WO2023114984A1

WO2023114984A1 - Tead inhibitors and uses thereof

Info

Publication number: WO2023114984A1
Application number: PCT/US2022/081772
Authority: WO
Inventors: III James M. NOLAN; Sergio Luis SANTILLANA SOTO; Karim Sami MALEK
Original assignee: Ikena Oncology, Inc.
Priority date: 2021-12-17
Filing date: 2022-12-16
Publication date: 2023-06-22

Abstract

The present invention provides TEAD inhibitors, formulations and unit dosage forms thereof, and methods of use thereof.

Description

TEAD INHIBITORS AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Patent Application No. 63/265,627, filed December 17, 2021, the contents of which are herein incorporated by reference in their entirety.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to solid formulations and unit dosage forms of TEAD inhibitor N-methyl-3-(l-methyl-lH-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide (Compound A), and methods of use thereof.

BACKGROUND OF THE INVENTION

[0003] Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with TEAD transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers.

SUMMARY OF THE INVENTION

[0004] It has been found that TEAD inhibitor N-methyl-3-(l-methyl-lH-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide (Compound A) solid formulations and unit dosage forms of the invention have certain advantages in treating cancer.

[0005] Accordingly, in one aspect, the present invention provides a solid formulation comprising Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a solid formulation of the present invention is a spray dried intermediate (SDI) formulation, as described herein. In some embodiments, a solid formulation of the present invention is a unit dosage form, as described herein. In some embodiments, a unit dosage form of the present invention is a tablet, as described herein. In some embodiments, a solid formulation or unit dosage form of the present invention comprises HPMCAS-HG (HPMCAS-HG). In some embodiments, a solid formulation or unit dosage form of the present invention comprises mannitol. In some embodiments, a solid formulation or unit dosage form of the present invention comprises microcrystalline cellulose. In some embodiments, a solid formulation or unit dosage form of the present invention comprises croscarmellose sodium. In some embodiments, a solid formulation or unit dosage form of the present invention comprises colloidal silicon dioxide. In some embodiments, a solid formulation or unit dosage form of the present invention comprises magnesium stearate.

[0006] In another aspect, the present invention provides a method for treating cancer comprising administering a solid formulation or a unit dosage form as described herein.

[0007] In some embodiments, the present invention provides a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method provided herein comprises administering daily to a patient about 25 - 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method provided herein comprises administering once daily, or twice daily, or thrice daily, or four-times daily, Compound A, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, a cancer is selected from those as described herein. In some embodiments, the cancer is an NF2-deficient solid tumors, including, but not limited to, mesothelioma, meningioma, cholangiocarcinoma, thymoma, NSCLC, HCC, and others. In some embodiments, the NF2-deficient solid tumor has NF2 loss-of-function mutations. In some embodiments, the NF2-deficient solid tumor has NF2 copy number loss. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE). In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE) with a TAZ-CAMTA1 or YAP1-TFE3 gene fusion. In some embodiments, the cancer is a solid tumor with a YAP1 or TAZ gene fusion.

DETAILED DESCRIPTION OF THE INVENTION

1. General Description of Certain Embodiments of the Invention

[0009] Compound A is a novel, synthetic, small molecule inhibitor designed to target and selectively inhibit TEAD. The TEAD family comprises 4 members (TEAD1, TEAD2, TEAD3, and TEAD4) and henceforth will be referred to collectively as TEAD. TEAD functions as the ultimate step in the Hippo signal transduction pathway by driving expression of genes involved in cell proliferation, adhesion, migration, biogenesis, angiogenesis, and apoptosis (Calses 2019). Activation of TEAD transcription depends on formation of a heterodimeric complex with either of the two key transcriptional coactivators, Yesl associated transcriptional regulator (YAP1) or WW domain containing transcription regulator 1 (TAZ/WWTR1), as well as binding of the lipid palmitate to TEAD’s central lipid pocket (Chan 2016). TAZ is encoded by the WWTR1 gene and TAZ is used when describing either the protein or the gene, herein.

[0010] When the upstream Hippo pathway is turned on, YAP1/TAZ are phosphorylated and sequestered to the cytoplasm or targeted for proteasomal degradation and TEAD-dependent gene expression is reduced. On the contrary, when YAP1/TAZ are not phosphorylated, the co-activators are able to translocate into the nucleus, bind TEAD transcription factors, and activate transcription of TEAD-dependent target genes (Holden 2018).

[0011] The Hippo pathway is frequently mutated in human cancers, which leads to an aberrant activation of TEAD-dependent transcription (Kulkami 2020). Genetic alterations in the Hippo pathway are linked to the etiology of many cancers, are generally associated with poor patient outcome, and drive resistance to both chemotherapies and targeted therapies.

[0012] The Hippo pathway is genetically altered in approximately 10% of all cancers; however, in certain rare tumors, the genetic alterations of the Hippo pathway can be found in over 40% of cases, including malignant pleural mesothelioma (MPM), that have mutations and copy number losses associated with neurofibromin 2 (NF2) deficiency (Sato 2018). NF2 is a tumor suppressor gene that encodes merlin, a key regulator of the Hippo signaling pathway. Complete loss of the NF2 function can lead to an inability to suppress TEAD-dependent transcription, driving the expression of multiple genes leading to enhanced tumor cell growth. Malignant mesothelioma is a rare cancer in the tissue lining the lungs and is a very aggressive cancer with a poor prognosis. There are few effective treatment options for advanced unresectable malignant mesothelioma, and to date, only two treatments have been approved by the FDA for the treatment of this condition in the last 16 years. Even with a newly approved treatment in 2020, the median overall survival of these patients is 18 months, with most of the patients eventually progressing and dying from their disease. [0013] NF2 deficiency also occurs at high incidence in meningiomas, cholangiocarcinomas, thymoma, and schwannoma. Meningiomas are the most common brain tumor, accounting for 36.4% of all primary brain tumors in the United States (Ostrom 2015). Notably, multiple studies found NF2 gene aberrations in 40% to 60% of sporadic meningiomas, in addition to those that appeared alongside neurofibromatosis type 2, which is defined by NF2 germline mutations (Yuzawa 2016; Bi 2017; Harmanci 2017; Pemov 2020). Initial therapy for meningioma is surgery with or without radiation. While complete resection can be curative in most cases, no therapies have been shown to prolong progression-free or overall survival in patients with recurrent or unresectable meningiomas, and there are no approved treatments for this subset of patients.

[0014] Certain solid tumors have high nuclear YAP1 or TAZ protein, indicating high TEAD activation, and YAP1/TAZ gene amplification or fusion. This includes, but is not limited to, epithelioid hemangioendothelioma (EHE), where 90% of the cases are associated with TAZ- CAMTA1 gene fusion, and the other 10% of cases have YAP1-TFE3 gene fusion. In the case of EHE, localized disease is treated by organ involvement with surgery, but there is no systemic treatment approved for EHE with advanced or metastatic disease (Stacchiotti 2021). Typically, this disease is refractory to the anticancer drugs used to treat other soft tissue sarcomas. Treatment options include retrospective data on interferons, thalidomide, some small Phase 2 studies testing anti angiogenic agents like bevacizumab and pazopanib, and, more recently, use of MEK inhibitors associated with an ORR of 7% (Schuetze 2021; Stacchiotti 2021).

[0015] Other solid tumors also express YAP1/TAZ gene alterations including angiosarcoma, liposarcomas, synovial sarcomas, NSCLC, cervical cancer, mesothelioma, and others (Fullenkamp 2016; Merritt 2018; Isfort 2019; Yoshida 2019; Kao 2020; Massoth 2020; Puls 2020; Schuetze 2021; Stacchiotti 2021).

[0016] Hippo pathway alterations or dysregulations are associated with a subset of rare tumors with poor prognosis and limited therapeutic options, thus constituting a significant unmet medical need. Therefore, inhibiting TEAD function in these tumors targeting the Hippo pathway represents a promising strategy for developing novel anticancer therapies.

[0017] Compound A is a novel synthetic small molecule inhibitor that binds to the central lipid pocket of TEAD, prevents palmitate binding, and disrupts aberrant TEAD-dependent transcription. As discussed above, Compound A exhibits antitumor activity in mice bearing established MSTO-211H human mesothelioma xenograft tumors that contain Hippo pathway genetic alterations. Compound A also demonstrated antitumor activity and inhibited TEAD- dependent gene expression in mice bearing established NF2-deficient NCI-H226 human mesothelioma xenograft tumors. Published nonclinical data (Pobbati 2020) have also shown that TEAD inhibition can inhibit tumor growth in tumors that harbor YAP1 or TAZ gene fusions.

[0018] Robust efficacy was demonstrated when Compound A was combined with trametinib (MEK1/2 inhibitor) in a KRAS-mutant A549 lung cancer model. In addition, Compound A administered in combination with trametinib and osimertinib (third-generation EGFR inhibitor) had greater antitumor activity in mice bearing established NCI-H1975 human NSCLC xenografts. [0019] Accordingly, in some embodiments, the present invention provides a method for treating cancer, such as those as described herein, comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the present invention provides a solid formulation, or a unit dosage form, as described herein, which comprises Compound A, or a pharmaceutically acceptable salt thereof.

2. Definitions

[0021] As used herein, the term “Compound A” or “Compound A free base” refers to a TEAD inhibitor N-methyl-3-(l-methyl-lH-imidazol-4-yl)-4-((4-(trifluoromethyl)benzyl)amino), of formula:

. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is in crystal form.

[0022] 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, incorporated herein by reference. 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 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, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0023] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(Ci^alkyl)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.

[0024] 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.

[0025] As used herein, the terms “about” or “approximately” have the meaning of within 20% of a given value or range. 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.

3. Description of Exemplary Methods and Uses

[0026] In some embodiments, the present invention provides a method for treating cancer in a patient with advanced solid tumors with gene alterations in the Hippo pathway for whom there are no further treatment options known to confer clinical benefit, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the present invention provides a method for treating solid tumors in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a solid tumor is a locally advanced or metastatic solid tumor.

[0028] In some embodiments, the present invention provides a method for treating cancer 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 cancer is malignant mesothelioma. In some embodiments, the cancer is advanced unresectable malignant mesothelioma. In some embodiments, the cancer is sarcomatoid malignant mesothelioma. In some embodiments, the cancer is epitheliod malignant mesothelioma. In some embodiments, the cancer is meningioma. In some embodiments, the cancer is sporadic menongioma. In some embodiments, the cancer is recurrent or unresectable meningioma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is non-small cell lung cancer (NSCLC; both squamous and adenocarcinoma, including mucoepidermoid NSCLC). In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the cancer is esophageal carcinoma. In some embodiments, the cancer is ovarian carcinoma. In some embodiments, the cancer is endometrial carcinoma. In some embodiments, the cancer is cervical carcinoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is a neurofibromatosis type 2. In some embodiments, the cancer is a brain tumor. In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE). In some embodiments, the cancer is thymoma. In some embodiments, the cancer is a schwannoma. In some embodiments, the cancer is malignant pleural mesothelioma (MPM). In some embodiments, the cancer is angiosarcoma. In some embodiments, the cancer is liposarcoma. In some embodiments, the cancer is synovial sarcoma. In some embodiments, the cancer is myxoid liposarcoma. In some embodiments, the cancer is soft tissue sarcoma. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a locally advanced or metastatic solid tumor.

[0029] In some embodiments of a method provided herein, the method comprises administering to the patient about 25 - 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof, daily.

[0030] 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.

[0031] As used herein, a patient or subject "in need of prevention," "in need of treatment," or "in need thereof," refers to one, who by the judgment of an appropriate medical practitioner e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of nonhuman mammals), would reasonably benefit from a given treatment or therapy. [0032] A "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent, such as Compound A, is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a patient or subject against the onset of a disease, such as cancer, or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0033] In preferred embodiments, a therapeutically effective amount of the drug, such as Compound A, promotes cancer regression to the point of eliminating the cancer. The term "promote(s) cancer regression" means that administering an effective amount of the drug, alone or in combination with another therapeutic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. In addition, the terms "effective" and "effectiveness" with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient. Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.

[0034] As used herein, the terms “therapeutic benefit” or "benefit from therapy" refers to an improvement in one or more of overall survival, progression-free survival, partial response, complete response, and overall response rate and can also include a reduction in cancer or tumor growth or size, a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.

[0035] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0036] The term “subject,” as used herein, has the same meaning as the term “patient”. [0037] In some embodiments, a patient is 18 years or older.

[0038] In some embodiments, if feasible, a patient must be willing to consent to the submission of formalin-fixed paraffin-embedded tissue blocks of tumor tissue, preferably from pre-treatment fresh tumor biopsy. Alternatively, archival tumor FFPE blocks or, preferably, 10 unstained slides of tumor tissue from available archival sources are acceptable.

[0039] In some embodiments, a patient is a subject with histologically proven advanced, unresectable, locally recurrent, or metastatic malignancy that has progressed on or following standard-of-care therapies, and for whom there is no available therapy known to confer clinical benefit, regardless of the presence or absence of NF2 deficiency or other genetic alterations of the Hippo pathway. Cytological diagnosis can be used, in some embodiments.

[0040] In some embodiments, a patient is a subject with malignant pleural mesothelioma (MPM). In some embodiments, a patient is a subject with histological confirmation of malignant pleural mesothelioma (MPM).

[0041] In some embodiments, a patient is a subject with NF2-deficient MPM, which can be determined, in some embodiments, by test results. NF2-deficient tumors are defined, in some embodiments, as any NF2 loss-of-function mutations or copy number loss, as documented, for example, by test results at screening, either from archival tumor tissue or from fresh tumor samples. Test results for NF2 testing based on liquid biopsies testing are acceptable, in some embodiments. [0042] In some embodiments, a patient is a subject with any other solid tumors with documented NF2 deficiency, including, but not limited to, meningioma, cholangiocarcinoma, thymoma, mucoepidermoid NSCLC, HCC and others. NF2-deficient tumors are defined, in some embodiments, as any NF2 loss-of-function mutations or copy number loss, as documented by results at screening, either from archival tumor tissue or from fresh tumor samples. Test results for NF2 testing based on liquid biopsies testing are acceptable, in some embodiments.

[0043] In some embodiments, a patient is a subject with EHE. In some embodiments, a patient is diagnosed with EHE with documented TAZ-CAMTA1 or YAP1-TFE3 gene fusions, as determined, for example, by RNA-seq, FISH, or IHC.

[0044] In some embodiments, a patient is a subject with solid tumors who have YAP1/TAZ gene fusions as determined, for example, by RNA-seq, FISH or IHC. [0045] In some embodiments, a patient can have measurable or evaluable disease by RECIST 1.1 criteria as assessed by an investigator physician or local radiologist.

[0046] In some embodiments, a patient is a subject who has a histological diagnosis of an advanced, unresectable, locally recurrent, or metastatic disease with no available therapy known to confer clinical benefit, as evaluated by a physician.

[0047] In some embodiments, a patient is a subject with MPM. In some embodiments, a patient is a subject with histological confirmed MPM and that has documented NF2 deficiency, defined, for example, as any loss-of-function mutations or NF2 copy number loss. In some embodiments, a patient is a subject with histological confirmed MPM and any NF2 loss-of-function mutations. In some embodiments, a patient is a subject with histological confirmed MPM and any NF2 copy number loss.

[0048] In some embodiments, a patient is a subject with other documented NF2-deficient solid tumors agnostic to tumor type, defined as any loss-of-function mutations or NF2 copy number loss, including, but not limited to, meningioma, cholangiocarcinoma, thymoma, NSCLC, HCC, and others. In some embodiments, a patient is a subject with meningioma and any NF2 loss-of- function mutations. In some embodiments, a patient is a subject with meningioma and any NF2 copy number loss. In some embodiments, a patient is a subject with cholangiocarcinoma and any NF2 loss-of-function mutations. In some embodiments, a patient is a subject with cholangiocarcinoma and any NF2 copy number loss. In some embodiments, a patient is a subject with thymoma and any NF2 loss-of-function mutations. In some embodiments, a patient is a subj ect with thymoma and any NF2 copy number loss. In some embodiments, a patient is a subj ect with NSCLC and any NF2 loss-of-function mutations. In some embodiments, a patient is a subject with NSCLC and any NF2 copy number loss. In some embodiments, a patient is a subject with HCC and any NF2 loss-of-function mutations. In some embodiments, a patient is a subject with HCC and any NF2 copy number loss.

[0049] In some embodiments, a patient is a subject with epithelioid hemangioendothelioma (EHE). In some embodiments, a patient is a subject with histopathological diagnosis of epithelioid hemangioendothelioma (EHE). In some embodiments, a patient is a subject with histopathological diagnosis of epithelioid hemangioendothelioma (EHE) and documented TAZ-CAMTA1 or YAP1- TFE3 gene fusions, as determined, for example, by RNA-seq, FISH, or IHC. In some embodiments, a patient is a subject with epithelioid hemangioendothelioma (EHE) and a TAZ- CAMTA1 gene fusion. In some embodiments, a patient is a subject with epithelioid hemangioendothelioma (EHE) and a YAP1-TFE3 gene fusion. Subjects who have objective disease progression to prior therapy or have active disease and cancer-related pain requiring narcotics for management can be patients, in some embodiments.

[0050] In some embodiments, a patient is a subject with any solid tumor with documented YAP1/TAZ gene fusions, as determined, for example, by RNA-seq, FISH, or IHC.

[0051] In some embodiments, a patient does not have untreated or symptomatic primary central nervous system (CNS) tumors or with intracranial metastases (excluding primary CNS tumors that may be eligible, in some embodiments, e.g., NF2-deficient meningioma). Subjects with leptomeningeal metastases are excluded. In some embodiments, a patient is not a patient who has uncontrolled or life-threatening symptomatic concomitant disease. In some embodiments, a patient is not a patient who has clinically significant cardiovascular disease. In some embodiments, a patient is not pregnant or breastfeeding. In some embodiments, a method of the present invention comprises orally administering a solid formulation as described herein. In some embodiments, a method of the present invention comprises orally administering a unit dosage form as described herein.

[0052] In some embodiments, a method of the present invention comprises administering once daily to a patient about 25 - 1200 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily 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 once daily 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 once daily 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 once daily to a patient about 100 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily 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 once daily 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 once daily to a patient about 200 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 250 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 300 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 350 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 400 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 450 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 500 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 550 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 600 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 650 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 700 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 750 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 800 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 850 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 900 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 950 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 1000 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 1100 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient about 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, a method of the present invention comprises administering once daily in the morning to a patient about 25 - 1200 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient in a fasting state about 25 - 1200 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering once daily to a patient, without the use of proton pump inhibitors (PPIs) or other acid reducing agents (ARAs), about 25 - 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the fasting state may be about 6-24 hours prior to administration of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the fasting state may be about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 22, or about 24 hours prior to administration of Compound A, or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, a method of the present invention comprises administering twice daily to a patient about 25 - 1200 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily 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 twice daily 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 twice daily 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 twice daily to a patient about 100 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily 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 twice daily 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 twice daily to a patient about 200 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient about 250 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient about 300 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient about 350 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient about 400 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient about 450 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient about 500 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient about 550 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient about 600 mg of Compound A, or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, a method of the present invention comprises administering twice daily in the morning to a patient about 25 - 600 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient in a fasting state about 25 - 600 mg of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of the present invention comprises administering twice daily to a patient, without the use of proton pump inhibitors (PPIs) or other acid reducing agents (ARAs), about 25 - 600 mg of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the fasting state may be about 6-24 hours prior to administration of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the fasting state may be about 6, about 8, about 10, about 12, about 14, about 16, about 18, about 20, about 22, or about 24 hours prior to administration of Compound A, or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the patient is not taking proton pump inhibitors (PPIs) or other acid reducing agents (ARAs) during the course of treatment with Compound A, or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the Compound A, or a pharmaceutically acceptable salt thereof, is administered on a continuous dosing schedule. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered on an intermittent dosing schedule. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered every day for the entire course of treatment. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered every day for two weeks followed by one week where Compound A, or a pharmaceutically acceptable salt thereof, is not administered. In some embodiments, Compound A is administered every day for two weeks followed by two weeks where Compound A, or a pharmaceutically acceptable salt thereof, is not administered.

[0058] In some embodiments, the present invention provides a use of Compound A, or a pharmaceutically acceptable salt thereof, or a formulation or unit dosage form thereof, for the treatment of solid tumors and/or cancers, such as those as described herein. In some embodiments, a formulation or unit dosage form of Compound A, or a pharmaceutically acceptable salt thereof, is as described herein.

4. Description of Exemplary Formulations and Dosage Forms

[0059] In some embodiments, the present invention provides a formulation and/or unit dosage form comprising Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a Compound A formulation of the invention is a spray dried intermediate (SDI) formulation comprising Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a Compound A unit dosage form of the invention is a tablet comprising Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a tablet of the present invention is an immediate release (IR) tablet.

[0060] In some embodiments, a tablet of the present invention comprises Compound A free base. In some embodiments, an SDI formulation of the present invention comprises Compound A free base. In some embodiments, Compound A free base is amorphous. In some embodiments, Compound A free base is in crystal form.

[0061] In some embodiments, a tablet of the present invention comprises a pharmaceutically acceptable salt of Compound A. In some embodiments, an SDI formulation of the present invention comprises a pharmaceutically acceptable salt of Compound A. In some embodiments, a pharmaceutically acceptable salt of Compound A is amorphous. In some embodiments, a pharmaceutically acceptable salt of Compound A is in crystal form.

[0062] In some embodiments, a tablet of the present invention comprises an amorphous solid dispersion of Compound A, or a pharmaceutically acceptable salt thereof, manufactured by spray drying. In some embodiments, a dispersion-containing tablet of the present invention provided enhanced oral bioavailability of Compound A.

[0063] In some embodiments, a tablet of the invention comprises a pharmaceutically acceptable polymer. In some embodiments, an SDI formulation of the invention comprises a pharmaceutically acceptable polymer. In some embodiment, a pharmaceutically acceptable polymer is selected from polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA), hypromellose (HPMC), hypromellose phthalate (HPMCP-55), hypromellose acetate succinate MG grade (HPMCAS-M), hypromellose acetate succinate LG grade (HPMCAS-L), hypromellose acetate succinate HG grade (HPMCAS-HG), vitamin E TPGS (TPGS), and microcrystalline Cellulose (MCC). In some embodiment, a pharmaceutically acceptable polymer is HPMCAS-HG.

[0064] In some embodiments, an SDI formulation comprises about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, or about 95 %wt Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, an SDI formulation comprises about 10 - 75 %wt Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, an SDI formulation comprises about 10 - 70, about 15 - 65, about 15 - 60, about 20 - 55, about 20 - 50, about 25 - 45, about 25 - 40, or about 25 - 35 %wt Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, an SDI formulation comprises about 30 %wt Compound A free base.

[0065] In some embodiments, an SDI formulation comprises a pharmaceutically acceptable polymer at about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, or 95 %wt. In some embodiments, an SDI formulation comprises a pharmaceutically acceptable polymer at about 5 - 95, about 10 - 90, about 15 - 85, about 20 - 85, about 25 - 85, about 30 - 80, about 35 - 80, about 40 - 80, about 45 - 75, about 50 - 75, about 55 - 75, or about 60 - 75 %wt. In some embodiments, an SDI formulation comprises a pharmaceutically acceptable polymer at about 70 %wt. In some embodiments, an SDI formulation comprises HPMCAS-HG at about 70 %wt. [0066] In some embodiments, the present invention provides an SDI formulation comprising about 30:70 (wt %) Compound A free base: HPMCAS-HG.

[0067] In some embodiments, an SDI formulation of the present invention is selected from those described in the examples herein.

[0068] In some embodiments, a tablet of the invention comprises an SDI formulation of the invention, and a pharmaceutically acceptable excipient or carrier. In some embodiments, a tablet of the invention comprises about 50 wt% of an SDI formulation of the invention. In some embodiments, a tablet of the invention comprises about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, or about 85 wt% of an SDI formulation of the invention. In some embodiments, a tablet of the invention comprises about 30-80, about 35-75, about 40-70, about 45-70, about 50-65, or about 55-65 wt% of an SDI formulation of the invention.

[0069] In some embodiments, a tablet of the invention comprises mannitol. In some embodiments, a tablet of the invention comprises mannitol as an intragranular component. In some embodiments, a tablet of the invention comprises mannitol at about 10-25, about 15-25, or about 10-20 wt%. In some embodiments, a tablet of the invention comprises mannitol at about 5, about 10, about 15, about 18, about 20, or about 25 wt%. In some embodiments, a tablet of the invention comprises mannitol at about 10-25 or about 10-20 wt%. In some embodiments, a tablet of the invention comprises mannitol at about 11.5, about 15.5, about 16.5, about 19.5, or about 20.5 wt%. In some embodiments, a tablet of the invention comprises mannitol as an intragranular component at about 18.00 wt%.

[0070] In some embodiments, a tablet of the invention comprises microcrystalline cellulose at about 5-40 wt%. In some embodiments, a tablet of the invention comprises microcrystalline cellulose as an intragranular component. In some embodiments, a tablet of the invention comprises microcrystalline cellulose as an extragranular component. In some embodiments, a tablet of the invention comprises microcrystalline cellulose as an intragranular component and an extragranular component. In some embodiments, a tablet of the invention comprises microcrystalline cellulose at about 5, about 10, about 15, about 20, about 25, about 30, about 35, or about 40 wt%. In some embodiments, a tablet of the invention comprises microcrystalline cellulose at about 10-25 or about 10-20 wt%. In some embodiments, a tablet of the invention comprises microcrystalline cellulose at about 10.5, about 11.5, about 15.5, about 16.5, about 18.0, about 19.5, about 20.5, or about 28.5 wt%. In some embodiments, a tablet of the invention comprises microcrystalline cellulose as an intragranular component at about 10.5, about 11.5, about 15.5, about 16.5, about 18.0, about 20, or about 25 wt%. In some embodiments, a tablet of the invention comprises microcrystalline cellulose as an extragranular component at about 5, about 7.5, about 10.5, about 12.5, or about 15 wt%.

[0071] In some embodiments, a tablet of the invention comprises croscarmellose sodium at about 0.5-2.5wt%. In some embodiments, a tablet of the invention comprises croscarmellose sodium as an intragranular component. In some embodiments, a tablet of the invention comprises croscarmellose sodium as an extragranular component. In some embodiments, a tablet of the invention comprises croscarmellose sodium as an intragranular component and an extragranular component. In some embodiments, a tablet of the invention comprises croscarmellose sodium at about 0.5, about 1.0, about 1.5, about 2.0, or about 2.5wt%. In some embodiments, a tablet of the invention comprises croscarmellose sodium as an intragranular component at about 0.8, about 0.9, about 1.0, about 1.1, or about 1.2 wt%. In some embodiments, a tablet of the invention comprises croscarmellose sodium as an extragranular component at about 0.8, about 0.9, about 1.0, about 1.1, or about 1.2 wt%.

[0072] In some embodiments, a tablet of the invention comprises colloidal silicon dioxide at about 0.5-2.5wt%. In some embodiments, a tablet of the invention comprises colloidal silicon dioxide as an intragranular component. In some embodiments, a tablet of the invention comprises colloidal silicon dioxide at about 0.5, about 1.0, about 1.5, about 2.0, or about 2.5wt%. In some embodiments, a tablet of the invention comprises colloidal silicon dioxide as an intragranular component at about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 wt%.

[0073] In some embodiments, a tablet of the invention comprises magnesium stearate at about 0.5-2.5wt%. In some embodiments, a tablet of the invention comprises magnesium stearate as an intragranular component. In some embodiments, a tablet of the invention comprises magnesium stearate as an extragranular component. In some embodiments, a tablet of the invention comprises magnesium stearate as an intragranular component and an extragranular component. In some embodiments, a tablet of the invention comprises magnesium stearate at about 0.5, about 1.0, about 1.5, about 2.0, or about 2.5wt%. In some embodiments, a tablet of the invention comprises magnesium stearate as an intragranular component at about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 wt%. In some embodiments, a tablet of the invention comprises magnesium stearate as an extragranular component at about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, or about 0.8 wt%.

[0074] In some embodiments, a tablet of the invention comprises a non-functional film coating. In some embodiments, a tablet of the invention comprises a non-functional film coating of Opadry II White 85F 18422.

[0075] In some embodiments, a tablet of the invention comprises a filler. In some embodiments, a filler is selected from mannitol or microcrystalline cellulose. In some embodiments, a filler is mannitol. In some embodiments, a filler is microcrystalline cellulose. In some embodiments, a tablet comprises a filler at about 10-25 wt%. In some embodiments, a tablet comprises a filler at about 10, about 10.5, about 15, about 18, about 20, about 25, or about 46.5 wt%. In some embodiments, a tablet comprises a filler at about 15-20 wt%. In some embodiments, a tablet comprises a filler at about about 10.5 about 18, about 36, or about 46.5 wt%.

[0076] In some embodiments, a tablet of the invention comprises a disintegrant. In some embodiments, a disintegrant is croscarmellose sodium (Ac-Di-Sol). In some embodiments, a tablet comprises a disintegrant at about 0.5-10 wt%. In some embodiments, a tablet comprises a disintegrant at about 0.5, about 1, about 2, about 4, about 6, about 8, or about 10 wt%. In some embodiments, a tablet comprises a disintegrant at about 0.5-4 wt%. In some embodiments, a tablet comprises a disintegrant at about 1, about 2, or about 4 wt%.

[0077] In some embodiments, a tablet of the invention comprises a glidant. In some embodiments, a glidant agent is colloidal silicon dioxie (Cab-O-Sil). In some embodiments, a tablet comprises a glidant at about 0.5-5 wt%. In some embodiments, a tablet comprises a glidant at about 0.5, about 1, about 1.5, about 2, about 3, about 4, or about 5 wt%. In some embodiments, a tablet comprises a glidant at about 0.5-1.5 wt%. In some embodiments, a tablet comprises a glidant at about .05 wt%.

[0078] In some embodiments, a tablet of the invention comprises magnesium stearate. In some embodiments, a tablet comprises magnesium stearate at about 0.5-5 wt%. In some embodiments, a tablet comprises magnesium stearate at about 0.5, about 1, about 1.5, about 2, about 3, about 4, or about 5 wt%. In some embodiments, a tablet comprises magnesium stearate at about 0.5-1.5 wt%. In some embodiments, a tablet comprises magnesium stearate at about 0.5 wt%. In some embodiments, a tablet comprises magnesium stearate at about 1 wt%.

[0079] In some embodiments, a tablet of the invention comprises a non-functional coating. In some embodiments, non-functional coating is Opadry II White 85F 18422. In some embodiments, a tablet comprises a non-functional coating at about 3 wt%. In some embodiments, a tablet comprises non-functional coating at about 2-4 wt%.

[0080] In some embodiments, the present invention provides an IR tablet which has a full release in about 10 minutes in a sink dissolution test. In some embodiments, an IR tablet of the present invention has a full release in about 9, 8, 7, 6, or 5 minutes in a sink dissolution test. In some embodiments, an IR tablet of the present invention has a full release in about 4 minutes in a sink dissolution test. In some embodiments, an IR tablet of the present invention has a full release in about 3 minutes in a sink dissolution test. In some embodiments, an IR tablet of the present invention has a full release in about 2 minutes in a sink dissolution test. In some embodiments, an IR tablet of the present invention has a full release in about 1 minute in a sink dissolution test.

[0081] In some embodiments, a tablet of the present invention comprises one or more pharmaceutically acceptable excipient or carrier, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide. In some embodiments, an IR tablet of the present invention comprises one or more pharmaceutically acceptable excipient or carrier including, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. It will be understood by those in the art that some substances serve more than one purpose in a pharmaceutical composition. For instance, some substances are binders that help hold a tablet together after compression, yet are also disintegrants that help break the tablet apart once it reaches the target delivery site. Selection of excipients and amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works available in the art.

[0082] In certain embodiments, a tablet of the present invention is manufactured using standard, art-recognized tablet processing procedures and equipment. In certain embodiments, the method for forming the tablets is direct compression of a powdered, crystalline and/or granular composition comprising a solid form provided herein, alone or in combination with one or more excipients or carriers, such as, for example, carriers, additives, polymers, or the like. In certain embodiments, as an alternative to direct compression, the tablets may be prepared using wet granulation or dry granulation processes. In certain embodiments, the tablets are molded rather than compressed, starting with a moist or otherwise tractable material. In certain embodiments, compression and granulation techniques are used. In some embodiments, a tablet of the present invention is manufactured using the process described in Example 2 below.

[0083] Suitable binders include, but are not limited to, starch (including potato starch, corn starch, and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone (PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxy ethyl cellulose (HEC), carboxymethyl cellulose and the like), veegum, carbomer (e.g., carbopol), sodium, dextrin, guar gum, hydrogenated vegetable oil, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), microcrystalline cellulose, among others. Binding agents also include, e.g., acacia, agar, alginic acid, cabomers, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioner's sugar, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethylacrylates, povidone, sodium alginate, sodium carboxymethylcellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein.

[0084] Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, Marcus Hook, Pa.), and mixtures thereof. In some embodiment, a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC- 581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103.TM. and Starch 1500 LM.

[0085] Suitable fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0086] In certain embodiments, a tablet of the present invention comprises one or more diluents. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT), potassium chloride, sodium chloride, sorbitol and talc, among others. Diluents also include, e.g., ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lacitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, powered cellulose, polydextrose, polymethylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutylether-.beta.-cyclodextrin, talc, tragacanth, trehalose, and xylitol. [0087] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.

[0088] In some embodiments, a tablet of the present invention comprises one or more lubricants. Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof.

[0089] In some embodiments, a tablet of the present invention comprises one or more glidants. Suitable glidants include, but are not limited to, colloidal silicon dioxide (CAB-O-SIL), and asbestos-free talc.

[0090] In some embodiments, a tablet of the present invention comprises one or more coloring agents. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.

[0091] In some embodiments, a tablet of the present invention comprises one or more flavoring agents. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. [0092] In certain embodiments, a tablet of the present invention comprises one or more sweetening agents. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.

[0093] In certain embodiments, a tablet of the present invention comprises one or more emulsifying agents. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN®20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.

[0094] In certain embodiments, a tablet of the present invention comprises one or more suspending and dispersing agents. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0095] In certain embodiments, a tablet of the present invention comprises one or more preservatives. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

[0096] In certain embodiments, a tablet of the present invention comprises one or more wetting agents. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0097] In certain embodiments, a tablet of the present invention comprises one or more solvents. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.

[0098] In certain embodiments, a tablet of the present invention comprises one or more nonaqueous liquids. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.

[0099] In certain embodiments, a tablet of the present invention comprises one or more organic acids. Suitable organic acids include, but are not limited to, citric and tartaric acid.

[00100] In certain embodiments, a tablet of the present invention comprises one or more sources of carbon dioxide. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate. [00101] In certain embodiments, a tablet of the present invention can be a multiple compressed tablet, an enteric-coating tablet, or a sugar-coated or film-coated tablet. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

[00102] A tablet of the present invention can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants.

[00103] Components of a tablet of the present invention can be intragranular or extragranular. In some embodiments, a tablet comprises intragranularly Compound A, HPMCAS-HG, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. In some embodiments, a tablet of the present invention comprises extragranularly microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, a tablet of the present invention is film coated. In some embodiments, a table of the present invention is coated with Opadry II White 85F18422.

[00104] In some embodiments, a tablet of the present invention is selected from those described in Example 2 below. In some embodiments, a tablet of the present invention is a 25 mg strength tablet listed in Table 2. In some embodiments, a tablet of the present invention is a 100 mg strength tablet listed in Table 2.

5. Methods and Uses for Treatins Cancer The Hippo Signaling Network

[00105] The Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control. In an un- phosphorylated/de-phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and antiapoptosis leads to development of cancer. In some instances, overexpression of YAP/TAZ is associated with cancer.

[00106] Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Latsl/2 (homologues of Warts/Wts), and their adaptor proteins Savl (homologue of Salvador/Sav) and Mob (M0BKL1A and MOBKL1B; homologues of Mats), respectively. In general, MST1/2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl/2 kinase. Latsl/2 is also activated by the scaffold protein Mob. The activated Latsl/2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.

[00107] In some instances, Latsl/2 phosphorylates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl/2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates YAP at all five of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation. [00108] Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK16/s in the degradation motif, which then signals for interaction with the P-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[00109] In some instances, Latsl/2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues. In some instances, Latsl/2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[00110] In some embodiments, phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCF^|l'^{I PC} -mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skpl, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme. In some cases, the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, PTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g. SCF^pTrCP1) interacts with an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate. Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFCE In some embodiments, the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome.

[00111] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.

YAP/TAZ Interaction with TEAD

[00112] In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus. Within the nucleus, YAP/TAZ interacts with the TEAD family of transcription factors (e.g., human TEAD1 (UniProtKB ID P28347-1), human TEAD2 (UniProtKB ID Q15562), human TEAD3 (UniProtKB ID Q99594), and human TEAD4 (UniProtKB ID Q15561) to activate genes involved in anti-apoptosis and proliferation, such as for example CTFG, Cyr61, and FGF1.

[00113] Proteomic and biochemical studies have shown that the TEAD (TEA Domain) transcription factors are palmitoylated at evolutionarily conserved cysteine residues. Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation. The C359S mutant showed the greatest loss of palmitoylation, and C327S and C53S also showed decreased palmitoylation. These results suggest that C359 plays a critical role in TEAD1 palmitoylation. Furthermore, combination mutation of all three cysteine residues, C53/327/359S (3CS), completely ablated TEAD1 palmitoylation, indicating that these residues are involved in TEAD1 palmitoylation. It has been found that TEADs undergo PAT -independent autopalmitoylation, under physiological concentrations of palmitoy 1-CoA. Furthermore, autopalmitoylation plays critical roles in regulating TEAD-YAP association and their physiological functions in vitro and in vivo. Chan, el al. Nature Chem. Biol. 12, pages 282-289 (2016); Noland, et al. Structure, 24, 1-8 (2016); Gibault et al. J. Med. Chem. 61, 5057-5072 (2018). Therefore, palmitoylation of TEADs play important roles in regulating Hippo pathway transcriptional complexes. YAP/TAZ regulation mediated by G-proteins/GPCRs

[00114] In some embodiments, the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins. G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some instances, the latter class of complexes comprise of alpha (Ga), beta (Gp), and gamma (G_y) subunits. In some cases, there are several classes of G_a subunits: G_q/ua, Gi2/i3a, Gi/_Oa (G inhibitory, G other), and G_sa (G stimulatory).

[00115] In some instances, Gia (G inhibitory), G_oa (G other), G_q/l la, and G12/13a coupled GPCRs activate YAP/TAZ and promote nuclear translocation. In other instances, G_sa (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.

[00116] In some cases, Gia (G inhibitory), G_oa (G other), G_q/ua, and Gi2/i3a coupled GPCRs activate YAP/TAZ through repression of Latsl/2 activities. In contrast, G_sa, in some embodiments, induces Latsl/2 activity, thereby promoting YAP/TAZ degradation.

Gq Family

[00117] G_qa (also known as G_q/u protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca²⁺) release from intracellular storage through the activation of phospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol 4, 5 -bisphosphate (PIP2) to diacyl glycerol (DAG) and IP3. In some instances, IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca²⁺ channel. In some cases, the binding triggers the opening of the Ca²⁺ channel, and thereby increases the release of Ca²⁺ into the cytoplasm.

[00118] In some embodiments, the GPCRs that interact with G_qa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and M5; and trace amine-associated receptor 1. [00119] In some instances, there are several types of G_qa: G_q, G_q/u, G_q/i4, and G_q/i5. The G_q protein is encoded by GNAQ. G_q/n is encoded by GNA11. G_q/i4 is encoded by GNA14. G_q/i5 is encoded by GNA15.

[00120] In some instances, mutations or modifications of the G_qa genes have been associated with cancer. Indeed, studies have shown that mutations in G_qa promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.

[00121] In some instances, mutations or modifications of the G_qa genes have been associated with congenital diseases. In some instances, mutations of G_qa have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome. In some instances, about 92% of Port-Wine stain cases harbors a mutation in GNAQ. In some instances, about 88% of Sturge- Weber Syndrome harbors a mutation in GNAQ.

G12/13 Family

[00122] Gi2/i3a modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g, Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.

[00123] In some embodiments, the GPCRs that interact with Gi2/i3a include, but are not limited to, purinergic receptors (e.g, P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1 -phosphate (e.g., SIP2, SIP3, SIP4 and SIP5); lysophosphatidic acid e.g., LPAi, LPA2, LPA3); angiotensin II (ATI); serotonin (5-HT2_C and 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; Ai adenosine receptors; on adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors. [00124] In some instances, Gi2/na is further subdivided into G12 and G13 types which are encoded by GNA12 and GNA13, respectively.

Gi/o Family

[00125] Gi/_Oa (G inhibitory, G other) (also known as Gi/G₀ or Gi protein) suppresses the production of 3’, 5 ’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.

[00126] In some embodiments, the GPCRs that interact with Gia include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HT5; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as oi2A, ct2B, and a2_C; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GABAB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors such as H3 and H4 receptors; melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACR1 and NIACR2; opioid receptors such as 6, K, p, and nociceptin receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EPi), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors ssti, sst2, sst3, sst4, and ssts; and trace amine-associated receptor 8.

[00127] In some instances, there are several types of Gia: Gial, Gia2, Gia3, Gia4, G_oa, Gt, Ggust, and G_z. Gial is encoded by GNAI1. Gia2 is encoded by GNAI2. Gia3 is encoded by GNAI3. G_oa, the a₀ subunit, is encoded by GNA01. Gt is encoded by GNAT1 and GNAT2. Ggust is encoded by GNAT3. G_z is encoded by GNAZ.

G_s Family

[00128] G_sa (also known as G stimulatory, G_s alpha subunit, or G_s protein) activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3’,5’-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, the GPCRs that interact with G_sa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HTe, and 5-HT?; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and Ait,; arginine vasopressin receptor 2 (AVPR2); P-adrenergic receptors Pi, P2, and P3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor DI -like family receptors such as Di and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H2 receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2 and I2; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1; and box jellyfish opsin.

[00129] In some instances, there are two types of G_sa: G_s and G_oif. G_s is encoded by GNAS. Goif is encoded by GN AL.

Additional Regulators of the Hippo signaling network

[00130] In some embodiments, the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity. In some instances, CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.

[00131] In some instances, the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1.

[00132] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity. In some embodiments, E-cad- associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Latsl/2 kinase activity, thereby preventing inactivation of YAP/TAZ.

[00133] In some embodiments, additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.

[00134] In some embodiments, the present invention provides a use of a compound, or a pharmaceutical salt or composition thereof, for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.

[00135] The activity of compound A utilized in this invention as an inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, can be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof. Detailed conditions for assaying compound A are known in the art. See, for example, WO 2020243423 and WO 2020243415, the contents of each of which are incorporated herein by reference in their entireties.

[00136] 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 can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can 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 can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[00137] The provided compound A is an inhibitor of TEAD and is therefore useful for treating one or more disorders associated with activity of TEAD or the Hippo pathway. Thus, in certain aspects and embodiments, the present invention provides a method for treating a TEAD-mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.

[00138] As used herein, the term “TEAD-mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, is known to play a role. Accordingly, another aspect or embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which TE D (e.g, TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are known to play a role.

[00139] As used herein, the term “a therapeutically effective amount of’ refers to the amount of a TEAD inhibitor or a pharmaceutically acceptable salt thereof, which is effective to reduce or attenuate the biological activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof, provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition in a biological sample or in a patient. In some embodiments, “a therapeutically effective amount of’ refers to the amount of a TEAD inhibitor or a pharmaceutically acceptable salt thereof that measurably decreases the binding or signaling activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, or any TEAD-mediated activity. The term “therapeutically effective amount” can encompass, in some embodiments, an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibition of a TEAD transcription factor. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease.

[00140] In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof. In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof. In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of the Hippo pathway is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.

[00141] In some aspects and embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a TEAD inhibitor compound as described herein, or a pharmaceutical salt or composition thereof. In some embodiments, a cellular proliferative disorder is cancer. In some embodiments, the cancer is characterized by increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity.

[00142] As used herein, the terms "increased," “elevated,” or “enhanced,” are used interchangeably and encompass any measurable increase in a biological function and/or biological activity and/or a concentration. For example, an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.

[00143] As used herein, the terms “increased expression” and/or “increased activity” of a substance, such as TEAD, in a sample or cancer or patient, refers to an increase in the amount of the substance, such as TEAD, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50- fold, about 100-fold, or higher, relative to the amount of the substance, such as TEAD, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control, as determined by techniques known in the art. A subject can also be determined to have an “increased expression” or “increased activity” of TEAD if the expression and/or activity of TEAD is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of TEAD in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples. As practiced in the art, such control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.

[00144] As used herein, a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease can be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes, such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (/. e. , “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

Cancer

[00145] The cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.

[00146] In some embodiments of the methods and uses described herein, a cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcription coactivator (TAZ/YAP). In some embodiments of the methods and uses described herein, a cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4). In some embodiments of the methods and uses described herein, the cancer is characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity. In some embodiments of the methods and uses described herein, the cancer is a cancer in which YAP is localized in the nucleus of the cancer cells.

[00147] In some embodiments of the methods and uses described herein, the cancer is characterized or associated with a genetic alteration in one or more Hippo pathway genes. As used herein, the term “genetic alteration in one or more Hippo pathway genes” refers to that certain percentage of cells in a sample, such as a tumor sample, having a detectable amount of genetic alteration in one or more Hippo pathway genes. As used herein, a genetic alteration in a gene, such as a Hippo pathway gene, can refer, for example, to a loss-of-function mutation in the gene (including, for example, frameshifts, nonsense mutations and splicing mutations), a change in gene copy number (including, for example, copy gain, amplification, copy loss, or deletion), or a fusion of the gene with another gene, such as, for example, a TAZ-CAMTA1 fusion or YAP1-TFE3 fusion. In some embodiments, a genetic alteration in Hippo pathway genes refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%of cells, such as tumor cells, in a sample have at least about three copies of genetically altered Hippo pathway genes, at least about four copies of genetically altered Hippo pathway genes, at least about five copies of genetically altered Hippo pathway genes, at least about six copies of genetically altered Hippo pathway genes, at least about seven copies of genetically altered Hippo pathway genes, at least about eight copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes, at least about thirteen copies of genetically altered Hippo pathway genes, at least about fourteen copies of genetically altered Hippo pathway genes, at least about fifteen copies of genetically altered Hippo pathway genes, at least about twenty copies of genetically altered Hippo pathway genes, or more. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about 15 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 40% tumor cells in a sample have at least about 4 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about four copies of genetically altered Hippo pathway genes.

[00148] In some embodiments, a Hippo pathway gene is NF2. In some embodiments, the genetic alteration in the one or more Hippo pathway genesis NF2 deficiency. In some embodiments, NF2 deficiency refers to NF2 loss of function mutations. In some embodiments, NF2 deficiency refers to NF2 copy losses or deletions. In some embodiments, NF2 deficiency refers to absent or very low NF2 mRNA expression. In some embodiments, a Hippo pathway gene is YAP1. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is YAP1 amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a YAP1 fusion, such as a YAP1-TFE3 fusion. In some embodiments, a Hippo pathway gene is TAZ. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is TAZ amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a TAZ fusion, such as a TAZ-CAMTA1 fusion. In some embodiments, a Hippo pathway gene is LATS 1/2. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is LATS 1/2 copy number loss or deletion. In some embodiments, a Hippo pathway gene is MST1/2. In some embodiments, a Hippo pathway gene is BAP1

[00149] In some embodiments, a cancer is characterized by a mutant Ga-protein. In some embodiments, a mutant Ga-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, a mutant Ga-protein is G12. In some embodiments, a mutant Ga-protein is G13. In some embodiments, a mutant Ga-protein is Gq. In some embodiments, a mutant Ga-protein is Gl 1. In some embodiments, a mutant Ga-protein is Gi. In some embodiments, a mutant Ga-protein is Go. In some embodiments, a mutant Ga-protein is Gs. [00150] In some embodiments, the cancer is selected from a mesothelioma, meningioma, cholangiocarcinoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), esophageal carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, brain tumor, epithelioid hemangioendothelioma (EHE), thymoma, schwannoma, angiosarcoma, liposarcoma, synovial sarcoma, and soft tissue sarcoma.

[00151] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a locally advanced or metastatic solid tumor.

[00152] In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is malignant mesothelioma. In some embodiments, the cancer is advanced unresectable malignant mesothelioma. In some embodiments, the cancer is malignant pleural mesothelioma (MPM). In some embodiments, the cancer is sarcomatoid malignant mesothelioma. In some embodiments, the cancer is epithelioid malignant mesothelioma.

[00153] In some embodiments, the cancer is meningioma. In some embodiments, the cancer is sporadic meningioma. In some embodiments, the cancer is recurrent or unresectable meningioma. [00154] In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is squamous NSCLC, adenocarcinoma NSCLC, and mucoepidermoid NSCLC.

[00155] In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC).

[00156] In some embodiments, the cancer is esophageal carcinoma.

[00157] In some embodiments, the cancer is ovarian carcinoma.

[00158] In some embodiments, the cancer is endometrial carcinoma.

[00159] In some embodiments, the cancer is cervical carcinoma.

[00160] In some embodiments, the cancer is hepatocellular carcinoma.

[00161] In some embodiments, the cancer is a neurofibromatosis type 2 (NF2)-defi cient cancer.

[00162] In some embodiments, the cancer is a brain tumor.

[00163] In some embodiments, the cancer is epithelioid hemangioendothelioma (EHE).

[00164] In some embodiments, the cancer is thymoma.

[00165] In some embodiments, the cancer is a schwannoma.

[00166] In some embodiments, the cancer is angiosarcoma.

[00167] In some embodiments, the cancer is liposarcoma. [00168] In some embodiments, the cancer is synovial sarcoma.

[00169] In some embodiments, the cancer is myxoid liposarcoma.

[00170] In some embodiments, the cancer is soft tissue sarcoma.

[00171] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a locally advanced or metastatic solid tumor.

[00172] In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer malignant pleural mesothelioma (MPM).

[00173] In some embodiments, the cancer is an NF2-defi cient MPM. NF2-deficient tumors are defined, in some embodiments, as any NF2 loss-of-function mutations or copy number loss.

[00174] In some embodiments, the cancer is EHE. In some embodiments, the EHE has TAZ- CAMTA1 or YAP1-TFE3 gene fusions.

[00175] In some embodiments, the cancer is a solid tumors with one or more YAP1/TAZ gene fusions.

[00176] In some embodiments, cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[00177] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[00178] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.

[00179] Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, 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, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. [00180] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/ stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma.

[00181] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.

[00182] In some embodiments, a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma.

[00183] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.

[00184] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.

[00185] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[00186] In some embodiments, a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papillomavirus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https://clinicaltrials.gov/ct2/show/study/NCT02488759; see also https://clinicaltrials.gov/ct2/show/study/NCT0240886; https://clinicaltrials.gov/ct2/show/ NCT02426892).

[00187] In some embodiments, the present invention provides a method for treating cancer in a patient comprising orally administering to the patient a formulation as described herein. In some embodiments, the present invention provides a method for treating cancer in a patient comprising orally administering to the patient a unit dosage form as described herein. In some embodiments, the present invention provides a method for treating cancer in a patient comprising orally administering to the patient a tablet as described herein.

[00188] In some embodiments, the methods or uses described herein inhibit or reduce or arrest the growth or spread of a cancer or tumor. In some embodiments, the tumor or cancer is treated by arresting, reducing, or inhibiting further growth of the tumor. In some embodiments, the cancer or tumor is treated using the methods or uses described herein by reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the size of the cancer or tumor prior to treatment. In some embodiments, cancers or tumors are treated using the methods or uses described herein by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the quantity of tumors prior to treatment.

[00189] In some embodiments, the tumor is treated by arresting further growth of the tumor. In some embodiments, the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the size of the tumor prior to treatment. In some embodiments, tumors are treated by reducing the quantity of the tumors in the patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the quantity of tumors prior to treatment.

[00190] In some embodiments, a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. [00191] In some embodiments, a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of a metabolite of Compound A, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. In some embodiments, a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of a metabolite of Compound A, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[00192] In some embodiments, a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

Co-Administration with One or More Other Therapeutic Agent(s)

[00193] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions and methods described herein. 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.”

[00194] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of compound A or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[00195] Compound A can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, compound A is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[00196] Compound A can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of compound A or a pharmaceutically acceptable salt thereof and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. Compound A or a pharmaceutically acceptable salt thereof can besides, or in addition, be administered especially for tumor therapy 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.

[00197] One or more other therapeutic agent(s) can be administered separately from a compound A or a pharmaceutically acceptable salt thereof, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with compound A or a pharmaceutically acceptable salt thereof in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent(s) and a compound A or a pharmaceutically acceptable salt thereof can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent(s) and compound A or a pharmaceutically acceptable salt thereof are administered as a multiple dosage regimen within greater than 24 hours apart.

[00198] 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 example, compound A or a pharmaceutically acceptable salt thereof can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising compound A or a pharmaceutically acceptable salt thereof, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[00199] The amount of compound A or a pharmaceutically acceptable salt thereof and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Preferably, a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered.

[00200] In those compositions which comprise one or more other therapeutic agent(s), the one or more other therapeutic agent(s) and compound A or a pharmaceutically acceptable salt thereof can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that other therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 pg/kg body weight/day of the one or more other therapeutic agent(s) can be administered.

[00201] The amount of one or more other therapeutic agent(s) present in the compositions of this invention may 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 one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.

[00202] Compound A or a pharmaceutically acceptable salt thereof can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

Exemplary Other Therapeutic Agents

[00203] In some embodiments, the one or more other therapeutic agents is a MEK inhibitor. As used herein, a “MEK inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits mitogen-activated protein kinase enzymes MEK1 and/or MEK2. In some embodiments, an MEK inhibitor is selected from those as described in Cheng et al. , “Current Development Status of MEK Inhibitors,” Molecules 2017, 22, 1551, the contents of which are incorporated herein by reference in its entirety. In certain embodiments, the MEK inhibitor is selected from binimetinib (MEK 162, ARRY-438162, ARRAY BIOPHARMA INC ), cobimetinib (COTELLIC®, Exelexis/Genentech/Roche), refametinib (BAY 86-9766, RDEA119; Bayer AG), selumetinib (AZD6244, ARRY-142886; ASTRAZENECA), trametinib (MEKINIST®, Novartis), mirdametinib (PD-0325901, Spring Works Therapeutics), pimasertib (AS703026, MSC1936369B, Merck KGaA)or a pharmaceutically acceptable salt and/or solvate of any of the foregoing. In certain embodiments, the other therapeutic agent is binimetinib, cobimetinib, selumetinib, trametinib, mirdametinib, pimasertib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.

[00204] Other examples of MEK inhibitors for use as an other or second therapeutic agent in the methods and uses described herein include, but are not limited to, E6201 (Eisai Co Ltd./Strategia Theraputics), GDC-0623 (RG 7421, Genentech, Inc.), CH5126766 (RO5126766, Chugai 232Pharmaceutical Co., Roche), HL-085 (Shanghai Kechow Pharma, Inc.), SHR7390 (HENGRUI MEDICINE), TQ-B3234 (CHIATAI TIANQING), CS-3006 (CSTONE Pharmaceuticals), FCN-159 (FosunPharmaceuticals), VS-6766 (Verastem Oncology), and IMM- 1-104 (Immuneering Corp.). Other examples of MEK inhibitors for use as second anti-cancer agents or other therapeutic agents in the methods and uses described herein include, but are not limited to, those described in W02005/121142, WO2014/169843, WO2016/035008, WO20 16/168704, WO2020/125747, WO2021/142144, WO2021/142345, WO2021/149776, the contents of each of which are herein incorporated by reference in their entireties.

[00205] In some embodiments, the one or more other therapeutic agents is an EGFR inhibitor. As used herein, an “EGFR inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits epidermal growth factor receptor (EGFR). In some embodiments, an EGFR inhibitor is selected from those as described in Ayati et al., “A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy,” Bioorganic Chemistry 2020, 99: 103811, the contents of which are incorporated herein by reference in its entirety. In some embodiments, an EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab. In some embodiments, an EGFR inhibitor is cetuximab. In some embodiments, an EGFR inhibitor is necitumumab. In some embodiments, an EGFR inhibitor is panitumumab. In some embodiments, an EGFR inhibitor is zalutumumab. In some embodiments, an EGFR inhibitor is nimotuzumab. In some embodiments, an EGFR inhibitor is matuzumab.

[00206] In some embodiments, an EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib. In some embodiments, an EGFR inhibitor is osimertinib. In some embodiments, an EGFR inhibitor is gefitinib. In some embodiments, an EGFR inhibitor is erlotinib. In some embodiments, an EGFR inhibitor is lapatinib. In some embodiments, an EGFR inhibitor is neratinib. In some embodiments, an EGFR inhibitor is vandetanib. In some embodiments, an EGFR inhibitor is afatinib. In some embodiments, an EGFR inhibitor is brigatinib. In some embodiments, an EGFR inhibitor is dacomitinib. In some embodiments, an EGFR inhibitor is icotinib.

[00207] In some embodiments, an EGFR inhibitor is a “1st generation EGFR tyrosine kinase inhibitor” (1st generation TKI). A 1^st generation TKI refers to reversible EGFR inhibitors, such as gefitinib and erlotinib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations such as deletions in exon 19 and exon 21 L858R mutation.

[00208] In some embodiments, an EGFR inhibitor is a “2nd generation EGFR tyrosine kinase inhibitor” (2nd generation TKI). A 2^nd generation TKI refers to covalent irreversible EGFR inhibitors, such as afatinib and dacomitib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations such as deletions in exon 19 and exon 21 L858R mutation. [00209] In some embodiments, an EGFR inhibitor is a “3rd generation EGFR tyrosine kinase inhibitor” (3rd generation TKI). A 3rd generation TKI refers to covalent irreversible EGFR inhibitors, such as osimertinib and lazertinib, which are selective to the EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R, alone or in combination with T790M mutation, and have lower inhibitory activity against wild-type EGFR.

[00210] In some embodiments, one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).

[00211] In some embodiments, one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor is selected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®, Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (EPIDAZA®, HBI-8000, Chipscreen Biosciences, China).

[00212] In some embodiments, one or more other therapeutic agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6 inhibitor is selected from palbociclib (IBRANCE®, Pfizer); riboci clib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[00213] In some embodiments, one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, a PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[00214] In some embodiments, one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. In some embodiments, a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi -Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[00215] In some embodiments, one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some embodiments, a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis/Celgene), cabazitaxel (JEVTANA®, Sanofi -Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[00216] In some embodiments, one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.

[00217] In some embodiments, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, SYNRTBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ERWINAZE®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, JEVTANA®, Sanofi -Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, TREANDA®, Cephalon/Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine- based nucleoside analog and thymidine phosphorylase inhibitor, LONSURF®, Taiho Oncology). In some embodiments, one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist.

[00218] In some embodiment, one or more other therapeutic agent is selected from approved VEGF inhibitors and kinase inhibitors including: bevacizumab (AVASTIN®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/Sanofi). VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech/Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEEVA®, Genentech/Roche/Astellas); lapatinib (TYKERB®, Novartis); afatinib (GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib (SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, such as crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); and alectinib (ALECENZa®, Genentech/Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (IMBRUVICA®, Pharmacyclics/Janssen); and Flt3 receptor inhibitors, such as midostaurin (R YD APT®, Novartis).

[00219] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib ( Amgen/T akeda) .

[00220] In some embodiments, one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).

[00221] In some embodiments, one or more other therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).

[00222] In some embodiments, one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).

[00223] In some embodiments, one or more other therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).

[00224] In some embodiments, one or more other therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (ODOMZO®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma.

[00225] In some embodiments, one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).

[00226] In some embodiments, one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan). [00227] In some embodiments, one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[00228] In some embodiments, one or more other therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[00229] In some embodiments, one or more other therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).

[00230] In some embodiments, one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (RITUXAN®, Genentech/Biogenldec); ofatumumab (anti-CD20, ARZERRA®, GlaxoSmithKline); obinutuzumab (anti-CD20, GAZYVA®, Genentech), ibritumomab (anti- CD20 and Yttrium-90, ZEVALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, KADCYLA®, Genentech); and pertuzumab (anti-HER2, PERJETA®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, ADCETRIS®, Seattle Genetics).

[00231] In some embodiments, one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).

[00232] In some embodiments, one or more other therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie/Genentech); and blinatumomab (BLINCYTO®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[00233] In some embodiments, one or more other therapeutic agent is an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (XTANDI®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Feiring Pharmaceuticals).

[00234] In some embodiments, one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (EVISTA®, Eli Lilly).

[00235] In some embodiments, one or more other therapeutic agent is an inhibitor of bone resorption. An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases. Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).

[00236] In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[00237] In some embodiments, one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFB). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of T GF -beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PD- Ll/TGF-P trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgGl antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF-P“trap.”

[00238] In some embodiments, one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti -gly coprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.

[00239] In some embodiments, one or more other therapeutic agents is an antiproliferative compound. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17- DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, TEMODAL CNF 1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZde244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

[00240] The term “aromatase inhibitor” as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name AROMASIN™. Formestane is marketed under the trade name LENTARON™. Fadrozole is marketed under the trade name AFEMA™. Anastrozole is marketed under the trade name ARIMIDEX™. Letrozole is marketed under the trade names FEMARA™ or FEMAr™. Aminoglutethimide is marketed under the trade name ORIMETEN™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[00241] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name NOLVADEX™. Raloxifene hydrochloride is marketed under the trade name EVISTA™. Fulvestrant can be administered under the trade name FASLODEX™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[00242] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name ZOLADEX™.

[00243] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR™. Topotecan is marketed under the trade name HYCAMPTIN™.

[00244] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CAELYX™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name ETOPOPHOS™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name ACRIBLASTIN™ or ADRIAMYCIN™. Epirubicin is marketed under the trade name FARMORUBICIN™. Idarubicin is marketed, under the trade name ZAVEDOS™. Mitoxantrone is marketed under the trade name NOVANTRON™. [00245] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name TAXOL™. Docetaxel is marketed under the trade name TAXOTERE™. Vinblastine sulfate is marketed under the trade name VINBLASTIN R.P™. Vincristine sulfate is marketed under the trade name FARMISTIN™.

[00246] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CYCLOSTIN™. Ifosfamide is marketed under the trade name HOLOXAN™.

[00247] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[00248] The term "antineoplastic antimetabolite" includes, but is not limited to, 5 -fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name XELODA™. Gemcitabine is marketed under the trade name GEMZAR™. [00249] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN™.

[00250] The term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factorreceptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD 180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin- dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (HERCEPTIN™), cetuximab (ERBITUX™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, El.l, E2.4, E2.5, E6.2, E6.4, E2.l l, E6.3 or E7.6.3, and 7H- pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[00251] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to PI3Ka, PI3Ky, PI3K6, PI3Kp, PI3K-C2a, PI3K-C2p, PI3K- C2y, Vps34, pl 10-a, pl 10-p, pl 10-y, pl 10-6, p85-a, p85-P, p55-y, pl50, p 101 , and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[00252] The term “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see W02008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see W02004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ, of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.

[00253] The term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.

[00254] The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[00255] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02008039218 and WO2011090760, the entirety of which are incorporated herein by reference. [00256] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02003063794, W02005007623, and W02006078846, the entirety of which are incorporated herein by reference. [00257] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02004019973, W02004089925, W02007016176, US8138347, W02002088112, W02007084786,

W02007129161, W02006122806, W02005113554, and W02007044729 the entirety of which are incorporated herein by reference.

[00258] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02009114512, W02008109943, W02007053452, W02000142246, and W02007070514, the entirety of which are incorporated herein by reference.

[00259] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. , unrelated to protein or lipid kinase inhibition e.g. , thalidomide (THALOMID™) and TNP-470.

[00260] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3 -gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[00261] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[00262] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- y- or 6- tocopherol or a- y- or 6-tocotrienol.

[00263] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX™), rofecoxib (VIOXX™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[00264] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name DIDRONEL™. Clodronic acid is marketed under the trade name BONEFOS™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name AREDIA™. Alendronic acid is marketed under the trade name FOSAMAX™. Ibandronic acid is marketed under the trade name BONDRANAT™. Risedronic acid is marketed under the trade name ACTONEL™. Zoledronic acid is marketed under the trade name ZOMETA™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (RAPAMUNE®), everolimus (CERTICAN™), CCI-779 and ABT578.

[00265] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.

[00266] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "famesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (Z ARNE STR A™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.

[00267] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[00268] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VELCADE™) and MLN 341.

[00269] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[00270] The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-P-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.

[00271] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

[00272] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.

[00273] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (HERCEPTIN™), Trastuzumab-DMl, erbitux, bevacizumab (AVASTIN™), rituximab (RITUXAN®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

[00274] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412. [00275] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HD AC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl){2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4^th Edition, Vol. 1 , pp. 248-275 (1993). [00276] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.

[00277] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATIN™; ENDOSTATIN™; anthranilic acid amides; ZD4190; Zd₆474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (AVASTIN™).

[00278] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as VISUDYNE™ and porfimer sodium.

[00279] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxy corticosterone, testosterone, estrone and dexamethasone.

[00280] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

[00281] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.

[00282] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International (e.g., IMS World Publications).

Exemplary Immuno-Oncology agents

[00283] 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.

[00284] 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. [00285] 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. [00286] 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/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI/TL I A, TRAMP/DR3, EDAR, EDAI, XEDAR, EDA2, TNFR1, Lymphotoxin a/TNFP, TNFR2, TNFa, LTpR, Lymphotoxin aip2, FAS, FASL, RELT, DR6, TROY, NGFR.

[00287] In some embodiments, an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL- 10, TGF-P, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.

[00288] 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, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[00289] In some embodiments, an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonist of activating receptors on NK cells. In some embodiments, an immuno-oncology agent is an antagonist of KIR, such as lirilumab. [00290] 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).

[00291] 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 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.

[00292] 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.

[00293] 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), or MED 1-0680 (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 IgGl, called AMP -224.

[00294] 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 (W02007/005874), and MSB0010718C (WO2013/79174). [00295] 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 (W010/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

[00296] 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).

[00297] 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, W0009/009116), or MK- 4166 (WO11/028683).

[00298] 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); 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 (W009/73620, WO009/1156652, WO11/56652, WO12/142237).

[00299] In some embodiments, an immuno-oncology agent is an 0X40 agonist. In some embodiments, an 0X40 agonist is an agonistic 0X40 antibody. In some embodiments, an 0X40 antibody is MEDI-6383 or MEDI-6469.

[00300] In some embodiments, an immuno-oncology agent is an OX40L antagonist. In some embodiments, an OX40L antagonist is an antagonistic 0X40 antibody. In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

[00301] 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. [00302] 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.

[00303] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO 11/109400).

[00304] 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.

[00305] 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 etal. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO®, 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.

[00306] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma).

[00307] 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 (NCTO 1622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCTO 1166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAdl), 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-lh68/GLV-lhl53, Genelux GmbH), vaccinia viruses engineered to express betagalactosidase (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).

[00308] 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 designated: Ad5/3-E2F-delta24-hTNFa-IRES- hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8⁺ T cell response. [00309] 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.

[00310] 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.

[00311] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al. hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD 19), 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 CD 19, 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=l].

[00312] In some embodiments, an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor y (RORyt). RORyt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Thl7) and CD8+ (Tcl7) 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 RORyt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[00313] In some embodiments, an immunostimulatory agent is an agonist or activator of a tolllike 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).

[00314] 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-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.

[00315] In some embodiments, an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORyt.

[00316] 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.

[00317] 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, the content of which is incorporated herein by reference in its entirety. In some embodiments, 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-oncology 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 selected from those listed in Table 2 of Jerry L. Adams et al.

[00318] 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 reference in its entirety. In some embodiments, an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.

[00319] 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, the content of which is incorporated herein by reference in its entirety. In some embodiments, an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct is a CD19/CD3 bispecific antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct activates T cells. In some embodiments, 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 embodiments, 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®-activated T cells. In some embodiment, the bystander cells comprises tumor-associated antigen (TAA) negative cancer cells. In some embodiments, 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 Immune Checkpoint Inhibitors [00320] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[00321] 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.

[00322] 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.

[00323] 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 -turn or immune response.

[00324] 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 inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, 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, PDL1, PDL2, PD1, 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. [00325] 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, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, y5, and memory CD8⁺ (aP) 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-L1 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-L1, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3.

[00326] 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®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-Ll antibody, TECENTRIQ®, Genentech). [00327] 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.

[00328] 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 IgGl anti-PD-Ll 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).

[00329] 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). [00330] 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 monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[00331] 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).

[00332] Checkpoint inhibitors that can be used in the present invention include 0X40 agonists. 0X40 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).

[00333] 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).

[00334] 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).

[00335] 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 malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270);

INCAGN0 1876 (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 IgGl Fc domain, in advanced solid tumors (NCT02583165). [00336] 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).

[00337] 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). [00338] 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 IgGl, 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).

[00339] 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).

[00340] 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 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).

[00341] 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-lR antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((lR,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2- carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[00342] 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).

[00343] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[00344] The following examples are provided for illustrative purposes only and are not to be construed as limiting this invention in any manner.

Exemplary Embodiments of the Invention

Embodiment 1. A spray dried intermediate (SDI) formulation comprising compound A,

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymer. Embodiment 2. The SDI formulation of Embodiment 1, comprising compound A free base. Embodiment 3. The SDI formulation of any one of Embodiments 1-2, wherein the pharmaceutically acceptable polymer is selected from PVP-VA, HPMC, HPMCP-55, HPMCAS- M, TPGS, HPMCAS-L, HPMCAS-HG, and MCC.

Embodiment 4. The SDI formulation of any one of Embodiments 1-3, comprising about 20 - 40 %wt compound A, or a pharmaceutically acceptable salt thereof.

Embodiment 5. The SDI formulation of any one of Embodiments 1-4, wherein the pharmaceutically acceptable polymer is about 60 - 80 %wt.

Embodiment 6. The SDI formulation of any one of Embodiments 1-5, comprising 30:70 (wt %) compound A free base: HPMCAS-HG. Embodiment 7. A unit dosage form comprising the SDI formulation of any one of Embodiments 1-6.

Embodiment 8. The unit dosage form of Embodiment 7, wherein the SDI formulation is about 45-55 wt% of the unit dosage form.

Embodiment 9. The unit dosage form of Embodiment 7, wherein the SDI formulation is about 50 wt% of the unit dosage form.

Embodiment 10. The unit dosage form of Embodiments 7-9, which is an immediate release (IR) tablet.

Embodiment 11. The unit dosage form of any one of Embodiments 7-10, further comprising a filler/diluent.

Embodiment 12. The unit dosage form of Embodiment 11, wherein the filler/diluent is mannitol or microcrystalline cellulose.

Embodiment 13. The unit dosage form of any one of Embodiments 7-12, further comprising a disintegrant.

Embodiment 14. The unit dosage form of Embodiment 13, wherein the disintegrant is croscarmellose sodium.

Embodiment 15. The unit dosage form of any one of Embodiments 7-14, further comprising a glidant.

Embodiment 16. The unit dosage form of Embodiment 15, wherein the glidant is colloidal silicon dioxide.

Embodiment 17. The unit dosage form of any one of Embodiments 7-16, further comprising a lubricant.

Embodiment 18. The unit dosage form of Embodiment 17, wherein the lubricant is magnesium stearate.

Embodiment 19. The unit dosage form of any one of Embodiments 7-18, further comprising a film coating.

Embodiment 20. The unit dosage form of Embodiment 19, wherein the film coating is Opadry II White 85F 18422. Embodiment 21. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effect amount of the SDI formulation of any one of Embodiments 1-6, or the unit dosage form of any one of Embodiments 7-20.

Embodiment 22. The method of Embodiment 21, wherein the cancer is meningioma.

Embodiment 23. The method of Embodiment 21, wherein the cancer is cholangiocarcinoma.

Embodiment 24. The method of Embodiment 21, wherein the cancer is thymoma.

Embodiment 25. The method of Embodiment 21, wherein the cancer is schwannoma. Embodiment 26. The method of Embodiment 21, wherein the cancer is a solid tumor. Embodiment 27. The method of Embodiment 21, wherein the cancer is a locally advanced or metastatic solid tumor.

Embodiment 28. The method of Embodiment 21, wherein the cancer is a brain tumor.

Embodiment 29. The method of Embodiment 21, wherein the cancer is non-small cell lung cancer (NSCLC; both squamous and adenocarcinoma, including mucoepidermoid NSCLC). Embodiment 30. The method of Embodiment 21, wherein the cancer is head and neck squamous cell carcinoma (HNSCC).

Embodiment 31. The method of Embodiment 21, wherein the cancer is esophageal carcinoma.

Embodiment 32. The method of Embodiment 21, wherein the cancer is ovarian carcinoma.

Embodiment 33. The method of Embodiment 21, wherein the cancer is endometrial carcinoma. Embodiment 34. The method of Embodiment 21, wherein the cancer is cervical carcinoma. Embodiment 35. The method of Embodiment 21, wherein the cancer is hepatocellular carcinoma.

Embodiment 36. The method of Embodiment 21, wherein the cancer is epithelioid hemangioendothelioma (EHE).

Embodiment 37. The method of Embodiment 21, wherein the cancer is soft tissue sarcoma. Embodiment 38. The method of Embodiment 21, wherein the cancer is myxoid liposarcoma.

Embodiment 39. The method of Embodiment 21, wherein the cancer is angiosarcoma.

Embodiment 40. The method of Embodiment 21, wherein the cancer is liposarcoma.

Embodiment 41. The method of Embodiment 21, wherein the cancer is synovial sarcoma. Embodiment 42. The method of Embodiment 21, wherein the cancer is mesothelioma. Embodiment 43. The method of Embodiment 21, wherein the cancer is malignant mesothelioma. Embodiment 44. The method of Embodiment 21, wherein the cancer is advanced unresectable malignant mesothelioma.

Embodiment 45. The method of Embodiment 21, wherein the cancer is malignant pleural mesothelioma (MPM).

Embodiment 46. The method of Embodiment 21, wherein the cancer is epithelioid malignant mesothelioma.

Embodiment 47. The method of Embodiment 21, wherein the cancer is sarcomatoid malignant mesothelioma.

Embodiment 48. The method of Embodiment 21, wherein the cancer is head and neck squamous cell carcinoma (HNSCC).

Embodiment 49. The method of Embodiment 21, wherein the cancer is sporadic meningioma.

Embodiment 50. The method of Embodiment 21, wherein the cancer is advanced unresectable malignant mesothelioma.

Embodiment 51. The method of Embodiment 21, wherein the cancer is recurrent or unresectable meningioma.

Embodiment 52. The method of Embodiment 21, wherein the cancer is a neurofibromatosis type 2 (NF2)-deficient cancer, or associated with NF2-deficiency .

Embodiment 53. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 25 - 1200 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

Embodiment 54. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 25 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

Embodiment 55. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 75 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

Embodiment 56. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 150 mg of compound A, or a pharmaceutically acceptable salt thereof, daily. Embodiment 57. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 300 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

Embodiment 58. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 450 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

Embodiment 59. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 600 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

Embodiment 60. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 800 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

Embodiment 61. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 1000 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

Embodiment 62. The method of any one of Embodiments 21-30, wherein the method comprises administering to the patient about 1200 mg of compound A, or a pharmaceutically acceptable salt thereof, daily.

EXEMPLIFICATION

[00345] Compound A can be prepared as described herein and by methods known to one of ordinary skill in the art, for example, as described in US 2020/0407327, the contents of which are incorporated herein by reference in their entireties.

[00346] LIST OF ABBREVIATIONS

AE adverse event

AHR aryl hydrocarbon receptor

ALP alkaline phosphatase

ALT alanine aminotransferase

ANC absolute neutrophil count aPTT activated partial thromboplastin time ARNT aryl hydrocarbon receptor nuclear translocator

AST aspartate aminotransferase

AUC area under the plasma concentration-time curve

AUCo-24 area under the plasma concentration-time curve from time 0 to 24 hours

BCRP breast cancer resistance protein

BID twice a day

BOR best overall response

C#D# cycle number day number

CI confidence interval

CL clearance

Cmax maximum observed {plasma/blood/serum} concentration

CNS central nervous system

CR complete response

CSR clinical study report

CT computed tomography

CYP cytochrome

DCR disease control rate

DLT dose-limiting toxicity

DOR duration of response

DOT duration of treatment

DRE dioxin response elements

ECG electrocardiogram

ECI events of clinical interest

ECOG Eastern Cooperative Oncology Group eCRF case report form (electronic or paper)

EOS end of study

EOT end of treatment

ET early termination

FDA Food and Drug Administration

FDG fluoro-2-deoxyglucose

FIH first-in-human

FSH follicle stimulating hormone GCP Good Clinical Practice

G-CSF granulocyte colony-stimulating factor

GI gastrointestinal

GFR glomerular filtration rate

GLP Good Laboratory Practice

GM-CSF granulocyte-macrophage colony-stimulating factor

HED human equivalent dose

HIV human immunodeficiency virus

HRT hormone replacement therapy

HNSTD highest non-severely toxic dose

IB Investigator Brochure

IC₅₀ half maximal inhibitory concentration

ICF informed consent form

ICH International Council for Harmonisation

IDO1 indoleamine 2, 3 -dioxygenase

IEC Institutional Ethics Committee

IL interleukin

INR international normalised ratio irAE immune-related adverse event iRECIST immune Response Evaluation Criteria in Solid Tumors

IRB institutional review board

IV intravenous(ly)

LLN lower limit of normal

LV left ventricular

LVEF left ventricular ejection fraction

MedDRA Medical Dictionary for Regulatory Activities

MRI magnetic resonance imaging

MTD maximum tolerated dose mTPI modified Toxicity Probability Interval trial design mTPI-2 Revision of modified Toxicity Probability Interval trial design

NCLCTCAE National Cancer Institute Common Terminology Criteria for Adverse Events NLNT new lesions non-target

NLT new lesions-target

NSAIDs nonsteroidal anti-inflammatory drugs

ORR objective response rate

PCR polymerase chain reaction

PD progressive disease

PD-1 programmed cell death 1

PET positron emission tomography

PFS progression-free survival

PK pharmacokinetics

PO orally

PR partial response

PT prothrombin time q8h every 8 hours ql2h every 12 hours q4w every 4 weeks

QD once daily

QID four times a day

QTcF QT interval corrected by the Fridericia's Correction formula

RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 1.1

RP2D recommended phase 2 dose

SAE serious adverse event

SD stable disease

SAP statistical analysis plan

S oE S chedul e of Events

SRM study reference manual

STD10 Severely toxic dose to 10% of animals

SRC Safety Review Committee

SUS AR suspected unexpected serious adverse reactions ti/2 half-life

TDO2 tryptophan 2,3 -dioxygenase 2 TEAE treatment-emergent adverse event

TID three times per day

Tregs regulatory T cells

ULN upper limit of normal

Vss steady state volume of distribution

WHO World Health Organization

WOCBP women of child-bearing potential

Example 1. Preparation of Compound A

[00347] The title compound was prepared according to the scheme below.

[00348] Step 1 Intermediate 1 is dissolved in MTBE and reacted with MeNEE aqueous solution. Upon complete reaction, after aqueous workup, intermediate 2 in MTBE is solventswapped to heptane, resulting in precipitation of intermediate 2. After filtration, intermediate 2 is isolated as solid in good purity.

[00349] Step 2 Intermediate 2 is heated with intermediate 2B in NMP. Upon complete reaction, the mixture is diluted with EtOAc-MTBE. After aqueous workup, intermediate 3 in EtOAc-MTBE is solvent-swapped to heptane, resulting in precipitation of 3. After filtration, intermediate 3 is isolated as solid in good purity.

[00350] Step 3. Intermediate 3 is subjected to Miyaura borylation with bis(pinacolato)diboron (BPD) at the presence of Pd catalyst and KO Ac in dioxane. Upon complete reaction, the mixture is diluted with toluene, filtered, and distilled off dioxane. The toluene solution is passed through a silica plug, eluted with MTBE-heptane and solvent-swapped to DMF. Intermediate 4 in DMF is used in step 4.

[00351] Step 4 Intermediate 4 in DMF solution is submitted to Suzuki reaction with intermediate 4B in the presence of Pd catalyst and K2CO3 aqueous solution. Upon complete reaction, MTBE and water are added to the reaction mixture, resulting in precipitation of crude Compound A. Compound A is isolated by filtration and dissolved in acetone, treated with Pd scavenger, and crystallized from acetone-EtOH,

Example 2. Preparation of Compound A Formulations and Unit Dosages

1. Materials

[00352] The formulations and unit dosages are prepared using Compound A free base (FB).

[00353] The excipients used in the manufacture of Compound A 25 mg and 100 mg strength tablets are all compendial NF, USP and Ph. Eur. grade. The compatibility of the drug substance and excipients have been evaluated in exploratory short term accelerated stability studies and are placed on long term stability. One-month stability on development batches of the 25 mg and 100 mg strength show consistent results.

[00354] The choice of excipients along with their concentration in the formulation is provided in Table 2. The Compound A drug product formulation uses standard compendial excipients NF, USP and Ph. Eur. grade. All excipients used have demonstrated acceptable physical and chemical compatibility with the Compound A SDI. Compatibility of the excipients have been established in exploratory accelerated stability studies and confirmed by the 1 -month stability results of the development batches.

2. Development of tablet formulations

[00355] Formulation development was initiated to identify a formulation suitable for solid oral clinical dosing and provide comparable exposure in nonclinical species to that of the liquid suspension formulation of Compound A in 5% DMSO/95% PEG 400 used in nonclinical studies. The design of a solid dosage form for Compound A tablets is based on the established solid state and physicochemical characteristics of Compound A Spray Dried Intermediate (SDI) and the intended route of administration. Based on the physicochemical characteristics of the drug substance and the chemical stability of the drug substance in the formulation matrix, a tablet formulation for oral route of delivery was developed.

[00356] During formulation development, Compound A free base of various particle sizes, as generated in the drug substance process and micronized, along with several spray dried dispersion formulations were evaluated, to identify a suitable form of Compound A drug substance that would provide a preferable dissolution profile in a two-stage non-sink dissolution assay. The various SDI formulations provide improved solubility compared to the Compound A free base, regardless of particle size, and therefore significantly improved the two-stage non-sink dissolution profiles. The amorphous spray-dried dispersion (SDD) that is comprised of 30% of Compound A and 70% of HPMCAS-HG was ultimately selected due to a preferrable dissolution profile, higher relative drug loading, and minimal change in impurity profile during accelerated short term stability study. The stability data for representative development batches of Compound A SDI stored for 4 months at 25 °C/60% RH and 40 °C/75% RH can be found in Table 1.

Table 1. Stability of Compound A SDI , Stored at 25 °C/60% RH and 40 °C/75% RH

[00357] The development of an immediate-release, oral solid dose tablets formulation containing Compound A SDD, microcrystalline cellulose, mannitol, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate was performed to identify a formulation and process to generate 25 mg and 100 mg active tablets for clinical use. The tablet cores developed were coated with a non-functional film-coating.

[00352] The formulation parameters evaluated were:

• Ratio of SDI loading

• Disintegrant type and concentration

• Use of a binding agent

• Type of filler used

• Grade of MCC used

[00353] The tablet quality attributes monitored and optimized were:

• Particle Size Distribution of Blend

• Physical Integrity

• Weight Control/Flow

• Content Uniformity

• Hardness/Thickness/Friability

• Disintegration/Dissolution

[00354] The 25 mg and 100 mg strength Compound A tablets were developed using a common blend approach, to facilitate manufacturing and handling. The two tablet strengths contain the same inactive ingredients and are produced using the same manufacturing process and process train.

[00355] The 25 mg strength Compound A SDI tablets are compositionally proportional to the 100 mg strength tablets, as they are produced from a common blend. Development batches were manufactured with comparable process as the intended clinical batches, adjusting for scale and appropriated sized equipment. The drug product development batches utilized the SDI batch that was generated from Compound A drug substance development batch. Preliminary data revealed that the development batch exhibits elevated impurities compared to that of the clinical batch.

[00356] Compound A drug product consists of the amorphous form of the Compound A free base drug substance in a spray-dried dispersion with HPMCAS-HG polymer. The Compound A tablet formulation contains 30:70 Compound A : HPMCAS-H SDI, microcrystalline cellulose, mannitol, croscarmellose sodium, silicone dioxide, and magnesium stearate. The non-functional film-coat contains polyvinyl alcohol, titanium dioxide, macrogol/PEG and talc. [00357] The tablets are manufactured from a common blend formulation. The unit dose composition for each strength differs only in the amount of blend compressed into tablets. The tablet cores are formulated as an immediate-release drug product containing either 25 mg or 100 mg of Compound A API. The tablet cores are then coated with a non-functional film coating. The quantitative composition of Compound A tablets, 25 mg and 100 mg are listed in Table 2.

Table 2. Master Formula for Compound A Tablets, 25 mg and 100 mg

e. Acetone is removed during spray -drying and secondary drying processes f. Opadry II White 85F18422 contains 40.00% w/w Polyvinyl Alcohol Partially Hydrolyzed (USP, Ph.Eur., JPE), 25.00% w/w Titanium Dioxide (USP, Ph.Eur., JP, ChP, GB), 20.20% w/w Macrogol/PEG (USP, FCC, Ph. Eur. JP), 14.80% w/w Talc (USP, Ph. Eur., JP) g. Represents 3% weight gain of film-coat with an allowable range of 2 to 4% h. Purified water is used for film-coating and is removed during the process i. The composition of Opadry II White 85F18422 in the 25 mg Compound A tablets is: 40.00% w/w (2.00 mg) Polyvinyl Alcohol Partially Hydrolyzed (USP, Ph.Eur., JPE), 25.00% w/w (1.25 mg) Titanium Dioxide (USP, Ph.Eur., JP, ChP, GB), 20.20% w/w (1.01 mg) Macrogol/PEG (USP, FCC, Ph. Eur. JP), 14.80% w/w (0.74 mg) Talc (USP, Ph. Eur., JP) j. The composition of Opadry II White 85F18422 in the 100 mg Compound A tablets is: 40.00% w/w (8.00 mg) Polyvinyl Alcohol Partially Hydrolyzed (USP, Ph.Eur., JPE), 25.00% w/w (5.00 mg) Titanium Dioxide (USP, Ph.Eur., JP, ChP, GB), 20.20% w/w (4.04 mg) Macrogol/PEG (USP, FCC, Ph. Eur. JP), 14.80% w/w (2.96 mg) Talc (USP, Ph. Eur., JP)

3. Manufacturing Process Description

[00358] The manufacturing procedure for Compound A SDI tablets can be broken down into the following unit processes: blending, dry granulation, milling, blending, tablet compression, film-coating, and packaging. The proposed drug product manufacturing process was performed on equipment representative of commercial process to demonstrate process performance, confirm parameters, and generate drug product for an ICH compliant stability protocol prior to the execution of the clinical manufacturing campaign.

Compound A Spray-dried dispersion intermediate

[00359] The Compound A feed solution contains a mass fraction ratio 30:70 of Compound A (free base) API and HPMCAS-HG in acetone which accounts for 10% (w/w) of the total feed solution. The feed solution is prepared by adding Compound A (free base) to acetone with stirring in a stainless-steel reactor. Upon complete dissolution of drug substance, HPMCAS-HG is added and dissolved to yield the feed solution. The spray-drying is performed under controlled conditions and followed by secondary drying at elevated temperature (~40°C) under a vacuum.

Compound A Inter-granular blend

[00360] The 30:70 Compound A:HPMCAS-HG spray-dried intermediate is blended with microcrystalline cellulose, mannitol, croscarmellose sodium, and colloidal silicon dioxide. The mixture was then de-lumped by milling and blended again after the addition of intragranular magnesium stearate.

Compound A Granulation [00361] The intra-granular blend was transferred into a roller compactor, where the blend is pressed into ribbons between two rollers and then broken into granules with a granulator oscillating against a mill screen.

Compound A Final Common Blend

[00362] The Compound A granulation is blended with microcrystalline cellulose, and croscarmellose sodium, followed by blending with magnesium stearate to yield the final common blend.

Compound A Tablet Core Compression

[00363] The Compound A final common blend is fed the tablet compression process of either the 25 mg tablet or 100 mg tablet. The 25 mg strength tablets are compressed into 0.3437-inch standard round convex tablets averaging approximately 167 mg per tablet. The 100 mg strength tablets are compressed into 0.3250 x 0.6500-inch modified capsule tablets averaging approximately 667 mg per tablet.

Compound A Tablet Film-coating

[00364] The core tablets are film-coated with Opadry II White 85F 18422 to a target weight gain of 3%.

Compound A Primary Packaging

[00365] Compound A tablets (25 mg strength) intended for clinical use are packaged into a 30cc white, high-density polyethylene (HDPE) round bottle, and 33mm white child resistance (CR) cap with a heat-induction (HIS) tamper evident seal. Each bottle contains thirty (30) tablets, polyester coil, and a 0.5 g canister desiccant.

[00366] Compound A tablets (100 mg strength) for clinical use were packaged into a 60cc white, high-density polyethylene (HDPE) round bottle, and 33 mm white child resistance (CR) cap with a heat-induction (HIS) tamper evident seal. Each bottle contains thirty (30) tablets, polyester coil, and a 1 g canister desiccant.

4. Stability

Design of Stability Studies [00367] A representative stability protocol for the development batch of Compound A

Tablets, 25 mg and 100 mg, is summarized in Table 3. A representative stability protocol for the clinical batch of Compound A Tablets, 25 mg and 100 mg, is summarized in Table 4.

[00368] The stability samples are packaged in white, high-density polyethylene (HDPE) bottle with heat-induction sealed child resistant cap, containing desiccant and polyester coil.

Table 3: Representative Stability Protocol for Development Batches of Compound A Tablets, 25 mg and 100 mg

X: Appearance, Assay and Impurities (RP-HPLC), Water Content (KF), Dissolution NT: Not Tested

Table 4: Representative Stability Protocol for Clinical Batches of Compound A Tablets, 25 mg and 100 mg

X: Appearance, Assay and Impurities (RP-HPLC), Water Content (KF), DissolutionM: Microbial enumeration and specified microorganism (E. coli) NT: Not Tested

Summary of Stability Studies

[00369] One month of stability data are available for development Compound A Tablets, 25 mg dose strength batch and Compound A Tablets, 100 mg dose strength batch . No significant changes in chemical and physical stability have been observed for Compound A Tablets, 25 mg and 100 mg, after one month of storage at the 5 °C storage, the intended long term storage of 25°C/60% RH, the intermediate storage condition of 30°C/65% RH, and the accelerated storage condition of 40°C/75% RH. Compound A Tablets, 25 mg and 100 mg, remained within specifications when stored in the container closure system described herewith.

[00370] Clinical Compound A Tablets, 25 mg dose strength batch and Compound A Tablets, 100 mg dose strength batch have been placed on stability. Stability of the clinical batches is closely monitored to ensure the batches remain within specifications during use in clinic.

Shelf Life and Storage Conditions

[00371] The results of long term and accelerated stability studies on the demonstration batch of Compound A Tablets, 25 mg and 100 mg, demonstrate the chemical and physical stability of Compound A Tablets, 25 mg and 100 mg, when stored at controlled room temperature in the container closure system described herewith. The shelf life of Compound A Tablets, 25 mg and 100 mg, is continually evaluated based on the available stability data.

Example 3. A Phase 1, Study of Compound A, a Transcriptional Enhanced Associate Domain (TEAD) Inhibitor, in Patients with Advanced Solid Tumors with gene alterations in the Hippo pathway for whom there are no further treatment options known to confer clinical benefit.

Study Design

[00372] This is a first-in-human (FIH), Phase 1 clinical study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary antitumor activity, and RP2D and/or MTD of Compound A, an oral TEAD inhibitor, administered orally (PO) as monotherapy in subjects with advanced solid tumors in whom there are no further treatment options known to confer clinical benefit.

[00373] The study consists of a Dose Escalation phase that enrolls at least 3 subjects per dose level using BOIN design (Yuan 2016) with a target toxicity rate of 25% to establish RP2D and/or MTD for Compound A monotherapy. The Dose Escalation phase is followed by a Dose Expansion phase to assess the preliminary antitumor activity of Compound A monotherapy, with four (4) histologically and/or genetically defined cohorts of solid tumors, including: NF2-deficient MPM (Cohort 1), other NF2-deficient solid tumors agnostic to tumor type (Cohort 2), epithelioid hemangioendothelioma (EHE) with TAZ-CAMTA1 or YAP1-TFE3 gene fusions (Cohort3), and a cohort of solid tumors with documented YAP1/TAZ gene fusions agnostic to tumor type (Cohort 4). A Simon 2-stage design (Simon 1989) is used to determine the sample size of the four expansion cohorts.

[00374] A Safety Review Committee (SRC), composed of study Investigators and the Sponsor, assesses all safety data available and use BOIN design to guide dose escalation or de-escalation decisions. The SRC is responsible for monitoring the safety, PK, PD, and preliminary antitumor activity data of Compound A.

[00375] Archival or fresh tumor tissue can be used to retrospectively confirm the local test results of NF2 deficiency at a central diagnostic laboratory in subjects with MPM and other solid tumors for NF2 deficiency. Archival or fresh tumor tissue can also be used to confirm the local test results of YAP1/TAZ gene fusions at a central diagnostic laboratory. Liquid biopsy tests to detect circulating cell-free nucleic acids can be used to confirm the presence of NF2 deficiency or YAP1/TAZ gene fusion. Whenever feasible, subjects can undergo a pre-treatment fresh tumor biopsy and an on-treatment biopsy on C2D8 (-5/+6 days) for pharmacodynamic and genetic studies. Please refer to the Schedule of Events for the optimal timing of optional fresh paired biopsies.

[00376] The dose and schedule of Compound A monotherapy administration in the Dose Expansion phase (RP2D) are determined based on the totality of clinical, PK, and PD data available at the end of the Dose Escalation phase.

Determination of NF2 Deficiency and Other Mutations of Interest

[00377] For enrollment purposes, NF2 deficiency and YAP1/TAZ gene fusions status are determined by local test results, which are routinely used by Investigators, be it institutional or commercially available tests. Examples of commercially available tests are given in the Laboratory Manual. Additionally, archival or fresh tumor tissue are collected from all subjects and used to confirm the above local test results of NF2 deficiency or YAP1/TAZ gene fusion retrospectively by analytically validated assays at a central CAP/CLIA diagnostic laboratory. Confirmatory tests are not required prior to subject enrollment. Subjects in the Dose Expansion phase are replaced if the central confirmatory assay results return negative for these genetic alterations. Liquid biopsy tests to detect circulating cell-free nucleic acids can be used to confirm the presence of NF2 deficiency or YAP1/TAZ gene fusion. Whenever feasible, subjects can undergo a pre-treatment fresh tumor biopsy and an on-treatment biopsy on C2D8 (-5/+6 days) for pharmacodynamic and genetic studies.

Schedule of Administration

[00378] Subjects who tolerate Compound A without clinically significant AEs are allowed to receive Compound A at a continuous schedule of administration, z.e., DI to D21 of a 21-day cycle. Further dose and/or schedule modifications can be adapted to the subject’s individual tolerance.

[00379] Compound A, or a pharmaceutically acceptable salt thereof, can be administered in a fasting state (avoid food 2 hours prior to and 1 hour after administration of Compound A), in some embodiments.

[00380] Compound A, or a pharmaceutically acceptable salt thereof, can be administered without the use of proton pump inhibitors (PPIs) or other acid-reducing agents (ARAs), in some embodiments.

[00381] Subjects can continue treatment until disease progression, unacceptable toxicity, or consent withdrawal. At a minimum, the 30-Day and 90-Day Follow-up visits should occur 30 days and 90 days (±7 days), respectively, after the last study drug administration. If an alternate non-study anticancer drug therapy is initiated during this period, the 30-Day and/or 90-Day Follow-up visits should be conducted prior to the first dose of alternate therapy.

[00382] Toxicity is evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Physical examinations, vital signs, and 12-lead triplicate electrocardiograms (ECGs) can be obtained to evaluate the safety and tolerability of Compound A as monotherapy. Adverse events (AEs) and laboratory values including chemistry, hematology, coagulation, and urinalysis can be assessed.

Starting Dose in the Dose Escalation Phase

[00383] The first-in-human starting dose of Compound A is 25 mg taken orally (PO) once daily (QD).

[00384] The proposed maximum recommended starting dose was calculated in accordance with the International Conference on Harmonisation S9 Nonclinical Evaluation for Anticancer Pharmaceuticals (CDER 2010). The human equivalent dose (HED) normalized for human body surface area (BSA) for subjects with cancer (1.73 m2) equals 259.5 mg/day, which results in a maximum recommended starting dose of 26 mg/day. For the Phase 1 study, this was rounded down to a proposed starting dose of 25 mg QD.

[00385] Human PK simulations were conducted using multi-species allometry to predict absorption, CL, and Vss. The human predicted CL is 4.0 mL/min/kg and Vss is 2.93 L/kg, with a tl/2 calculated to be 8.4 hours. The PK modeling and simulations predicted human bioavailability of 59.5%, and steady-state plasma Cmax and AUCO-24 values associated with a single human dose of 25 mg (tablet, PO) are 48 ng/mL and 886 ng*h/mL, respectively, for a 70-kg human.

[00386] Subjects treated with Compound A are routinely monitored for biological markers of renal toxicity, including renal function tests and proteinuria (albuminuria). Subjects with > 1+ proteinuria have a 24-hour urine protein or albumin determination or a urine albumin: creatinine ratio on a randomly collected urine sample, preferably that of morning void.

Study Population

Dose Escalation Phase

[00387] During the Dose Escalation phase, subjects with histological or cytological diagnosis of advanced, unresectable, locally recurrent, or metastatic solid tumors with gene alterations in the Hippo pathway for whom there is no known treatment that confers clinical benefit are enrolled regardless of the presence or absence of NF2 deficiency or other genetic alterations of the Hippo pathway, including, but not limited to, the following tumors:

• Locally advanced or metastatic solid tumors for whom there is no known treatment that confers clinical benefit

• Malignant Pleural mesothelioma (MPM) with or without NF2 deficiency

• Other NF2-deficient solid tumors, including, but not limited to, meningioma, cholangiocarcinoma, thymoma, NSCLC, HCC, and others

• Epithelioid hemangioendothelioma (EHE) with TAZ-CAMTA1 or YAP1-TFE3 gene fusions

• Solid tumors harboring YAP1/TAZ gene fusions agnostic to tumor type, including, but not limited to, angiosarcoma, myxoid liposarcoma, synovial sarcoma, NSCLC, cervical cancer, and mesothelioma [00388] The Dose Escalation phase is conducted according to BOIN design as detailed in the Statistical Considerations Section below, with a minimum of 3 subjects per dose level (see Table 5). It is estimated that approximately 50 subjects are enrolled in the Dose Escalation phase of the study.

Table 5. Planned Dose Escalation Levels

Abbreviations: DL: dose level, mg: milligram

[00389] During the conduct of Dose Escalation phase, backfilling is also allowed with approximately 3 additional subjects once a dose escalation level is deemed safe by the SRC. Backfilling consists of subjects with tumors selected based on the presence of a genetic alteration, including NF2-deficient MPM, other NF2-deficient solid tumors agnostic to tumor type, EHE, and other solid tumors harboring YAP1/TAZ gene fusion, agnostic to tumor type. These backfilled cohorts allow additional safety, PK, PD, and preliminary antitumor activity data to be collected.

Dose Expansion Phase

[00390] All subjects must have a histological diagnosis of an advanced, unresectable, locally recurrent, or metastatic disease with no available therapy known to confer clinical benefit as evaluated by the treating physician. There is no upper limit on the number of prior lines of anticancer therapy received. Subjects are enrolled in one of the following four cohort groups: a. Cohort 1 : Subjects with histological confirmed MPM and that have documented NF deficiency as determined by local test results, defined as any loss-of-function mutations or NF2 copy number loss. b. Cohort 2: Subjects with other documented NF2-deficient solid tumors agnostic to tumor type defined as any loss-of-function mutations or NF2 copy number loss as determined by local test results, including, but not limited to, meningioma, cholangiocarcinoma, thymoma, NSCLC, HCC, and others. c. Cohort 3: Subjects with histopathological diagnosis of epithelioid hemangioendothelioma (EHE) with documented TAZ-CAMTA1 or YAP1-TFE3 gene fusions, as determined by local test results for RNA-seq, FISH or IHC. Subjects who have objective disease progression to prior therapy or have active disease and cancer-related pain requiring narcotics for management are eligible. d. Cohort 4: Subjects with any solid tumor with documented YAP1/TAZ gene fusions as determined by local test results for RNA-seq, FISH or IHC.

[00391] A Simon 2-stage design (Simon 1989) is used for the conduct of the four expansion cohorts. Sample size considerations are found herein.

[00392] It is estimated that 108 subjects (27 subjects x 4 cohorts) are enrolled in the Dose Expansion phase of the study.

Definition of Dose-Limiting Toxicity

[00393] The DLT period is defined as Cycle 1 of Compound A administration, i.e., 28 days. All toxi cities are graded using NCI-CTCAE version 5.0 based on the Investigator’s assessment.

The occurrence of any of the following toxicities during Cycle 1 are considered a DLT, unless toxicity is clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc. :

1. Grade 5 toxicity.

2. Grade 4 hematologic toxicity, except for afebrile neutropenia that resolves within 7 days, and Grade 4 lymphopenia.

3. > Grade 3 febrile neutropenia:

• Grade 3 is defined as absolute neutrophil count (ANC) < 1000/mm3 with a single temperature of > 38.3 °C (101 °F) or a sustained temperature of > 38 °C (100.4 °F) for more than 1 hour.

• Grade 4 is defined as with life-threatening consequences; urgent intervention indicated. 4. Grade 3 thrombocytopenia associated with clinically significant bleeding.

5. > Grade 3 serum creatinine increased.

6. > Grade 3 acute kidney injury.

Symptomatic Grade 2 or any > Grade 3 proteinuria

7. Any nonhematologic and non-lab oratory AE > Grade 3 in severity should be considered a DLT, with the following exceptions:

• Grade 3 fatigue lasting < 7 days.

• Grade 3 diarrhea, nausea, or vomiting without use of antiemetics or antidiarrheals per standard of care lasting < 72 hours.

8. Any Grade 3 or Grade 4 nonhematologic laboratory value that results in any of the following:

• Clinically significant medical intervention is required to treat the subject, or

• The abnormality leads to hospitalization, or

• The abnormality results in a drug induced-liver injury.

• Grade 4 nonhematologic, non-lab oratory toxicity

9. Missing > 25% of Compound A doses as a result of study drug-related AE(s) during the first cycle.

[00394] Subjects who are withdrawn from treatment during the DLT period for reasons other than study drug-related AEs are considered DLT non-evaluable and are replaced.

Assessments

Evaluation of Preliminary Antitumor Activity

[00395] Although the primary endpoint of both phases of the study is to determine the safety and tolerability of oral Compound A, the Dose Expansion phase primary endpoint of preliminary antitumor activity is assessed by measuring changes in tumor size by computed tomography scan or magnetic resonance imaging. Tumor assessment is performed every 8 weeks (±7 days) up to 24 weeks, then every 12 weeks (±7 days) up to 52 weeks, then every 16 weeks (±7 days) afterward. Evaluation is performed according to the Response Evaluation Criteria Solid Tumors version 1.1 (RECIST 1.1, Eisenhauer 2009). Exploratory endpoints include the evaluation of response in MPM with modified RECIST 1.1 (Armato 2018). Similarly, the Response Assessment in Neuro Oncology criteria (RANO) (Wen 2010; Huang 2019) is used as an exploratory endpoint for the evaluation of response in primary brain tumors such as meningioma.

PK Evaluation

[00396] Serial blood samples are obtained to characterize the plasma PK of Compound A. The initial sampling strategy is based on the predicted human PK of this compound. If in the course of evaluating the PK, it is determined that an alternative sampling scheme would be more informative, then that alternative sampling scheme can be implemented if the total amount of blood and blood draws obtained for PK is not increased. Moreover, the total number of samples can be decreased at any time if the initial sampling scheme is considered unnecessarily intensive.

PD Evaluation

[00397] When feasible, each subject has paired tumor biopsies for exploratory pharmacodynamic endpoints. Tumor tissue samples are used to confirm TEAD target engagement by evaluating changes in connective tissue growth factor (CTGF) and other TEAD target gene expression levels. The initial sampling strategy is based on the predicted human PD of Compound A. Whenever feasible, subjects undergo a pre-treatment fresh tumor biopsy and an on-treatment biopsy on C2D8 (-5/+6 days) for pharmacodynamic and genetic studies. If in the course of evaluating the PD, it is determined that an alternative sampling scheme would be more informative, then the alternative sampling scheme can be implemented if the number of tumor biopsies is not increased.

Exploratory Biomarkers

[00398] For enrollment purposes, NF2 deficiency and YAP1/TAZ gene fusions status are determined by local test results, which are routinely used by Investigators, be it institutional or commercially available tests. Examples of commercially available tests are known in the art.

[00399] Additionally, archival or fresh tumor tissue is collected from all subjects and used to confirm the above local test results of NF2 deficiency or YAP1/TAZ gene fusion retrospectively by analytically validated assays at a designated central CAP/CLIA diagnostic laboratory.

[00400] Confirmatory tests are not required prior to subject enrollment. Subjects in the Dose Expansion phase are replaced if the central confirmatory assay results return negative for these genetic alterations. Liquid biopsy tests to detect circulating cell-free nucleic acids can be used to confirm the presence of NF2 deficiency or YAP1/TAZ gene fusion. Whenever feasible, subjects undergo a pre-treatment fresh tumor biopsy and an on-treatment biopsy on C2 D8 (-5/+6 days) for pharmacodynamic and genetic studies.

Dose Escalation Phase

1. Objectives:

Primary:

• To determine the safety and tolerability of Compound A

• To determine the RP2D and/or MTD of Compound A

Secondary:

• To assess the preliminary antitumor activity of Compound A

• To determine the pharmacokinetics of Compound A

Exploratory:

• To evaluate the pharmacodynamic effects of Compound A on the expression of multiple TEAD target genes in paired tumor biopsies

• To evaluate candidate baseline biomarkers in tumors or blood predictive of clinical response to Compound A

• For subj ects with MPM, to assess the preliminary antitumor activity of Compound A using modified RECIST 1.1 criteria

• For subjects with primary CNS tumors (e.g., meningioma), to assess the preliminary antitumor activity of Compound A using RANO criteria

• Evaluation of exploratory biomarkers of kidney injury

2. Endpoints:

Primary:

• Frequency and severity of treatment-emergent adverse events (TEAEs)

• Frequency and severity of treatment-related adverse events (TRAEs)

• Number and percentage of subjects with 1 or more treatment-emergent SAE

• Number of subjects with dose-limiting toxicities (DLTs)

• Number and percentage of subjects with 1 or more TEAE leading to dose modifications and treatment discontinuation

Secondary: Response assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 by the Investigator:

• Disease control rate (DCR) (confirmed complete response [cCR] + confirmed partial response [cPR] + Stable Disease [SD] > 6 weeks)

• Time to response (TTR)

• Duration of response (DOR)

• Overall response rate (ORR) (cCR + cPR)

Summary of Compound A plasma PK parameters including half-life (t 1/2), area under the plasma concentration-time curve (AUC), and maximum (Cmax) and minimum (Cmin) observed plasma concentration after a single oral dose and at steady state after multiple oral doses for monotherapy

Exploratory:

• Changes in CTGF and other TEAD target gene expression in paired tumor biopsies

• Correlation of baseline tumor and blood biomarkers including, but not limited to, NF2 gene mutation/copy number loss and expression; YAP1 and TAZ gene fusion, gene amplification, and nuclear protein expression; and other Hippo pathway genetic alterations with clinical outcomes including DCR, TRR, DOR, and ORR

• For subjects with MPM, response assessments per modified Response Evaluation Criteria in Solid Tumors (modified RECIST) 1.1 by the Investigator:

- ORR (cCR + cPR)

- DCR (cCR + cPR + Minimal Response [MR] > 8 weeks + SD > 8 weeks)

- TTR

- DOR

• For subjects with primary CNS tumors (e.g., meningioma), response assessments per the Response Assessment in Neuro-Oncology (RANO) Working Group Criteria by the Investigator :

- ORR (cCR > 8 weeks + cPR > 8 weeks)

- DCR (cCR + cPR + MR > 8 weeks + SD > 8 weeks)

- TTR

- DOR • Measurements of urinary KIM-1, osteopontin, and NGAL on Days 1 and 15 of each Compound A cycle

Dose Expansion Phase

1. Objectives:

Primary:

• To determine the safety and tolerability of Compound A

• To assess the preliminary antitumor activity of Compound A

Secondary:

• To assess the pharmacokinetics of Compound A

• To assess additional parameters of preliminary antitumor activity of Compound A

Exploratory:

• Evaluation of exploratory biomarkers of kidney injury

2. Endpoints:

Primary:

• Frequency and severity of TEAEs

• Frequency and severity of TRAEs

• Number and percentage of subjects with 1 or more treatment-emergent SAE

• Number of subj ects with DLT s

Safety endpoints are evaluated according to the NCI-CTCAE version 5.0

• Response assessments per RECIST .1.1 by the Investigator: - ORR (cCR + cPR)

- DCR (cCR + cPR + SD > 6 weeks)

- TTR

- DOR

Secondary:

• Summary of Compound A plasma PK parameters including half-life (ti/2), area under the plasma concentration-time curve (AUC), and maximum (Cmax) and minimum (Cmin) observed plasma concentration after a single oral dose and at steady state after multiple oral doses for monotherapy

• For subjects in each of the four described expansion cohorts:

- Median progression-free survival (PFS)

- Median overall survival (OS)

Exploratory:

• Correlation of baseline tumor and blood biomarkers including, but not limited to, NF2 gene mutation/copy number loss and expression; YAP1 and TAZ gene fusion, gene amplification, and nuclear protein expression; and other Hippo pathway genetic alterations with clinical outcomes including ORR, DCR, TRR, and DOR

- ORR (cCR + cPR)

- DCR (cCR + cPR + SD > 6 weeks)

- TTR

- DOR

• For subjects with primary CNS tumors (e.g., meningioma), response assessments per the RANO Working Group Criteria by the Investigator:

- DCR (cCR + cPR + MR > 8 weeks + SD > 8 weeks)

- TTR

- DOR Measurements of urinary KIM-1, osteopontin, and NGAL on Days 1 and 15 of each Compound A cycle

Main Inclusion Criteria for All Subjects (Dose Escalation and Dose

Expansion):

[00401] 1. Subjects > 18 years of age.

[00402] 2. If feasible, subjects must be willing to consent to the submission of formalin-fixed paraffin-embedded tissue blocks of tumor tissue, preferably from pre-treatment fresh tumor biopsy. Alternatively, archival tumor FFPE blocks or, preferably, 10 unstained slides of tumor tissue from available archival sources are acceptable.

Additional Criteria for Inclusion for Dose Escalation Subjects:

[00403] 1. The following subjects are enrolled in the dose escalation cohort: a. Subj ects with histologically proven advanced, unresectable, locally recurrent, or metastatic malignancy that has progressed on or following standard-of-care therapies and for whom there is no available therapy known to confer clinical benefit, regardless of the presence or absence of NF2 deficiency or other genetic alterations of the Hippo pathway. Cytological diagnosis is an acceptable alternative during dose escalation. b. Subjects with histological confirmation of MPM. c. Subjects with NF2-deficient MPM determined by local test results for testing. NF2- deficient tumors are defined for this study as any NF2 loss-of-function mutations or copy number loss, as documented by local test results at screening, either from archival tumor tissue or from fresh tumor samples. Local test results for NF2 testing based on liquid biopsies testing are acceptable for enrollment. d. Subj ects with any other solid tumors with documented NF2 deficiency determined by local test results for testing, including, but not limited to, meningioma, cholangiocarcinoma, thymoma, mucoepidermoid NSCLC, HCC and others. NF2-deficient solid tumors. NF2- deficient tumors are defined for this study as any NF2 loss-of-function mutations or copy number loss, as documented by local results at screening, either from archival tumor tissue or from fresh tumor samples. Local test results for NF2 testing based on liquid biopsies testing are acceptable for enrollment. e. Subjects diagnosed with EHE with documented TAZ-CAMTA1 or YAP1-TFE3 gene fusions, as determined by RNA-seq, FISH or IHC. f. Subjects with solid tumors who have YAP1/TAZ gene fusions as determined by RNA-seq, FISH or IHC, as documented by local test results.

[00404] 2. Subjects can have measurable or evaluable disease by RECIST 1.1 criteria as assessed by the Investigator/local radiologist.

Additional Criteria for Inclusion for Dose Expansion Subjects:

[00405] 1. All subjects must have a histological diagnosis of an advanced, unresectable, locally recurrent, or metastatic disease with no available therapy known to confer clinical benefit as evaluated by the treating physician. There is no upper limit on the number of prior lines of anticancer therapy received.

[00406] 2. Subjects must have at least 1 measurable lesion per RECIST 1.1 criteria as assessed by the Investigator/local radiologist.

[00407] 3. Subjects must be enrolled in one of the following four cohort groups: a. Cohort 1 : Subjects with histological confirmed MPM and that have documented NF2 deficiency, defined as any loss-of-function mutations or NF2 copy number loss. b. Cohort 2: Subjects with other documented NF2-deficient solid tumors agnostic to tumor type defined as any loss-of-function mutations or NF2 copy number loss, including, but not limited to, meningioma, cholangiocarcinoma, thymoma, NSCLC, HCC, and others. c. Cohort 3: Subjects with histopathological diagnosis of epithelioid hemangioendothelioma (EHE) and documented TAZ-CAMTA1 or YAP1-TFE3 gene fusions, as determined by local test results for RNA-seq, FISH or IHC. Subjects who have objective disease progression to prior therapy or have active disease and cancer-related pain requiring narcotics for management are eligible. d. Cohort 4: Subjects with any solid tumor with documented YAP1/TAZ gene fusions as determined by local test results for RNA-seq, FISH or IHC.

Exclusion Criteria

1. Subjects with untreated or symptomatic primary central nervous system (CNS) tumors or with intracranial metastases (excluding primary CNS tumors that can be eligible, in some embodiments,, e.g., meningioma). Subjects with leptomeningeal metastases are excluded. 2. Uncontrolled or life-threatening symptomatic concomitant disease (

3. Clinically significant cardiovascular disease:

4. Breastfeeding or expecting to conceive or father children within the projected duration of the study.

5. Subjects who are unable to swallow or retain oral medication.

Number of Subjects (Planned):

[00408] It is anticipated that a total of approximately 158 subjects are enrolled in the study. The overall sample size for this study depends on the observed DLT profiles of Compound A as monotherapy. A target sample size of approximately 50 subjects for the Dose Escalation phase is planned for the study (Table 6). The sample size for the expansion cohorts is detailed in Table 6. Up to 27 subjects per Dose Expansion phase cohort can be enrolled. These estimates are based on a Simon 2-stage design where subjects with specific tumor types are enrolled in Stage 1, followed by additional subjects in each cohort if at least 1 response is observed. Approximately 108 subjects for the Dose Expansion phase cohorts are planned.

Table 6. Subject Enrollment - Monotherapy Treatment

Dosing Schedules:

[00409] During the Dose Escalation phase, subjects who tolerate Compound A without clinically significant AEs through Cycle 2 are allowed to receive Cycle 3 at a continuous schedule of administration.

[00410] Compound A can be administered in a fasting state (avoid food 2 hours prior to and 1 hour after administration of Compound A).

[00411] Compound A can be administered without the use of proton pump inhibitors (PPIs) or other acid-reducing agents (ARAs), in some embodiments. [00412] Patients can continue treatment until disease progression, unacceptable toxicity, or consent withdrawal. At a minimum, the 30-Day and 90-Day Follow-up visits should occur 30 (±7 days) and 90 days (±7 days), respectively, after the last study drug administration. If an alternate non- study anticancer drug therapy is initiated during this period, the 30-Day and/or 90-Day Follow- up visits should be conducted prior to the first dose of alternate therapy.

[00413] Regimen choice is optimized based on the totality of safety, PK, and PD available data from the 28-day and 21 -day schedules as guided by the SRC.

Statistical Considerations:

[00414] Determination of the sample size for dose escalation:

[00415] During dose escalation, at least 3 subjects are enrolled in each dose level cohort using the BOIN design (Yuan 2016) with a target toxicity rate of 25%. Backfilling is allowed with approximately 3 additional subjects once a dose escalation level is deemed safe by the SRC.

[00416] Dose escalation can occur when the DLT rate is < 0.197. Dose de-escalation occurs when the DLT rate is > 0.298. These decision boundaries and initial cohort size follow a 3 + 3 design. The BOIN design allows for subj ects to be placed in a cohort without waiting for the results of the initial 3 subjects to be complete to take advantage of the rolling 6 design (Skolnik 2008), which allows for a shortened study without increasing risk to subjects. The BOIN design allows for more than 6 subjects to be treated at a single dose level. The maximum number of subjects at each dose level including de-escalation and re-escalation is 14.

[00417] The BOIN dose escalation and de-escalation boundaries (ke of 0.197 and a kd of 0.298) follow Yuan et al. (Yuan 2016) and are shown below in Table 7:

Table 7. Dose esca ation and de-escalation

[00418] Determination of the sample size for dose escalation:

[00419] A Simon 2-stage design (Simon 1989) is used to determine whether Compound A has sufficient anticancer activity to warrant further development. Enrollment per cohort can be terminated early independently of other cohorts. No adjustment for multiple hypothesis testing is made. Once the minimum number of responses is reached, a given cohort can close prior to enrolling the prespecified total number of subjects.

[00420] While we have described a number of 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 application and claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. A spray dried intermediate (SDI) formulation comprising compound A,

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymer.

2. The SDI formulation of claim 1, comprising compound A free base.

3. The SDI formulation of any one of claims 1 or 2, wherein the pharmaceutically acceptable polymer is selected from PVP-VA, HPMC, HPMCP-55, HPMCAS-M, TPGS, HPMCAS-L, HPMC-HG, and MCC.

4. The SDI formulation of any one of claims 1-3, comprising about 25 - 35 % wt compound A, or a pharmaceutically acceptable salt thereof.

5. The SDI formulation of any one of claims 1-4, wherein the pharmaceutically acceptable polymer is about 65 - 75 %wt.

6. The SDI formulation of any one of claims 1-5, comprising 30:70 (wt %) compound A free base: HPMCAS-HG.

7. A unit dosage form comprising the SDI formulation of any one of claims 1-6.

8. The unit dosage form of claim 7, wherein the SDI formulation is about 45-55 wt% of the unit dosage form.

9. The unit dosage form of claim 8, wherein the SDI formulation is about 50 wt% of the unit dosage form.

10. The unit dosage form of any one of claim 7-9, which is an immediate release (IR) tablet.

11. The unit dosage form of any one of claims 7-10, further comprising a filler selected from mannitol and microcrystalline cellulose.

12. The unit dosage form of any one of claims 7-11, further comprising a disintegrant croscarmellose sodium.

13. The unit dosage form of any one of claims 7-12, further comprising a glidant colloidal silicon dioxide.

14. The unit dosage form of any one of claims 7-13, further comprising magnesium stearate.

15. The unit dosage form of any one of claims 7-14, further comprising a film coat.

16. The unit dosage form of claim 15, wherein the film coat is Opadry II White 85F 18422.

17. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effect amount of the SDI formulation of any one of claims 1-6, or the unit dosage form of any one of claims 7-16.

18. The method of claim 17, wherein the cancer is a solid tumor, a locally advanced or metastatic solid tumor, or a brain tumor.

19. The method of claim 17, wherein the cancer is selected from non-small cell lung cancer (NSCLC), squamous NSCLC, adenocarcinoma NSCLC, mucoepidermoid NSCLC, head and neck squamous cell carcinoma (HNSCC), esophageal carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, malignant mesothelioma, advanced unresectable malignant mesothelioma, sarcomatoid malignant mesothelioma, epitheliod malignant mesothelioma, malignant pleural mesothelioma (MPM), meningioma, sporadic menongioma, recurrent or unresectable meningioma, thymoma, schwannoma, cholangiocarcinoma, epithelioid hemangioendothelioma (EHE), synovial sarcoma, myxoid liposarcoma, soft tissue sarcoma, angiosarcoma, liposarcoma, mesothelioma, and a neurofibromatosis type 2 (NF2)-deficient cancer.

20. The method of claim 17, wherein the cancer is an NF2-deficient solid tumor.

21. The method of claim 20, wherein the NF2-deficient solid tumor is mesothelioma, meningioma, cholangiocarcinoma, thymoma, NSCLC, or HCC.

22. The method of claims 20 or 21, wherein the NF2-deficient solid tumor has NF2 loss-of- function mutations.

23. The method of claims 20 or 21, wherein the NF2-deficient solid tumor has NF2 copy number loss.

24. The method of claim 17, wherein the cancer is epithelioid hemangioendothelioma (EHE).

25. The method of claim 24, wherein the epithelioid hemangioendothelioma (EHE) has a TAZ-CAMTA1 or YAP1-TFE3 gene fusion.

26. The method of claim 17, wherein the cancer is a solid tumor with a YAP1 or TAZ gene fusion.

27. The method of any one of claims 17-26, wherein the method comprises administering to the patient about 25 - 1200 mg (for example, about 25 mg, about 75, about 150, about 300, about

118 45 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg) of compound A, or a pharmaceutically acceptable salt thereof, daily.

28. Use of a therapeutically effect amount of the SDI formulation of any one of claims 1-6, or the unit dosage form of any one of claims 7-16, for treating cancer in a patient.

29. The use of claim 28, wherein the cancer is a solid tumor, a locally advanced or metastatic solid tumor, or a brain tumor.

30. The use of claim 28, wherein the cancer is selected from non-small cell lung cancer (NSCLC), squamous NSCLC, adenocarcinoma NSCLC, mucoepidermoid NSCLC, head and neck squamous cell carcinoma (HNSCC), esophageal carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, hepatocellular carcinoma, malignant mesothelioma, advanced unresectable malignant mesothelioma, sarcomatoid malignant mesothelioma, epitheliod malignant mesothelioma, malignant pleural mesothelioma (MPM), meningioma, sporadic menongioma, recurrent or unresectable meningioma, thymoma, schwannoma, cholangiocarcinoma, epithelioid hemangioendothelioma (EHE), synovial sarcoma, myxoid liposarcoma, soft tissue sarcoma, angiosarcoma, liposarcoma, mesothelioma, and a neurofibromatosis type 2 (NF2)-deficient cancer.

31. The use of claim 28, wherein the cancer is an NF2-deficient solid tumor.

32. The use of claim 31, wherein the NF2-deficient solid tumor is mesothelioma, meningioma, cholangiocarcinoma, thymoma, NSCLC, or HCC.

33. The use of claims 31 or 32, wherein the NF2-deficient solid tumor has NF2 loss-of- function mutations.

34. The use of claims 31 or 32, wherein the NF2-deficient solid tumor has NF2 copy number loss.

119

35. The use of claim 28, wherein the cancer is epithelioid hemangioendothelioma (EHE).

36. The use of claim 35, wherein the epithelioid hemangioendothelioma (EHE) has a TAZ- CAMTA1 or YAP1-TFE3 gene fusion.

37. The use of claim 28, wherein the cancer is a solid tumor with a YAP1 or TAZ gene fusion.

38. The use of any one of claims 28-37, wherein the SDI formulation or the unit dosage form comprises about 25 - 1200 mg (for example, about 25 mg, about 75, about 150, about 300, about 45 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg) of compound A, or a pharmaceutically acceptable salt thereof, daily.

120