WO2025096647A1 - Methods of treating tumors - Google Patents

Abstract

The present invention relates to methods of treating tumors using HPK1 inhibitors. The invention also provides doses and schedules for treating tumors in a patient.

Description

METHODS OF TREATING TUMORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Appl. No. 63/594,354, filed October 30, 2023, the content of which is herein incorporated by reference. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to methods of treating tumors using HPK1 inhibitors. The invention also provides doses and schedules for treating tumors in a patient. BACKGROUND OF THE INVENTION [0003] Hematopoietic progenitor kinase 1 (HPK1, also known as MAP4K1) is a member of the MAP4K family of protein serine/threonine kinases, involved in negatively regulating signal transduction cascades in cells of hematopoietic lineage. Inhibition of HPK1 has the potential to enhance and prime a patient’s immune system to recognize and eliminate tumor cells and also to augment immune checkpoint blockade (ICB) therapies on T cell responses (Sawasdikosol and Burakoff. "A perspective on HPK1 as a novel immuno-oncology drug target." Elife 9 (2020): e55122). [0004] There is an urgent and compelling unmet medical need for effective dosing and schedules of HPK1 inhibitors to provide single-agent and combination therapy activity in tumors. SUMMARY OF THE INVENTION [0005] It has been found that certain HPK1 inhibitors are suitable for administration to a patient for treating tumors. Accordingly, in one aspect, the present invention provides a method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of less than 200 mg to the patient; and wherein Compound A is (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo [1,2-a]pyridin-3-yl)isoindolin-1-one. [0006] In one aspect, the the present invention provides a method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor; wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of less than 200 mg to the patient; and _32197324.1 Page 1 of 77 _{398110-86HPWO (213250)} wherein Compound A is (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)- 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one. [0007] In some embodiments, a tumor selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer. [0008] These and other aspects of this disclosure will be apparent upon reference to the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS [0009] FIG.1 shows that Compound A inhibits HPK1-mediated phosphorylation of BLNK in purified human B cells. [0010] FIG.2 shows that Compound A dose-dependently increased B cell proliferation. [0011] FIG. 3 shows CT-26 model data where Compound A treatment enhances KLH-specific antibody production in vivo. [0012] FIG.4 shows Compound A treatment induces robust tumor growth inhibition, increased serum cytokines and circulating antibodies in CT-26 syngeneic animals. [0013] FIGs.5-8 shows Compound A treatment induces robust tumor growth inhibition in the EMT6 syngeneic model characterized by increased circulating IgG antibodies and significant B cell tumor infiltration. [0014] FIG. 9 depicts the overall clinical study scheme. ^a Response triggers opening of additional tumor-specific cohorts. [0015] FIG.10 depicts the dose escalation and refinement scheme (n=25). [0016] FIG. 11 depicts the duration of treatment/best overall response (BOR), according to RECIST 1.1 (response-evaluable analyst set; n=13). [0017] FIG. 12 depicts a waterfall plot showing percent change in tumor size (n=13). Analysis population included all patients with a post-baseline assessment. [0018] FIG.13 depicts CT scans of the patient with RCC and a CR. [0019] FIG. 14 depicts the mean Compound A concentration of Cycle 1 Day 1 in the PK analysis set (n=27). The PK analysis set includes patients with at least one post-baseline plasma sample available for PK analysis who received at least one dose of Compound A. Concentrations below the limit of quantification were plotted at half-BLQ. [0020] FIG. 15 depicts the change in percentage pSLP76 from baseline to Day 15 of Cycle 1 in the _32197324.1 Page 2 of 77 _{398110-86HPWO (213250)} PD analysis set (n=16). Patients with a plasma sample available for pSLP76 analysis. [0021] FIG. 16 depicts the percentage of pSLP76 at Cycle 1 Day 1 relative to baseline according to Compound A plasma concentrations. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0022] Compound A is a novel small molecule inhibitor of HPK1 that was identified through structure- based drug design and was selected for clinical development based on potency against HPK1, its effects on T cell, B cell, and dendritic cell activation in vitro, and its ability to modulate immune responses and inhibit tumor growth in mouse tumor models. Compound A has high selectivity for HPK1 versus other kinases and has limited potential for other “off-target” effects at high multiples of the concentrations that inhibit HPK1 in vitro. Compound A is provided by oral administration at the doses and schedules described herein. [0023] In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention. [0024] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. 2. Definitions: [0025] As used in the specification and appended claims, unless specified to the contrary, the following terms and abbreviations have the following meanings. _32197324.1 Page 3 of 77 _{398110-86HPWO (213250)} [0026] As used herein, the term “about” refers to within 20% of a given value. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value. For example, the term “about” recited in reference to a provided dose can refer to ± 5 mg, ± 4 mg, ± 3 mg, ± 2 mg, or ± 1 mg of a provided dose. [0027] As used herein, the term “Compound A” refers to ((S)-7-((6-((dimethylamino)methyl)-5- (tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one having the formula: is an active antagonist of HPK1.

and its synthesis is described in Example 21 of WO 2021/050964. [0028] As used herein, the term “inhibitor” is defined as a compound that binds to and/or inhibits HPK1 with measurable affinity. In certain embodiments, an inhibitor has an IC₅₀ and/or binding constant of less than about 10 µM, less than about 1 µM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. [0029] The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human. [0030] As used herein, the term “mg/kg” or “mpk” refers to the milligram of medication (for example, Compound A) per kilogram of the body weight of the subject taking the medication. [0031] 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 humans and lower animals 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, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic _32197324.1 Page 4 of 77 _{398110-86HPWO (213250)} acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0032] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0033] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, a warhead moiety, R¹, of a provided compound comprises one or more deuterium atoms. In certain embodiments, Ring B of a provided compound may be substituted with one or more deuterium atoms. [0034] As used herein, a "HPK1 antagonist" or a "HPK1 inhibitor" is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of HPK1 (e.g., serine/threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with a protein binding partner, such as SLP76). Antagonism using the HPK1 antagonist does not necessarily indicate a total elimination of the HPK1 activity. Instead, the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, _32197324.1 Page 5 of 77 _{398110-86HPWO (213250)} 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of HPK1 compared to an appropriate control. In some embodiments, the HPK1 antagonist reduces, inhibits, or otherwise diminishes the serine/threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist reduces, inhibits, or otherwise diminishes the HPK1-mediated phosphorylation of SLP76 and/or Gads. The presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity. [0035] By "specific antagonist" is intended an agent that reduces, inhibits, or otherwise diminishes the activity of a defined target greater than that of an unrelated target. For example, a HPK1 specific antagonist reduces at least one biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine/threonine kinases). In some embodiments, the IC50 of the antagonist for the target is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% or less of the IC50 of the antagonist for a non-target. The presently disclosed compounds may or may not be a specific HPK1 antagonist. A specific HPK1 antagonist reduces the biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine/threonine kinases). In certain embodiments, the HPK1 antagonist specifically inhibits the serine/threonine kinase activity of HPK1. In some of these embodiments, the IC50 of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC50 of the HPK1 antagonist for another serine/threonine kinase or other type of kinase (e.g., tyrosine kinase). [0036] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. [0037] The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration _32197324.1 Page 6 of 77 _{398110-86HPWO (213250)} into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR). [0038] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. 3. Description of Exemplary Embodiments: [0039] According to one aspect, the invention provides a method for treating a tumor in a patient in need thereof, comprising administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering less than 200 mg of Compound A or a pharmaceutically acceptable salt thereof in a single oral dose. In some embodiments, the method comprises administering less than 200 mg of Compound A or a pharmaceutically acceptable salt thereof in a single oral dose in combination with a checkpoint inhibitor. In some embodiments, a patient has a tumor (i.e., a tumor patient). In some embodiments, a tumor patient has a relapsed and/or refractory tumor. In some embodiments, a tumor patient has a relapsed and/or refractory solid tumor. In some embodiments, a tumor patient has a relapsed and/or refractory liquid tumor. In some embodiments, the patient has received no prior therapy (i.e., the treatment with Compound A or Compound A and a checkpoint inhibitor of the present invention is a first line therapy). In some embodients, the patient has received at least one prior therapy. In some embodiments, the patient has received at least two prior therapies. [0040] >Y ^ZXQ QXNZPUXQY_^% M _`XZ] [M_UQY_ U^ XMWQ Z] RQXMWQ [M_UQY_ MSQP g*1 dQM]^' [0041] >Y ^ZXQ QXNZPUXQY_^% M _`XZ] [M_UQY_ TM^ M WURQ Qc[QO_MYOd ZR g*+ bQQV^' [0042] In some embodiments, a tumor patient has measurable or non-measurable disease. [0043] In some embodiments, a tumor patient has measurable disease using RECIST v1.1. [0044] In some embodiments, a tumor patient has recovered from prior therapy (per NCI CTCAE aQ]^UZY .')$ _Z <]MPQ f * Z] ]Q_`]Y _Z NM^QWUYQ ^_M_`^ #QcOQ[_ RZ] MWZ[QOUM$' _32197324.1 Page 7 of 77 _{398110-86HPWO (213250)} [0045] In some embodiments, a tumor patient has Eastern Cooperative Oncology Group (ECOG) performance status 0-1. [0046] In some embodiments, a tumor patient has adequate bone marrow function defined by one or more of the following: · 6B8 ZR g *'.i*)⁹/L without the use of hematopoietic growth factors within 6 weeks prior to dosing of Compound A; · CWM_QWQ_ OZ`Y_ ZR g *))')i*)<sup>9</sup>/L; and · =QXZSWZNUY ZR g 2') S(P@ #bU_T Z] bU_TZ`_ _]MY^R`^UZY$' [0047] In some embodiments, a tumor patient has adequate renal function, including serum creatinine 5*'. c `[[Q] WUXU_ ZR YZ]XMW #H@B$ Z] Q^_UXM_QP O]QM_UYUYQ OWQM]MYOQ #8]8W$ g.) X@(XUY OMWO`WM_QP Nd _TQ Cockcroft-Gault formula. [0048] In some embodiments, a tumor patient has adequate hepatic function defined as one or more of the following: · FQ]`X _Z_MW NUWU]`NUY f *'. i H@B; · 6^[M]_M_Q MXUYZ_]MY^RQ]M^Q #6FG$ MYP MWMYUYQ MXUYZ_]MY^RQ]M^Q #6@G$ f +'. i H@B #Z] f . i H@B in patients with liver metastases; and · f , c H@B UY [M_UQY_^ bU_T <UWNQ]_h^ ^dYP]ZXQ$' [0049] In some embodiments, a tumor patient is a woman of childbearing potential (WOCBP) and uses a highly effective contraceptive method from the time of informed consent until 6 months after treatment with Compound A as described herein. [0050] In some embodiments, a tumor patient that is WOCBP must have a negative serum or urine pregnancy test within 48 hours prior to Cycle 1 Day 1 of treatment. [0051] In some embodiments, a tumor patient has a histologically or cytologically confirmed advanced or metastatic solid tumor for which no standard therapies are available or are refractory to standard therapy. [0052] In some embodiments, a tumor patient has a histologically or cytologically confirmed advanced or metastatic G/GEJ, NSCLS or RCC for which no standard therapy is available or are refractory to standard therapy, such as defined by one of the following: · HER2-positive disease patients (G/GEJ) must have received prior HER2-directed antibody. HER2- positive disease defined as either IHC3+ or IHC2+/ISH+ (ISH positivity is defined as a HER2: OQY_]ZXQ]Q QY`XQ]M_UZY []ZNQ RZ] OT]ZXZ^ZXQ *0 K8:C*0L ]M_UZ ZR g +$4 · NSCLC patients must have been treated with at least 1 but not more than 2 prior lines of systemic chemotherapy AND received prior anti-PD-1 or anti-PD-L1 therapy for metastatic or recurrent disease; and _32197324.1 Page 8 of 77 _{398110-86HPWO (213250)} · RCC patients must have received at least 1 prior line of systemic therapy for advanced metastatic and unresectable disease. [0053] In some embodiments, a tumor patient does not have previous solid organ or hematopoietic stem cell transplant. [0054] In some embodiments, a tumor patient does not have a central nervous system (CNS) malignant disease not previously treated, active leptomeningeal disease, uncontrolled symptomatic CNS involvement, or CNS malignant disease requiring steroid or other therapeutic intervention. [0055] In some embodiments, a tumor patient has not had prior anticancer treatment, including one or more of the following: · Systemic anticancer treatment: chemotherapy, antibody, or other biologic anticancer therapeutic <4 weeks prior to first dose of Compound A as described herein (<6 weeks for nitrosoureas or mitomycin C); · Radiation therapy (including radiofrequency ablation) <4 weeks prior to the first dose of Compound A as described herein; · Stereotactic body radiation therapy <2 weeks prior to the first dose of Compound A as described herein; · Chemoembolization or radioembolization < 4 weeks prior to the first dose of Compound A as described herein; and · Small molecule therapies, included targeted therapies <2 weeks or 5 half-lives whichever is longer. [0056] In some embodiments, a tumor patient does not have a clinically significant cardiovascular disease including one or more of the following: · Myocardial infarction/stroke within 3 months prior to the first dose of Compound A as described herein; · Unstable angina within 3 months prior to the first dose of Compound A as described herein; · Congestive heart failure or cardiomyopathy with New York Heart Association Class 3 or 4 by clinical assessment; · History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes); · Uncontrolled hypertension (as defined per institutional standards) despite 2 concomitant antihypertensive therapies; and · DG UY_Q]aMW OZ]]QO_QP Nd _TQ ;]UPQ]UOUM OZ]]QO_UZY RZ]X`WM #DGO;$ g-1) X^QO ZY _TQ FO]QQYUYS ECG. <sub>32197324.1</sub> Page 9 of 77 <sub>398110-86HPWO (213250)</sub> [0057] In some embodiments, a tumor patient does not have a history of severe immune-related adverse events (irAE) that led to permanent discontinuation of prior immunotherapy. [0058] >Y ^ZXQ QXNZPUXQY_^% M _`XZ] [M_UQY_ PZQ^ YZ_ TMaQ M TU^_Z]d ZR <]MPQ g , U]6: bU_TUY _TQ past 16 weeks or any Grade 4 life-threatening irAE (regardless of duration) or neurologic or ocular AE of any grade while receiving prior immunotherapy. [0059] In some embodiments, a tumor patient does not have a history of severe hypersensitivity reaction to treatment with monoclonal antibody(ies) (for combination therapy cohorts only). [0060] In some embodiments, a tumor patient does not requires systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to Day 1 of treatment of Compound A as described herein. [0061] In some embodiments, a tumor patient does not have a history of interstitial lung disease, idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on chest computed tomography scan in the last 6 months. [0062] In some embodiments, a tumor patient has not had major surgery within 4 weeks of starting dose of Compound A as described herein or not recovered from any effects of prior major surgery. [0063] In some embodiments, a tumor patient does not have gastrointestinal disorders that may interfere with absorption of the study medication. [0064] In some embodiments, a tumor patient does not have uncontrolled active infection requiring intravenous (IV) antibiotic, antiviral, or anti-fungal medications within 14 days prior to first dose of Compound A as described herein. [0065] In some embodiments, a tumor patient does not have a known additional malignancy that is active and/or in progression requiring treatment. Exceptions include basal cell or squamous cell skin cancer, or other cancer for which the patient has been disease-free for at least two years. [0066] In some embodiments, a tumor patient does not have active infection with human immunodeficiency virus (HIV). [0067] In some embodiments, a tumor patient does not have active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). [0068] In some embodiments, a tumor patient does not have known current drug or alcohol abuse. [0069] In some embodiments, a tumor patient does not have an unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes, thromboembolic event within the past 3 months) or any important medical or psychiatric illness or abnormal laboratory finding. [0070] In some embodiments, a tumor patient has not had prior treatment with an HPK1 inhibitor. _32197324.1 Page 10 of 77 _{398110-86HPWO (213250)} [0071] In some embodiments, a tumor patient in not taking medications that are strong inducers or inhibitors of CYP3A4 that cannot be discontinued prior to treatment with Compound A. Pharmaceutically acceptable compositions [0072] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit HPK1, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit HPK1, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [0073] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. [0074] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions. [0075] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. Administration and Dosage [0076] In some embodiments, a method of the present invention comprises administering Compound A as described herein. In some embodiments, a method of the present invention comprises orally administering Compound A as described herein. In some embodiments, a method of the present invention comprises orally administering Compound A daily as described herein. In some embodiments, a method of the present invention comprises administering a unit dosage form as described herein. In some embodiments, a method of the present invention comprises orally administering a unit dosage form as _32197324.1 Page 11 of 77 _{398110-86HPWO (213250)} described herein. In some embodiments, a method of the present invention comprises orally administering a unit dosage form daily as described herein. In some embodiments, a method of the present invention comprises orally administering to a patient Compound A or a unit dosage form as described herein. [0077] In some embodiments, a method of the present invention comprises administering to a patient less than 400 mg of Compound A or pharmaceutically acceptable salt thereof, for example, less than 395 mg, less than 390 mg, less than 385 mg, less than 380 mg, less than 375 mg, less than 370 mg, less than 365 mg, less than 360 mg, less than 355 mg, less than 350 mg, less than 345 mg, less than 340 mg, less than 335 mg, less than 330 mg, less than 325 mg, less than 320 mg, less than 315 mg, less than 310 mg, less than 305 mg, less than 300 mg, less than 295 mg, less than 290 mg, less than 285 mg, less than 280 mg, less than 275 mg, less than 270 mg, less than 265 mg, less than 260 mg, less than 255 mg, less than 250 mg, less than 245 mg, less than 240 mg, less than 235 mg, less than 230 mg, less than 225 mg, less than 220 mg, less than 215 mg, less than 210 mg, less than 205 mg, less than 200 mg, less than 195 mg, less than 190 mg, less than 185 mg, less than 180 mg, less than 175 mg, less than 170 mg, less than 165 mg, less than 160 mg, less than 155 mg, less than 150 mg, less than 145 mg, less than 140 mg, less than 135 mg, less than 130 mg, less than 125 mg, less than 120 mg, less than 115 mg, less than 110 mg, less than 105 mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg, less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, less than 60 mg, less than 55 mg, or less than 50 mg of Compound A or pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering daily to a patient less than 170 mg, less than 160 mg, or less than 150 mg of Compound A or pharmaceutically acceptable salt thereof. [0078] In some embodiments, a method of the present invention comprises administering to a patient about 20 mg to 200 mg (for example, 20 mg to 30 mg, 20 mg to 40 mg, 20 mg to 50 mg, 20 mg to 60 mg, 20 mg to 70 mg, 20 mg to 80 mg, 20 mg to 90 mg, 20 mg to 100 mg, 20 mg to 110 mg, 20 mg to 120 mg, 20 mg to 130 mg, 20 mg to 140 mg, 20 mg to 150 mg, 20 mg to 160 mg, 20 mg to 170 mg, 20 mg to 180 mg, 20 mg to 190 mg, 20 mg to 200 mg, 30 mg to 40 mg, 30 mg to 50 mg, 30 mg to 60 mg, 30 mg to 70 mg, 30 mg to 80 mg, 30 mg to 90 mg, 30 mg to 100 mg, 30 mg to 110 mg, 30 mg to 120 mg, 30 mg to 130 mg, 30 mg to 140 mg, 30 mg to 150 mg, 30 mg to 160 mg, 30 mg to 170 mg, 30 mg to 180 mg, 30 mg to 190 mg, 30 mg to 200 mg, 40 mg to 50 mg, 40 mg to 60 mg, 40 mg to 70 mg, 40 mg to 80 mg, 40 mg to 90 mg, 40 mg to 100 mg, 40 mg to 110 mg, 40 mg to 120 mg, 40 mg to 130 mg, 40 mg to 140 mg, 40 mg to 150 mg, 40 mg to 160 mg, 40 mg to 170 mg, 40 mg to 180 mg, 40 mg to 190 mg, 40 mg to 200 mg, 50 mg to 60 mg, 50 mg to 70 mg, 50 mg to 80 mg, 50 mg to 90 mg, 50 mg to 100 mg, 50 mg to 110 mg, 50 mg to 120 mg, 50 mg to 130 mg, 50 mg to 140 mg, 50 mg to 150 mg, 50 mg to 160 mg, 50 mg to 170 mg, 50 mg to 180 mg, 50 mg to 190 mg, 50 mg to 200 mg, 60 mg to 70 mg, 60 mg to 80 mg, 60 mg to 90 mg, 60 mg to 100 mg, 60 mg to 110 mg, 60 mg to 120 mg, 60 mg to 130 mg, 60 mg to 140 mg, 60 mg to 150 _32197324.1 Page 12 of 77 _{398110-86HPWO (213250)} mg, 60 mg to 160 mg, 60 mg to 170 mg, 60 mg to 180 mg, 60 mg to 190 mg, 60 mg to 200 mg, 70 mg to 80 mg, 70 mg to 90 mg, 70 mg to 100 mg, 70 mg to 110 mg, 70 mg to 120 mg, 70 mg to 130 mg, 70 mg to 140 mg, 70 mg to 150 mg, 70 mg to 160 mg, 70 mg to 170 mg, 70 mg to 180 mg, 70 mg to 190 mg, 70 mg to 200 mg, 80 mg to 90 mg, 80 mg to 100 mg, 80 mg to 110 mg, 80 mg to 120 mg, 80 mg to 130 mg, 80 mg to 140 mg, 80 mg to 150 mg, 80 mg to 160 mg, 80 mg to 170 mg, 80 mg to 180 mg, 80 mg to 190 mg, 80 mg to 200 mg, 90 mg to 100 mg, 90 mg to 110 mg, 90 mg to 120 mg, 90 mg to 130 mg, 90 mg to 140 mg, 90 mg to 150 mg, 90 mg to 160 mg, 90 mg to 170 mg, 90 mg to 180 mg, 90 mg to 190 mg, 90 mg to 200 mg, 100 mg to 110 mg, 100 mg to 120 mg, 100 mg to 130 mg, 100 mg to 140 mg, 100 mg to 150 mg, 100 mg to 160 mg, 100 mg to 170 mg, 100 mg to 180 mg, 100 mg to 190 mg, 100 mg to 200 mg, 110 mg to 120 mg, 110 mg to 130 mg, 110 mg to 140 mg, 110 mg to 150 mg, 110 mg to 160 mg, 110 mg to 170 mg, 110 mg to 180 mg, 110 mg to 190 mg, 110 mg to 200 mg, 120 mg to 130 mg, 120 mg to 140 mg, 120 mg to 150 mg, 120 mg to 160 mg, 120 mg to 170 mg, 120 mg to 180 mg, 120 mg to 190 mg, 120 mg to 200 mg, 130 mg to 140 mg, 130 mg to 150 mg, 130 mg to 160 mg, 130 mg to 170 mg, 130 mg to 180 mg, 130 mg to 190 mg, 130 mg to 200 mg, 140 mg to 150 mg, 140 mg to 160 mg, 140 mg to 170 mg, 140 mg to 180 mg, 140 mg to 190 mg, 140 mg to 200 mg, 150 mg to 160 mg, 150 mg to 170 mg, 150 mg to 180 mg, 150 mg to 190 mg, 150 mg to 200 mg, 160 mg to 170 mg, 160 mg to 180 mg, 160 mg to 190 mg, 160 mg to 200 mg, 170 mg to 180 mg, 170 mg to 190 mg, 170 mg to 200 mg, 180 mg to 190 mg, 180 mg to 200 mg, or 190 mg to 200 mg) of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering daily to a patient 20 mg to 160 mg, 40 mg to 150 mg, 50 mg to 170 mg, or 100 mg to 150 mg of Compound A or a pharmaceutically acceptable salt thereof. [0079] In some embodiments, a method of the present invention comprises administering to a patient about 20 mg, 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 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, or about 395 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering _32197324.1 Page 13 of 77 _{398110-86HPWO (213250)} to a patient about 50 mg or about 100 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 20 mg, 30 mg, 40 mg, or 50 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 20 mg, 30 mg, 40 mg, or 50 mg of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [0080] In some embodiments, a method of the present invention comprises administering to a patient 20 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 25 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 30 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 35 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 40 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 45 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 50 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 55 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 60 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 65 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 70 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 75 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 80 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 85 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 90 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 95 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 100 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention _32197324.1 Page 14 of 77 _{398110-86HPWO (213250)} comprises administering to a patient about 105 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 110 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 115 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 120 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 125 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 130 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 135 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 140 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 145 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 150 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 155 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 160 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 165 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 170 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 175 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 180 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 185 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 190 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient about 195 mg of Compound A or a pharmaceutically acceptable salt thereof. [0081] In some embodiments, a method of the present invention comprises administering to a patient 0.7 mg/kg to 3.1 mg/kg (for example, 0.8 mg/kg to 1.1 mg/kg, 0.8 mg/kg to 1.2 mg/kg, 0.8 mg/kg to 1.3 _32197324.1 Page 15 of 77 _{398110-86HPWO (213250)} mg/kg, 0.8 mg/kg to 1.4 mg/kg, 0.8 mg/kg to 1.5 mg/kg, 0.8 mg/kg to 1.6 mg/kg, 0.8 mg/kg to 1.7 mg/kg, 0.8 mg/kg to 1.8 mg/kg, 0.8 mg/kg to 1.9 mg/kg, 0.8 mg/kg to 2.0 mg/kg, 0.8 mg/kg to 2.1 mg/kg, 0.8 mg/kg to 2.2 mg/kg, 0.8 mg/kg to 2.3 mg/kg, 0.8 mg/kg to 2.4 mg/kg, 0.8 mg/kg to 2.5 mg/kg, 0.8 mg/kg to 2.6 mg/kg, 0.8 mg/kg to 2.7 mg/kg, 0.8 mg/kg to 2.8 mg/kg, 0.8 mg/kg to 2.9 mg/kg, 0.8 mg/kg to 3. mg/kg, 0.9 mg/kg to 1.2 mg/kg, 0.9 mg/kg to 1.3 mg/kg, 0.9 mg/kg to 1.4 mg/kg, 0.9 mg/kg to 1.5 mg/kg, 0.9 mg/kg to 1.6 mg/kg, 0.9 mg/kg to 1.7 mg/kg, 0.9 mg/kg to 1.8 mg/kg, 0.9 mg/kg to 1.9 mg/kg, 0.9 mg/kg to 2.0 mg/kg, 0.9 mg/kg to 2.1 mg/kg, 0.9 mg/kg to 2.2 mg/kg, 0.9 mg/kg to 2.3 mg/kg, 0.9 mg/kg to 2.4 mg/kg, 0.9 mg/kg to 2.5 mg/kg, 0.9 mg/kg to 2.6 mg/kg, 0.9 mg/kg to 2.7 mg/kg, 0.9 mg/kg to 2.8 mg/kg, 0.9 mg/kg to 2.9 mg/kg, 0.9 mg/kg to 3.0 mg/kg, 1.0 mg/kg to 1.3 mg/kg, 1.0 mg/kg to 1.4 mg/kg, 1.0 mg/kg to 1.5 mg/kg, 1.0 mg/kg to 1.6 mg/kg, 1.0 mg/kg to 1.7 mg/kg, 1.0 mg/kg to 1.8 mg/kg, 1.0 mg/kg to 1.9 mg/kg, 1.0 mg/kg to 2.0 mg/kg, 1.0 mg/kg to 2.1 mg/kg, 1.0 mg/kg to 2.2 mg/kg, 1.0 mg/kg to 2.3 mg/kg, 1.0 mg/kg to 2.4 mg/kg, 1.0 mg/kg to 2.5 mg/kg, 1.0 mg/kg to 2.6 mg/kg, 1.0 mg/kg to 2.7 mg/kg, 1.0 mg/kg to 2.8 mg/kg, 1.0 mg/kg to 2.9 mg/kg, 1.0 mg/kg to 3.0 mg/kg, 1.1 mg/kg to 1.4 mg/kg, 1.1 mg/kg to 1.5 mg/kg, 1.1 mg/kg to 1.6 mg/kg, 1.1 mg/kg to 1.7 mg/kg, 1.1 mg/kg to 1.8 mg/kg, 1.1 mg/kg to 1.9 mg/kg, 1.1 mg/kg to 2.0 mg/kg, 1.1 mg/kg to 2.1 mg/kg, 1.1 mg/kg to 2.2 mg/kg, 1.1 mg/kg to 2.3 mg/kg, 1.1 mg/kg to 2.4 mg/kg, 1.1 mg/kg to 2.5 mg/kg, 1.1 mg/kg to 2.6 mg/kg, 1.1 mg/kg to 2.7 mg/kg, 1.1 mg/kg to 2.8 mg/kg, 1.1 mg/kg to 2.9 mg/kg, 1.1 mg/kg to 3.0 mg/kg, 1.2 mg/kg to 1.5 mg/kg, 1.2 mg/kg to 1.6 mg/kg, 1.2 mg/kg to 1.7 mg/kg, 1.2 mg/kg to 1.8 mg/kg, 1.2 mg/kg to 1.9 mg/kg, 1.2 mg/kg to 2.0 mg/kg, 1.2 mg/kg to 2.1 mg/kg, 1.2 mg/kg to 2.2 mg/kg, 1.2 mg/kg to 2.3 mg/kg, 1.2 mg/kg to 2.4 mg/kg, 1.2 mg/kg to 2.5 mg/kg, 1.2 mg/kg to 2.6 mg/kg, 1.2 mg/kg to 2.7 mg/kg, 1.2 mg/kg to 2.8 mg/kg, 1.2 mg/kg to 2.9 mg/kg, 1.2 mg/kg to 3.0 mg/kg, 1.3 mg/kg to 1.6 mg/kg, 1.3 mg/kg to 1.7 mg/kg, 1.3 mg/kg to 1.8 mg/kg, 1.3 mg/kg to 1.9 mg/kg, 1.3 mg/kg to 2.0 mg/kg, 1.3 mg/kg to 2.1 mg/kg, 1.3 mg/kg to 2.2 mg/kg, 1.3 mg/kg to 2.3 mg/kg, 1.3 mg/kg to 2.4 mg/kg, 1.3 mg/kg to 2.5 mg/kg, 1.3 mg/kg to 2.6 mg/kg, 1.3 mg/kg to 2.7 mg/kg, 1.3 mg/kg to 2.8 mg/kg, 1.3 mg/kg to 2.9 mg/kg, 1.3 mg/kg to 3.0 mg/kg, 1.4 mg/kg to 1.7 mg/kg, 1.4 mg/kg to 1.8 mg/kg, 1.4 mg/kg to 1.9 mg/kg, 1.4 mg/kg to 2.0 mg/kg, 1.4 mg/kg to 2.1 mg/kg, 1.4 mg/kg to 2.2 mg/kg, 1.4 mg/kg to 2.3 mg/kg, 1.4 mg/kg to 2.4 mg/kg, 1.4 mg/kg to 2.5 mg/kg, 1.4 mg/kg to 2.6 mg/kg, 1.4 mg/kg to 2.7 mg/kg, 1.4 mg/kg to 2.8 mg/kg, 1.4 mg/kg to 2.9 mg/kg, 1.4 mg/kg to 3.0 mg/kg, 1.5 mg/kg to 1.8 mg/kg, 1.5 mg/kg to 1.9 mg/kg, 1.5 mg/kg to 2.0 mg/kg, 1.5 mg/kg to 2.1 mg/kg, 1.5 mg/kg to 2.2 mg/kg, 1.5 mg/kg to 2.3 mg/kg, 1.5 mg/kg to 2.4 mg/kg, 1.5 mg/kg to 2.5 mg/kg, 1.5 mg/kg to 2.6 mg/kg, 1.5 mg/kg to 2.7 mg/kg, 1.5 mg/kg to 2.8 mg/kg, 1.5 mg/kg to 2.9 mg/kg, 1.5 mg/kg to 3.0 mg/kg, 1.6 mg/kg to 1.9 mg/kg, 1.6 mg/kg to 2.0 mg/kg, 1.6 mg/kg to 2.1 mg/kg, 1.6 mg/kg to 2.2 mg/kg, 1.6 mg/kg to 2.3 mg/kg, 1.6 mg/kg to 2.4 mg/kg, 1.6 mg/kg to 2.5 mg/kg, 1.6 mg/kg to 2.6 mg/kg, 1.6 mg/kg to 2.7 mg/kg, 1.6 mg/kg to 2.8 mg/kg, 1.6 mg/kg to 2.9 mg/kg, 1.6 mg/kg to 3.0 mg/kg, 1.7 mg/kg to 2.0 mg/kg, 1.7 mg/kg to 2.1 mg/kg, 1.7 mg/kg to 2.2 mg/kg, 1.7 _32197324.1 Page 16 of 77 _{398110-86HPWO (213250)} mg/kg to 2.3 mg/kg, 1.7 mg/kg to 2.4 mg/kg, 1.7 mg/kg to 2.5 mg/kg, 1.7 mg/kg to 2.6 mg/kg, 1.7 mg/kg to 2.7 mg/kg, 1.7 mg/kg to 2.8 mg/kg, 1.7 mg/kg to 2.9 mg/kg, 1.7 mg/kg to 3.0 mg/kg, 1.8 mg/kg to 2.1 mg/kg, 1.8 mg/kg to 2.2 mg/kg, 1.8 mg/kg to 2.3 mg/kg, 1.8 mg/kg to 2.4 mg/kg, 1.8 mg/kg to 2.5 mg/kg, 1.8 mg/kg to 2.6 mg/kg, 1.8 mg/kg to 2.7 mg/kg, 1.8 mg/kg to 2.8 mg/kg, 1.8 mg/kg to 2.9 mg/kg, 1.8 mg/kg to 3.0 mg/kg, 1.9 mg/kg to 2.2 mg/kg, 1.9 mg/kg to 2.3 mg/kg, 1.9 mg/kg to 2.4 mg/kg, 1.9 mg/kg to 2.5 mg/kg, 1.9 mg/kg to 2.6 mg/kg, 1.9 mg/kg to 2.7 mg/kg, 1.9 mg/kg to 2.8 mg/kg, 1.9 mg/kg to 2.9 mg/kg, 1.9 mg/kg to 3.0 mg/kg, 2.0 mg/kg to 2.3 mg/kg, 2.0 mg/kg to 2.4 mg/kg, 2.0 mg/kg to 2.5 mg/kg, 2.0 mg/kg to 2.6 mg/kg, 2.0 mg/kg to 2.7 mg/kg, 2.0 mg/kg to 2.8 mg/kg, 2.0 mg/kg to 2.9 mg/kg, 2.0 mg/kg to 3.0 mg/kg, 2.1 mg/kg to 2.4 mg/kg, 2.1 mg/kg to 2.5 mg/kg, 2.1 mg/kg to 2.6 mg/kg, 2.1 mg/kg to 2.7 mg/kg, 2.1 mg/kg to 2.8 mg/kg, 2.1 mg/kg to 2.9 mg/kg, 2.1 mg/kg to 3.0 mg/kg, 2.2 mg/kg to 2.5 mg/kg, 2.2 mg/kg to 2.6 mg/kg, 2.2 mg/kg to 2.7 mg/kg, 2.2 mg/kg to 2.8 mg/kg, 2.2 mg/kg to 2.9 mg/kg, 2.2 mg/kg to 3.0 mg/kg, 2.3 mg/kg to 2.6 mg/kg, 2.3 mg/kg to 2.7 mg/kg, 2.3 mg/kg to 2.8 mg/kg, 2.3 mg/kg to 2.9 mg/kg, 2.3 mg/kg to 3.0 mg/kg, 2.4 mg/kg to 2.7 mg/kg, 2.4 mg/kg to 2.8 mg/kg, 2.4 mg/kg to 2.9 mg/kg, 2.4 mg/kg to 3.0 mg/kg, 2.5 mg/kg to 2.8 mg/kg, 2.5 mg/kg to 2.9 mg/kg, 2.5 mg/kg to 3.0 mg/kg, 2.6 mg/kg to 2.9 mg/kg, 2.6 mg/kg to 3.0 mg/kg, 2.7 mg/kg to 3.0 mg/kg) of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering to a patient 0.7 mg/kg to 3.1 mg/kg, 1.0 mg/kg to 2.8 mg/kg, or 1.5 mg/kg to 2.5 mg/kg of Compound A or a pharmaceutically acceptable salt thereof. [0082] In some embodiments, a method of the present invention comprises administering to a patient one or more unit doses of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form comprises 10 mg to 200 mg, 10 mg to 175 mg, 10 mg to 150 mg, 10 mg to 125 mg, 10 mg to 100 mg, 10 mg to 75 mg, 10 mg to 50 mg, 10 mg to 25 mg, 10 mg to 20 mg, 20 mg to 200 mg, 20 mg to 175 mg, 20 mg to 150 mg, 20 mg to 125 mg, 20 mg to 100 mg, 20 mg to 75 mg, 20 mg to 50 mg, 20 mg to 25 mg, 25 mg to 200 mg, 25 mg to 175 mg, 25 mg to 150 mg, 25 mg to 125 mg, 25 mg to 100 mg, 25 mg to 75 mg, 25 mg to 50 mg, 50 mg to 200 mg, 50 mg to 175 mg, 50 mg to 150 mg, 50 mg to 125 mg, 75 mg to 100 mg, 50 mg to 75 mg, 75 mg to 200 mg, 75 mg to 175 mg, 75 mg to 150 mg, 75 mg to 125 mg, 75 mg to 100 mg, 100 mg to 200 mg, 100 mg to 175 mg, 100 mg to 150 mg, 100 mg to 125 mg, 125 mg to 200 mg, 125 mg to 175 mg, 125 mg to 150 mg, 150 mg to 200 mg, or 150 mg to 175 mg, or Compound A or or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form comprises 10-150 mg of Compound A or a pharmaceutically acceptable salt thereof, for example, the unit dosage form comprises 10 mg, 20 mg, 50 mg, and 150 mg of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form of any of the above doses is in the form of a capsule. _32197324.1 Page 17 of 77 _{398110-86HPWO (213250)} [0083] In some embodiments, a method of the present invention comprises administering daily to a patient about 20 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as a single 20 mg unit dosage form. In some embodiments, a method of the present invention comprises administering daily to a patient about 30 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as single 10 mg and 20 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 40 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as two 20 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 50 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as a single 50 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 60 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as single 50 mg and 10 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 70 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as single 50 mg and 20 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 80 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as single 50 mg, 20 mg, and 10 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 90 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as single 50 mg and two 20 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 100 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as two 50 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 110 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as two 50 mg and a single 10 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 120 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as two 50 mg and a single 20 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 130 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as two 50 mg and a single 20 mg and 10 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 140 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as two 50 mg and two 20 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 150 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as a single 150 mg unit dosage form. In some embodiments, a method of the present invention comprises administering daily to a patient about 160 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as single 150 mg and 10 mg unit dosage forms. In _32197324.1 Page 18 of 77 _{398110-86HPWO (213250)} some embodiments, a method of the present invention comprises administering daily to a patient about 170 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as single 150 mg and 20 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 180 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as a single 150 mg, 20 mg, and 10 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 190 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example as a single 150 mg and two 20 mg unit dosage forms. [0084] In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein once daily (QD). In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein twice daily. In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein three times daily. In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein four times daily. [0085] In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein every other day. In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein once weekly. In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein twice weekly. In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein three times weekly. In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein four times weekly. [0086] In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein once daily, continuously in 4-week cycles (28 days). In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein once daily, continuously in 3-week cycles (21 days). In some such embodiments, a method of the present invention further comprises administering a checkpoint inhibitor every cycle on Day 1 of the three week cycle (21-days). In some embodiments, a method of the present invention comprises administering Compound A or a unit dosage form as described herein and optionally a checkpoint inhibitor as described in Example 2, below. [0087] In some embodiments, the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein a C_max of up to 600 ng/mL of Compound A in plasma is achieved. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as _32197324.1 Page 19 of 77 _{398110-86HPWO (213250)} described herein) achieves a C_max of up to 500 ng/mL of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein) achieves a C_max of up to 400 ng/mL of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein) achieves a C_max of up to 300 ng/mL of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein) achieves a C_max of up to 200 ng/mL of Compound A in plasma. [0088] In some embodiments, a C_max of Compound A in plasma includes about 10 ng/mL, about 20 ng/mL, about 30 ng/mL, about 40 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL, about 260 ng/mL, about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL, about 370 ng/mL, about 380 ng/mL, about 390 ng/mL, about 400 ng/mL, about 410 ng/mL, about 420 ng/mL, about 430 ng/mL, about 440 ng/mL, about 450 ng/mL, about 460 ng/mL, about 470 ng/mL, about 480 ng/mL, about 490 ng/mL, about 500 ng/mL, about 510 ng/mL, about 520 ng/mL, and about 530 ng/mL, or any range of Cmax created by using two of the aforementioned concentrations as endpoints. In some embodiments, a Cmax of Compound A in plasma is 100 ng/mL to 500 ng/mL. In some embodiments, a Cmax of Compound A in plasma is 100 ng/mL to 400 ng/mL. In some embodiments, the method comprises administering Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein a Cmax of 100 ng/mL to 200 ng/mL, 150 ng/mL to 250 ng/mL, 150 ng/mL to 300 ng/mL, 200 ng/mL to 300 ng/mL, 250 to 350 ng/mL, 300 to 400 ng/mL, 350 to 450 ng/mL, 400 to 500 ng/mL, or 450 to 550 ng/mL of of Compound A in plasma is achieved. In some embodiments, the method comprises daily administering Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein a Cmax of 100 ng/mL to 200 ng/mL, 150 ng/mL to 250 ng/mL, 200 ng/mL to 300 ng/mL, 250 to 350 ng/mL, 300 to 400 ng/mL, 350 to 450 ng/mL, 400 to 500 ng/mL, or 450 to 550 ng/mL of Compound A is achieved. In some embodiments, a C_max of Compound A in plasma, as listed in Table 4 below, is achieved. [0089] In some embodiments, the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein an AUC_0-24h of up to 6000 ng*h/mL of Compound A in plasma is achieved. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form _32197324.1 Page 20 of 77 _{398110-86HPWO (213250)} as described herein) achieves an AUC_0-24h of up to 5000 ng*h/mL of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein) achieves an AUC_0-24h of up to 4000 ng*h/mL of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein) achieves an AUC_0-24h of up to 3000 ng*h/mL Compound A in plasma. [0090] In some embodiments, an AUC_0-24h of Compound A in plasma includes about 100 ng*hr/mL, 200 ng*h/mL, about 300 ng*h/mL, about 400 ng*h/mL, about 500 ng*h/mL, about 600 ng*h/mL, about 700 ng*h/mL, about 800 ng*h/mL, about 900 ng*h/mL, about 1000 ng*h/mL, about 1100 ng*h/mL, about 1200 ng*h/mL, about 1300 ng*h/mL, about 1400 ng*h/mL, about 1500 ng*h/mL, about 1600 ng*h/mL, about 1700 ng*h/mL, about 1800 ng*h/mL, about 1900 ng*h/mL, about 2000 ng*h/mL, about 2100 ng*h/mL, about 2200 ng*h/mL, about 2300 ng*h/mL, about 2400 ng*h/mL, about 2500 ng*h/mL, about 2600 ng*h/mL, about 2700 ng*h/mL, about 2800 ng*h/mL, about 2900 ng*h/mL, about 3000 ng*h/mL, about 3100 ng*h/mL, about 3200 ng*h/mL, about 3300 ng*h/mL, about 3400 ng*h/mL, about 3500 ng*h/mL, about 3600 ng*h/mL, about 3700 ng*h/mL, about 3800 ng*h/mL, about 3900 ng*h/mL, about 4000 ng*h/mL, about 4100 ng*h/mL, about 4200 ng*h/mL, about 4300 ng*h/mL, about 4400 ng*h/mL, about 4500 ng*h/mL, about 4600 ng*h/mL, about 4700 ng*h/mL, about 4800 ng*h/mL, about 4900 ng*h/mL, about 5000 ng*h/mL, about 5100 ng*h/mL, about 5200 ng*h/mL, about 5300 ng*h/mL, about 5400 ng*h/mL, and about 5500 ng*h/mL, or any range of AUC0-24h created by using two of the aforementioned concentrations as endpoints. In some embodiments, an AUC0-24h of Compound A in plasma is 500 ng*h/mL to 5000 ng*h/mL. In some embodiments, an AUC0-24h of Compound A in plasma is 1000 ng*h/mL to 4000 ng*h/mL. In some embodiments, the method comprises administering Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein an AUC0- 24h of 500 ng*h/mL to 1000 ng*h/mL, 1000 ng*h/mL to 1500 ng*h/mL, 1500 ng*h/mL to 2000 ng*h/mL, 2000 ng*h/mL to 2500 ng*h/mL, 2500 ng*h/mL to 3000 ng*h/mL, 3000 ng*h/mL to 3500 ng*h/mL, 3500 to 4000 ng*h/mL, 4000 to 4500 ng*h/mL, 4500 to 5000 ng*h/mL, or 5000 to 5500 ng*h/mL of Compound A in plasma is achieved. In some embodiments, the method comprises daily administering Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein an AUC_0-24h of 500 ng*h/mL to 1000 ng*h/mL, 1000 ng*h/mL to 1500 ng*h/mL, 1500 ng*h/mL to 2000 ng*h/mL, 2000 ng*h/mL to 2500 ng*h/mL, 2500 ng*h/mL to 3000 ng*h/mL, 3000 ng*h/mL to 3500 ng*h/mL, 3500 to 4000 ng*h/mL, 4000 to 4500 ng*h/mL, 4500 to 5000 ng*h/mL, or 5000 to 5500 ng*h/mL of Compound A in plasma is achieved. In some embodiments, the method comprises administering Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein an AUC_0-24h of 500 ng*h/mL to 3000 ng*h/mL of Compound A in plasma is achieved. In some _32197324.1 Page 21 of 77 _{398110-86HPWO (213250)} embodiments, the method comprises administering Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein an AUC_0-24h of 1000 ng*h/mL to 2500 ng*h/mL of Compound A in plasma is achieved. In some embodiments, an AUC_0-24h of Compound A in plasma, as listed in Table 4 below, is achieved. [0091] In some embodiments, the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a formulation or a unit dose form as described herein), wherein a T_max of Compound A in plasma is achieved in up to 9 hours. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein) achieves a Tmax of up to 8 hours of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein) achieves a Tmax of up to 7 hours of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein) achieves a Tmax of up to 6 hours of Compound A in plasma. [0092] In some embodiments, a Tmax of Compound A in plasma achieved includes about 1 hrs, about 2 hrs, about 3 hrs, about 4 hrs, about 5 hrs, about 6 hrs, about 7 hrs, and about 8 hrs, or any range of Tmax created by using two of the aforementioned times as endpoints. In some embodiments, the method comprises administering Compound A or a pharmaceutically acceptable salt thereof (e.g., in a unit dose form as described herein), wherein a Tmax of Compound A in plasma is achieved in from 1 hrs to 8 hrs or 2 hrs to 7 hrs. In some embodiments, a Tmax of Compound A in plasma is 1 hour to 8 hours. In some embodiments, a Tmax of Compound A in plasma is 2 hours to 7 hours. In some embodiments, a Tmax of Compound A in plasma, as listed in Table 4 below, is achieved. Uses of Compounds and Pharmaceutically Acceptable Compositions [0093] The compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase inhibited by the compounds and methods of the invention is HPK1. [0094] The presently disclosed compounds find use in inhibiting the activity of the enzyme HPK1. HPK1 is a member of the germinal center kinase subfamily of Ste20-related serine/threonine kinases. HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3 and TAK1, leading to the activation of the MAPK Jnk. [0095] In one embodiment, the subject matter disclosed herein is directed to a method of inhibiting HPK1, the method comprising contacting HPK1 with an effective amount of a compound of the invention or a pharmaceutical composition described herein. _32197324.1 Page 22 of 77 _{398110-86HPWO (213250)} [0096] In certain embodiments, the subject matter disclosed herein is directed to a method for enhancing an immune response in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, the T cells in the subject have at least one of enhanced priming, enhanced activation, enhanced migration, enhanced proliferation, enhanced survival, and enhanced cytolytic activity relative to prior to the administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the T cell activation is characterized by an elevated frequency of g-IFN+ CD8 T cells or enhanced levels of IL-2 or granzyme B production by T cells relative to prior to administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the number of T cells is elevated relative to prior to administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the T cell is an antigen-specific CD8 T cell. In certain aspects of this embodiment, the antigen presenting cells in the subject have enhanced maturation and activation relative prior to the administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the antigen presenting cells are dendritic cells. In certain aspects of this embodiment, the maturation of the antigen presenting cells is characterized by increased frequency of CD83+ dendritic cells. In certain aspects of this embodiment, the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells. [0097] The presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the presently disclosed compounds reduce, inhibit, or otherwise diminish the HPK1- mediated phosphorylation of SLP76 and/or Gads. [0098] The presently disclosed compounds may or may not be a specific HPK1 antagonist. A specific HPK1 antagonist reduces the biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine/threonine kinases). In certain embodiments, the presently disclosed compounds specifically inhibit the serine/threonine kinase activity of HPK1. In some of these embodiments, the IC50 of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC50 of the HPK1 antagonist for another serine/threonine kinase or other type of kinase (e.g., tyrosine kinase). [0099] The presently disclosed compounds can be used in a method for inhibiting HPK1. Such methods comprise contacting HPK1 with an effective amount of a presently disclosed compound. By "contact" is intended bringing the compound within close enough proximity to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibit the activity of HPK1. The compound can be contacted with HPK1 in vitro or in vivo via administration of the compound to a subject. _32197324.1 Page 23 of 77 _{398110-86HPWO (213250)} [00100] Any method known in the art to measure the kinase activity of HPK1 may be used to determine if HPK1 has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or the measurement of a downstream biological effect of HPK1 kinase activity, such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or T or B cell activation. [00101] The presently disclosed compounds can be used to treat a HPK1-dependent disorder. As used herein, a "HPK1-dependent disorder" is a pathological condition in which HPK1 activity is necessary for the genesis or maintenance of the pathological condition. In some embodiments, the HPK1-dependent disorder is cancer. [00102] The presently disclosed compounds also find use in enhancing an immune response in a subject in need thereof. Such methods comprise administering an effective amount of a compound of the invention. [00103] As used herein, "enhancing an immune response" refers to an improvement in any immunogenic response to an antigen. Non-limiting examples of improvements in an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells), enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and/or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells), improved antigen clearance, increase in production of cytokines by T cells (e.g., interleukin-2), increased resistance to prostaglandin E2-induced immune suppression, and enhanced priming and/or cytolytic activity of CD8 T cells. [00104] In some embodiments, the CD8 T cells in the subject have enhanced priming, activation, proliferation and/or cytolytic activity relative to prior to the administration of the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the CD8 T cell priming is characterized by elevated CD44 expression and/or enhanced cytolytic activity in CD8 T cells. In some embodiments, the CD8 T cell activation is characterized by an elevated frequency of g-IFN⁺ CD8 T cells. In some embodiments, the CD8 T cell is an antigen-specific T-cell. [00105] In some embodiments, the antigen presenting cells in the subject have enhanced maturation and activation relative to prior to the administration of the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the antigen presenting cells are dendritic cells. In some embodiments, the maturation of the antigen presenting cells is characterized by an increased frequency of CD83⁺dendritic cells. In some embodiments, the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells. _32197324.1 Page 24 of 77 _{398110-86HPWO (213250)} [00106] In some embodiments, the serum levels of cytokine IL-10 and/or chemokine IL-8, a human homolog of murine KC, in the subject are reduced relative to prior to the administration of the compound of Formula I or Ia or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. [00107] Engagement of the TCR leads to HPK1 activation, which functions as a negative regulator of TCR-induced AP-1 response pathway. It is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, which leads to T cell dysfunction, including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol 195(5):839-853). [00108] In some embodiments, administration of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof to a subject results in an enhancement of T cell function. [00109] Accordingly, the presently disclosed compounds of the invention or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof are useful in treating T cell dysfunctional disorders. A "T cell dysfunctional disorder" is a disorder or condition of T cells characterized by decreased responsiveness to antigenic stimulation. In a particular embodiment, a T cell dysfunctional disorder is a disorder that is specifically associated with increased kinase activity of HPK1. In another embodiment, a T cell dysfunctional disorder is one in which T cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity. In a specific aspect, the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen. Examples of T cell dysfunctional disorders characterized by T-cell dysfunction include unresolved acute infection, chronic infection and tumor immunity. [00110] Thus, the presently disclosed compounds can be used in treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer. [00111] The term "dysfunction" in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and/or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth. [00112] The term "dysfunctional", as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2, g-IFN) and/or target cell killing. [00113] The term "anergy" refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor (e.g. increase in intracellular Ca⁺² _32197324.1 Page 25 of 77 _{398110-86HPWO (213250)} in the absence of ras-activation). T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation. The unresponsive state can often be overridden by the presence of Interleukin- 2. Anergic T-cells do not undergo clonal expansion and/or acquire effector functions. [00114] The term "exhaustion" refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory (costimulatory) pathways (PD-1, B7-H3, B7-H4, etc.). [00115] "Immunogenecity" refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response. [00116] “Enhancing T cell function" means to induce, cause or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells. Examples of enhancing T cell function include: increased secretion of cytokines (e.g., g-interferon, IL-2, IL-12, and TNFa), increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention, and increased effector granule production by CD8 T cells, such as granzyme B. In one embodiment, the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to one of ordinary skill in the art. [00117] "Tumor immunity" refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance. [00118] The present disclosure provides methods of modulating (e.g., inhibiting) HPKl activity, said method comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof. [00119] In some embodiments, Compound A or a unit dose thereof is for use in medicine. [00120] In one aspect, provided herein is a method for treating of cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. _32197324.1 Page 26 of 77 _{398110-86HPWO (213250)} [00121] In the methods described herein, a compound of the invention or a pharmaceutical composition thereof is administered to a patient that has cancer. In some embodiments, a patient has a relapsed and/or refractory cancer. In some embodiments, a patient has a relapsed and/or refractory tumor. In some embodiments, a patient has a relapsed and/or refractory solid tumor. In some embodiments, a patient has a relapsed and/or refractory liquid tumor. In some embodients, the patient has received at least one prior therapy. In some embodiments, the patient has received at least two prior therapies. In some embodiments, the patient has received at least three prior therapies. In some embodiments, the patient has received at least four prior therapies. In some embodiments, the patient has received at least five prior therapies. In some embodiments, the patient has received at least six prior therapies. [00122] In certain embodiments, the subject matter disclosed herein is directed to a method for treating a HPK1-dependent disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, the HPK1-dependent disorder is a cancer. In certain aspects of this embodiment, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, a hematological malignancy, and a renal cell carcinoma. In certain aspects of this embodiment, the cancer has elevated levels of T-cell infiltration. In certain aspects of this embodiment, the cancer cells in the subject selectively have elevated expression of MHC class I antigen expression relative to prior to the administration of the compound or composition. [00123] In some embodiments, the subject matter disclosed herein is directed to a method for treatment of chronic viral infections. In some embodiments, the subject matter disclosed herein is directed to the use of an HPK1 inhibitor as an adjuvant treatment for increasing the efficacy of vaccination. [00124] In some embodiments, the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier. [00125] In certain aspects, the invention provides a method of treating cell proliferation disorders, including cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma. [00126] In one aspect, the invention provides a method of treating a cell proliferation disorder in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, to the subject. [00127] In certain embodiments, the cell proliferation disorder is cancer. [00128] Examples of cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or _32197324.1 Page 27 of 77 _{398110-86HPWO (213250)} intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T -cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. [00129] In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer, etc.), liquid tumors such as hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers. [00130] In some embodiments, the present invention provide a method of treating a leukemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00131] In some embodiments, the present invention provide a method of treating a lymphoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00132] In some embodiments, the present invention provide a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00133] In some embodiments, the present invention provide a method of treating colon cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. _32197324.1 Page 28 of 77 _{398110-86HPWO (213250)} [00134] In some embodiments, the present invention provide a method of treating esophageal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00135] In some embodiments, the present invention provide a method of treating endometrial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00136] In some embodiments, the present invention provide a method of treating cervical cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00137] In some embodiments, the present invention provide a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00138] In some embodiments, the present invention provide a method of treating uterine cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00139] In some embodiments, the present invention provide a method of treating urothelial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00140] In some embodiments, the present invention provide a method of treating renal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00141] In some embodiments, the present invention provide a method of treating kidney cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00142] In some embodiments, the present invention provide a method of treating liver cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00143] In some embodiments, the present invention provide a method of treating pancreatic cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00144] In some embodiments, the present invention provide a method of treating gastric cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. _32197324.1 Page 29 of 77 _{398110-86HPWO (213250)} [00145] In some embodiments, the present invention provide a method of treating breast cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00146] In some embodiments, the present invention provide a method of treating lung cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00147] In some embodiments, the present invention provide a method of treating skin cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00148] In some embodiments, the present invention provide a method of treating cancers of the head and neck in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00149] In some embodiments, the present invention provide a method of treating thyroid cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00150] In some embodiments, the present invention provide a method of treating glioblastoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00151] In some embodiments, the present invention provide a method of treating sarcoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00152] In some embodiments, the present invention provide a method of treating bladder cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. [00153] In some embodiments, the present invention provide a method of treating a leukemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00154] In some embodiments, the present invention provide a method of treating a lymphoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00155] In some embodiments, the present invention provide a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. _32197324.1 Page 30 of 77 _{398110-86HPWO (213250)} [00156] In some embodiments, the present invention provide a method of treating colon cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00157] In some embodiments, the present invention provide a method of treating esophageal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00158] In some embodiments, the present invention provide a method of treating endometrial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00159] In some embodiments, the present invention provide a method of treating cervical cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00160] In some embodiments, the present invention provide a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00161] In some embodiments, the present invention provide a method of treating uterine cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00162] In some embodiments, the present invention provide a method of treating urothelial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00163] In some embodiments, the present invention provide a method of treating renal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00164] In some embodiments, the present invention provide a method of treating kidney cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00165] In some embodiments, the present invention provide a method of treating liver cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00166] In some embodiments, the present invention provide a method of treating pancreatic cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. _32197324.1 Page 31 of 77 _{398110-86HPWO (213250)} [00167] In some embodiments, the present invention provide a method of treating gastric cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00168] In some embodiments, the present invention provide a method of treating breast cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00169] In some embodiments, the present invention provide a method of treating lung cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00170] In some embodiments, the present invention provide a method of treating skin cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00171] In some embodiments, the present invention provide a method of treating cancers of the head and neck in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00172] In some embodiments, the present invention provide a method of treating thyroid cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00173] In some embodiments, the present invention provide a method of treating glioblastoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00174] In some embodiments, the present invention provide a method of treating sarcoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00175] In some embodiments, the present invention provide a method of treating bladder cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor. [00176] In certain embodiments, the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma. _32197324.1 Page 32 of 77 _{398110-86HPWO (213250)} [00177] In certain embodiments, the cancer is selected from brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary (cancers in which a metastasized cancer is found but the original cancer site is not known). In particular embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In particular embodiments, the cancer is AIDS-related. [00178] In a further embodiment, the cancer is selected from brain and spinal cancers. In particular embodiments, the cancer is selected from anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (olfactory blastomas). In particular embodiments, the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma), oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astorcytoma/malignant glioma, visual pathway and hypothalmic glioma, and primary central nervous system lymphoma. In specific instances of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumors (sPNET). [00179] In specific embodiments, the cancer is selected from cancers of the head and neck, including nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), and cancers of the eye or ocular cancers. In particular embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma. [00180] In specific embodiments, the cancer is selected from leukemia and cancers of the blood. In particular embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high risk MDS or AML, blast- _32197324.1 Page 33 of 77 _{398110-86HPWO (213250)} phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas. Leukemias referenced herein may be acute or chronic. [00181] In specific embodiments, the cancer is selected from skin cancers. In particular embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers. [00182] In specific embodiments, the cancer is selected from cancers of the reproductive system. In particular embodiments, the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, prostate cancers, penile cancers, and testicular cancers. In specific instances of these embodiments, the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors. In specific instances of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In specific instances of these embodiments, the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas. In specific instances of these embodiments, the cancer is an ovarian cancer selected from the group consisting of epithelial cancers. [00183] In specific embodiments, the cancer is selected from cancers of the gastrointestinal system. In particular embodiments, the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers), gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer. In instances of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas. [00184] In specific embodiments, the cancer is selected from liver and bile duct cancers. In particular embodiments, the cancer is liver cancer (hepatocellular carcinoma). In particular embodiments, the cancer is bile duct cancer (cholangiocarcinoma); in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. [00185] In specific embodiments, the cancer is selected from kidney and bladder cancers. In particular embodiments, the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers. In particular embodiments, the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas. _32197324.1 Page 34 of 77 _{398110-86HPWO (213250)} [00186] In specific embodiments, the cancer is selected from bone cancers. In particular embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma. [00187] In specific embodiments, the cancer is selected from lung cancers. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas. [00188] In specific embodiments, the cancer is selected from malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids. [00189] In specific embodiments, the cancer is selected from sarcomas. In particular embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma. [00190] In specific embodiments, the cancer is selected from lymphomas. In particular embodiments, the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., Reed-Sternberg cells), non- Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphomas, and primary central nervous system lymphomas. [00191] In specific embodiments, the cancer is selected from glandular cancers. In particular embodiments, the cancer is selected from the group consisting of adrenocortical cancer, pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas. [00192] In specific embodiments, the cancer is selected from thyroid cancers. In particular embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas. [00193] In specific embodiments, the cancer is selected from germ cell tumors. In particular embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In specific instances of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas. [00194] In specific embodiments, the cancer is selected from heart tumors. In particular embodiments, the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma. [00195] In specific embodiments, the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases. In particular embodiments, the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma. In particular embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and _32197324.1 Page 35 of 77 _{398110-86HPWO (213250)} gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors). [00196] In some embodiments, the subject has melanoma. The melanoma may be at early stage or at late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer may be at early stage or at late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer may be at early stage or at late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer may be at early stage or late state. In some embodiments, the subject has a hematological malignancy. The hematological malignancy may be at early stage or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer may be at early stage or at late stage. In some embodiments, the subject has breast cancer. The breast cancer may be at early stage or at late stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma may be at early stage or at late stage. In some embodiments, the cancer has elevated levels of T-cell infiltration. [00197] In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer and small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure. [00198] In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers. [00199] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma. [00200] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma. _32197324.1 Page 36 of 77 _{398110-86HPWO (213250)} [00201] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma. [00202] Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer. [00203] Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma). [00204] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma. [00205] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors [00206] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease. [00207] Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma). _32197324.1 Page 37 of 77 _{398110-86HPWO (213250)} [00208] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma. [00209] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancers, thyroid and parathyroid cancers. [00210] In some embodiments, HPKl inhibitors may be used to treat tumors producing PGE2 (e.g., Cox-2 overexpressing tumors) and/or adenosine (CD73 and CD39 over-expressing tumors). Overexpression of Cox-2 has been detected in a number of tumors, such as colorectal, breast, pancreatic and lung cancers, where it correlates with a poor prognosis. Overexpression of COX-2 has been reported in hematological cancer models such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia) as well as in patient's blast cells. CD73 is up-regulated in various human carcinomas including those of colon, lung, pancreas and ovary. Importantly, higher expression levels of CD73 are associated with tumor neovascularization, invasiveness, and metastasis and with shorter patient survival time in breast cancer. [00211] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease. [00212] In some embodiments, the present invention provides a method of inhibiting tumor growth in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor is any of the cancers described herein. [00213] In some embodiments, the present invention provides a method of decreasing a PD biomarker in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the PD biomarker is phosphor-BLNK or pSLP76. In some embodiments, the method of decreasing a PD biomarker is dose-dependent. [00214] In some embodiments, the present invention provides a method of increasing pro-inflammatory cytokine secretion and proliferation in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the []Z&UYRWMXXM_Z]d Od_ZVUYQ U^ >@&+% >@&/% Z] >;Bm' >Y ^ZXQ QXNZPUXQY_^% _TQ XQ_TZP ZR UYO]QM^UYS []Z& _32197324.1 Page 38 of 77 _{398110-86HPWO (213250)} inflammatory cytokine secretion and proliferation is dose-dependent. In some embodiments, the present invention provides a method of increasing IL-6 production in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of increasing IL-6 production is dose-dependent. [00215] In some embodiments, the present invention provides a method of increasing B cell proliferation in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of increasing B cell proliferation is dose-dependent. [00216] In some embodiments, the present invention provides a method of increasing CD69 surface expression in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of increasing CD69 surface expression is dose-dependent. [00217] In some embodiments, the present invention provides a method of increasing serum circulating antibodies in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the circulation antibodies are IgM or IgG. In some embodiments, the IgG antibody is IgG1, IgG2a, or IgG2b. In some embodiments, the method of increasing serum circulating antibodies is dose-dependent. Combination Therapies [00218] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” [00219] In certain embodiments, Compound A, or a pharmecutically acceptable salt thereof, or a unit dose thereof as described herein is administered in combination with another therapeutic agent. [00220] Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. [00221] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For _32197324.1 Page 39 of 77 _{398110-86HPWO (213250)} example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. [00222] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. [00223] In one embodiment, the present invention provides a composition comprising Compound A or a unit dose thereof as described herein and one or more additional therapeutic agents. The therapeutic agent may be administered together with Compound A or a unit dose thereof as described herein, or may be administered prior to or following administration of Compound A or a unit dose thereof as described herein. Suitable therapeutic agents are described in further detail below. In certain embodiments, Compound A or a unit dose thereof as described herein may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, Compound A or a unit dose thereof as described herein may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent. [00224] In another embodiment, the present invention provides a method of treating tumor comprising administering to a patient in need thereof Compound A or a unit dose thereof as described herein and one or more immuno-oncology agent described below. Exemplary Immuno-Oncology agents [00225] In some embodiments, one or more other therapeutic agent is an immuno-oncology agent. As used herein, the term “an immuno-oncology agent” refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject. In some embodiments, the administration of an immuno-oncology agent with a compound of the invention has a synergic effect in treating a cancer. [00226] An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human. _32197324.1 Page 40 of 77 _{398110-86HPWO (213250)} [00227] In some embodiments, an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses. [00228] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co- inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, 78A6% @GlE% @><=G% 9OE,% =I:A% I:<>(G@*6% GE6AC(9E,% :96E% :96*% J:96E% :96+% GB;E*% @dX[TZ_ZcUY j(GB;l% GB;E+% GB;j% @GlE% @dX[TZ_ZcUY j*l+% ;6F% ;6F@% E:@G% 9E/% TROY, NGFR. [00229] In some embodiments, an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g.% >@&/% >@&*)% G<;&l% I:<;% MYP Z_TQ] UXX`YZ^`[[]Q^^UaQ Od_ZVUYQ^$ Z] M Od_ZVUYQ _TM_ ^_UX`WM_Q^ G cell activation, for stimulating an immune response. [00230] In some embodiments, a combination of a compound of the invention and an immuno-oncology agent can stimulate T cell responses. In some embodiments, an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD- L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H. [00231] In some embodiments, an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonists of activating receptors on NK cells. In some embodiments, an immuno-oncology agent is an antagonist of KIR, such as lirilumab. [00232] In some embodiments, an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357). [00233] In some embodiments, an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents <sub>32197324.1</sub> Page 41 of 77 <sub>398110-86HPWO (213250)</sub> that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti- CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites. [00234] In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab. [00235] In some embodiments, an immuno-oncology agent is a PD-1 antagonist. In some embodiments, a PD-1 antagonist is administered by infusion. In some embodiments, an immuno-oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death- 1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), LIBTAYO (cemiplimab), TYVYT (sintilimab), TEVIMBRA (tislelizumab), or MEDI-0680 (AMP-514; WO2012/145493). In some embodiments, an immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224. [00236] In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. In some embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174). [00237] In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. In some embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273). [00238] In some embodiments, an immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, a CD137 antibody is urelumab or PF-05082566 (WO12/32433). [00239] In some embodiments, an immuno-oncology agent is a GITR agonist. In some embodiments, a GITR agonist is an agonistic GITR antibody. In some embodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116), or MK-4166 (WO11/028683). [00240] In some embodiments, an immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDO antagonist is selected from epacadostat (INCB024360, Incyte); <sub>32197324.1</sub> Page 42 of 77 <sub>398110-86HPWO (213250)</sub> indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237). [00241] In some embodiments, an immuno-oncology agent is an OX40 agonist. In some embodiments, an OX40 agonist is an agonistic OX40 antibody. In some embodiments, an OX40 antibody is MEDI-6383 or MEDI-6469. [00242] In some embodiments, an immuno-oncology agent is an OX40L antagonist. In some embodiments, an OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879). [00243] In some embodiments, an immuno-oncology agent is a CD40 agonist. In some embodiments, a CD40 agonist is an agonistic CD40 antibody. In some embodiments, an immuno-oncology agent is a CD40 antagonist. In some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab. [00244] In some embodiments, an immuno-oncology agent is a CD27 agonist. In some embodiments, a CD27 agonist is an agonistic CD27 antibody. In some embodiments, a CD27 antibody is varlilumab. [00245] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO11/109400). [00246] In some embodiments, an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab. [00247] In some embodiments, an immuno-oncology agent is an immunostimulatory agent. For example, antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212–1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO<sup>®</sup>, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti-angiogenic therapy. [00248] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be used in the present invention include <sub>32197324.1</sub> Page 43 of 77 <sub>398110-86HPWO (213250)</sub> pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma). [00249] In some embodiments, an immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate- resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, an immuno-oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express beta- galactosidase (beta-gal)/beta-glucoronidase or beta-gal/human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818). [00250] In some embodiments, an immuno-oncology agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5-fluorocytosine to the cytotoxic drug 5- fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus PQ^USYM_QP3 6P.(,&:+;&PQW_M+-&TGB;j&>E:F&hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus <sub>32197324.1</sub> Page 44 of 77 <sub>398110-86HPWO (213250)</sub> (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8<sup>+</sup> T cell response. [00251] In some embodiments, an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR. The T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells. [00252] CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex. [00253] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al.), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently in progress employing CAR-T in a wide range of indications. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1]. [00254] In some embodiments, an immunostimulatory agent is an activator of retinoic acid receptor- related orphan receptor g (RORgt). RORgt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells. In some embodiments, an activator of RORgt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862). [00255] In some embodiments, an immunostimulatory agent is an agonist or activator of a toll-like receptor (TLR). Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 which may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559). [00256] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti- <sub>32197324.1</sub> Page 45 of 77 <sub>398110-86HPWO (213250)</sub> OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody. [00257] In some embodiments, an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORgt. [00258] In some embodiments, an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453). In some embodiments, an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, an IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124. [00259] In some embodiments, an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol.14, pages 603-622. In some embodimetne, an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule targeting an immuno-oncoloby target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule agent selectd from those listed in Table 2 of Jerry L. Adams et al. [00260] In some embodiments, an immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol.28, pages 319-329, the content of which is incorporated herein by refenrece in its entirety. In some embodiments, an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood. [00261] In some embodiments, an immune-oncology agent is a T Cell Engager (TCE). In some embodiments, the TCE is a bi-spectific antibody, tri-specific antibody, or a BITE small molecule, such as teclistamab or talquetamab. In some embodiments, an immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BITE® ) antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390. In some embodiments, an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct. In some embodimens, a bispecific T cell <sub>32197324.1</sub> Page 46 of 77 <sub>398110-86HPWO (213250)</sub> engager (BITE®) antibody construct is a CD19/CD3 bispecific antibody construct. In some embodimens, a bispecific T cell engager (BITE®) antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis. In some embodiments, the bystander cells are in solid tumors. In some embodiments, the bystander cells being lysed are in proximity to the BITE®-acticvated T cells. In some embodiment, the bystander cells comprises tumor-associated antigen (TAA) negatgive cancer cells. In some embodiment, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, an immuno-oncology agent is an antibody which blocks the PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncology agent is an ex vivo expanded tumor-infiltrating T cell. In some embodiments, an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs). Exemplary Checkpoint Inhibitors [00262] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein. [00263] The term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient. One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions. [00264] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed. [00265] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti-tumor immune response. [00266] In some embodiments, the checkpoint inhibitor is a biologic therapeutic or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof. In some embodiments, the checkpoint inhibitor <sub>32197324.1</sub> Page 47 of 77 <sub>398110-86HPWO (213250)</sub> inhibits a checkpoint protein selected from CTLA-4, PDLl, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDLl, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine. [00267] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, ?>E% +7- #NQWZYS^ _Z _TQ 89+ RMXUWd ZR XZWQO`WQ^ MYP U^ Qc[]Q^^QP ZY MWW B?% mk% MYP XQXZ]d 891⁺ #jl$ T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-Ll monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS- 936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to PD-Ll, PD- L2, B7-H3, B7-H4, CD28, CD86 and TIM-3. [00268] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, _32197324.1 Page 48 of 77 _{398110-86HPWO (213250)} Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, TECENTRIQ®, Genentech). [00269] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab. [00270] In some embodiments, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti- PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non- small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822). [00271] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the present invention include TSR- 022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which is being studied in advanced malignancies (NCT02608268). [00272] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT _32197324.1 Page 49 of 77 _{398110-86HPWO (213250)} monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428). [00273] In some embodiments, a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene- 3 (LAG-3). LAG-3 inhibitors that may be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934). [00274] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti- OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475). [00275] Checkpoint inhibitors that can be used in the present invention include CD137 (also called 4- 1BB) agonists. CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol- Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti- CD137 antibody in metastatic or locally advanced malignancies (NCT03881488). [00276] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038). [00277] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other _32197324.1 Page 50 of 77 _{398110-86HPWO (213250)} malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgG1 Fc domain, in advanced solid tumors (NCT02583165). [00278] Checkpoint inhibitors that can be used in the present invention include inducible T-cell co- stimulator (ICOS, also known as CD278) agonists. ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226). [00279] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102/BMS- 986015, Innate Pharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045). [00280] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgG1, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509). [00281] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141). [00282] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). Agonists _32197324.1 Page 51 of 77 _{398110-86HPWO (213250)} of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936). [00283] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6- yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723). [00284] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516). [00285] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, pidilizumab, cemiplimab, sintilimab, or tislelizumab. [00286] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. [00287] A compound of the current invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. [00288] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered. _32197324.1 Page 52 of 77 _{398110-86HPWO (213250)} [00289] In some embodiments, a checkpoint inhibitor is administered under standard of care for the treatment of a particular tumor. For example in some embodiments, 200 mg of pembrolizumab is administered intravenously as described in Example 2, below. [00290] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 mg/kg body weight/day of the additional therapeutic agent can be administered. [00291] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. EXEMPLIFICATION General Synthetic Methods [00292] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Compound A can be prepare by methods known to one of ordinary skill in the art, for example, as described in of WO 2021/050964. Abbreviations AE adverse event CBR clinical benefit rate ALT alanine aminotransferase C1D1 Cycle 1 Day 1 ANC absolute neutrophil count CL/F clearance AST aspartate aminotransferase Cmax maximum plasma AUC area under the concentration- concentration time curve CNS central nervous system AUC)&e area under the concentration- COVID-19 coronavirus Disease 2019 time curve extrapolated to infinity CR complete response AUC0-t area under the concentration- CRO contract research organisation time curve from time zero to CSR clinical study report the last observable CTCAE Common Terminology concentration Criteria for Adverse Events BCR B cell receptor ctDNA circulating tumor DNA BLQ Below limit of quantification DBP diastolic blood pressure BMI body mass index DC dendritic cell MedDRA Medical Dictionary for DLT dose-limiting toxicity Regulatory Activities DNA deoxyribonucleic acid MTD maximum tolerated dose DOR duration of response NCI National Cancer Institute ECG electrocardiogram NCI CTCAE National Cancer Institute Common Terminology ECOG Eastern Cooperative Criteria for Adverse Events Oncology Group NE Not evaluable ET early termination NSCLC Non-small cell lung cancer EOT end-of-treatment NTD non-tolerated dose FDG-PET fluorodeoxyglucose positron emission tomography NTL non-target lesion FIH first-in-human NYHA New York Heart Association FSH follicle-stimulating hormone ORR objective response rate GCP Good Clinical Practices OS overall survival G/GEJ Gastric/gastroesophageal PBMC peripheral blood mononuclear junction cell HBV hepatitis B virus PD progression of disease HCV hepatitis C virus PD-1 programmed cell death protein 1 HNSTD highest non-severely toxic dose PD-L1 programmed death-ligand 1 HPK1 hematopoietic progenitor PFS progression-free survival kinase 1 PGE2 prostaglandin E2 IB Investigator’s Brochure PK pharmacokinetic ICB immune checkpoint blockade PR partial response ICH International Council for PT preferred term Harmonization RECIST Response Evaluation Criteria IEC Independent Ethics in Solid Tumors Committee RCC Renal cell carcinoma ICF informed consent form RNA ribonucleic acid IMP investigational medicinal product RP2D recommended Phase 2 dose irAE immune-related adverse event SAE serious adverse event IRB Institutional Review Board SAP statistical analysis plan iRECIST RECIST adapted for response SARS-CoV-2 serious acute respiratory with immunotherapeutics syndrome coronavirus-2 IRR infusion-related reaction SBP systolic blood pressure SD stable disease _32197324.1 Page 54 of 77 _{398110-86HPWO (213250)} SoA schedule of assessments TRAE Treatment-resistant adverse SOC system organ class event SOP standard operating procedure _tmax time to maximum plasma concentration SSC Study Safety Committee TTR time to response STD10 severely toxic dose in 10% of the animals ULN upper limit of normal t_1/2 elimination half-life Vd volume of distribution TCR T cell receptor Vz/F volume of distribution TEAE treatment-emergent adverse WOCBP women/woman of event childbearing potential 5-HT3 5-hydroxytryptamine 3 Example 1. Preclinical Results. In vitro Experiments [00293] Biochemical and cell-based assays were used to characterize the potency and selectivity of Compound A, respectively (Table 1). Table 1. In vitro assays used to assess selectivity of Compound A against MAP4K and T cell kinases Assay Compound A [00294] A structure

-based drug design approach was used to generate potent and selective inhibitors of HPK1. Biochemical and biophysical assays, as well as primary human and mouse immune cell-based activation assays, were utilized for multiple rounds of structure-activity relationship studies. Ultimately, Compound A was identified as a highly potent HPK1 inhibitor that shows high selectivity against T cell- specific kinases and kinases in the MAP4K family (Table 2). Table 2. Compound A is a potent and selective HPK1 inhibitors Compound A

_32197324.1 Page 55 of 77 _{398110-86HPWO (213250)} TNIK (@ 1 mM ATP) 1,336 HGK (@ 1 mM ATP) >10,000 [00295] FIG.1 show

rylation of BLNK in purified human B cells. CD19+ B cells were purified from human donors and allowed to rest overnight. The following day, cells were treated with Compound A or DMSO for 1 hour before stimulating with IL-21, IL- 4, and anti-CD40 antibody for 30 minutes. WCEs were prepared and phospho-BLNK (Thr 152) was detected by western blot. The primary human B cell pBLNK IC₅₀ value of 48 nM was similar to the primary human T cell pSLP-76 IC₅₀ value of 28 nM. CT-26 Model Data [00296] FIG. 3 shows CT-26 model data where Compound A treatment enhances KLH-specific antibody production in vivo. FIG.4 shows Compound A treatment induces robust tumor growth inhibition, increased serum cytokines and circulating antibodies in CT-26 syngeneic animals. EMT-6 Model Data [00297] FIGs.5-8 shows Compound A treatment induces robust tumor growth inhibition in the EMT6 syngeneic model characterized by increased circulating IgG antibodies and significant B cell tumor infiltration. FIG.6 shows tumor infiltration of different B cell immunophenotypes on Day 8 (Table 3). Table 3. Day 8 GO: Biological Process Adjusted p-value

_32197324.1 Page 56 of 77 _{398110-86HPWO (213250)} Leukocyte-mediated immunity 0.02 CD4+ jl T cell differentiation 003 [00298] F

aining. [00299] FIG.8 shows change in percent and absolute cell count of CD45⁺ cells and B cells. Conclusions [00300] Compound A is a highly potent and selective inhibitor of HPK1 achieving sub-nanomolar biochemical potency and greater than 300-fold selectivity across the MAP4K family. HPK1 inhibition results in a dose-dependent decrease in phosphor-BLNK, a validated PD biomarker in B cells isolated from human PBMCs (FIG. 1). Compound A enhances the activity of human B cells ex vivo as shown by increasing pro-inflammatory cytokine secretion and proliferation as well as enhanced cell-surface expression of activation markers and antibody production (FIG. 2). HPK1 inhibition results in increased antigen-specific antibody production in vivo in response to immunization with KLH (FIG. 3). Compound A induces robust tumor growth inhibition in the EMT6 syngeneic model which is characterized by increased circulating antibody levels, enhanced B cell activation and infiltration into tumors (FIGs.5-8). Example 2. A Phase 1/2, Open-label Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Compound A Administered as Monotherapy or in Combination with Pembrolizumab in Patients with Solid Tumors. [00301] Primary Study Objectives Dose Escalation Phase

_32197324.1 Page 57 of 77 _{398110-86HPWO (213250)} Secondary Objectives Secondary Endpoints · To characterize the safety and tolerability of · Incidence of adverse events (AEs) and serious n of s s to

_32197324.1 Page 58 of 77 _{398110-86HPWO (213250)} Exploratory Exploratory Objectives Exploratory Endpoints s n y

_32197324.1 Page 59 of 77 _{398110-86HPWO (213250)} · To evaluate additional measures of the · PFS, CBR, DOR, and TTR according to antitumor activity of Compound A monotherapy RECIST v1.1 as assessed by the Investigator s

Study Design [00302] This is a multicenter, open-label, first-in-human, Phase 1/2 study to determine the MTD and the recommended Phase 2 dose(s) (RP2D) and to investigate the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of Compound A given as monotherapy (Arm 1) or in combination with pembrolizumab (Arm 2) in adult patients with advanced solid tumors. The study will consist of 2 phases (FIG.9): · The Dose Escalation Phase is designed to evaluate the safety and tolerability of Compound A as monotherapy (Arm 1) and in combination with pembrolizumab (Arm 2) in patients with advanced solid tumors. The Arm 2 combination dose escalation will start at an Compound A dose lower than the highest tolerated dose in dose escalation for monotherapy in Arm 1. To assess the impact of food on the Compound A bioavailability and tolerability, a pilot food effect cohort will also be investigated during _32197324.1 Page 60 of 77 _{398110-86HPWO (213250)} monotherapy dose escalation (Arm 1) which will be comprised of six total patients studied at one or more dose levels that have previously cleared dose escalation criteria. · The Dose Expansion Phase is designed to further evaluate the safety and efficacy of Compound A as monotherapy (Arm 1) and in combination with pembrolizumab (Arm 2) in disease-specific dose expansion cohorts: gastric/gastroesophageal junction (G/GEJ), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). [00303] For purposes of dose optimization, up to 2 doses of Compound A will be studied in each disease-specific solid tumor expansion cohort, with the number of subjects in each dose cohort not to exceed 40 subjects. [00304] Additional disease-specific cohorts may also be studied if preliminary efficacy or scientific rationale suggest a potential benefit to patients. [00305] The study will consist of 3 periods: · Screening period of up to 28 days during which patient eligibility will be reviewed and approved by the Sponsor prior to Cycle 1 Day 1 (C1D1) (or Cycle 0 Day 1 (C0D1) for those subjects participating in the Food Effect cohort) · Treatment period that will extend from C1D1 (or C0D1 for those subjects in the Food Effect cohort) until death, progression of disease (PD), unacceptable toxicity, withdrawal of consent, start of a new systemic anticancer treatment, discontinuation of the patient by the Investigator, or termination of the study by the Sponsor. This will also include Safety Follow-up Visit 30 days [+3 days] after the last dose of IMP. · Post treatment Follow-up period which will continue until patient’s death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever comes first). [00306] In both phases of the study, for the monotherapy cohorts, Compound A capsules will be administered orally once daily continuously in 4-week cycles (28 days). For the combination therapy cohorts, Compound A capsules will be administered orally once daily continuously in 3-week cycles (21 days) and pembrolizumab 200 mg will be administered intravenously every cycle on Day 1 (21-day cycles). [00307] Safety monitoring (AE monitoring; clinical laboratory tests, vital signs, 12-lead electrocardiogram [ECG], Eastern Cooperative Oncology Group (ECOG) Performance Score, and physical examination), serial blood samples for PK and pharmacodynamic assessment, and tumor biopsies will be performed at specific time points. Patients will be monitored continuously for toxicity while receiving the IMP. Adverse event severity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. If a patient experiences an AE of a defined severity or an AE assessed as related to the IMP at any time beyond the DLT evaluation period, dose modifications _32197324.1 Page 61 of 77 _{398110-86HPWO (213250)} will be made according to the guidelines set forth in the clinical study protocol. [00308] During the conduct of the study, safety oversight will be provided by the Study Safety Committee (SSC). Study Duration [00309] It is anticipated that enrolment in the monotherapy (Arm 1) and combination (Arm 2) cohorts for the Phase will take approximately 12 months. Dose escalation for the pembrolizumab combination arm (Arm 2) will begin after at least one dose in expansion is selected in Arm 1. For the Dose Expansion Phase, it is anticipated that enrolment in the monotherapy (Arm 1) and combination disease-specific (Arm 2) cohorts will each take approximately 12 months. [00310] Patients will remain on study treatment (either Compound A monotherapy or Compound A in combination with pembrolizumab) until PD, unacceptable toxicity, withdrawal of consent, start of new systemic anticancer treatment, discontinuation of the patient by the Investigator, or termination of the study by the Sponsor. [00311] Patients will be followed for safety for 30 days (+3 days) after last dose of IMP or until resolution or stabilization of SAEs (regardless of attribution) and ongoing AEs deemed related to study treatment. [00312] Patients will be followed for progression of disease and survival approximately every 3 months for up to 24 months from the first dose of study treatment or for up to 12 months after treatment [00313] a number of discontinuation (whichever is longer). Investigational Medicinal Product [00314] Compound A oral capsules once daily continuously in 4-week cycles (monotherapy cohorts) or 3-week cycles (combination therapy cohorts). Pembrolizumab 200 mg IV every 3 weeks (combination therapy cohorts only). Number of Patients [00315] Approximately 54 patients are planned for inclusion in Dose Escalation and approximately 180 patients in Dose Expansion. Study population Inclusion criteria Patients who meet the following criteria will be considered eligible to participate in the clinical study: 1. AMWQ Z] RQXMWQ [M_UQY_ MSQP g*1 dQM]^ M_ _TQ _UXQ ZR _TQ FO]QQYUYS aU^U_' 2. @URQ Qc[QO_MYOd ZR g*+ bQQV^' 3. Capable of giving signed informed consent. 4. Measurable or non-measurable disease for Dose Escalation; measurable disease using RECIST v1.1 is required for Dose Expansion. _32197324.1 Page 62 of 77 _{398110-86HPWO (213250)} 5. EQOZaQ]QP R]ZX []UZ] _TQ]M[d #[Q] B8> 8G86: aQ]^UZY .')$ _Z <]MPQ f * Z] ]Q_`]Y _Z NM^QWUYQ ^_M_`^ (except for alopecia). 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 7. 6PQ\`M_Q NZYQ XM]]Zb R`YO_UZY PQRUYQP Nd 6B8 ZR g *'.i*)⁹/L without the use of hematopoietic S]Zb_T RMO_Z]^ bU_TUY / bQQV^ []UZ] _Z PZ^UYS% [WM_QWQ_ OZ`Y_ ZR g *))')i*)<sup>9</sup>(@% MYP TQXZSWZNUY ZR g 9.0 g/dL (with or without transfusion). 8. Adequate renal function, including serum creatinine <1.5 x upper limit of normal (ULN) or estimated O]QM_UYUYQ OWQM]MYOQ #8]8W$ g.) X@(XUY OMWO`WM_QP Nd _TQ 8ZOVO]ZR_&<M`W_ RZ]X`WM' 9. 6PQ\`M_Q TQ[M_UO R`YO_UZY PQRUYQP M^ ^Q]`X _Z_MW NUWU]`NUY f *'. i H@B% M^[M]_M_Q MXUYZ_]MY^RQ]M^Q #6FG$ MYP MWMYUYQ MXUYZ_]MY^RQ]M^Q #6@G$ f +'. i H@B #Z] f . i H@B UY [M_UQY_^ bU_T WUaQ] XQ_M^_M^Q^% f , c H@B UY [M_UQY_^ bU_T <UWNQ]_h^ ^dYP]ZXQ$' 10. Female patients who are women of childbearing potential (WOCBP) and male patients must be willing to use a highly effective contraceptive method from the time of informed consent until 6 months after treatment discontinuation. For a non-pregnant partner who is a WOCBP, contraception recommendations should also be considered. NOTE: Women are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause) and have an elevated follicle-stimulating hormone (FSH) at screening. 11. WOCBP must have a negative serum or urine pregnancy test within 48 hours prior to Cycle 1 Day 1 of treatment. 12. Ability to swallow and retain oral medications. ^13. Willing to avoid sun exposure, wear protective clothing, and/or apply broad-spectrum (ultraviolet A [UVA] and ultraviolet B [UVB] protection) sunscreen if sun exposure is unavoidable 14. Capable of understanding and complying with protocol requirements. ^15. Ability to understand and willingness to sign an Institutional Review Board (IRB)-approved written Informed Consent Form (ICF) and authorization permitting release of personal health information. For Dose Escalation Phase Only (Dose Escalation, Monotherapy and Combination Therapy): 16. Histologically or cytologically confirmed advanced or metastatic solid tumors for which no standard therapies are available or are refractory to standard therapy. For Dose Expansion Phase (Dose Expansion, Monotherapy and Combination Therapy): 17. For Dose Expansion, willing to consent to required tumor biopsy(ies). NOTE: Tumor biopsies are optional for patients enrolled in Dose Escalation. 18. Histologically or cytologically confirmed advanced or metastatic G/GEJ, NSCLS or RCC for which no standard therapy is available or are refractory to standard therapy, defined as: _32197324.1 Page 63 of 77 _{398110-86HPWO (213250)} · Patients with HER2-positive disease (G/GEJ), must have received prior HER2-directed antibody. HER2-positive disease defined as either IHC3+ or IHC2+/ISH+ (ISH positivity is defined as a =:E+3 OQY_]ZXQ]Q QY`XQ]M_UZY []ZNQ RZ] OT]ZXZ^ZXQ *0 K8:C*0L ]M_UZ ZR g +$' · Patients with NSCLC must have been treated with at least 1 but not 2 prior lines of systemic chemotherapy AND received prior anti-PD-1 or anti-PD-L1 therapy for metastatic or recurrent disease. · Patients with RCC must have received at least 1 prior line of systemic therapy for advanced metastatic and unresectable disease. Exclusion criteria Patients who meet 1 or more of the following criteria will not be considered eligible to participate in the clinical study: 1. Previous solid organ or hematopoietic stem cell transplant. 2. Central nervous system (CNS) malignant disease not previously treated, active leptomeningeal disease, uncontrolled symptomatic CNS involvement, or CNS malignant disease requiring steroid or other therapeutic intervention. 3. Prior anticancer treatment, including: · Systemic anticancer treatment: chemotherapy, antibody, or other biologic anticancer therapeutic <4 weeks prior to first dose of study treatment (<6 weeks for nitrosoureas or mitomycin C). · Radiation therapy (including radiofrequency ablation) <4 weeks prior to the initiation of study treatment. · Stereotactic body radiation therapy <2 weeks prior to the initiation of study treatment. · Chemoembolization or radioembolization < 4 weeks prior to the initiation of study treatment. · Small molecule therapies, included targeted therapies <2 weeks or 5 half-lives whichever is longer. 4. Clinically significant cardiovascular disease including: · Myocardial infarction/stroke within 3 months prior to the initiation of study treatment. · Unstable angina within 3 months prior to the initiation of study treatment. · Congestive heart failure or cardiomyopathy with New York Heart Association Class 3 or 4 by clinical assessment. · History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes). · Uncontrolled hypertension (as defined per institutional standards) despite 2 concomitant antihypertensive therapies. <sub>32197324.1</sub> Page 64 of 77 <sub>398110-86HPWO (213250)</sub> · DG UY_Q]aMW OZ]]QO_QP Nd _TQ ;]UPQ]UOUM OZ]]QO_UZY RZ]X`WM #DGO;$ g-1) X^QO ZY _TQ FO]QQYUYS ECG. 5. History of severe immune-related AE (irAE) that led to permanent discontinuation of prior immunotherapy. 6. =U^_Z]d ZR <]MPQ g , U]6: bU_TUY _TQ [M^_ */ bQQV^ Z] MYd <]MPQ - WURQ&_T]QM_QYUYS U]6: #]QSM]PWQ^^ ZR duration) or neurologic or ocular AE of any grade while receiving prior immunotherapy; NOTE: Patients with endocrine AEs of any grade are permitted to enroll if they are stably maintained on appropriate replacement therapy and have no history of adrenal crisis and be asymptomatic. 7. History of severe hypersensitivity reaction to treatment with monoclonal antibody(ies) (for combination therapy cohorts only). 8. Requires systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to Day 1 of treatment. Inhaled, intranasal, intra- articular and topical (including ocular) steroids are allowed. Adrenal replacement (i.e., physiologic replacement) doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 9. History of interstitial lung disease, idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on chest computed tomography scan in the last 6 months; NOTE: history of radiation pneumonitis in the radiation field (fibrosis) is permitted. 10. Major surgery within 4 weeks of starting study treatment or not recovered from any effects of prior major surgery (uncomplicated central line placement or fine needle aspirate are not considered major surgery). 11. Gastrointestinal disorders that may interfere with absorption of the study medication. 12. Uncontrolled active infection requiring intravenous (IV) antibiotic, antiviral, or anti-fungal medications within 14 days prior to first dose of study treatment. 13. Known additional malignancy that is active and/or in progression requiring treatment; exceptions include basal cell or squamous cell skin cancer, or other cancer for which the patient has been disease- free for at least two years. 14. Active infection with human immunodeficiency virus (HIV). 15. Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). 16. Known current drug or alcohol abuse. 17. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes, thromboembolic event within the past 3 months) or any important _32197324.1 Page 65 of 77 _{398110-86HPWO (213250)} medical or psychiatric illness or abnormal laboratory finding that would, in the Investigator’s judgment, increase the risk to the patient associated with his or her participation in the study. 19. Prior treatment with an HPK1 inhibitor. 20. Are taking medications that are strong inducers or inhibitors of CYP3A4 that cannot be discontinued prior to treatment with Compound A. Sample Size Considerations Dose Escalation [00316] The Monotherapy Dose Escalation Phase may enroll approximately 36 patients. The sample size for the monotherapy dose escalation is based on a standard 3+3 design. Following the determination of at least one RP2D monotherapy dose, a combination dose escalation phase will examine up to 3 combination dose cohorts in up to 6 evaluable patients each. [00317] The Combination Dose Escalation Phase may enroll approximately 18 patients (up to 6 patients at each combination dose level). Dose Expansion Dose Expansion Cohorts (Monotherapy) [00318] Following the determination of at least one RP2D for monotherapy, disease-specific monotherapy expansion cohorts will be initiated. [00319] G/GEJ cancer: Monotherapy expansion cohort for G/GEJ will employ a minimax Simon’s 2- Stage design with a 1-sided alpha of 0.05, power of 80%, null hypothesis of 5% objective response rate (ORR) and alternative hypothesis of 20% ORR. Stage 1 of each single-IMP cohort will evaluate 13 patients for confirmed response. If there is no response in Stage 1 with monotherapy, the cohort will be closed. If there are 1 or more responses, Stage 2 will initiate with an additional 14 patients. If there are 4 or more responses out of the total 27 patients, the null hypothesis of 5% ORR will be rejected. [00320] NSCLC: The assumptions, sample sizes and decision rules for NSCLC monotherapy expansion cohort are the same as the ones calculated above for G/GEJ. A total of 27 patients will be included in the NSCLC monotherapy dose escalation cohort. [00321] RCC: Monotherapy expansion cohort for RCC patients will employ the minimax Simon’s 2- Stage design with a 1-sided alpha of 0.15, power of 75%, null hypothesis of 14% objective response rate (ORR) and alternative hypothesis of 30% ORR. [00322] Using Simon’s two-stage design, 13 patients will be accrued in the first stage. If there is 1 or fewer responder in 13 patients, this cohort will stop enrolling. Otherwise, 7 additional patients will be accrued for a total of 20. The null hypothesis will be rejected if there are 5 or more responders in the overall cohort of N=20. [00323] If more than one dose is selected for study in expansion cohorts, the underlying null and _32197324.1 Page 66 of 77 _{398110-86HPWO (213250)} alternative hypotheses will remain the same for all doses. For example, if two doses are selected for RCC dose expansion, the total sample size of the RCC expansion cohorts will target between 26 to 40 patients, depending on whether there are interim futility stops for one or both cohorts. The minimum sample size is 26 if both cohorts are stopped at the interim futility analysis, and the maximum sample size is 40 if there is no interim futility stop for any cohort. Dose Expansion Cohorts (Combination Therapy) [00324] Following the completion of the combination dose escalation, which will enroll patients with any advanced solid tumor (similar to Dose Escalation Arm 1), disease-specific combination cohort expansion will be initiated. [00325] G/GEJ cancer: A minimax Simon’s 2-Stage design will be employed with a 1-sided alpha of 0.05, 80% power, with a null hypothesis of 10% ORR and alternative hypothesis of 30% ORR. Stage 1 of this cohort will evaluate 15 patients for efficacy. If there are less than 2 responses in Stage 1 with combination therapy, the cohort will be closed; if there are 2 or more responses, Stage 2 will initiate with an additional 10 patients. If there are 6 or more responses out of the total 25 patients, the null hypothesis of 10% ORR will be rejected. [00326] NSCLC: The assumptions, sample sizes and decision rules for NSCLC combination therapy expansion cohort are the same as the ones calculated above for G/GEJ. [00327] If more than one dose is selected for study in expansion cohorts, the underlying null and alternative hypotheses for a specific disease will remain the same as outlined above. [00328] RCC: Combination therapy expansion cohort for RCC patients will employ the minimax Simon’s 2-Stage design with a 1-sided alpha of 0.05, power of 80%, null hypothesis of 20% objective response rate (ORR) and alternative hypothesis of 40% ORR. Stage 1 of each combination cohort will evaluate 18 patients for confirmed response. If there are 4 or less responses in Stage 1 with combination, the cohort will be closed. If there are 5 or more responses, Stage 2 will initiate with an additional 15 patients. If there are 11 or more responses out of the total 33 patients, the null hypothesis of 20% ORR will be rejected. [00329] If more than one dose is selected for study in expansion cohorts for combination therapy, the underlying null and alternative hypotheses for a specific disease will remain the same for all doses. The number of subjects studied at a single dose will be reduced such that the overall number of subjects with a particular disease studied in expansion will not exceed 40. [00330] The total sample size for both monotherapy and combination therapy expansion cohorts for the G/GEJ, NSCLC and RCC is approximately 180. Data Presentation/Descriptive Statistics [00331] All demographic, safety, and PK data will be listed and summarized in tabular format by _32197324.1 Page 67 of 77 _{398110-86HPWO (213250)} descriptive statistics as appropriate; PK and pharmacodynamics data may be displayed graphically as appropriate. [00332] For antitumor activity, summaries will include ORR, CBR, DOR, TTR and 6-month and 9- month PFS probabilities, 6-month and 12-month OS probabilities. Time-to event endpoints (PFS, OS, DOR and TTR) will be analyzed using the Kaplan-Meier method. Point estimates (median, 6-month, 9-month, and 12-month estimates) will be presented with their 95% confidence intervals. In addition, progression date, death date, date of first response and last tumor assessment date will be listed, together with the above- mentioned endpoints. [00333] Analyses will be conducted after dose escalation for deciding dose(s) in the dose expansion cohorts and after Stage 1 for each expansion to assess futility criteria. The Study Safety Committee (SSC) will review these results to decide whether the cohort is stopped or continued into Stage 2 for each of the cohorts. [00334] Pharmacodynamic analyses will be conducted for exploratory purposes. Results Baseline Characteristics [00335] Twenty-five patients were studied at five Compound A dose levels: 50 mg, 100 mg, 140 mg, and 200 mg followed by 150 mg (FIG.10). The median age of the patients was 65.5 years (range: 46–84) and most patients (64%) were female. The tumor types were pancreatic cancer, colon cancer, NSCLC, RCC, endometrial cancer (16.0%, 12%, 12%, 8%, and 8% respectively) and 96% were Stage IV. 40%, -)"% MYP +)" ZR [M_UQY_ TMP ]QOQUaQP *&+% ,&. MYP g/ []UZ] _TQ]M[UQ^ ]Q^[QO_UaQWd' Safety [00336] GbQY_d&ZYQ [M_UQY_^ #1-"$ Qc[Q]UQYOQP g* _]QM_XQY_&related adverse event (TRAE); five patients (20%) experienced serious TRAEs. The most common TRAEs were vomiting, nausea, diarrhea, and fatigue, with the majority being grade 1 or 2 in severity. Compound A dose level 4 (200 mg/day) was considered a non-tolerated dose, with 2 of 9 patients experiencing the only dose-limiting toxicities observed (grade 3 pneumonitis and grade 3 acute kidney injury in the setting of vomiting and diarrhea; both were considered serious TRAEs) (FIG.11). Immune-related adverse events (irAEs) occurred in 8 patients (32%). No treatment-related deaths occurred. Efficacy [00337] Three patients have achieved clinical benefit defined as: objective response of partial response (PR) or complete response (CR), or maintenance of stable disease (SD) for >6 months. One patient with renal cell carcinoma (RCC) in the 50 mg cohort 1 experienced a CR (FIGs 11-13). Two additional patients (with RCC and pancreatic cancer in the 140 mg and 200 mg cohorts, respectively) have experienced prolonged SD with evidence of tumor shrinkage and reduction in cancer antigen 19.9, respectively (FIG. _32197324.1 Page 68 of 77 _{398110-86HPWO (213250)} 11). The patient with RCC remains on treatment at Cycle 17 after experiencing primary refractory disease to first-line pembrolizumab/axitinib. The patient with pancreatic cancer came off treatment in Cycle 10 due to an irAE of grade 3 colitis. Of 13 patients undergoing at least 1 response assessment, 4 had a reduction in target lesion sum of diameters (FIG. 12). Pharmacokinetics/Pharmacodynamics [00338] Table 4 shows a summary of the average preliminary PK parameters for Compound A from the Phase 1/2 open label study. _32197324.1 Page 69 of 77 _{398110-86HPWO (213250)} 2 y 1 d ^u _t ^Sl _eba ^{L n} _ep ^{O 2} _/ ^{1 e} _sahP _e 1 h ^t m ^o _r ^{f A}dnuop mo C_r ^o _f

_s ^c _i ^r _e ^t _s n n n n n n n n n n n^t _e ⁱ _t ^{a a} _e D ^a _e D ^a _e D ^a _e D ^a _e D ^a D ^a D ^a D ^a D ^a D ^a D t M S M S M S M S M S _e M S _e M S _e S _e S _e S _e S S M M M M m ^{a e} _{l r} ba ^P ) ^a _c 5 )3 )5 ) ) ) ) ) ) ) ⁱ _lK 1 = 1= 2= 21= 14= 22= 15= 24= 11= 19= 2 p ^P _e ^{l y} _{c e r} y ^l n c ⁽ _e ^l n y ¹ _c ⁽ _e ^l n y ¹ _c ⁽ _e ^l n y ¹ _c ⁽ _e ^l n y ¹ _c ⁽ _e ^l n y ¹ _c ⁽ _e ^l n y ¹ _c ⁽ _e ^l n ⁽ _e ^l n ⁽ _e ^l n ⁽ _e ^{l 13}) y ¹ _cy ¹ _cy ¹ _cy ¹ _c ^y _a 4 ^p _a = _toa C ⁿ _i C^y _a C^y _a C^y _a C^y _a C^y _a C^y _a C^y _a C^y _a C^y y a C^y _a C Dⁿ ₍ ^N D D D D D D D D D D ⁼mⁱ _l y y y y ^A _/ ^e _{r t} P _e ⁿ _{e e} ^p n a^{r o} _i ^{t p} n a ^o _i ^{t p} _a ^p y a ^p y a ^p N a _, dg ^mp _e h _a ^{r n} _{i e} h _a ^{r n} _{i e} ^{r h} _e ^{r h} _e ^r _{e e} ^t _ra _{t e} ay _t b _t b _{t t} ^h _t ^h _t o^r T on on on on on on ^pv ^e _r o mo o mo o o o o _e ^A T R _. M C M C M M M M _t ⁴ o^e _l ^e b _s) og 0 0 5 0 0 1 4 0 0 ^N 1 51 0 ⁼a T D^m ₍ 2 R N ^s _ruo h- 8hgu o_rh ^{t e} _lb^a _l ⁱ _a v_{a a} ^t _ad e v_a h ^y _lno₎g m04 1dn ^an o_i ^t _a n_ib mo Cg m0 5_{( s} ^t _c e_jb u_{s e} ¹ m ^y _a o ^{s D s} _a ² s ^e _l e c s y o ^C e ^p _r n g u ^{o n p} n a ^r n ^o _i d o n ^s _i ^t _cu a ^r _a n p ^d _e ^{r a} _i m d_e ^o _c ^e _so m _ro ^d s a ^{f a} d d d_e ^{e e} _c t _{t r} ^a _l n o ^{u p} _c ^e _i ^r e ^l _e r _a p t_s ^c x a_l ^s _a ^{et T}d ^w n h _{. c} a ⁸- ^e 0 _s ^e _jb o ^{u x} C ^d _{- s a} m U ^t _{s e} o n 1T 2A p 3O _32197324.1 Page 71 of 77 _{398110-86HPWO (213250)} [00339] Preliminary pharmacokinetic data from the Phase 1/2 open label study with Compound A demonstrated a nearly dose-proportional increases in mean exposure on Cycle 1 Day 1 (FIG. 14). Steady state was achieved at or before Cycle 2 Day 1. Accumulation of 1.2-3.7 fold was observed between Cycle 1 and Cycle 2. PD results demonstrated >50% reduction of pSLP76 (proposed therapeutic target inhibition) in each cohort by Cycle 1 Day 15 (FIG. 15). Dose-dependent decreases in % pSLP76 were observed as Compound A plasma concentration increased (FIG.16). Conclusions [00340] Compounds A demonstrated an acceptable safety profile at doses less than 200 mg/day; most adverse events were mild in severity and easily managed. Emergence of irAEs supports the proposed mechanism of action of HPK1 inhibition, resulting in immune activation. Clinical benefit was observed, including a CR and two patients with prolonged SD. Compound A showed a dose-dependent increase in plasma concentration and accumulation at steady-state, with pSLP76 inhibited at all doses. The observed clinical benefit and safety profile support HPK1 as a viable next-generation immunotherapy target and continued clinical evaluation of Compound A. Monotherapy dose optimization, and combination dose escalation with pembrolizumab are ongoing. [00341] While we have described embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. _32197324.1 Page 72 of 77 _{398110-86HPWO (213250)}

Claims

CLAIMS 1. A method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of less than 200 mg to the patient; and wherein Compound A is (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2- yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one. 2. A method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor; wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of less than 200 mg to the patient; and wherein Compound A is (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2- yl)amino)-4-(7-fluoroimidazo[1,

2-a]pyridin-3-yl)isoindolin-1-one.

3. The method of claim 2, wherein the checkpoint inhibitor is a PD-1 inhibitor selected from nivolumab, pembrolizumab, cemiplimab, sintilimab, and tislelizumab.

4. The method of claim 2, wherein the checkpoint inhibitor is a PD-L1 inhibitor selected from atezolizumab, avelumab, and durvalumab.

5. The method of any one of claims 1-4, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of less than 170 mg to the patient.

6. The method of any one of claims 1-5, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of less than 160 mg to the patient.

7. The method of any one of claims 1-6, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of less than 150 mg to the patient.

8. The method of claim 2, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of from 20 mg to 160 mg. _32197324.1 Page 73 of 77 _{398110-86HPWO (213250)}

9. The method of any one of claims 1-8, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of from 40 mg to 150 mg.

10. The method of any one of claims 1-9, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of from 50 mg to 150 mg.

11. The method of any one of claims 8-10, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of from 100 mg to 150 mg.

12. The method of any one of claims 1-9, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg.

13. The method of any one of claims 1-10, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg.

14. The method of any one of claims 1-7, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 mg, 30 mg, 40 mg, or 50 mg.

15. The method of claim 1 or claim 2, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of from 0.7 mg/kg to 3.1 mg/kg.

16. The method of claim 15, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of from 1.0 mg/kg to 2.8 mg/kg.

17. The method of claim 15 or claim 16, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of from 1.5 mg/kg to 2.5 mg/kg.

18. A method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, wherein a C_max of up to 600 ng/mL of Compound A in plasma is achieved, and wherein Compound A is (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2- yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one. _32197324.1 Page 74 of 77 _{398110-86HPWO (213250)}

19. The method of claim 15, wherein the C_max of Compound A in plasma is 100 ng/mL to 500 ng/mL.

20. The method of claim 15 or claim 16, wherein the C_max of Compound A in plasma is 100 ng/mL to 400 ng/mL.

21. A method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, wherein an AUC_0-24h of up to 6000 ng*h/mL of Compound A in plasma is achieved, and wherein Compound A is (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2- yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one.

22. The method of claim 18, wherein the AUC0-24h of Compound A in plasma is 500 ng*h/mL to 5000 ng*h/mL.

23. The method of claim 18 or claim 19, wherein the AUC0-24h of Compound A in plasma is 1,000 ng*h/mL to 4000 ng*h/mL.

24. A method of treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, wherein a Tmax of up to 8 hours of Compound A in plasma is achieved, and wherein Compound A is (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2- yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one.

25. The method of claim 24, wherein the Tmax of Compound A in plasma is 1 hour to 8 hours.

26. The method of claim 24 or claim 25, wherein the Tmax of Compound A in plasma is 2 hours to 7 hours.

27. The method of any one of claims 1-26, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally to the patient.

28. The method of any one of claims 1-27, wherein Compound A or a pharmaceutically acceptable salt thereof is administered to the patient daily. _32197324.1 Page 75 of 77 _{398110-86HPWO (213250)}

29. The method of any one of claims 1-28, wherein Compound A or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition comprising one or more pharmaceutically acceptable excipient or carrier.

30. The method of any one of claims 1-29, wherein the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.

31. The method of any one of claims 1-30, wherein the patient has received no prior therapy.

32. The method of any one of claims 1-30, wherein the patient has received at least one prior therapy.

33. The method of any one of claims 1-30, wherein the patient has received at least two prior therapies.

34. The method of any one of claims 1-33, wherein the patient is a human.

35. The method of any one of claims 1-34, wherein the patient does not have one or more of the exclusion criteria as set forth in Example 2.

36. The method of any one of claims 1-35, wherein the patient has one or more of the inclusion criteria as set forth in Example 2. _32197324.1 Page 76 of 77 _{398110-86HPWO (213250)}