “escalation dosing schedule,” refer to a step-wise increase in the amount of an agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, administered to a subject over a period of time (sometimes referred to herein as a dose escalation period of time). In certain embodiments, the step-wise increase is an increase in the dose amount of the agent administered to the subject. In certain embodiments, the step-wise increase is an increase in the dose per day of the agent administered to the subject. In certain embodiments, the period of time over which completion of the step-wise increase occurs (the dose escalation period of time) is 2 days, 3 days, 7 days (1 week), 10 days, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments, a step-wise increase in the amount of the agent occurs (or is scheduled to occur) every 1 day, 2 days, 3 days, 7 days (1 week), 10 days, or 2 weeks, during the dose escalation period of time. In certain embodiments, the increase, such as the step-wise increase or the total increase, in the amount of the agent administered to the subject is a 10%-99%, such as 10%, 25%, 30%, 33%, 50%, 66%, 75%, 90%, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, or 4 fold increase in the amount of the agent administered to the subject, relative to an initial amount of the agent administered to the subject at the beginning of the dose escalation period of time, or relative to the prior step-wise increased amount of the agent administered to the subject during the dose escalation period of time. In certain embodiments, the final amount of an agent administered at the end of the dose escalation period of time is an effective amount of the agent, such as the effective amount of the agent administered during a treatment cycle, such as a 28-day treatment cycle. In certain embodiments, the amount of only one agent of a combination of agents administered to a subject is increased step-wise over the course of the dose escalation period of time while the amounts of remaining agents of the combination are held constant. For example, in certain embodiments, the amount of the compound of Formula (I) or a pharmaceutically acceptable form thereof administered to a subject is increased over the course of the dose escalation period of time while the amount of a VEGFR inhibitor administered to the subject is held constant. In certain embodiments, the amount of a first agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof, and the amount of a second agent, such as a VEGFR inhibitor, of a combination of agents administered to a subject are each independently increased step-wise over the course of the dose escalation period of time.

[0083] As used herein, the terms “dose reduction,” “dose reduction interval,” “reduced dosing,” “dose reduction period,” and “dose reduction schedule,” refer to a step-wise decrease in the amount of an agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, administered to a subject over a period of time (sometimes referred to herein as a dose reduction period of time). In certain embodiments, the step-wise decrease is a decrease in the dose amount of the agent administered to the subject. Tn certain embodiments, the step-wise decrease is a decrease in the dose per day of the agent administered to the subject. In certain embodiments, the period of time over which completion of the step- wise decrease occurs (the dose reduction period of time) is 2 days, 3 days, 7 days (1 week), 10 days, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments, a step-wise decrease in the amount of the agent occurs (or is scheduled to occur) every 1 day, 2 days, 3 days, 7 days (1 week), 10 days, or 2 weeks, during the dose reduction period of time. In certain embodiments, the decrease, such as the step-wise decrease or the total decrease, in the amount of the agent administered to the subject is a 10%-99%, such as 10%, 25%, 30%, 33%, 50%, 66%, 75%, 90%, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, or 4 fold decrease in the amount of the agent administered to the subject, relative to an initial amount of the agent administered to the subject at the beginning of the dose reduction period of time, or relative to the prior step-wise decreased amount of the agent administered to the subject during the dose reduction period of time. In certain embodiments, the final amount of an agent administered at the end of the dose reduction period of time is an effective amount of the agent, such as the effective amount of the agent administered during a treatment cycle, such as a 28-day treatment cycle. In certain embodiments, the amount of only one agent of a combination of agents administered to a subject is decreased step-wise over the course of the dose reduction period of time while the amounts of remaining agents of the combination are held constant. For example, in certain embodiments, the amount of the compound of Formula (I) or a pharmaceutically acceptable form thereof administered to a subject is decreased over the course of the dose reduction period of time while the amount of a VEGFR inhibitor administered to the subject is held constant. In certain embodiments, the amount of a first agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof, and the amount of a second agent, such as a VEGFR inhibitor, of a combination of agents administered to a subject are each independently decreased step-wise over the course of the dose reduction period of time.

[0084] As used herein, the term “loading dosing cycle” refers to administering a higher dose (sometimes referred to herein as a loading dose) of an agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, than the maintenance dose (e.g., the dose administered during a treatment cycle). In certain embodiments, the loading dosing cycle continues until a therapeutic steady-state concentration of the agent is achieved. In certain embodiments, a loading dose of an agent, such as the compound of Formula (T) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, can range from about 1.1 to about 10 times the dose of the agent administered during a treatment cycle. In certain embodiments, a loading dose per day of an agent, such as the compound of Formula (I) or a pharmaceutically acceptable form thereof or a VEGFR inhibitor, can range from about 1.1 to about 10 times the dose per day of the agent administered during a treatment cycle.

[0085] As used herein, the term “first-line therapy” refers to therapies for treating advanced solid tumors that include the use of a platinum-based chemotherapy (e.g., cisplatin, carboplatin, or oxaliplatin, and combinations such as cisplatin/5-FU or carboplatin/paclitaxel), and for HNSCC or other advanced solid tumors, optionally in combination with anti-EGFR antibody therapy (e.g., cetuximab, panitumumab, afatinib). In some embodiments, the first-line therapy options may be surgery, surgery followed by chemotherapy and radiation, or systemic therapy, such as pembrolizumab monotherapy, VEGFR monotherapy such as pazopanib or sunitinib monotherapy, pembrolizumab in combination with platinum-based chemotherapy, axitinib, or lenvatinib, nivolumab in combination with cabozantinib or ipilimumab, axitinib in combination with avelumab, or a combination of a TKI with an immune checkpoint inhibitor. In some embodiments, the first-line therapy is in the context of a patient having recurrent or metastatic HNSCC or an HNSCC patient only having received a localized or loco-regional disease therapy. First-line therapy of an advanced solid tumor is the first time a patient is treated after recurrence or diagnosis of unresectable or metastatic disease.

[0086] As used herein, the term “second-line therapy” refers to therapies for treating recurrent, unresectable, or metastatic advanced solid tumors, or where at least one prior treatment has failed to mitigate or reduce the severity of at least one symptom associated with the advanced solid tumor. For example, a second-line therapy can include the use of taxanes, methotrexate, and/or cetuximab for HNSCC. Second-line therapy of an advanced solid tumor is treatment after the patient has progressed on or after their first-line treatment.

[0087] As used herein and unless otherwise indicated, the term “subject” to which administration is contemplated, can be an animal, including, but not limited to, a human (e.g., a male or female of any age group, such as an adult subject or an adolescent subject); primates (e.g., cynomolgus monkeys, rhesus monkeys), and/or other mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, rodents, and/or birds (e.g., commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adolescent human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a patient, for example, a human patient. In some embodiments, the subject is a smoker. In some embodiments, the subject is a non-smoker. In some embodiments, the subject is a non-smoker who had previously been a smoker.

[0088] In some embodiments, the subject has, suffers from, has symptoms associated with, or is diagnosed as having, an advanced solid tumor. In some embodiments, the subject has or suffers from an advanced solid tumor. In some embodiments, the subject has symptoms associated with an advanced solid tumor. In some embodiments, the subject is diagnosed as having an advanced solid tumor. In some embodiments, the subject may be diagnosed as having an advanced solid tumor by one skilled in the art, for example, a physician, such as an oncologist. In some embodiments, the subject may be diagnosed as having an advanced solid tumor by analysis of plasma or a tissue biopsy from the subject, such as a tumor tissue biopsy. In some embodiments, the subject may be diagnosed as having an advanced solid tumor by one or more imaging tests (e.g., MRI, CT, PET, PET-CT, nuclear scan, ultrasound), optionally in combination with analysis of plasma or tumor tissue biopsy. In some embodiments, the subject may be diagnosed as having an advanced solid tumor by a blood analysis. In some embodiments, the analysis includes a circulating tumor DNA (ctDNA) analysis. In some embodiments, the subject is a previously treated an advanced solid tumor subject. In some embodiments, the subject previously received one treatment for the advanced solid tumor and the current methods comprise a “second line” treatment. In some embodiments, the subject previously received one treatment, relapsed or was refractory to the treatment, and then received a second treatment, such that the current methods comprise the “third line” treatment. In some embodiments, the subject is a VEGR inhibitor-naive subject. In some embodiments, the subject is a subject naive to treatment with one or more of cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzalintinib. In some embodiments, the subject has been treated previously with a TKI, such as one TKI or two TKIs or three TKIs in prior lines of therapy. In some embodiments, the subject has been treated previously with a VEGFR inhibitor, for example, the subject has been treated previously with a VEGFR inhibitor and is not currently being treated with a VEGFR inhibitor. In some embodiments, the subject has been treated previously with one or more of cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzalintinib, optionally wherein the subject is not currently being treated with the same agent. In some embodiments, the subject has been treated with chemotherapy (such as platinum chemotherapy, oxaliplatin chemotherapy, or irinotecan chemotherapy), or with radioactive iodine (for thyroid cancer), imitanib (for GIST), systemic therapy, anti-VEGF therapy, anti-EGFR therapy, surgery (e.g., resection, nephrectomy), or radiation, or in some instances, is intolerant to other therapies. In some embodiments, the subject is currently being treated with a VEGFR inhibitor, such as currently being treated with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib. In some embodiments, the advanced solid tumor is a drug resistant advanced solid tumor, such as a TKI-resistant or VEGFR inhibitor-resistant advanced solid tumor. In some embodiments, the subject is an advanced solid tumor subject in remission. In some embodiments, the an advanced solid tumor subject has a metastatic advanced solid tumor, relapsed advanced solid tumor, or refractory advanced solid tumor. In some embodiments, the subject has a metastatic advanced solid tumor. In some embodiments, the subject has a relapsed advanced solid tumor or a refractory advanced solid tumor.

[0089] As used herein and unless otherwise indicated, the terms “treat,” “treating,” “treatment,” and “ameliorating” are used interchangeably herein, and means an alleviation, in whole or in part, of a disorder, disease or condition, such as an advanced solid tumor, or one or more of the symptoms associated with a disorder, disease, or condition, such as an advanced solid tumor, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself, such as an advanced solid tumor. In some embodiments, these terms refer to an approach for obtaining beneficial or desired results including, but not limited to, a therapeutic benefit or a prophylactic benefit. A therapeutic benefit resulting from the methods of treatment provided herein includes the eradication or amelioration of the underlying disorder, such as an advanced solid tumor, being treated, the eradication or amelioration of one or more of the physiological signs or symptoms associated with the underlying disorder (e.g., an advanced solid tumor) such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disease or disorder (e.g., an advanced solid tumor). For example, when used in reference to a patient having an advanced solid tumor, therapeutic benefit refers to an action that reduces the severity of the advanced solid tumor, or retards or slows the progression of the advanced solid tumor, including (a) inhibiting the advanced solid tumor growth, or arresting development of the advanced solid tumor, and (b) causing regression of the advanced solid tumor, or delaying or minimizing one or more symptoms associated with the presence of the advanced solid tumor. A prophylactic benefit resulting from the methods of treatment provided herein includes delaying or eliminating the appearance of a disease or disorder (e.g., an advanced solid tumor), delaying or eliminating the onset of symptoms of a disease or disorder (e.g., an advanced solid tumor), slowing, halting, or reversing the progression of a disease or disorder (e. ., an advanced solid tumor), or any combination thereof.

[0090] In the context of an advanced solid tumor, treatment may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor- related symptoms, inhibition of tumor secreted factors, delayed appearance of primary or secondary tumors, delaying time to emergence of drug resistance, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time to Progression (TTP), increased Progression-Free Survival (PFS), increased Overall Survival (OS), among others. OS as used herein means the time from treatment onset until death from any cause. TTP, as used herein, means the time from treatment onset until tumor progression; TTP does not include deaths. In some embodiments, PFS means the time from treatment onset until tumor progression or death. In some embodiments, PFS means the time from the first dose of compound to the first occurrence of disease progression or death from any cause. In some embodiments, PFS rates are computed using the Kaplan-Meier estimates. Event-Free survival (EFS) means the time from treatment onset until any treatment failure, including disease progression, treatment discontinuation for any reason, or death. In some embodiments, overall response rate (ORR) means the percentage of patients who achieve a response. In some embodiments, ORR means the sum of the percentage of patients who achieve complete responses (CR) and partial responses (PR). In some embodiments, ORR means the percentage of patients whose best response is greater than or equal to a partial response (PR). In some embodiments, duration of response (DoR) is the time from achieving a response until relapse or disease progression. In some embodiments, DoR is the time from achieving a response is greater than or equal to a partial response (PR) until relapse or disease progression. In some embodiments, DoR is the time from the first documentation of a response until the first documentation of progressive disease or death. In some embodiments, DoR is the time from the first documentation of a response is greater than or equal to a partial response (PR) until to the first documentation of progressive disease or death. In some embodiments, time to response (TTR) means the time from the first dose of compound or combination of compounds (e.g., the compound of Formula (I) or a pharmaceutically acceptable form thereof and/or the VEGFR inhibitor) to the first documentation of a response. In some embodiments, TTR means the time from the first dose of compound or combination of compounds to the first documentation of a response is greater than or equal to a partial response (PR). In some embodiments, efficacy outcomes of the methods disclosed herein are determined according to applicable RECIST criteria (e.g., RECIST v.1.1). For example, in some embodiments, the RECIST criteria is applied to the evaluation of one or more Target Lesions (TL), including a quantitative assessment (the sum of the diameters of the lesions), to the evaluation of one or more NonTarget Lesions (NTL), including a qualitative assessment (present, absent or unequivocal progression), and evaluating the presence or not of a new lesion. In some embodiments, efficacy outcomes of the methods disclosed herein are determined relative to treatment of an advanced solid tumor with VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with VEGFR inhibitor monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib. In some embodiments, efficacy outcomes of the methods disclosed herein are determined relative to standard of care advanced solid tumor treatment, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof. In some embodiments, efficacy outcomes of the methods disclosed herein are determined relative to no treatment for an advanced solid tumor.

6.1 COMPOUNDS

[0091] In some embodiments, the methods of treating provided herein include administering (a) a compound of Formula (I) or a pharmaceutically acceptable form thereof and (b) a VEGFR inhibitor to a subject. The compound of Formula (I) or pharmaceutically acceptable form thereof is a farnesyltransferase inhibitor, and is a selective farnesyltransferase inhibitor that selectively inhibits famesyltransferase with greater potency (lower ICso value) relative to the level of inhibition of geranylgeranyl transferase type-1.

[0092] In some embodiments is a compound of Formula (I), which can be named (S)-3- amino-3-(l -methyl- lZf-imidazol-5-yl)-6-oxa-2(4,6)-quinolina- 1,4(1, 3)- dibenzenacyclohexaphane-2²,4⁴-dicarbonitrile, and which has the structure:

Formula (I).

[0093] In some embodiments is a compound of Formula (II), which can be named (R)-3- amino-3 -( 1 -methyl- 1 //-i mi dazol -5-yl )-6-oxa-2(4,6)-quinol i na- 1 ,4( 1 ,3 )- dibenzenacyclohexaphane-2²,4⁴-dicarbonitrile, and which has the structure:

Formula (II).

[0094] In some embodiments is a compound of Formula (III), which can be named (3-amino- 3-(l-methyl-177-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-2²,4⁴- di carbonitrile, and which has the structure: Formula (III).

Compounds useful as described herein include the compounds of Formula (I), (II), and (III), and pharmaceutically acceptable forms thereof. [0095] The synthesis and certain uses, inhibition activities, and metabolic stabilities, of the compounds of Formula (I), (II), and (III), and pharmaceutically acceptable forms thereof, as provided herein, are described in International Patent Application No. PCT/US2022/80565, the entirety of which is incorporated herein by reference, and illustrated in Example 1 disclosed herein. In some embodiments, the compound for use in the methods of treating provided herein is a compound of Formula (I), or a pharmaceutically acceptable form thereof. Throughout the instant application, disclosures involving the use of the compound of Formula (I), or pharmaceutically acceptable form thereof, such disclosures equally apply to the compound of Formula (II), or pharmaceutically acceptable form thereof, or the compound of Formula (III), or pharmaceutically acceptable form thereof.

[0096] In certain embodiments, the use of the farnesyltransferase inhibitor, in particular the compound of Formula (I), (II), or (III), and the pharmaceutically acceptable form thereof, is applicable to the farnesyltransferase inhibitor tipifarnib.

[0097] In some embodiments, the VEGFR inhibitor used as provided herein is cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, and zanzalintinib, which list includes pharmaceutically acceptable forms thereof. In some embodiments, the VEGFR inhibitor used as provided herein is cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzalintinib fumarate. In some embodiments, the VEGFR inhibitor used as provided herein is a pharmacologically-active metabolite of the VEGFR inhibitor as described herein. Such metabolites include, for example, regorafenib M-2 and M-5 metabolites and the des-methyl metabolite of vandetanib.

6.2 PHARMACEUTICAL COMPOSITIONS, KITS, AND PACKAGING

[0098] In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, provided herein is a pharmaceutical composition comprising a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, or a pharmaceutically acceptable form thereof, such as cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzalintinib fumarate, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable form thereof, a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, or cabozantinib (S)- malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzalintinib fumarate, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the pharmaceutical composition comprises the compound of Formula (I), or pharmaceutically acceptable form thereof, and cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, or cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzalintinib fumarate, and the pharmaceutically acceptable carrier, diluent, or excipient.

[0099] In some embodiments, provided herein is a pharmaceutical kit comprising (a) a compound of Formula (I), or a pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor. In some embodiments, the pharmaceutical kit further comprises instructions that detail a dosing regimen for administering each compound for one or more treatment cycles. In some embodiments, the pharmaceutical kit further comprises a color-coded system that details a dosing regimen for administering each compound independently for one or more treatment cycles. In some embodiments, the pharmaceutical kit is a pharmaceutical packaging.

[00100] In some embodiments, the pharmaceutical kit or the pharmaceutical packaging further comprises instructions for administering the contents of the kit to a subject having an advanced solid tumor. For example, in some embodiments, the instructions may detail the dosing regimen for administering the compound of Formula (I), or a pharmaceutically acceptable form thereof, such as administering once or twice per day, or for example, during a 28-day treatment cycle, such as administering once or twice per day on days 1-7, on days 1-7 and 15-21, on days 1-21, or on each day of a 28-day treatment cycle, and detailing the dosing regimen for administering the VEGFR inhibitor, such as administering once or twice per day, or for example, during a treatment cycle, such as administering once or twice per day on each day of a treatment cycle such as a 28-day treatment cycle, or such as once or twice daily during weeks 1-4 of a 6-week treatment cycle. In some embodiments, the instructions for administering each agent may be color-coded, with different colors for instructions for each agent. In some embodiments, the instructions may include details for an escalation dosing period, a reduction dosing period, or a loading dosing period, optionally color-coded, for administering the compound of Formula (I) or pharmaceutically acceptable form thereof. For example, in some embodiments, the instructions may be color-coded, detailing an escalation dosing period or reduction dosing period for administering the VEGFR inhibitor.

[00101] In some embodiments, the pharmaceutical composition, or the pharmaceutical kit or pharmaceutical packaging comprising the same, comprises an effective amount of the compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the pharmaceutical composition, or the pharmaceutical kit or pharmaceutical packaging comprising the same, comprises 0.5-2400 mg of the compound of Formula (I), or pharmaceutically acceptable form thereof, such as an amount selected from the group consisting of 0.5-2.5 mg, 0.5-5 mg, 0.5-10 mg, 0.5-25 mg, 0.5-50 mg, 0.5-75 mg, 0.5-100 mg, 0.5-300 mg, 0.5-600 mg, 0.5-1200 mg, 1-5 mg, 1-10 mg, 1-25 mg, 1-50 mg, 1-75 mg, 1-100 mg, 1-300 mg, 1-600 mg, 1-1200 mg, 1-2400 mg, 20-100 mg, 40-75 mg, 50-75 mg, 50-100 mg, 50-150 mg, 75-100 mg, 100-200 mg, 125-200 mg, 150-300 mg, 200-250 mg, 200-400 mg, 300-600 mg, 250-500 mg, 400-600 mg, 500-750 mg, 600-900 mg, 700-100 mg, 650-1000 mg, 800-1200 mg, 900-1500 mg, 1000-1600 mg, 1000- 2000 mg, 1200-1600 mg, 1500-2000 mg, 1500-2400 mg, 1800-2400 mg, and 2000-2400 mg of the compound of Formula (I), or pharmaceutically acceptable form thereof. In some embodiments, the pharmaceutical composition, or the pharmaceutical kit or pharmaceutical packaging comprising the same, comprises about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, and about 2400 mg of the compound of Formula (I), or a pharmaceutically acceptable form thereof. [00102] In some embodiments, the pharmaceutical composition, or the pharmaceutical kit or pharmaceutical packaging comprising the same, comprises 0.2 to 1500 mg of the VEGFR inhibitor, such as an amount selected from 0.5-10 mg, 2-15 mg, 10-30 mg, 10-40 mg, 10-240 mg, 20-50 mg, 20-240 mg, 30-50 mg, 35-70 mg, 40-80 mg, 60-100 mg, 80-120 mg, 80-160 mg, 80-240 mg, 160-250 mg, 160-300 mg, 100-600 mg, or 200-1000 mg of the VEGFR inhibitor. In some embodiments, the pharmaceutical composition, or the pharmaceutical kit or pharmaceutical packaging comprising the same, comprises 0.89 mg, 1 mg, 1.34 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 12.5 mg, 14 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, 30 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg,

165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg,

220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg,

275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg of the

VEGFR inhibitor. In some embodiments, the VEGFR inhibitor is in the form of a salt and/or solvate, in which case amounts of the VEGFR inhibitor are expressed as free base equivalent amounts.

[00103] In some embodiments, the pharmaceutical composition, kit, or packaging comprises (Table 1): Table 1

[00104J In some embodiments, the pharmaceutical composition, or the pharmaceutical kit or pharmaceutical packaging comprising the same, comprising the VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is formulated in an oral formulation, such as tablet or capsule. In some embodiments, the pharmaceutical composition comprising the VEGFR inhibitor further comprises an excipient. In some embodiments, the excipient is selected from the group consisting of mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, lactose anhydrous, lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, calcium carbonate, mannitol, talc, povidone, calcium hydrogen phosphate dihydrate, crospovidone, corn starch, and sodium starch glycolate. In some embodiments, tablets comprise a film coating and capsules comprise a capsule shell. In some embodiments, the VEGFR inhibitor is formulated with excipients selected from (Table 2):

Table 2

[00105] In some embodiments, the effective amounts of the compound of Formula (I), or pharmaceutically acceptable form thereof, and for combination methods with a VEGFR inhibitor, the VEGFR inhibitor, included in the pharmaceutical compositions, pharmaceutical kits, or pharmaceutical packaging provided herein, are effective for mitigating or ameliorating one or more symptoms of an advanced solid tumor, or are effective for treating, retarding progression, delaying the time to emergence of drug resistance in an advanced solid tumor relative to: (a) for combination methods, treatment of an advanced solid tumor with VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with VEGFR inhibitor monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib; (b) relative to standard of care treatment for an advanced solid tumor, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof; or (c) relative to no treatment for an advanced solid tumor. In some embodiments, effective amounts of the compound of Formula (I), or pharmaceutically acceptable form thereof, or for VEGFR inhibitor combinations the VEGFR inhibitor, or combination thereof, include amounts effective for: reducing or delaying the risk of relapse of an advanced solid tumor, increasing PFS and/or OS, increasing PFS, increasing OS, increasing ORR, increasing, CR, increasing TTP, increasing PFS, increasing EFS, or increasing DoS, or combinations thereof, relative to: (a) for combination methods with a VEGFR inhibitor, treatment of an advanced solid tumor with VEGFR inhibitor monotherapy such as relative to treatment of an advanced solid tumor with VEGFR inhibitor monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib; (b) relative to standard of care treatment for an advanced solid tumor, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof; or (c) relative to no treatment for an advanced solid tumor. In some embodiments, the effective amount of the compound of Formula (I), or pharmaceutically acceptable form thereof, and/or the VEGFR inhibitor, in the pharmaceutical composition, or the pharmaceutical kit or pharmaceutical packaging comprising the same, can depend on absorption, tissue distribution, metabolism, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art. The effective amount may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans.

[00106] In some embodiments, the pharmaceutical compositions are provided for administration to a subject in unit dosage forms, such as tablets, capsules, microcapsules, pills, powders, granules, troches, suppositories, injections, syrups, patches, creams, lotions, ointments, gels, sprays, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions provided herein are in the form of a tablet. In some embodiments, the pharmaceutical compositions provided herein are in the form of a capsule. In some embodiments, the capsules contain a compound provided herein without an additional carrier, excipient or vehicle. Typically, the compound disclosed herein is formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999). In some embodiments, the pharmaceutical compositions are formulated and administered in unit dosage forms or multiple dosage forms. Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. Unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dose forms include ampules and syringes and individually packaged tablets or capsules. Unit dose forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses which are not segregated in packaging.

[00107] The compounds and pharmaceutical compositions provided herein may be administered at once, or may be divided into a number of smaller doses, to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease (e.g., an advanced solid tumor) being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed pharmaceutical compositions.

[00108] The compounds and pharmaceutical compositions are intended to be administered by a suitable route, including but not limited to orally, parenterally, rectally, topically and locally. For oral administration, capsules and tablets can be formulated. The pharmaceutical compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration. In one embodiment, when administered orally, a compound provided herein is administered with a meal and water. In another embodiment, the compound provided herein is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a solution or a suspension. In one embodiment, a compound provided herein is administered when the subject is fed. In one embodiment, a compound provided herein is administered when the subject is fed with high-fat and/or high-calorie food. In one embodiment, a compound provided herein is administered when the subject is fed with FDA-standard high-fat high-calorie breakfast. In one embodiment, a compound provided herein is administered when the subject is fasted. In one embodiment, a compound provided herein is administered after the subject has an at least 8-hour overnight fast. In one embodiment, a compound provided herein is administered with or without food.

[00109] The compounds and pharmaceutical compositions provided herein can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the healthcare practitioner, and can depend in-part upon the site of the medical condition. Depending on the state of the disease to be treated and the subject’s condition, a composition may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compound of Formula (I), or pharmaceutically acceptable form thereof, and/or the VEGFR inhibitor, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

[00110] In some embodiments, the pharmaceutical compositions provided herein can be delayed or prolonged pharmacokinetics by proper formulation. For example, in some embodiments, the pharmaceutical compositions provided herein delay or prolong dissolution of compound of Formula (I), or pharmaceutically acceptable form thereof, or of the VEGFR inhibitor, or of a combination thereof. For example, a slowly soluble pellet of the compound provided herein can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Parenteral preparations can be made long-acting by dissolving or suspending a compound as provided herein in oily or emulsified vehicles that allow it to disperse slowly in the serum.

6.3 METHODS, DOSING REGIMENS AND SCHEDULES

6.3.1 THERAPEUTIC METHODS

[00111] In some embodiments, provided herein is a method of treating an advanced solid tumor in a subject comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), and a VEGFR inhibitor. In some embodiments, provided herein is a method of treating an advanced solid tumor in a subject comprising administering to the subject an effective amount of the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), and an effective amount of a VEGFR inhibitor. [00112] In another aspect is a method of mitigating, slowing the progression of, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), and a VEGFR inhibitor. In another aspect is a method of mitigating, slowing the progression of, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject an effective amount of the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), and an effective amount of a VEGFR inhibitor. In some embodiments, the drug resistance is TKI resistance. In some embodiments, the drug resistance is TKI resistance in an advanced solid tumor subject currently or previously treated with a TKI. In some embodiments, the drug resistance is VEGFR inhibitor resistance, for example, in a TKI-resistant or VEGFR inhibitor-resistant advanced solid tumor, wherein subject is currently being treated or was previously treated with a TKI or a VEGFR inhibitor.

[00113] In some embodiments, provided herein is a method of preventing or delaying emergence of TKI resistance in an advanced solid tumor in a TKI-naive subject, comprising administering to the subject a compound of Formula (I), or pharmaceutically acceptable form thereof, and a VEGFR inhibitor. In some embodiments, provided herein is a method of preventing or delaying emergence of TKI resistance in an advanced solid tumor in a TKI-naive subject, comprising administering to the subject an effective amount of the compound of Formula (I), or pharmaceutically acceptable form thereof, and an effective amount of a VEGFR inhibitor. In some embodiments, the TKI resistance is TKI resistance in a TKI-naive or VEGFR inhibitor-naive advanced solid tumor.

[00114] In some embodiments, provided herein is a method of treating an advanced solid tumor with an HRAS amplification and/or HRAS overexpression, optionally in combination the an HRAS mutation, in a subject comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, provided herein is a method of treating an advanced solid tumor with squamous histology and an HRAS amplification and/or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, provided herein is a method of treating an advanced solid tumor with squamous histology and an HRAS amplification and/or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject comprising administering to the subject an effective amount of the compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, such method comprise administering the compound of Formula (I), or a pharmaceutically acceptable form thereof, as the only antitumor agent in the treatment regimen, e.g., as monotherapy. In some aspects, the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with an HRAS amplification.

[00115] In some embodiments, provided herein is a method of treating an advanced solid tumor with squamous histology and an NRAS amplification and/or NRAS overexpression, optionally in combination with an NRAS mutation, in a subject comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, provided herein is a method of treating an advanced solid tumor with squamous histology and an /W amplification and/or NRAS overexpression, optionally in combination with an NRAS mutation, in a subject comprising administering to the subject an effective amount of the compound of Formula (I), or a pharmaceutically acceptable form thereof. In some embodiments, such method comprise administering the compound of Formula (I), or a pharmaceutically acceptable form thereof, as the only antitumor agent in the treatment regimen, e.g., as monotherapy. In some aspects, the advanced solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with an NRAS amplification.

[00116] In some embodiments, the subject treated according to the methods of treating provided herein has, suffers from, has symptoms associated with, or is diagnosed as having, an advanced solid tumor. In some embodiments, the subject is a TKI-naive subject, or is a VEGFR inhibitor-naive subject. In some embodiments, the subject is a relapsed or refractory advanced solid tumor subject previously, but not currently being, treated with a TKI or with a VEGFR inhibitor.

[00117] In some embodiments, the subject to whom the compounds are administered in the methods provided herein has, suffers from, has symptoms associated with, or is diagnosed as having, an advanced solid tumor. In some embodiments, the subject has or suffers from an advanced solid tumor. In some embodiments, the subject has symptoms associated with an advanced solid tumor. In some embodiments, the subject is diagnosed as having an advanced solid tumor. In some embodiments, the subject is a previously treated advanced solid tumor subject. In some embodiments, the subject is a TKI-naive subject, or is a VEGFR inhibitor-naive subject. In some embodiments, the subject is naive to treatment with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib. In some embodiments, the subject has been treated previously with a TKI, or with a VEGFR inhibitor, or with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib or zanzalintinib. In some embodiments, the subject has been treated previously with cabozantinib. In some embodiments, the subject is an advanced solid tumor subject in remission. In some embodiments, the advanced solid tumor subject is a TKI-resistant advanced solid tumor subject, such as VEGFR inhibitor-resistant advanced solid tumor subject. In some embodiments, the subject is a mammal, for example, a human, such as a human having, suffering from, having symptoms associated with, or diagnosed as having, an advanced solid tumor.

[00118] In some embodiments, the VEGFR inhibitor is cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib. In some embodiments, the VEGFR inhibitor is in the form of cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzalintinib fumarate. In some embodiments, the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib. In some embodiments, the VEGFR inhibitor is cabozantinib, such as cabozantinib (S)-malate. In some embodiments, the VEGFR inhibitor is zanzalintinib, such as zanzalintinib fumarate. In some embodiments, the VEGFR inhibitor is fruquintinib such as fruquintinib free base.

[00119] In some embodiments, the advanced solid tumor is a metastatic solid tumor, a recurrent solid tumor, an unresectable solid tumor, a relapsed solid tumor, or a refractory solid tumor. In some embodiments, the advanced solid tumor is a metastatic solid tumor. In some embodiments, the advanced solid tumor is an unresectable solid tumor. In some embodiments, the advanced solid tumor is a relapsed solid tumor. In some embodiments, the advanced solid tumor is a refractory solid tumor.

[00120] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable form thereof, that is administered according to the methods provided herein inhibits farnesylation of a protein, for example inhibits famesylation of a farnesylati on-dependent protein. Without being bound by any one theory, in some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, administered according to the methods provided herein inhibits famesylation of one or more farnesylation-dependent proteins selected from RhoB, RhoE, and Lamin B, or a combination thereof. In some embodiments, the farnesylation- dependent protein is a dysregulated farnesylation-dependent protein.

[00121] In some embodiments, inhibition of the famesylation of the farnesylation-dependent protein, according to the methods of treating provided herein, occurs in a cell, such as in a cell of the subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell a human cell. Without being bound by any one theory, in some embodiments, inhibiting famesylation of the farnesylation-dependent protein by administering a compound of Formula (I), or pharmaceutically acceptable form thereof, in combination with a VEGFR inhibitor, provides a therapeutic benefit, such as a synergistic benefit, to the subject: (a) relative to, for combinations with a VEGFR inhibitor, to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor therapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib; (b) relative to standard of care treatment for an advanced solid tumor, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof; or (c) relative to no treatment for an advanced solid tumor. For example, in some embodiments, the therapeutic benefit, such as a synergistic benefit, provided by administering a compound of Formula (I), or pharmaceutically acceptable form thereof, according to the methods provided herein, includes, but is not limited to, improving efficacy (e.g., suppressing tumor growth and inducing tumor regression); increasing PFS and/or OS, such as increasing PFS by 10-99%, such as by 10%, 25%, 50%, 80%, 90% 95%, or 99%, 2 fold, 3 fold, or 4 fold, or increasing OS by 10- 99%, such as by 10%, 25%, 50%, 80%, 90% 95%, or 99%, 2 fold, 3 fold, or 4 fold; for combinations with a VEGFR inhibitor, reducing the effective amount of the TKI or VEGFR inhibitor, reducing TKI- or VEGFR inhibitor-associated toxicity, such as reducing the severity, incidence, or risk of a toxicity selected from severe bleeding, disturbed wound healing, gastro- intestinal perforation, hypertension, fatigue, arterial and venous thromboembolic events, hemorrhage, cardiovascular events, cardiac failure, hepatotoxicity, and QT prolongation, or a combination thereof; or delaying emergence of TKI or VEGFR inhibitor resistance, such as unexpectedly delaying emergence of TKI or VEGFR inhibitor resistance, relative to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib; for all methods, relative to standard of care advanced solid tumor treatment, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof; or for all methods, relative to no treatment for an advanced solid tumor. In some embodiments, efficacy outcomes are determined according to applicable RECIST criteria (e.g., RECIST v. 1.1). In some embodiments, administering a compound of Formula (I), or pharmaceutically acceptable form thereof, in combination with a VEGFR inhibitor according to the methods disclosed herein can provide a therapeutic benefit, including a synergistic benefit, to the treated subject, relative to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzlintanib. In some embodiments, administering a compound of Formula (I), or pharmaceutically acceptable form thereof, according to the methods disclosed herein, can provide a therapeutic benefit, including a synergistic benefit, to the treated subject, relative to standard of care advanced solid tumor treatment, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof. In some embodiments, administering a compound of Formula (I), or pharmaceutically acceptable form thereof, according to the methods disclosed herein can provide a therapeutic benefit, including a synergistic benefit, to the treated subject, relative to no treatment for an advanced solid tumor. In some embodiments, the inhibition of the farnesyltransferase present in the cell takes place in a subject suffering from an advanced solid tumor.

[00122] In some embodiments, the methods provided herein provide one or more therapeutic benefits to the subject, (a) for the combination with a VEGFR inhibitor, relative to treatment of an advanced solid tumor with TKI or VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with TKI or VEGFR monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib; (b) relative to standard of care advanced solid tumor treatment, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof; or (c) relative to no treatment for an advanced solid tumor. For example, in some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes a delay the time to emergence of drug resistance or progression of drug resistance, for example, TKI drug resistance or VEGFR inhibitor resistance, and in some embodiments, the delay is an unexpected delay. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes a delay, halt, or prevent progression of an advanced solid tumor. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes a delay, halt, or prevent advanced solid tumor growth. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes a reduction of a primary advanced solid tumor, such as a reduction in the size, volume, or appearance of a primary advanced solid tumor or a reduction in the extent of metastasis from a primary advanced solid tumor. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes providing relief of advanced solid tumor-related symptoms. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes inhibiting advanced solid tumor-secreted factors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes delaying the appearance of primary or secondary solid tumors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes slowing the development of primary or secondary solid tumors, such as development to an advanced stage of the solid tumors. For example, in certain embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes slowing the progression to an advanced stage solid tumor and/or to metastasis of primary or secondary solid tumors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes decreasing the occurrence of primary or secondary solid tumors. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes slowing or decreasing the severity of secondary effects associated with an advanced solid tumor. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes the slowing, stopping (arresting), or reducing advanced solid tumor growth and/or reducing solid tumors. For example, in some embodiments, the methods provided herein reduce solid tumor volume or reduce solid tumor size. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes increasing Time to Progression (TTP), Progression-Free Survival (PFS), Event- Free survival (EFS), Overall Survival (OS), Overall Response Rate (ORR), Complete Response Rate (CR rate), or Duration of Response (DoR), or combinations thereof. In some embodiments, one or more therapeutic benefits provided by the methods disclosed herein includes decreasing time to response (TTR). In certain embodiments, the one or more above therapeutic benefits provided to the subject are, for combination methods with a VEGFR inhibitor, relative to treatment of an advanced solid tumor with TKI or VEGFR monotherapy, such as relative to treatment of an advanced solid tumor with TKI or VEGFR monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib. In certain embodiments, the one or more above therapeutic benefits provided to the subject are relative to standard of care advanced solid tumor treatment, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof. In certain embodiments, the one or more above therapeutic benefits provided to the subject are relative to no treatment for an advanced solid tumor.

[00123] In some embodiments, the methods provided herein can be for second line therapy, third line therapy, second or greater line therapy, or third or greater line therapy. In such cases, a subject may have received prior treatment selected from: chemotherapy, a TKI, or a VEGFR inhibitor, wherein the methods provide one or more therapeutic benefits to the subject, (a) for combinations with a VEGFR inhibitor, relative to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with TKI monotherapy or VEGFR inhibitor monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib; (b) relative to standard of care advanced solid tumor treatment, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof; or (c) relative to no treatment for an advanced solid tumor. In some embodiments, the methods provided herein include one or more prior treatments according to the NCCN Guidelines.

[00124] In some embodiments, the methods employing a combination of the compound of Formula (I), or pharmaceutically acceptable form thereof, and a VEGFR inhibitor comprise administering the combination in one or more of the following embodiments (Table 3):

Table 3

[00125] In some embodiments, the methods comprise administering to the subject (a) a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising a VEGFR inhibitor, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the methods comprise administering to the subject (a) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising an effective amount of a VEGFR inhibitor, and a pharmaceutically acceptable carrier, diluent, or excipient.

[00126] In some embodiments, the methods provided herein comprise administering to the subject a pharmaceutical kit or pharmaceutical packaging comprising (a) a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, and a pharmaceutically acceptable carrier, diluent, or excipient. For example, in some embodiments, the method provided herein comprises administering to the subject such a pharmaceutical kit or pharmaceutical packaging comprising (a) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, and (b) a pharmaceutical composition comprising an effective amount of a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical kit or pharmaceutical packaging comprises instructions detailing the dosing regimen for each agent, optionally for one or more treatment cycles.

[00127] In some embodiments of methods relating to advanced solid tumors with squamous histology and HRAS amplification and/or overexpression, and optionally HRAS mutation, the methods provided herein comprise administering to the subject a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments of methods relating to advanced solid tumors HRAS amplification and/or overexpression, and optionally HRAS mutation, the methods provided herein comprise administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the advanced solid tumor has squamous histology. In some embodiments, the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with an HRAS amplification.

[00128] In some embodiments of methods relating to advanced solid tumors with NRAS amplification and/or overexpression, and optionally NRAS mutation, the methods provided herein comprise administering to the subject a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments of methods relating to advanced solid tumors NRAS amplification and/or overexpression, and optionally NRAS mutation, the methods provided herein comprise administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some aspects, the advanced solid tumor is (a) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with an NRAS amplification.

6.3.2 DOSES AND REGIMENS

[00129] In some embodiments, the methods provided herein comprise administering to the subject (a) a compound of Formula (I), or pharmaceutically acceptable form thereof, and (b) a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, such as cabozantinib. For example, in some embodiments, the methods provided herein comprise administering to the subject (a) an effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and (b) an effective amount of a VEGFR inhibitor, such as cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, such as cabozantinib. In some embodiments, the methods comprise administering to the subject pharmaceutical compositions of each agent as describe herein. In some embodiments, the methods comprise administering to the subject pharmaceutical compositions comprising an effective amount of each agent as described herein. [00130] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject according to the methods provided herein at a dose of 1-2400 mg per day. In some embodiments, the dose of a compound of Formula (I), or pharmaceutically acceptable form thereof, is selected from 0.5-2.5 mg, 0.5-5 mg, 0.5-10 mg, 0.5- 25 mg, 0.5-50 mg, 0.5-75 mg, 0.5-100 mg, 0.5-300 mg, 0.5-600 mg, 0.5-1200 mg, 1-5 mg, 1-10 mg, 1 -25 mg, 1-50 mg, 1-75 mg, 1 -100 mg, 1-300 mg, 1-600 mg, 1-1200 mg, 1-2400 mg, 20-100 mg, 40-75 mg, 50-75 mg, 50-100 mg, 50-150 mg, 75-100 mg, 100-200 mg, 125-200 mg, 150- 300 mg, 200-250 mg, 200-400 mg, 300-600 mg, 250-500 mg, 400-600 mg, 500-750 mg, 600- 900 mg, 700-100 mg, 650-1000 mg, 800-1200 mg, 900-1500 mg, 1000-1600 mg, 1000-2000 mg, 1200-1600 mg, 1500-2000 mg, 1500-2400 mg, 1800-2400 mg, and 2000-2400 mg per day. In some embodiments, the dose of a compound of Formula (I), or pharmaceutically acceptable form thereof, is selected from about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg about 100 mg, about 125 mg, about

150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, and about 2400 mg per day. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered 1, 2, 3, or 4 times per day. In some embodiments, the per day dose of a compound of Formula (I), or pharmaceutically acceptable form thereof, is split into two, three, or four doses, such as two, three, or four equal doses, and particularly two doses or two equal doses, that are administered to the subject according to the methods provided herein. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered once or twice per day, or is administered once per day, or is administered twice per day.

[00131] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject according to the methods provided herein at a dose of 0.01-50 mg/kg body weight per day. In some embodiments, the dose of a compound of Formula (I), or pharmaceutically acceptable form thereof, is selected from 0.01-1 mg/kg, 0.01-2.5 mg/kg, 0.01-5 mg/kg, 0.1-5 mg/kg, 0.1-10 mg/kg, 0.1-20 mg/kg, 1-30 mg/kg, 1-40 mg/kg, 5-50 mg/kg, 10-50 mg/kg, 15-50 mg/kg, 20-50 mg/kg, 25-50 mg/kg, 30-50 mg/kg, 40-50 mg/kg, 20-40 mg/kg, and 25-25 mg/kg body weight per day. In some embodiments, the dose of a compound of Formula (I), or pharmaceutically acceptable form thereof, is selected from the group consisting of about 0.01 mg/kg, about 0.02 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, and about 50 mg/kg body weight per day. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered 1, 2, 3, or 4 times per day, for example, is administered once or twice per day, or is administered once per day, or is administered twice per day. In some embodiments, the per day dose of a compound of Formula (I), or pharmaceutically acceptable form thereof, is split into two, three, or four doses, such as two, three, or four equal doses, and particularly two doses or two equal doses, that are administered to the subject according to the methods provided herein.

[00132] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject monthly, weekly, or daily, according to the methods provided herein. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject 1, 2, 3, or 4 times per day for one or more treatment cycles. In some embodiments, the per day dose of a compound of Formula (I), or pharmaceutically acceptable form thereof, is split into two doses, such as two equal doses, that are administered to the subject on certain days of or each day for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered once or twice per day for one or more treatment cycles, such as twice per day for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject 1, 2, 3, or 4 times per day continuously or until remission is achieved in the subject. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject once per day (sometimes referred to as QD) for one or more treatment cycles, such as for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject twice per day (sometimes referred to as BID) for one or more treatment cycles, such as for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, a treatment cycle is 1 day, 7 days or 28 days. In some embodiments, a treatment cycle is 1 day. In some embodiments, a treatment cycle is 7 days. In some embodiments, a treatment cycle is 28 days. In some embodiments, the treatment cycle is a 28-day treatment cycle. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject twice per day for one or more 28-day treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject twice per day for one or more 28-day treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject once or twice per day every other week during a 28-day treatment cycle.

[00133] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject 1, 2, 3, or 4 times per day on days 1-7, days 8-14, days 15-21, days 22-28, days 1-7 and 15-21, days 8-14 and 21-28, days 1-14, days 1-21, or each day (i.e., days 1-28) of a 28-day treatment cycle, for one of more treatment cycles, according to the methods provided herein. For example, in some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject QD on days 1-7, days 8-14, days 15-21, days 22-28, days 1-7 and 15-21, cays 8-14 and 21-28, days 1-14, days 1-21, or each day (i.e., days 1-28) of a 28-day treatment cycle, for one of more treatment cycles. For example, in some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject BID on days 1-7, days 8-14, days 15-21, days 22-28, days 1-7 and 15-21, cays 8-14 and 21-28, days 1-14, days 1-21, or each day (i.e., days 1-28) of a 28-day treatment cycle, for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject on QD on days 1-7 of a 28-day treatment cycle, for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject BID on days 1-7 of a 28-day treatment cycle, for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject QD on days 1-7 and 15-21 of a 28-day treatment cycle, for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject BID on days 1-7 and 15-21 of a 28-day treatment cycle, for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject QD on days 1-21 of a 28-day treatment cycle, for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject BID on days 1-21 of a 28-day treatment cycle, for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject QD on each day (z.e., days 1-28) of a 28-day treatment cycle, for one or more treatment cycles. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject BID on each day (z.e., days 1-28) of a 28-day treatment cycle, for one or more treatment cycles.

[00134] In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject according to the methods of treating provided herein at a dose of 0.2 to 1500 mg per day. In some embodiments, the dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, administered to the subject is selected from 0.5-10 mg, 2-15 mg, 10-30 mg, 10-40 mg, 10-240 mg, 20-50 mg, 20-240 mg, 30-50 mg, 35-70 mg, 40-80 mg, 60-100 mg, 80-120 mg, 80-160 mg, 80-240 mg, 160-250 mg, 160-300 mg, 100-600 mg, or 200-1000 mg mg, per day. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject according to the methods provided herein at a dose selected from about 0.89 mg, 1 mg, 1.34 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 12.5 mg, 14 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, 30 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg, per day. Tn some embodiments, the dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, administered to the subject is selected from (Table 4):

Table 4 [00135] In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered 1, 2, 3, or 4 times per day. In some embodiments, the per day dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is split into two amounts, such as two equal amounts, that are administered to the subject according to the methods provided herein. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered once or twice per day, such as once per day.

[00136] In some embodiments, the dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject daily for one or more treatment cycles according to the methods provided herein. For example, in some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered 1, 2, 3, or 4 times per day for one or more treatment cycles. In some embodiments, the per day dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is split into two amounts, such as two equal amounts, that are administered to the subject according to the methods provided herein. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered once or twice per day for one or more treatment cycles, such as once per day for one or more treatment cycles. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject 1, 2, 3, or 4 times per day continuously or until remission is achieved in the subject. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject once per day (sometimes referred to as QD) for one or more treatment cycles, such as for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. For example, in some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject twice per day (sometimes referred to as BID) for one or more treatment cycles, such as for two or more treatment cycles, three or more treatment cycles, or four or more treatment cycles. In some embodiments, the treatment cycle is 1 day, 7 days, or 28 days. In some embodiments, the treatment cycle is 1 day. In some embodiments, the treatment cycle is 7 days. In some embodiments, the treatment cycle is 28 days. In some embodiments, the dose of the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject once per day for one or more 28-day treatment cycles. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject twice per day for one or more 28-day treatment cycles. In some embodiments, the VEGFR inhibitor, cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, is administered to the subject once or twice per day every other week during a 28-day treatment cycle. In some embodiments, the VEGFR inhibitor, such as fruquintinib, is administered on the first 21 days of each 28-day cycle.

[00137] In some embodiments, the methods provided herein comprise (1) an escalating dosing cycle, followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein comprise (1) an escalating dosing cycle, comprising administering (a) escalating doses of a compound of Formula (I), or pharmaceutically acceptable form thereof, and (b) the effective amount of the VEGFR inhibitor, followed by (2) one or more treatment cycles, comprising administering (a) the effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and (b) the effective amount of the VEGFR inhibitor. In some embodiments, the escalating dosing cycle is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, or 28 days. For example, an escalating dosing cycle can include a step-wise increase in the amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, administered to the subject while maintaining the amount of a VEGFR inhibitor administered to the subject. For example, an escalating dosing cycle can include administering a first amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, to a subject at the beginning of the escalating dosing cycle, and administering a second escalation amount (or final escalation amount) of the compound of Formula (T), or pharmaceutically acceptable form thereof, to the subject at the end of the escalating dosing cycle, optionally while maintaining the amount of the VEGFR inhibitor administered to the subject. For example, an escalating dosing cycle can include a step-wise increase in the amount of a VEGFR inhibitor administered to the subject while maintaining the amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, administered to the subject. In certain embodiments, the final escalation amount is an effective amount of the compound of Formula (I), or pharmaceutically acceptable form thereof, or the VEGFR inhibitor that is administered to the subject during the one or more treatment cycles. In some embodiments, inclusion of an escalating dosing cycle provides a synergistic or therapeutic benefit to the subject, including but not limited to, identifying an effective dose for the subject, improving the efficacy, mitigating or avoiding toxicities, adverse events or adverse symptoms (e.g., reducing the severity, incidence, or risk of such effects), or combinations thereof, associated with a compound of Formula (I), or pharmaceutically acceptable form thereof, or associated with the VEGFR inhibitor.

[00138] In some embodiments, the methods provided herein comprise (1) a loading dosing cycle, followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein comprise (1) a loading dosing cycle, comprising administering (a) a loading dose of a compound of Formula (I), or pharmaceutically acceptable form thereof, and (b) the effective amount of the VEGFR inhibitor, followed by (2) one or more treatment cycles, comprising administering (a) the effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and (b) the effective amount of the VEGFR inhibitor. In some embodiments, the loading dose (sometimes referred to as an elevated dose or a bolus dose) of a compound of Formula (I), or pharmaceutically acceptable form thereof, is 1.1 to 10 times the dose administered during the one or more treatment cycles. For example, in some embodiments, the loading dose is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the dose administered during the one or more treatment cycles. In some embodiments, administration of a compound of Formula (I), or pharmaceutically acceptable form thereof, during the loading dosing cycle is 1, 2, 3, or 4 times per day. In some embodiments, administration of a compound of Formula (I), or pharmaceutically acceptable form thereof, during the loading dosing cycle is once per day. In some embodiments, administration of a compound of Formula (I), or pharmaceutically acceptable form thereof, during the loading dosing cycle is twice per day. In some embodiments, the loading dosing cycle is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, or 28 days. In some embodiments, inclusion of a loading dosing cycle prior to one or more treatment cycles provides a synergistic or therapeutic benefit to the subject, including but not limited to, mitigating or avoiding toxicities, adverse events, or adverse symptoms (e.g., reducing the severity, incidence, or risk of such effects), or combinations thereof, associated with a compound of Formula (I), or pharmaceutically acceptable form thereof, or associated with the VEGFR inhibitor.

[00139] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, and the VEGFR inhibitor, are administered to the subject on an interval dosing schedule while the other is administered on a continuous dosing schedule, such as 1, 2, 3, or 4 times daily. In some embodiments, the interval dosing schedule comprises administering an agent on some days and not on other days of a treatment cycle, such as administering an agent only every other day, or only every other week (e g., one week on, one week off or vice versa), or only for two consecutive weeks (e.g., two weeks on, two weeks off or vice versa), or only for three consecutive weeks (e.g., three weeks on, one week off or vice versa) during a 28-day treatment cycle. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered on an interval dosing schedule. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered on an interval dosing schedule and the VEGFR inhibitor, is administered on a continuous dosing schedule. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject QD or BID on days 1-7, days 1-7 and 15-21, days 1- 21, or each day, of a 28-day treatment cycle, and the VEGFR inhibitor is administered QD or BID each day of the 28-day treatment cycle. For example, in some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject QD on days 1-7, days 1-7 and 15-21, days 1-21, or each day, of a 28-day treatment cycle, and the VEGFR inhibitor is administered QD each day of the 28-day treatment cycle. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject BID on days 1-7, days 1-7 and 15-21, days 1-21, or each day, of a 28- day treatment cycle, and the VEGFR inhibitor is administered QD each day of the 28-day treatment cycle. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject QD on days 1-7, days 1-7 and 15-21, days 1-21, or each day, of a 28-day treatment cycle, and the VEGFR inhibitor is administered BID each day of the 28-day treatment cycle. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered to the subject BID on days 1-7, days 1-7 and 15-21, days 1-21, or each day, of a 28-day treatment cycle, and the VEGFR inhibitor is administered BID each day of the 28-day treatment cycle. In some embodiments, in each regimen, the VEGFR inhibitor is administered for the first 21 days of each 28-day cycle rather than every day. In some embodiments, the two agents are to be administered at approximately the same time of day, in which case, the two agents can be administered concurrently or sequentially. For example, where a compound of Formula (I), or pharmaceutically acceptable form thereof, is administered QD in the morning, or BID in the morning and evening and the VEGFR inhibitor is administered QD in the morning, the two morning administrations can be concurrent or sequential.

[00140] In some embodiments, the methods provided herein comprise (1) an initiation dosing cycle followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein comprise (1) an initiation dosing cycle, comprising administering (a) the effective amount of the VEGFR inhibitor followed by (2) one or more treatment cycles, comprising administering (a) the effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and (b) the effective amount of the VEGFR inhibitor. In some embodiments, the methods provided herein, comprise (1) a delayed dosing schedule followed by (2) one or more treatment cycles. In some embodiments, the methods provided herein comprise (1) a delayed dosing schedule comprising one or more initiation dosing cycles, wherein the one or more initiation dosing cycles comprise administering (a) the effective amount of the VEGFR inhibitor followed by (2) one or more treatment cycles, comprising administering (a) the effective amount of a compound of Formula (I), or pharmaceutically acceptable form thereof, and (b) the effective amount of the VEGFR inhibitor. In some embodiments, the initiation dosing cycle is from 1 day to about 56 days, or is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the initiation dosing cycle is 28 days. In some embodiments, the initiation dosing cycle is 6 weeks or less. In some embodiments, the subject is an VEGFR inhibitor-naive subject. In some embodiments, the subject is a relapsed or refractory advanced solid tumor subject previously, but not currently being, treated with a VEGFR inhibitor. [00141] In some embodiments, the methods provided herein provide a therapeutic benefit, such as a synergistic benefit to the subject, (a) for combinations with a VEGFR inhibitor, relative to treatment of an advanced solid tumor with TKI or VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with TKI or VEGFR inhibitor monotherapy that eventually leads to relapse and/or resistance in the subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib; (b) relative to standard of care advanced solid tumor treatment, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof; or (c) relative to no treatment for an advanced solid tumor. For example, in some embodiments, the methods provided herein improve efficacy (e.g, suppresses tumor growth and induces tumor regression). In some embodiments, the methods provided herein provide unexpected synergistic efficacy relative to either agent alone, for example, wherein the methods increase PFS and/or OS. In some embodiments, the increased PFS is by 10-99%, such as by 10%, 25%, 50%, 80%, 90% 95%, or 99% 2 fold, 3 fold, or 4 fold. In some embodiments, the increased OS is by 10-99%, such as by 10%, 25%, 50%, 80%, 90% 95%, or 99% 2 fold, 3 fold, or 4 fold. In some embodiments, the effective amount of the VEGFR inhibitor for the combination is lower than the effective amount for the VEGFR inhibitor monotherapy. In some embodiments, the methods provided herein reduce VEGFR inhibitor-associated toxicity (e.g., the severity, incidence, or risk of such toxicity). In some embodiments, the reduced toxicity comprises or consists of a reduced severity, incidence, or risk of severe bleeding, disturbed wound healing, gastro-intestinal perforation, hypertension, fatigue, arterial and venous thromboembolic events, hemorrhage, cardiovascular events, cardiac failure, hepatotoxicity, and QT prolongation, or a combination thereof. In some embodiments, the methods provided herein delay emergence of drug resistance such as TKI resistance or VEGFR inhibitor resistance, optionally wherein the delay is an unexpected delay. In some embodiments, the delay in emergence of resistance comprises weeks, months, or years. In some embodiments, the above-noted efficacy outcomes are determined according to applicable RECIST criteria (e.g., RECIST v.1.1). In some embodiments, the abovenoted efficacy outcomes are: (a) for combinations with a VEGFR inhibitor, relative to treatment of an advanced solid tumor with TKI or VEGFR inhibitor monotherapy, such as relative to treatment of an advanced solid tumor with TKI or VEGFR inhibitor monotherapy that eventually leads to relapse and/or resistance in the advanced solid tumor subject, for example, relative to treatment of an advanced solid tumor with cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib; (b) relative to standard of care advanced solid tumor treatment, including but not limited to surgery, radiofrequency ablation, radiation therapy, or chemotherapy, or combinations thereof; or (c) relative to no treatment for an advanced solid tumor. In some embodiments, according to the methods provided herein, a compound of Formula (I), or pharmaceutically acceptable form thereof, and the VEGFR inhibitor unexpectedly act synergistically.

7. EXAMPLES

[00142] Abbreviations: ACN: Acetonitrile; AIBN: Azobisisobutyronitrile; BTEAC: Benzyltri ethylammonium chloride; Cu(OAc)2: Cupric acetate; DCE: 1,2-Dichloroethane; DCM: Dichloromethane; DEA: Diethylamine; DEAD: Diethyl azodicarboxylate; DIAD: Diisopropyl azodicarboxylate; DIBAL-H: Diisobutylaluminium hydride; DIPEA: N,N- Diisopropylethylamine; DIPEA: N,N-Diisopropylethylamine; DMA: Dimethylacetamide; DMF: Dimethylformamide; DMI: l,3-Dimethyl-2-imidazolidinone; DMSO: Dimethyl sulfoxide; DPPF: l,l'-Bis(diphenylphosphino)ferrocene; EtsSiCl: Chlorotriethylsilane; EtOAc: Ethyl acetate; EtOH: Ethanol; HATU: l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate; MeOH: Methanol; NaOMe: Sodium methoxide; NBS: N-Bromosuccinimide; n-BuLi: n-Butyllithium; PCC: Pyridinium chlorochromate;

Pd(Ph3)4i Tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3i Tris(dibenzylideneacetone)dipalladium(0); PPhi: Triphenylphosphine; SFC: Supercritical fluid chromatography; T3P: Propanephosphonic acid anhydride; TBAF: Tetra-n-butylammonium fluoride; t-BuOK: Potassium tert-butoxide; TEA: Triethylamine; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; TIPSC1: Triisopropylsilyl chloride; TMEDA: Tetramethylethylenediamine [00143J LCMS conditions:

[00144] Each LCMS conditions were conducted on instrument SHIMADZU LC20-MS2020, at an oven temperature of 50 °C, with an ESI mass spectrometry ionization, monitored at wavelengths 220 nm and 254 nm. It is understood that the molecular formula listed with the ESI calculated is the molecular formula of the detected ion (e.g., [M+H]⁺). For example, the molecular formula of compound 1A-1 is CnHnBrNO (i.e., [M]), while the molecular formula listed with the ESI calculated is the molecular formula of the detected ion, CnHisBrNO (i.e., [M+H]⁺).

[00145] The acidic LCMS methods are referred to with “AB” notation. Each of the acidic LCMS methods utilized a Xtimate C18 2.1x30mm (3 jam particle size) column (except where indicated), mobile phase A (water (4 L) and TFA (1.5 mL)), and mobile phase B (ACN (4 L) and TFA (0.75 mL)) (except where indicated). The conditions for each of the acidic LCMS methods utilized includes the following: 1.5 min method 5-95AB refers to using MERCK, RP-18e, 25x2mm column, with a gradient starting at 5% B and ending at 95% B, over a total time of 1.5 min. and at a flow rate of 1.5 mL/min.

[00146] The basic LCMS methods are referred to with “CD” notation. Each of the basic LCMS methods utilized a Titank C18 2.1x50mm (5 pm particle size) column, mobile phase A (water (4 L) and ammonium hydroxide (0.8 mL)), and mobile phase B (ACN). The conditions for each of the basic LCMS methods utilized includes the following: 3.0 min method 10-80CD refers to a gradient starting at 10% B and ending at 80% B, over a total time of 3 min. and at a flow rate of 1.0 mL/min.

[00147] SFC Chiral HPLC conditions:

[00148] Each SFC Chiral HPLC methods was conducted on either (1) Waters UPCC with PDA detector and QDa detector or (2) Agilent 1260 with DAD detector.

[00149] “AD_ETOH_DEA_5_40_4ML_4MIN_5CM” refers to using a Chiralpak AD-3 chiral column (5 cm column length), with CO2 (mobile phase A) and ethanol having 0.05% of diethylamine (v/v) (mobile phase B), and using a 5% B to 40% B gradient over a total time of 4 min. at a flow rate of 4 mL/min.

[00150] The following Examples are presented by way of illustration, not limitation.

[00151] EXAMPLE 1: Preparation of Compounds of Formula (I), (II), and (III)

[00152] It is understood that reference to a compound as disclosed herein having one or more sterocenters without designating the specific chirality (e.g., R- or S-enantionmer) will be understood to refer to the compound as racemic mixture (or a mixture of diastereomers), while inclusion of R- or S- designations will be understood to refer to an enantiomer (or a diastereomer) form of the compound, such as an enantiomerically (or diastereomerically) enriched form of the compound, or an enantiomeric excess of the specified enantiomer form of the compound, in accordance with discussion above regarding enantiomeric enriched and enantiomeric excess. Notation of a compound with an R- or S- designation is understood to include an enantiomerically enriched or an enantiomeric excess of the specified enantiomer of the compound, and not limited to only 100% of the single specified enantiomer of the compound. For example, reference to Compound of Formula (III) will be understood to refer to the compound prepared in Example 1 and in its racemic form: (/Y?c)-3-amino-3-(l-methyl-l/7- imidazol-5-yl)-6-oxa-2(4,6)-quinolina- 1,4(1, 3)-dibenzenacy cl ohexaphane-2²,4⁴-di carbonitrile. Similarly, reference to Compound of Formula (I) will be understood to refer to the compound prepared in Example 1 and in its single stereoisomer (S) form: (5)-3-amino-3-(l -methyl- 17/- imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l, 4(1, 3)-dibenzenacy cl ohexaphane-2²,4⁴-di carbonitrile.

Scheme 1

[00153] Scheme 1, Step 1 : Preparation of (1-1). A mixture of 4-bromo-3 -methylbenzoic acid (200 g, 930.04 mmol), NBS (248.29 g, 1.40 mol) and AIBN (30.54 g, 186.01 mmol) in CCh (1600 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 12 h under N2. The reaction mixture was filtered. The crude product was triturated by CH3CN (500 mL) to give a mixture of 1-1 and the corresponding dibromomethyl compound (215 g, 731.44 mmol, 78.65% yield) as a yellow solid. ’H NMR (400MHz, DMSO-tA) 6 =13.36 (br s, 1H), 8.17 (s, 1H) 7.78-7.82 (m, 2H), 4.82 (s, 2H).

[00154] Scheme 1, Step 2: Preparation of (1-2). To a solution of 1-1 and the dibromomethyl compound (160 g, 544.33 mmol) in H2O (1500 mL) was added Na2CCh (230.77 g, 2.18 mol). The mixture was stirred at 75 °C for 12 h. The reaction mixture was adjusted by HC1 (4 M in H2O) to give a white cake. The solvent was removed from the white cake. To the above product in MeOH (1000 mL) was added NaBFL (24.00 g, 634.42 mmol) under N2, and then the mixture was stirred at 15 °C for 1 h under N2. The reaction mixture was quenched by H2O (400 mL) and acidized by HC1 (1 M in H2O) to pH = 2. The mixture was placed under reduced pressure to remove the solvent and then fdtered. The white fdter cake was placed under the reduced pressure to remove the surplus solvent to give 1-2 (120 g, 519.38 mmol, 95.42% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-tL) 8 = 8.08-8.15 (m, 1H), 7.66-7.76 (m, 2H), 4.53 (s, 2H).

[00155] Scheme 1, Step 3: Preparation of (1-3). To a solution of 1-2 (100 g, 432.90 mmol), A,O-dimethylhydroxylamine (57.97 g, 594.31 mmol, HC1) and DIPEA (223.76 g, 1.73 mol, 301.56 mL) in DCM (1000 mL) was added T₃P (275.43 g, 865.64 mmol, 257.41 mL). The mixture was stirred at 15 °C for 5 min. Water (200 mL) was added to the reaction mixture and then extracted with DCM (500 mL x 2). The organic layers was separated, and washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0% to 35%) to give 1-3 (83 g, 302.80 mmol, 69.95 % yield) as a colorless oil. NMR (400 MHz, DMSO4) 8 = 7.92 (s, 1H), 7.72-7.76 (m, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.41 (dd, J= 8.4, 2.0 Hz, 1H), 4.53 (d, J= 5.6 Hz, 2H), 3.54 (s, 3H), 3.26 (s, 3H).

[00156] Scheme 1, Step 4: Preparation of 4-bromo-A-m ethoxy -A-methyl-3- (((triisopropylsilyl)oxy) methyl)benzamide (1-4). A solution of 1-3 (83 g, 302.80 mmol), TIPSC1 (58.5 g, 303.42 mmol, 64.93 mL) and imidazole (51.54 g, 756.99 mmol) in DCM (800 mL) was stirred at 15 °C for 16 h. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (600 mL x 2). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0 to 10%) to give 1-4 (104 g, 241.60 mmol, 79.79% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO- t/6) S - 7.81 (d, J - 2.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4, 2.4 Hz, 1H), 4.80 (s, 2H), 3.51 (s, 3H), 3.23-3.29 (m, 3H), 1.12-1.23 (m, 3H), 1.03-1.08 (m, 18H).

Scheme 2

[00157] Scheme 2, Step 1: Preparation of 2-1. To a mixture of (2-amino-5-bromophenyl)(3- methoxyphenyl)methanone (500 g, 1.63 mol) in toluene (3000 mL) was added AC2O (333.46 g, 3.27 mol, 305.93 mL) and the mixture was stirred at 110 °C for 14 h. The reaction mixture was concentrated under reduced pressure to obtain 2-1 (528 g, 1.52 mol, 92.85% yield) as a brown solid. LC-MS: Method: 5-95AB, Rt = 0.88 min, M/Z calculated for CisHisBrNCh [M+H]⁺ 350.0, found 349.9.

[00158] Scheme 2, Step 2: Preparation of 2-2. To a solution of 2-1 (528 g, 1 .52 mol) in DME (2000 mL) under ice water was added t-BuOK (340.31 g, 3.03 mol) in portions, while maintaining the temperature at 20 °C under N2. The resulting mixture was stirred at 20 °C for 12 h after which the reaction was quenched by water (200 mL). The mixture was concentrated under reduced pressure to remove DME. The residue was triturated with water (2000 mL, twice) then stirred with EtOAc (1000 mL) at 25 °C for 1 h to give 2-2 (487 g, 1.47 mol, 97.27% yield) as yellow solid. ' H NMR (400 MHz, DMSO-cL) 5 = 7.73-7.64 (m, 1H), 7.50-7.34 (m, 3H), 7.15- 6.93 (m, 3H), 6.46 (s, 1H), 3.81 (s, 3H).

[00159] Scheme 2, Step 3: Preparation of 2-3. To a solution of 2-2 (50 g, 143.42 mmol) in DCM (500 mL) at -40 °C under N2 was added BBra (53.90 g, 215.13 mmol, 20.73 mL). The mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into water (500 mL). The pH was adjusted to 7 with saturated NaHCCh solution. The aqueous layer was extracted with DCM (300 mL x 2). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was triturated with petroleum ether (300 mL) at 25 °C for 30 min and CHsCN (200 mL) at 25 °C for 30 min to give 2-3 (42 g, 125.53 mmol, 87.52% yield) as a yellow solid. ^JH NMR (400 MHz, DMSO4) 8 = 9.92 (br s, 1H), 8.03-7.91 (m, 3H), 7.56 (s, 1H), 7.43-7.37 (m, 1H), 6.99-6.91 (m, 3H).

[00160] Scheme 2, Step 4: Preparation of 2-4. To a solution of 2-3 (170 g, 508.08 mmol) in MeOH (800 mL) and THF (800 mL) at 25 °C was added CH₃ONa (54.89 g, 1.02 mol), and the mixture was stirred at 80 °C for 12 h. The solvents were removed under reduced pressure. The mixture was poured into water (1000 mL), stirred for 30 min, then filtered. The filtrate was concentrated under reduced pressure. The crude product was triturated with CH3CN (500 mL) at 25 °C for 30 min to give 2-4 (130 g, 393.73 mmol, 67.98% yield) as a yellow solid. NMR (400 MHz, DMSO-de) 8 = 7.79 (s, 3H), 7.43-7.29 (m, 1H), 6.99-6.84 (m, 4H), 4.01 (s, 3H), 3.64 (s, 1H).

[00161] Scheme 2, Step 4: Preparation of 6-bromo-2-methoxy-4-(3 - ((triisopropylsilyl)oxy)phenyl)-quinoline (2-5). Imidazole (58.97 g, 866.21 mmol) was added to a solution of 2-4 (130 g, 393.73 mmol) in DCM (1500 mL) under N2 at 0 °C. The mixture was stirred until a clear solution appeared, TIPSC1 (75.91 g, 393.73 mmol, 84.25 mL) was added dropwise, and the mixture was stirred at 0 °C for 1 h after which the ice bath was removed, and the mixture was stirred at 25 °C for 12 h. The residue was poured into water (1000 mL) and then extracted with DCM (1000 mL x 3). The combined organic phase was washed with brine (1000 mL), dried over anhydrous Na2SO4, fdtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0 to 5%) and then triturated with MeOH (300 mL) at 25 °C for 30 minutes to give 2-5 (160 g, 328.87 mmol, 83.52% yield) as a yellow solid. ' H NMR (400 MHz, CDCI3) 8 = 7.88 (d, J = 2.0 Hz, 1H), 7.79-7.73 (m, 1H), 7.67 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 7.35 (t, J= 8.0 Hz, 1H), 7.03-6.97 (m, 2H), 6.96-6.93 (m, 1H), 6.83 (s, 1H), 4.07 (s, 3H), 1.32-1.23 (m, 3H), 1.13-1.09 (m, 18H).

Scheme 3

[00162] Scheme 3, Step 1: Preparation of (3-1). To a solution of 6-bromo-2-methoxy-4-(3 - ((triisopropylsilyl)oxy)phenyl)quinoline (10 g, 20.55 mmol) in THF (100 mL) was added n-BuLi (2.5 M in n-hexane, 22.61 mmol, 9.04 mL) and the mixture was stirred at -70 °C under N2 for 0.5 h. A solution of 1-4 (9.00 g, 20.91 mmol) in THF (10 mL) was added to the above solution and the mixture was stirred at -70 °C for 0.5 h. Water (150 mL) was added to the mixture and the mixture was extracted with EtOAc (150 mL). The organic phase was washed with brine (150 mL), dried over anhydrous Na SO4, filtered and concentrated. The mixture was blended with another batch prepared from 18 g of 6-bromo-2-methoxy-4-(3- ((triisopropylsilyl)oxy)phenyl)quinoline. The crude was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0 to 5%) to give 3-1 (40 g, 51.48 mmol, 83.50% yield) as yellow oil. ' H NMR (400MHz, CDCh) 6 = 8.28 (s, 1H), 8.09-7.95 (m, 3H), 7.62-7.54 (m, 2H), 7.35-7.29 (m, 1H), 7.09-7.04 (m, 1H), 7.00-6.95 (m, 2H), 6.92 (s, 1H), 4.85 (s, 2H), 4.16 (s, 3H), 1.28-1.21 (m, 3H), 1.16-1.13 (m, 3H), 1.11-1.07 (m, 18H), 1.04-1.01 (m, 18H).

[00163] Scheme 3, Step 2: Preparation of (3-2). To a solution of 1 -methyl- 1/7-imidazole (1.16 g, 14.16 mmol, 1.13 mL) in THF (50 mL) was added n-BuLi (2.5 M in n-hexane, 14.16 mmol, 5.66 mL) and the mixture was stirred at -70 °C under N2 for 20 min. Then Eta S i Cl (2.13 g, 14.16 mmol, 2.41 mL) in THF (10 mL) was added to the above mixture and the mixture was stirred at -70 °C for 20 min. Then n-BuLi (2.5 M in n-hexane, 14.16 mmol, 5.66 mL) was added to the above mixture and the mixture was stirred at -70 °C for 20 min. Then 3-1 (10 g, 12.87 mmol) in THF (40 mL) was added to the above mixture and the mixture was stirred at -70 °C for 20 min. Water (500 mL) was added to the mixture and the mixture was extracted with EtOAc (500 mL). The organic phase was washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated. The mixture was blended with another batch prepared from 30 g of 3- 1. The crude was purified by flash chromatography on silica gel (MeOH in DCM = 0 to 10%) to give 3-2 (34 g, 39.58 mmol, 76.88% yield) as a light yellow solid. ¹H NMR (400MHz, CDCh) 5 = 7.70-7.63 (m, 2H), 7.36-7.32 (m, 1H), 7.30-7.25 (m, 2H), 7.11-7.04 (m, 3H), 6.81-6.76 (m, 2H), 6.75-6.71 (m, 1H), 6.69 (s, 1H), 6.14 (s, 1H), 4.63-4.54 (m, 2H), 3.96 (s, 3H), 3.18 (s, 3H), 1.13-1.06 (m, 3H), 0.96-0.92 (m, 18H), 0.89-0.84 (m, 3H), 0.80-0.77 (m, 18H).

[00164] Scheme 3, Step 3: Preparation of (3-3). A mixture of 3-2 (26.5 g, 30.85 mmol) and TBAF (1 M in THF, 46.27 mmol, 46.27 mL) in THF (250 mL) was stirred at 25 °C for 20 min. Water (500 mL) was added to the mixture and the mixture was extracted with EtOAc (500 mL). The organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by triturated from EtOAc : petroleum ether = 1 :5 (150 mL) to give 3-3 (16 g, 29.28 mmol, 94.93% yield) as an off-white solid. ’H NMR (400MHz, DMSO- d₆) 6 = 9.69 (s, 1H), 7.81 (d, J= 8.8 Hz, 1H), 7.74-7.68 (m, 1H), 7.64-7.54 (m, 2H), 7.53-7.44 (m, 2H), 7.29-7.21 (m, 1H), 7.04-6.96 (m, 1H), 6.91-6.84 (m, 3H), 6.83-6.75 (m, 2H), 6.05 (s, 1H), 5.42-5.35 (m, 1H), 4.52-4.41 (m, 2H), 4.03-3.98 (m, 3H), 3.35 (s, 3H). LCMS Rt = 0.80 min in 1.5 min chromatography, 5-95aB, ESI calcd. for C2sH25BrN3O4 [M+H] 546.1, found 545.9.

[00165] Scheme 3, Step 4: Preparation of (3-4). To a solution of 3-3 (5.7 g, 10.43 mmol) in DMF (85 mL) was added SOCh (2.48 g, 20.86 mmol, 1.51 mL) and the mixture was stirred at 25 °C for 1 h. To the above solution was added CS2CO3 (50.96 g, 156.41 mmol) and the mixture was stirred at 70 °C for 0.5 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The crude product was blended with another batch prepared from 10.15 g of 3-3 was triturated from water (150 mL) and filtered. The solid was re-dissolved in toluene (100 mL x 2) and concentrated to give 3-4 (13 g, 24.60 mmol, 84.84% yield) as a light yellow solid. ’H NMR (400MHz, DMSO-tfc) 6 = 8.09-8.01 (m, 1H), 7.92-7.87 (m, 1H), 7.69- 7.53 (tn, 4H), 7.38-7.34 (m, 1H), 7.26 (s, 1H), 7.19-7.10 (m, 3H), 7.07-7.00 (m, 2H), 6.29 (s, 1H), 5.49-5.37 (m, 2H), 4.05 (s, 3H), 3.50 (s, 3H). LCMS Rt = 2.00 min in 3.0 min chromatography, 10-80cD, ESI calcd. for C28H23BrNsO3 [M+H]⁺ 530.1, found 530.1.

[00166] Scheme 3, Step 5: Preparation of (3-5). A mixture of 3-4 (12 g, 22.71 mmol), Zn(CN)₂ (27.23 g, 231.89 mmol, 14.72 mL), Pd₂(dba)₃ (3.12 g, 3.41 mmol), dppf (3.78 g, 6.81 mmol) and Zn (891.01 mg, 13.63 mmol) in DMA (300 mL) was stirred at 120 °C under N2 for 2 h. The mixture was filtered through Celite. The cake was washed with EtOAc (100 mL x 2). The combined organic phase was concentrated. The crude was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 50% to 100%) and then triturated with MeOH (50 mL) to give 3-5 (6.55 g, 13.80 mmol, 60.78% yield) as a yellow solid. ’H NMR (400MHz, DMSO- de) 8 = 8.05-8.01 (m, 1H), 7.95-7.90 (m, 1H), 7.85-7.78 (m, 2H), 7.63-7.44 (m, 2H), 7.40-7.32 (m, 2H), 7.18 (s, 1H), 7.12 (d, J= 7.6 Hz, 1H), 7.07-7.01 (m, 3H), 6.94 (s, 1H), 5.52 (s, 2H), 4.06 (s, 3H), 3.62 (s, 3H). LCMS Rt = 1.77 min in 3.0 min chromatography, 10-80cD, ESI calcd. for C29H23N4O3 [M+H]⁺ 475.2, found 475.2.

[00167] Scheme 3, Step 6: Preparation of (3-6). To a solution of 3-5 (0.12 g, 251.82 pmol) in THF (10 mL) was added HC1 (4 M in H2O, 2.20 mL). The reaction mixture was stirred at 70 °C for 16 h. The mixture was cooled to 20 °C and added into water (20 mL). Saturated NaHCCh solution was added to adjust pH = 8. The aqueous phase was extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 3-6 (0.115 g, 249.74 pmol, 99.17% yield) as a colorless oil. 50 mg (108.58 pmol) of 3-6 was purified by Prep-HPLC (column: Phenomenex Gemini-NX 80 x 40mm x 3 pm; mobile phase: [water (lOmM NH4HCOi)-ACN]; B%: 26%-56%, 7.8 min) to give 3-6 (12.4 mg, 26.93 pmol, 24.80% yield) as an off-white solid.

NMR (400 MHz, DMSO-t/e) 6 = 11.71 (br s, 1H), 7.89 (dd, J= 2.0, 8.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.45 (d, .7= 8.8 Hz, 2H), 7.38-7.31 (m, 1H), 7.10-7.02 (m, 3H), 6.75 (s, 1H), 6.65 (s, 1H), 6.52 (s, 1H), 6.34 (s, 1H), 5.55-5.46 (m, 2H), 3.49 (s, 3H). LCMS Rt = 1.34 min in 3 min chromatography, 10-80cD, ESI calcd. for : C28H21N4O3 [M+H]⁺ 461.2, found 461.1. HPLC Rt = 2.22 min in 8 min chromatography, 220 nm, purity 100%.

[00168] Scheme 3, Step 7: Preparation of (3-7). Compound 3-6 (1.2 g, 2.61 mmol) was mixed with POCI3 (19.80 g, 129.13 mmol, 12.00 mL) at 25 °C. The mixture was stirred at 100 °C for 1 h. The mixture was concentrated. To the residue was added NaOH (1 M in H2O, 100 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and the filter cake was washed with EtOAc (20 mL). The combined filtrates were concentrated. The crude product was blended with another batch prepared from 0.5 g of 3-6. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0 to 10%) to give 3-7 (1.3 g, 2.71 mmol, 73.35% yield) as a yellow solid. LCMS Rt = 1.79 min in 3.0 min chromatography, 10-80 CD, ESI calcd. for C28H20CIN4O2 [M+H]⁺ 479.1, found 479.1.

[00169] Scheme 3, Step 8: Preparation of (3-8). To a solution of 3-7 (1.2 g, 2.51 mmol) in DMF (10 mL) was added Zn(CN)₂ (2.69 g, 22.91 mmol, 1.45 mL) and Pd(PPhr)4 (579.07 mg, 501.12 pmol) in a three-neck bottom flask at 25 °C under N2. The mixture was stirred at 100 °C for 2 h. The mixture was cooled to 25 °C and added into water (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, fdtered and concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0 to 3%) to give 3-8 (900 mg, 1.92 mmol, 76.51% yield) as a yellow solid. ’H NMR (400MHz, DMSO-cL) 5 = 8.33-8.22 (m, 2H), 8.10 (s, 1H), 7.94-7.76 (m, 2H), 7.69 (s, 1H), 7.52-7.39 (m, 2H), 7.28-7.02 (m, 5H), 6.36 (s, 1H), 5.54 (s, 2H), 3.56 (s, 3H).

[00170] Scheme 3, Step 9: Preparation of (rac)-3-amino-3-(l-methyl-l//-imidazol-5-yl)-6- oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-2²,4⁴-dicarbonitrile (Compound of Formula III). To a solution of 3-8 (800 mg, 1.70 mmol) in DMI (8 mL) was added SOCI2 (1.01 g, 8.52 mmol, 618.05 pL). The mixture was stirred at 40 °C for 1 h. To NH3 in MeOH (7 M, 100 mL) was added the above mixture at -10 °C. The mixture was stirred at 25 °C for 30 min. The reaction mixture was poured into H2O (100 mL). The aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, fdtered and the fdter cake was washed with EtOAc (20 mL). The combined fdtrates were concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM = 0 to 8%) to give Compound 3 (550 mg, 1.17 mmol, 68.89% yield) as a yellow solid. LCMS Rt = 1.71 min in 3.0 min chromatography, 10-80cD, ESI calcd. for C29H21N6O [M+H]⁺ 469.2, found 469.2.

[00171] Scheme 2, Step 10: Preparation of (5)-3-amino-3-(l-methyl-177-imidazol-5-yl)-6- oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-2²,4⁴-dicarbonitrile (Compound of Formula (I)) and (7?)-3-amino-3-(l-methyl-l//-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l, 4(1,3)- dibenzenacyclohexaphane-2²,4⁴-dicarbonitrile (Compound of Formula (II)).

[00172] Compound of Formula (III) (500 mg, 1.07 mmol) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: [O. /oNHJ EtOH]; B%: 45%-45%) to give the target compound (229.5 mg, 489.85 pmol, 45.90% yield) as an off- white solid. NMR (400MHz, DMSO-cC) 8 = 8.37 (d, J= 8.4 Hz, 1H), 8.23 (d, J= 9.2 Hz, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.58 (s, 1H), 7.48-7.19 (m, 4H), 7.18- 7.04 (m, 2H), 6.44 (s, 1H), 5.64-5.45 (m, 2H), 3.48 (s, 3H), 3.18 (s, 2H). LCMS Rt = 1.68 min in 3.0 min chromatography, 10-80CD, ESI calcd. for C29H21N6O [M+H]⁺ 469.2, found 469.2. HPLC Rt = 3.03 min in 8 min chromatography, 220 nm, purity 100%. Chiral HPLC (S)-l: Rt = 2.44 min in 4 min (ee 99.54%) (AD_ETOH_DEA_5_40_4ML_4MIN_5CM), ((/?)-2: Rt = 1.93 min (ee 99.44%)).

[00173] EXAMPLE 2: Combination Study in Cell Line-Derived Xenograft (CDX) and Patient-Derived Xenograft (PDX) in vivo Models

[00174] The combination of the compound of Formula (I), or a pharmaceutically acceptable form thereof, and an anti -angiogenic TKI may result in deeper and more durable responses in a VHL-mutant 786-0 RCC CDX model and RCC PDX models, compared to either agent alone. While the anti -angiogenic TKIs or the compound of Formula (I), or a pharmaceutically acceptable form thereof, alone may slow or occasionally arrest tumor growth, the combination of agents may induce greater arrest of tumor growth or may induce tumor regressions in treated animals.

[00175] VHL-mutant 786-0 tumor cells were maintained in vitro in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS). VHL-mutant A498 tumor cells were maintained in vitro in Eagle’s Minimum Essential Medium supplemented with 10% FBS. Cells were grown at 37 °C in an atmosphere of 5% CO2 in air. Cells were harvested while in exponential growth phase and quantified by cell counter before tumor inoculation. For the VHL mutant KI-0326 and KI-12-0073 ccRCC PDX models, fresh tumor tissues from mice bearing established primary human cancer tissues were harvested and cut into small pieces (approximately 2-3 mm in diameter). Each female BALB/c mouse was inoculated subcutaneously in the right upper flank region with the tumor cells at 5 x 10⁶ per mouse (CDX models) in 0.1 mL of phosphate-buffered saline (PBS) or was inoculated surgically (approx. 30 mm³ slice; PDX models) for tumor development. Randomization started when mean tumor size reached approximately 250-300 mm³. Animals were randomly allocated to study groups at 5-6 animals per study group, depending on the study design, based on “Matched distribution” method/“ Stratified” method (StudyDirector™ software, version 3.1.399.19)/randomized block design. Administration of test articles was initiated on the same day as randomization. The compound of Formula (I) was administered at 20 mg/kg twice daily, cabozantinib was administered at 8, 15 or 20 mg/kg p.o. once daily, and axitinib was administered at 36 mg/kg p.o., once daily. Animals were checked daily for morbidity and mortality after tumor cell inoculation. During routine monitoring, the animals were checked for any effects on tumor growth, on behavior, including mobility, food and water consumption, and on physical characteristics, including body weight gain/loss, eye/hair matting and any other abnormalities. Mortality and observed clinical signs were recorded for individual animal. Body weights and tumor volumes were measured twice per week after randomization. For tumor volumes, measurements were performed in two dimensions using a caliper and recorded in mm³ using the formula: V = (L x W x W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). Dosing as well as tumor and body weight measurements were conducted in a Laminar Flow Cabinet. Body weights and tumor volumes were measured using StudyDirector™ software, version 3.1.399.19. At study termination, tumors were harvested by taking a section for formalin fixing and paraffin embedding (FFPE) and snap freezing the rest. FFPE was performed using standard procedures. [00176] As shown in FIG. 1, A498 CDX continuously treated with the compound of Formula (I) (20 mg/kg, BID) and axitinib (36 mg/kg, QD) showed an increase in tumor regression relative to either agent alone. Error bars represent the standard error of the mean (n = 5).

[00177] As shown in FIG. 2 for KI-12-0073 PDX, continuous treatment with the compound of Formula (I) (20 mg/kg, BID) and axitinib (36 mg/kg, QD) resulted in increased tumor growth inhibition compared to either agent alone. Error bars represent the standard error of the mean (n = 8).

[00178] As shown in FIG. 3, 786-0 CDX (FIG. 3A) continuously treated with the compound of Formula (I) (20 mg/kg, BID) and cabozantinib (20 mg/kg, QD) (lane 3) showed increased percent tumor growth inhibition (% TGI) relative to the compound of Formula (I) (lane 1) or cabozantinib (lane 2) alone. A498 CDX (FIG. 3B) continuously treated with the compound of Formula (I) (20 mg/kg, BID) and cabozantinib (8 or 20 mg/kg, QD) (lanes 4 and 5, respectively) showed increased % TGI compared to compound of Formula (I) alone (20 mg/kg, BID) (lane 1) or cabozantinib alone (8 and 20 mg/kg, QD) (lanes 2 and 3, respectively). Error bars represent the standard error of the mean (786-0, n = 6, % TGI calculated 16 days post start of treatment; A498, n = 5, % TGI calculated 14 days post-start of treatment). % TGI was calculated with the following formula: [l-(mean volume of treated tumors) / (mean volume of control tumors)] x 100%.

[00179] As shown in FIG. 4, mice with KI-12-0073 VHL-mutant PDX, 786-0 VHL-mutant CDX, and KI-0326 VHL-mutant PDX treated continuously with the compound of Formula (I) (20 mg/kg, BID) and cabozantinib (8, 15, and 20 mg/kg, QD, respectively) exhibited reduced tumor growth (FIGS. 4A, 4C, and 4E), compared to either compound alone. Error bars represent the standard error of the mean. FIGS. 4B, 4D, and 4F show the graphs of percent of tumor volume change at endpoint relative to day 0 in the KI-12-0073, 786-0, and KI-0326 models, respectively, to show the variability in responses to cabozantinib, compared to the combination of compound of Formula (I) and cabozantinib, which resulted in regression of all but one tumor.

[00180] As shown in FIG. 5, mice with 786-0 VHL-mutant CDX continuously treated with the compound of Formula (I) (20 mg/kg, BID) and varying doses of cabozantinib (4, 8, 10, and 12 mg/kg, QD) showed dose-dependent tumor growth inhibition compared to the respective single agent cabozantinib or compound of Formula (I). Percent tumor volume change was calculated using endpoint tumor volume values (day 28) relative to day 0.

[00181] Mice with 786-0 CDX were treated continuously with cabozantinib (15 mg/kg, QD), the compound of Formula (I) (20 mg/kg, BID), lenvatinib (10 mg/kg, QD), lenvatinib plus everolimus (2 mg/kg, QD), the compound of Formula (I) plus cabozantinib, and the compound of Formula (I) with lenvatinib. As shown in FIG. 6, the combination of the compound of Formula (I) (20 mg/kg, BID) with either cabozantinib or lenvatinib reduced tumor growth more than any of the agents alone, and exhibited reduced tumor growth that compared favorably to treatment with lenvatinib (10 mg/kg, QD) and everolimus (kinase/mTOR inhibitor; 2 mg/kg, QD), which combination is an FDA-approved second-line treatment for RCC. Error bars represent the standard error of the mean.

[00182] Mice with 786-0 CDX were treated continuously with axitinib (36 mg/kg, QD) for 14 days. Starting at day 15, animals were dosed with one of the following: a) vehicle; b) the compound of Formula (I) (20 mg/kg, BID); (c) cabozantinib (15 mg/kg, QD); (d) axitinib (36 mg/kg, QD); or (e) the combination of compound of Formula (I) and cabozantinib. As shown in FIG. 7, 786-0 CDX that progressed during the 14-day treatment with axitinib and then were treated continuously with the compound of Formula (I) plus cabozantinib exhibited reduced tumor growth compared to any of the other amis over the subsequent 18 days. Results for dosing for a total of three to four weeks following axitinib pre-treatment may provide similar results. Error bars represent the standard error of the mean.

[00183] EXAMPLE S: Mechanism Studies

[00184] Study 1. To investigate the mechanism of action of the results of Example 2, VHL- mutant RCC cell lines can be subjected to hypoxia (1% O2) in vitro to mimic the hypoxic conditions induced by anti-angiogenic TKIs in vivo and may be treated with the compound of Formula (I) to evaluate its impact on signaling pathways in hypoxia-exposed cells. In this study, hypoxia may initially reduce mTOR signaling, but it may rebound after 24 hours in hypoxia, in which case it indicates that mTOR pathway reactivation is a potential mechanism of resistance to TKIs. Addition of the compound of Formula (I), or a pharmaceutically acceptable form thereof, may block hypoxia-induced mTOR reactivation. Mechanistically, the compound of Formula (I) potently inhibits the farnesylation, and hence the activity, of an obligate farnesylated protein RHEB, a positive regulator of mTOR, suggesting that the synergy may arise through RHEB inhibition in this model. The mechanistic data in cell lines suggest that the ability of the compound of Formula (I), or a pharmaceutically acceptable form thereof, to inhibit mTOR reactivation observed in ccRCC cell lines under hypoxic stress may contribute to enhanced treatment durability in vivo.

[00185] Study 2. 786-0 CDX were snap frozen after 14 days of treatment with vehicle, cabozantinib (15 mg/kg, QD), the compound of Formula (I) (20 mg/kg, BID), or the combination. Tumors were thawed in IX RIPA buffer (Thermo Scientific Cat # PI89901) supplemented with IX HALT protease and phosphatase inhibitor cocktail (Thermo Scientific Cat # PI78446) then homogenized using a bead mill homogenizer for 30 seconds at 4.5 m/s. Lysates were clarified by centrifugation for 10 min at 12k x g and quantified by BCA assay (Pierce). For SDS-PAGE and immunoblotting, 20-50 pg of lysate was loaded on to 4-12% Bis-Tris gels (Invitrogen NuPAGE) and transferred on to nitrocellulose membranes. Membranes were probed with the following antibodies: anti-phospho-ERKl/2 (CST Cat # 4695); anti-phospho-AKT (CST Cat # 4060); anti-phospho-S6 (Ser235/236) (CST Cat # 2211); anti-phospho-S6 (Ser240/244) (CST Cat # 2215); anti-total S6 (CST Cat # 2217); anti-phospho-RB (CST Cat # 8516); anti-cyclin DI (CST Cat # 55506); anti-RHEB (CST Cat # 13879) and anti-HSP90 (CST Cat # 4877). As shown in FIG. 8, treatment with the combination led to decreased phosphorylation of AKT and S6, two growth-promoting signaling proteins, and decreased phosphorylated RB, a cell cycle arrest marker, compared to either agent alone. A slight shift of RHEB was detected in the combination treatment, indicating defamesylation by the compound of Formula (I). HSP90 served as loading control.

[00186] Study 3. All immunohistochemistry (IHC) stains were performed at Histowiz, Inc. (Brooklyn, NY) using the Leica BOND RX automated Stainer (Leica Microsystems). The slides were dewaxed using xylene- and alcohol-based dewaxing solutions. Epitope retrieval was performed by heat-induced epitope retrieval (HIER) of the formalin-fixed, paraffin-embedded tissue in citrate-based pH 6 solution for 20 min at 95 °C. The tissues were first incubated with peroxide block buffer (Leica Microsystems), followed by incubation with the primary antibody at 1 : 100 dilution for 30 min, followed by DAB mouse secondary reagents: polymer, DAB refine, and hematoxylin (Leica Microsystems). The slides were dried, cover-slipped and visualized using a Leica Aperio AT2 slide scanner (Leica Microsystems). The following primary antibodies were used: anti-CD31 antibody (Sigma, 131M-94) and anti-VEGFR2 antibody (Cell Signaling Technology 9698).

[00187] As shown in Table 5, consistent with the anti angiogenic activity of cabozantinib, 786- O CDX treated with cabozantinib (15 mg/kg, QD) for 14 days resulted in decreased angiogenesis, which is evident as decreased expression of CD31 and VEGFR2, compared to vehicle. The combination of the compound of Formula (I) (20 mg/kg, BID) and cabozantinib (15 mg/kg, QD), however, led to greater reductions of CD31 and VEGFR2 expression, compared to cabozantinib alone.

Table 5.

[00188] As shown in Table 6, KI-0326 PDX treated with cabozantinib (20 mg/kg, QD) for 14 days led to reduced tumor vascularity compared to vehicle, as measured by CD31 immunohistochemistry. However, the combination of cabozantinib and compound of Formula (I) (20 mg/kg, BID) did not lead to greater reduction of CD31 expression. This suggests that the additive effect of the two drugs on tumor growth inhibition is not solely driven by the inhibition of angiogenesis.

Table 6.

[00189] Study 4. Early passage (less than passage 6) human umbilical vein endothelial cells (HUVEC) were seeded at 1,000 cells per well on a 96-well plate in endothelial cell medium with 0.2% fetal bovine serum (FBS) and allowed to sit overnight. The next day, media was replaced with fresh endothelial cell medium with 5% fetal bovine serum (FBS), 100 ng/mL recombinant VEGF-A, and endothelial cell growth supplement (ECGS) plus test article: DMSO as vehicle, varying concentrations of axitinib with or without 100 nM compound of Formula (I); or varying concentrations of cabozantinib with or without 100 nM compound of Formula (I). At Day 5, cell viability was assayed using Cell Titer-Gio 2 reagent (Promega) per manufacturer’s instructions, with luminescence recorded on the Tecan plate reader.

[00190] As shown in Table 7, addition of 100 nM compound of Formula (I) to axitinib or cabozantinib resulted in more potent inhibition of HUVEC proliferation, with reduced IC50 concentrations compared to axitinib or cabozantinib alone.

Table 7.

[00191] Study 5. Early passage (less than passage 6) human umbilical vein endothelial cells (HUVEC) were seeded at 1,000 cells per well on a 96-well plate in complete endothelial cell medium containing 5% fetal bovine serum (FBS) and endothelial cell growth supplement (ECGS) and allowed to sit overnight. The next day, test articles were added: DMSO as vehicle, varying concentrations of cabozantinib, axitinib, or lenvatinib, and varying concentrations of compound of Formula (I). At Day 7 post-test article addition, cell viability was assayed using Cell Titer-Gio 2 reagent (Promega) per manufacturer’s instructions, with luminescence recorded on the Tecan plate reader.

[00192] As shown in FIG. 9, addition of increasing doses of the compound of Formula (I) to cabozantinib (FIG. 9A), axitinib (FIG. 9B), or lenvatinib (FIG. 9C) resulted in more potent inhibition of HUVEC viability compared to the respective TKI agent alone. Additionally, the compound of Formula (I) inhibited HUVEC viability in vitro as a single agent with an IC50 of 223.4 ± 84.02 nM.

[00193] Study 6. Early passage (less than passage 6) HUVEC or GFP-labeled HUVEC cells were serum-starved overnight and seeded the following day at 6 x 10⁴ cells per well on a 48-well plate that was pre-coated with a layer of reduced growth factor base membrane extract (BME). At plating, cells were treated with DMSO (vehicle), 100 nM axitinib, 10 nM cabozantinib, 300 nM or 1 pM compound of Formula (I), 100 nM axitinib plus 1 M compound of Formula (I), or 10 nM cabozantinib plus 300 nM or 1 pM compound of Formula (I). Each treatment group had two technical replicates. Plates were incubated in an Incucyte at 37 °C in an atmosphere of 5% CO2 in air. Tube formation was monitored by imaging every 30 min for 18 h.

[00194] As shown in FIG. 10, treatment of primary endothelial cells with 100 nM axitinib or 10 nM cabozantinib with or without 1 pM compound of Formula (I) compromised the cells’ ability to form tubular structures on matrix proteins in vitro. (A - vehicle; B - axitinib; C - cabozantinib; D - compound of Formula (I); E - axitinib and compound of Formula (I); F - cabozantinib and compound of Formula (I).) FIG. 11 shows that treatment with 10 nM cabozantinib inhibited in vitro tube formation of GFP-labeled primary endothelial cells while 300 nM compound of Formula (I) did not (FIG. 11 A, GFP imaging; FIG. 11B, plots of number of master segments and total length of master segments). The combination of cabozantinib and compound of Formula (I) did not further decrease tube formation compared to cabozantinib alone, demonstrating that compound of Formula (I) does not affect this particular endothelial cell function.

[00195] Study 7. Early passage (less than passage 6) human umbilical vein endothelial cells (HUVEC) were seeded at 2,000 cells per well on a Nunc 96-well, flat-bottom plate in endothelial cell growth factor-supplemented endothelial cell medium (ECM) with 5% fetal bovine serum (FBS) and allowed to sit overnight. The next day, the media was removed and replaced with Incucyte Annexin V Orange dye (Sartorius) diluted (1 :200) in complete ECM media. The following test articles were added directly into Annexin V prepared media: DMSO as vehicle, 1000 nM staurosporine as positive control, 100 nM compound of Formula (I), 100 nM cabozantinib, or combination of the compound of Formula (I) and cabozantinib. Live-cell imaging and analysis was done for four days using an Incucyte SX5 system. [00196] As shown in FIG. 12, treatment of primary endothelial cells with the compound of Formula (I) and cabozantinib induced more apoptosis than either agent alone, as measured by Annexin V signal plotted with time. Staurosporine was included as positive control.

[00197] EXAMPLE 4: FTI Activity in HRAS High Cell Line Tumor Spheroid Growth Model

[00198] Cell lines were obtained from ATCC (SCC9) or Sigma (HSC3) and maintained in a humidified atmosphere with 5% CO2 at 37 °C, cultured in DMEM (HSC3) or DMEM/F12 (SCC9) supplemented with 10% FBS and penicillin/streptomycin. All lines tested negative for mycoplasma. Matrigel matrix was purchased from Coming and diluted in respective media prior to plating. Anti-GTPase HRAS antibody was purchased from Abeam. Active GTPase Pulldown kit was purchased from ThermoFisher. Cells were plated and lysed in a 10 cm dish. Lysates were collected and pulled down based on the pulldown kit protocol. 500 pg protein was loaded for pull down and 10 pg for input as comparison. An HRAS specific antibody (ab32417) was used to blot for active levels of HRAS in each cell line. Cells were resuspended in 4% Matrigel and seeded in 96-well ultralow attachment plates at a density of 1000-2000 cells/well. The following day, spheroids were treated with the compound of Formula (I) and DMSO as a control for normalization. The spheroids were incubated with test compound for 7 days and a luminescence reading taken using 3D Cell Titer Gio reagent (Promega). Results: The sensitivity of the compound of Formula (I) on head and neck squamous carcinoma (HNSCC) cell lines based on HRAS activity levels was assessed. SCC9 and HSC3 cell lines were identified based on active levels of HRAS assayed by the GTP pull-down kit, characterizing SCC9 as HRAS high and HSC3 as HRAS low as shown by immunoblot (FIG. 13). The cell lines were then cultured as 3D tumor spheroids and treated for 7 days with the compound of Formula (I) and DMSO. Cell viability was calculated by normalizing the compound-treated cells to the DMSO-treated cells. As shown in Table 7, the compound of Formula (I) was more efficacious in the high HRAS activity cell line (SCC9) than in the low HRAS level cell line (HSC3), based on percentage of cell viability.

Table 8.

[00199] EXAMPLE 5: Compound of Formula (I) activity in HRAS-altered patient- derived xenograft models

[00200] Female NOD/SCID mice were inoculated subcutaneously in the right upper flank with primary human tumor xenograft model tumor fragments (human head and neck, HN2594 (HRAS^WT'^hlgh, Crown Bioscience, Beijing; 2-3 mm in diameter) harvested from stock mice for tumor development. All animals were randomly allocated to 4 study groups, 5 mice in each group. Randomization started when the mean tumor size reached approximately 220 mm³. Randomization was performed based on “Matched distribution” method (StudyDirector™ software, version 3.1.399.19). Dosing was initiated on the date of randomization (Day 0). Mice were dosed orally for 35 days with control vehicle, QD, or compound of Formula (I), 20 mg/kg, BID. After tumor inoculation, the animals were checked daily for morbidity and mortality. During routine monitoring, the animals were checked for any effects of tumor growth and treatments on behavior such as mobility, food and water consumption, body weight gain/loss (body weights were measured three times/daily per week after randomization), eye/hair matting and any other abnormalities. Mortality and observed clinical signs were recorded for individual animals in detail. Tumor volumes were measured three times per week after randomization in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: V = (L x W x W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension), and W is tumor width (the longest tumor dimension perpendicular to L). Dosing and tumor and body weight measurements were conducted in a Laminar Flow Cabinet. The body weights and tumor volumes were measured by using Study Director™ software (version 3.1.399.19). As shown in FIG. 14, the compound of Formula (I) produced tumor regression in this model.

[00201] EXAMPLE 6: Compound of Formula (I) activity in HRAS-altered patient- derived xenograft model

[00202] Human head and neck squamous cell carcinoma patient-derived xenograft (PDX) models HN2576 and HN2594 (HRAS^WT‘^hlgh, Crown Bioscience, Beijing) in female NOD/SCID mice were used for this study. Fresh tumor tissues from mice bearing established primary human cancer tissues were harvested and cut into small pieces (approximately 2-3 mm in diameter). Each mouse was inoculated subcutaneously in the right front flank with a specific PDX tumor fragment (3x3x3 mm) for tumor development. Randomization started when the mean tumor size reached approximately 250 mm³. All animals were randomly allocated to 5 study groups, 5 mice in each group. Randomization was performed based on “Matched distribution” method (StudyDirector™ software, version 3.1.399.19). The date of randomization was denoted as Day 0. Dosing was initiated on the same day of randomization (Day 0) as per the study design. HN2576 and HN2594 xenografts were treated orally with vehicle control, BID; or Compound of Formula (I), 10 mg/kg, 20 mg/kg, or 40 mg/kg, BID. After tumor inoculation, the animals were checked daily for morbidity and mortality. During routine monitoring, the animals were checked for any effects of tumor growth and treatments on behavior such as mobility, food and water consumption, body weight gain/loss (body weights were measured three times/daily per week after randomization), eye/hair matting and any other abnormalities. Mortality and observed clinical signs were recorded for individual animals in detail. Tumor volumes were measured three times per week after randomization in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: V = (L x W x W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). Dosing as well as tumor and body weight measurements were conducted in a Laminar Flow Cabinet. The body weights and tumor volumes were measured by using Study Director ™ software (version 3.1.399.19). In these two wildtype HRAS-overexpressing xenograft models, HN2576 and HN2594, the compound of Formula (I) alone had significant anti-tumor effects compared to vehicle control. Single agent treatment with the compound of Formula (I) at increasing doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg led to tumor growth inhibition in the HN2576 PDX model (FIG. 15). In the HN2594 PDX model, increasing doses of the compound of Formula (I) led to a dose-dependent decrease in tumor growth (FIG. 16). These results suggest there is single agent activity of the compound of Formula (I) that leads to anti-tumor efficacy in HRAS-amplified HNSCC xenograft models.

[00203] EXAMPLE 6: Clinical Study

[00204] This study is designed to evaluate the safety, tolerability and preliminary efficacy of the compound of Formula (I), or a pharmaceutically acceptable form thereof, in patients with advanced solid tumors. Eligible patients for a Part la dose escalation phase (including an associated pharmacodynamic cohort) will have histologically or cytologically confirmed advanced solid tumors with confirmed HRAS mutation and/or amplification, or HRAS overexpression (e.g., for HNSCC), or with confirmed NRAS mutation and/or NRAS amplification, for example NSCLC, CRC, or PDAC, and must have progressed on or be refractory to or unsuitable for standard therapy or for which no standard therapy exists. Eligible patients for a Part lb combination dose escalation (including an associated pharmacodynamic cohort) and a Part 2 combination dose expansion will have histologically or cytologically confirmed, locally advanced or metastatic RCC with predominantly clear cell subtype (e.g., ccRCC), optionally having received at least one prior line of systemic therapy for such carcinoma. Patients must have at least one measurable lesion according to RECIST v.1.1 , confirmed by radiological assessment. Additional eligibility criteria may apply.

[00205] Dosing Regimens. During the Part la dose escalation phase, daily dosing amounts and regimens to be studied may include those listed in Table 8. Listed amounts are free base equivalent amounts.

Table 9: Daily Dosing Amounts for Part la Dose Escalation

[00206J The compound of Formula (I) or pharmaceutically acceptable form thereof will be administered on days 1 to 7 and 15 to 21 of a 28-day treatment cycle. Tn some instances, the compound will be administered with or without food, e.g., 40 mg QD.

[00207] In the Part lb dose escalation phase, the combination of the compound of Formula (I) or pharmaceutically acceptable form thereof and cabozantinib will be studied. Cabozantinib will be administered in the form of cabozantinib (S)-malate and amounts listed below are free base equivalent amounts. Doses and regimens to be studied may include those listed in Tables 9 and 10.

Table 10: Daily Dosing Amounts for Part lb Combination Study

Table 11. Dosing Regimens for Part lb Combination Study

[00208] In the Part 2 combination dose expansion phase, one or more dosing regimens from the Part lb dose escalation phase may be selected for continued evaluation of safety, tolerability, and preliminary efficacy.

[00209] Safety Evaluations. DLTs will be evaluated according to NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and will be assessed in cycle 1 (28 days) for all patients in the dose escalation phase. Patients will be DLT evaluable if they have experienced a DLT or have received at least 75% of the planned dose during the DLT evaluation period.

[00210] Efficacy Assessments. Efficacy assessments will be conducted throughout cycle 1 (28 days). Objective Response Rate (Complete Response (CR) and Partial Response (PR)) as determined by the patient’s best tumor response, DoR, and PFS will be assessed using RECIST vl.1 by Investigator assessment. Tumor response assessments will continue until disease progression, initiation of new anticancer therapy, or study withdrawal. Overall survival will also be documented.

[00211] Radiological assessments of tumor lesions will be made at screening, at least once approximately every 8 weeks (± 5 days) for the remainder of the first 12 months of study intervention (through and including Cycle 13), and once approximately every 12 weeks (± 5 days) for year 2 and beyond of study intervention. Additional tumor assessments may be conducted.

[00212] Lesions to be included in the tumor assessments should follow RECIST vl.l. Computed tomography (CT) scan with a contrast agent is the preferred imaging method and the same technique should be used at screening and post-treatment assessments. CT scan coverage at screening should encompass scans of the chest and abdomen (including the liver and adrenals), and pelvis. Any other areas of disease involvement should be scanned based on the patient’s signs and symptoms.

[00213] Pharmacokinetics and Pharmacodynamics. To evaluate the pharmacokinetics of the combination, blood samples will be collected at various timepoints and analyzed for area under the concentration-time curve (AUC), maximum plasma concentration, time to maximum observed concentration, terminal elimination rate constant, terminal half-life, apparent clearance, and apparent volume of distribution, for each agent. Plasma concentrations will be analyzed using a noncompartmental pharmacokinetic analysis (NCA).

[00214] Pharmacodynamic biomarkers and ctDNA will be evaluated during prescreening and during the study. Biomarker analyses may include, but are not limited to: HRAS overexpression, HRAS mutation (including G12D/N/S/V; G13C/D/R/V; Q22T; A59T; Q61R/K/L; K117N;

A146T), HRAS amplification, NRAS mutation (including G12C/D/S, G13V/R, Q61H/K/L/R, A146T), NRAS amplification, farnesylated target proteins, famesyltransferase enzyme activity, serum tumor markers, and ctDNA. These evaluations will be performed using a combination of biochemical, genomic, transcriptomic, and proteomic technology, which may include profiling of mutation, amplification and/or other somatic gene alteration in DNA, RNA, or protein levels in tumor tissue.

[00215] Biomarkers in tumor tissue and blood will be studied for potential correlation between efficacy and/or treatment resistance and underlying biology (e.g., famesylation status of target proteins, clearance rates).

6.1 EXEMPLARY EMBODIMENTS

[00216] One or more than one (including for instance all) of the following exemplary Embodiments may comprise each of the other embodiments or parts thereof.

[00217] Al . A method of treating an advanced solid tumor in a subject comprising administering to the subject a compound of Formula (I):

(I), or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor. [00218] A2. A method of mitigating, slowing the progression of, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject a compound of Formula (I):

(I), or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor.

[00219] A3. A method of preventing or delaying emergence of drug resistance in an advanced solid tumor in a TKI-naive subject, comprising administering to the subject a compound of Formula (I):

(I), or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor.

[00220] A4. The method of any one of embodiments Al to A3, wherein the subject has an advanced solid tumor, suffers from an advanced solid tumor, has symptoms associated with an advanced solid tumor, is diagnosed as having an advanced solid tumor, or is an advanced solid tumor subject in remission.

[00221] A5. The method of any one of embodiments Al to A4, wherein the advanced solid tumor is metastatic, recurrent, unresectable, relapsed, or refractory, or a combination thereof. [00222] A6. The method of any one of embodiments Al to A5, wherein the advanced solid tumor is selected from renal cell carcinoma (RCC) (optionally wherein the RCC is clear cell RCC, papillary RCC, chromophobe RCC, unclassified RCC, or RCC post-nephrectomy), thyroid cancer (optionally wherein the thyroid cancer is medullary thyroid cancer, differentiated thyroid cancer, or radioactive iodine-refractory), hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST) (optionally wherein the GIST is progressive on or intolerant to imatinib), soft tissue sarcoma, pancreatic neuroendocrine tumor (optionally wherein the pancreatic neuroendocrine tumor is progressive, differentiated, locally advanced, or metastatic), or endometrial carcinoma, such as wherein the advanced solid tumor is RCC or clear cell RCC

[00223] A7. The method of any one of embodiments Al to A6, comprising administering the

VEGFR inhibitor to the subject orally, optionally once or twice daily, optionally for one or more treatment cycles.

[00224] A8. The method of any one of embodiments Al to A7, wherein the VEGFR inhibitor is selected from cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, optionally wherein the VEGFR inhibitor is selected from cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, fruquintinib free base, or zanzalintinib fumarate, optionally wherein the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib, optionally wherein the VEGFR inhibitor is cabozantinib. In some embodiments, the VEGFR inhibitor is zanzalintinib. In some embodiments, the VEGFR inhibitor is fruquintinib. [00225] A9. The method of any one of embodiments Al to A8, wherein the method reduces or mitigates toxicities associated with the VEGFR inhibitor, improves the efficacy of the VEGFR inhibitor, delays, halts, or prevents progression of the advanced solid tumor, or increases Time to Progression (TTP), Progression-Free Survival (PFS), Event-Free survival (EFS), Overall Survival (OS), Overall Response Rate (ORR), Complete Response Rate (CR Rate), or Duration of Response (DoR), or a combination of two or more thereof relative to a comparative therapy, optionally wherein the VEGFR inhibitor is cabozantinib, and optionally wherein the advanced solid tumor is renal cell carcinoma or clear cell RCC.

[00226] A10. A method of treating an advanced solid tumor with HRAS amplification and/or

HRAS overexpression, optionally in combination with an HRAS mutation, and optionally with squamous histology, in a subject comprising administering to the subject a compound of Formula (I):

(I), or a pharmaceutically acceptable form thereof.

[00227] Al 1. The method of embodiment A10, wherein the advanced solid tumor is a HNSCC.

[00228] A12. The method of embodiment A10 or Al l, wherein the advanced solid tumor has squamous histology.

[00229] A13. The method of any one of embodiments A10 to A12, wherein the advanced solid tumor has an HRAS amplification.

[00230] A14. The method of any one of embodiments A10 to A13, wherein the advanced solid tumor overexpresses HRAS.

[00231] A15. The method of any one of embodiments A10 to A14, wherein the advanced solid tumor has an HRAS mutation.

[00232] A16. The method of any one of embodiments A10 to A15, wherein the HRAS mutation is a mutation in HRAS gene that encodes a mutant H-Ras protein.

[00233] Al 7. The method of embodiment Al 6, wherein the HRAS gene mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from a group consisting of G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant H-Ras protein, optionally wherein the modification is a G12C, G12D, G12A, G12V, G12S, G12F, G12R, G12N, G13A, G13C, G13V, G13D, GBR, G13S, G13N, G13V Q61E, Q61K, Q61H, Q61L, Q61P, Q61R, Q22K, Q22T, KI 17N, KI 17L, A146V, A146T, or A146P.

[00234] Al 8. A method of treating an advanced solid tumor with NRAS amplification and/or NRAS overexpression, optionally in combination with an NRAS mutation, in a subject comprising administering to the subject a compound of Formula (I):

(I), or a pharmaceutically acceptable form thereof.

[00235] A19. The method of embodiment A18, wherein the advanced solid tumor has NRAS amplification.

[00236] A20. The method of embodiment A18 or A19, wherein the advanced solid tumor overexpresses NRAS.

[00237] A21. The method of any one of embodiments Al 8 to A20, wherein the advanced solid tumor has an NRAS mutation.

[00238] A22. The method of any one of embodiments A18 to A21, wherein the NRAS mutation is a mutation in NRAS gene that encodes a mutant N-Ras protein.

[00239] A23. The method of embodiment A22, wherein the NRAS gene mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from a group consisting of G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant N-Ras protein, optionally wherein the modification is a G12C, G12D, G12S, G12V, G12R, Q61H, Q61K, Q61L, Q61R, or A146T substitution.

[00240] A23. The method of any one of embodiments A10 or A12 to A22, wherein the advanced solid tumor is melanoma, colorectal cancer (carcinoma or adenocarcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, small cell lung carcinoma), breast cancer, ovarian cancer, pancreatic cancer (e.g., carcinoma or ductal adenocarcinoma), glioma, HNSCC, and thyroid cancer, optionally wherein the advanced solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with an NRAS amplification..

[00241] A24. The method of any one of embodiments A10 to A23, wherein the advanced solid tumor is (a) an advanced solid tumor with HRAS amplification, (b) HNSCC with HRAS overexpression, or (c) non-small cell lung cancer, colorectal cancer, or pancreatic ductal adenocarcinoma with an HRAS amplification. [00242] A25. The method of any one of embodiments Al to A24, wherein the advanced solid tumor is metastatic, advanced, relapsed, unresectable, recurrent, or refractory, or a combination thereof.

[00243] A26. The method of any one of embodiments Al to A25, comprising administering the compound of Formula (I), or the pharmaceutically acceptable form thereof, to the subject orally.

[00244] A27. The method of embodiment A26, comprising administering the compound of

Formula (I), or the pharmaceutically acceptable form thereof, to the subject at a dose of 0.5 mg to 2400 mg per day.

[00245] A28. The method of embodiment A27, wherein the dose of the compound of

Formula (I), or the pharmaceutically acceptable form thereof, is 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about

1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about

1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about

2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about

2350 mg, and about 2400 mg per day.

[00246] A29. The method of any one of embodiments Al to A28, comprising administering the compound of Formula (I), or the pharmaceutically acceptable form thereof, once or twice per day, optionally once or twice per day during a 28-day treatment cycle on days 1 to 7, 8 to 14, 15 to 21, 21 to 28, 1 to 7 and 15 to 21, 1 to 21, or 1 to 28 of the treatment cycle.

[00247] A30. The method of embodiment A29, comprising administering the compound of Formula (I), or the pharmaceutically acceptable form thereof, once per day, optionally once per day during a 28-day treatment cycle on days 1 to 7, 8 to 14, 15 to 21, 21 to 28, 1 to 7 and 15 to 21, 1 to 21, or 1 to 28 of the treatment cycle.

[00248] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or are able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.

INCORPORATION BY REFERENCE

[00249] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In case of conflict, the present application, including any definitions herein, will control.

Claims

What is claimed is:

1. A method of treating an advanced solid tumor in a subject comprising administering to the subject a compound of Formula (I): or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor.

2. A method of mitigating, slowing the progression of, or overcoming drug resistance in an advanced solid tumor in a subject, comprising administering to the subject a compound of Formula (I): or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor.

3. A method of preventing or delaying emergence of drug resistance in an advanced solid tumor in a TKI-naive subject, comprising administering to the subject a compound of Formula or a pharmaceutically acceptable form thereof; and a VEGFR inhibitor.

4. The method of any one of claims 1 to 3, wherein the subject has an advanced solid tumor, suffers from an advanced solid tumor, has symptoms associated with an advanced solid tumor, is diagnosed as having an advanced solid tumor, or is an advanced solid tumor subject in remission.

5. The method of any one of claims 1 to 4, wherein the advanced solid tumor is metastatic, recurrent, unresectable, relapsed, or refractory, or a combination thereof.

6. The method of any one of claims 1 to 5, wherein the advanced solid tumor is selected from renal cell carcinoma (RCC) (optionally wherein the RCC is clear cell RCC, papillary RCC, chromophobe RCC, unclassified RCC, or RCC post-nephrectomy), thyroid cancer (optionally wherein the thyroid cancer is medullary thyroid cancer, differentiated thyroid cancer, or radioactive iodine-refractory), hepatocellular carcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST) (optionally wherein the GIST is progressive on or intolerant to imatinib), soft tissue sarcoma, pancreatic neuroendocrine tumor (optionally wherein the pancreatic neuroendocrine tumor is progressive, differentiated, locally advanced, or metastatic), or endometrial carcinoma, such as wherein the advanced solid tumor is RCC or clear cell RCC.

7. The method of any one of claims 1 to 6, comprising administering the VEGFR inhibitor to the subject orally, optionally once or twice daily, optionally for one or more treatment cycles.

8. The method of any one of claims 1 to 7, wherein the VEGFR inhibitor is selected from cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib, optionally wherein the VEGFR inhibitor is selected from cabozantinib (S)-malate, lenvantinib mesylate, axitinib free base, regorafenib monohydrate, vandetanib free base, pazopanib hydrochloride, sunitinib (S)-malate, sorafenib tosylate, tivozanib hydrochloride hydrate, or fruquintinib free base, zanzalintinib fumarate, optionally wherein the VEGFR inhibitor is cabozantinib, axitinib, sunitinib, or sorafenib, optionally wherein the VEGFR inhibitor is cabozantinib, optionally wherein the VEGFR inhibitor is zanzalintinib or fruquintinib.

9. The method of any one of claims 1 to 8, wherein the method reduces or mitigates toxicities associated with the VEGFR inhibitor, improves the efficacy of the VEGFR inhibitor, delays, halts, or prevents progression of the advanced solid tumor, or increases Time to Progression (TTP), Progression-Free Survival (PFS), Event-Free survival (EFS), Overall Survival (OS), Overall Response Rate (ORR), Complete Response Rate (CR Rate), or Duration of Response (DoR), or a combination of two or more thereof relative to a comparative therapy, optionally wherein the VEGFR inhibitor is cabozantinib, and optionally wherein the advanced solid tumor is renal cell carcinoma or clear cell RCC.

10. A method of treating an advanced solid tumor with squamous histology and an HRAS amplification and/or HRAS overexpression, optionally in combination with an HRAS mutation, in a subject comprising administering to the subject a compound of Formula (I): or a pharmaceutically acceptable form thereof.

11. The method of claim 10, wherein the advanced solid tumor is a HNSCC.

12. The method of claim 10 or claim 11, wherein the advanced solid tumor with squamous histology has an HRAS amplification.

13. The method of any one of claims 10 to 12, wherein the advanced solid tumor with squamous histology overexpresses HRAS.

14. The method of any one of claims 10 to 13, wherein the advanced solid tumor has an HRAS mutation.

15. The method of any one of claims 1 to 14, wherein the advanced solid tumor is metastatic, advanced, relapsed, unresectable, recurrent, or refractory, or a combination thereof.

16. The method of any one of claims 1 to 15, comprising administering the compound of Formula (I), or the pharmaceutically acceptable form thereof, to the subject orally.

17. The method of claim 16, comprising administering the compound of Formula (I), or the pharmaceutically acceptable form thereof, to the subject at a dose of 0.5 mg to 2400 mg per day.

18. The method of claim 17, wherein the dose of the compound of Formula (I), or the pharmaceutically acceptable form thereof, is 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, and 2.0 mg, about 2.5 mg, about 3.0 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, and about

2400 mg per day.

19. The method of any one of claims 1 to 18, comprising administering the compound of Formula (I), or the pharmaceutically acceptable form thereof, once or twice per day, optionally once or twice per day during a 28-day treatment cycle on days 1 to 7, 8 to 14, 15 to 21, 21 to 28, 1 to 7 and 15 to 21, 1 to 21, or 1 to 28 of the treatment cycle.

20. The method of claim 19, comprising administering the compound of Formula (I), or the pharmaceutically acceptable form thereof, once per day, optionally once per day during a 28-day treatment cycle on days 1 to 7, 8 to 14, 15 to 21, 21 to 28, 1 to 7 and 15 to 21, 1 to 21, or 1 to 28 of the treatment cycle.