Cancer treatments using MTA-cooperative PRMT5 inhibitors and mat2a inhibitors

Abstract

Described herein are methods of treating a MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A, or pharmaceutically acceptable salt thereof, at a total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and (b) Compound B, or pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg.

Description

CANCER TREATMENTS USING MTA-COOPERATIVE PRMT5 INHIBITORS AND MAT2A INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to each of U.S. Provisional Patent Application No. 63 / 653,019, filed May 29, 2024, and U.S. Provisional Patent Application No. 63 / 774,277, filed March 19, 2025.BACKGROUND

[0002] Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases. Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., PRMT5), many of which are associated with specific genetic alterations that can cause human disease. PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders.

[0003] The homozygous deletion of tumor suppressor genes is a key driver of cancer, frequently resulting in the collateral loss of passenger genes located in close genomic proximity to the tumor suppressor. Deletion of these passenger genes can create therapeutically tractable vulnerabilities that are specific to tumor cells. Homozygous deletion of the chromosome 9p21 locus, which harbors the well-known tumor suppressor CDKN2A (cyclin dependent kinase inhibitor 2A), occurs in 15% of all tumors and frequently includes the passenger gene MTAP (methylthioadenosine phosphorylase), a key enzyme in the methionine and adenine salvage pathways. Deletion of MTAP results in accumulation of its substrate, methylthioadenosine (MTA). MTA shares close structural similarity to S-adenosylmethionine (SAM), the substrate methyl donor for the type II methyltransferase PRMT5. Elevated MTA levels, driven by loss of MTAP, selectively compete with SAM for binding to PRMT5, placing the methyltransferase in a hypomorphic state, vulnerable to further PRMT5 inhibition. Multiple genome scale shRNA drop out screens performed in large tumor cell line panels have identified a strong correlation between MTAP loss and cell line dependency on PRMT5, further highlighting the strength of this metabolic vulnerability. However, PRMT5 is a known cell essential gene and conditional PRMT5 knockout and siRNA knockdown studies suggest that significant liabilities could be associated with inhibiting PRMT5 in normal tissues (e.g. pan-cytopenia, infertility, skeletal muscle loss, cardiac hypertrophy, others). Therefore, novel strategies are required to exploit this metabolic vulnerability and preferentially target PRMT5 in MTAP null tumors while sparing PRMT5 in normal tissues (MTAP WT). Targeting PRMT5 with an MTA-cooperative small molecule inhibitor could preferentially target the MTA bound state of PRMT5, enriched in MTAP null tumor cells, while providing an improved therapeutic index over normal cells where MTAP is intact and MTA levels are low.

[0004] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosyl methionine (SAM). SAM is a primary methyl donor in cellsused to methylate several substrates including DNA, RNA, and proteins. One methylase that utilizes SAM as a methyl donor is PRMT5. MTA is a competitive inhibitor for the SAM binding site of PRMT5.

[0005] MTAP is in a locus on chromosome 9 that is often deleted in cells of patients with cancers from several tissues of origin including central nervous system, pancreas, esophageal, bladder and lung. Loss of MTAP results in the accumulation of MTA making MTAP-deleted cells more dependent on SAM production, and thus MAT2A activity, compared to cells that express MTAP. In an shRNA cell-line screen across approximately 400 cancer cell lines, MAT2A knockdown resulted in the loss of viability in a larger percentage of MTAP-deleted (also referred to herein as MTAP-null) cells compare to MTAP WT cells (McDonald et. al. 2017 Cell 170, 577-592). Furthermore, inducible knockdown of MAT2A protein decreased tumor growth in vivo (Maqon et. al., 2016 Cell Reports 15(3), 574-587).SUMMARY

[0006] The disclosure provides methods of treating a MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A at total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and (b) Compound B at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg.DETAILED DESCRIPTION

[0007] The disclosure provides methods of treating a MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, or 1200 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg. In various cases, the methods comprise administering (a) Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 240 mg, 480 mg, 800 mg, or 1200 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg. In some cases, the methods comprise administering (a) Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg. In some cases, the methods comprise administering (a) Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, 60 mg, or 100 mg. In some cases, the methods comprise administering (a) Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 600 mg, 800 mg, 900 mg, or 1200 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg. In some cases, the methods comprise administering (a) Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 800 mg, 900 mg, or 1200 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg. In some cases, the methods comprise administering (a) Compound A,or a pharmaceutically acceptable salt thereof, at total daily dose of 800 mg or 1200 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg.

[0008] An amount of Compound A or Compound B as discussed throughout the present disclosure is based upon the free base weight of the compound. Thus, for example, if 600 mg of Compound A is to be administered to a patient, and Compound A is being administered in salt form, the actual amount of Compound A salt administered will be greater than 600 mg, to account for the mass of the salt entity.

[0009] The term "about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, and the like, the term "about” is meant to encompass variations of ±5%, including ±4%, ±3%, ±2%, and ±1%, from the specified value, as such variations are appropriate to perform the disclosed methods. Similarly, a dose disclosed herein encompasses variations of ±5%, including ±4%, ±3%, ±2%, and ±1%, from the specified value, as such variations are appropriate to perform the disclosed methods. In some embodiments, the dose is equal to the specified amount.

[0010] A "patient” or "subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)). The terms "patient” and "subject” are used interchangeably herein.

[0011] In another aspect, the present disclosure provides a use of Compound A, or a pharmaceutically acceptable salt thereof, at a total daily dose of 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, or 1200 mg; and Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg in the manufacture of a medicament for the treatment of a MTAP-null cancer. In various cases, the disclosure provides a use of Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 240 mg, 480 mg, 800 mg, or 1200 mg; and Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg in the manufacture of a medicament for the treatment of a MTAP- null cancer. In some cases, the disclosure provides a use of Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg in the manufacture of a medicament for the treatment of a MTAP-null cancer. In some cases, the disclosure provides a use of Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 600 mg, 800 mg, 900 mg, or 1200 mg; and Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg in the manufacture of a medicament for the treatment of a MTAP- null cancer. In some cases, the disclosure provides a use of Compound A, or a pharmaceutically acceptable salt thereof, at total daily dose of 800 mg, 900 mg, or 1200 mg; and Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg in the manufacture of a medicament for the treatment of a MTAP-null cancer. In some cases, the disclosure provides use of Compound A, or apharmaceutically acceptable salt thereof, at total daily dose of 800 mg or 1200 mg; and Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg in the manufacture of a medicament for the treatment of a MTAP-null cancer.

[0012] Compound A is a PRMT5 inhibitor that has a chemical name (S)-(4-amino-1 ,3-dihydrofuro[3,4- c][1 ,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone and has the following structureCompound A

[0013] Compound A can be synthesized using methods as described, e.g., in International Application Nos.PCT / US2022 / 075648 and PCT / US2021 / 063540.

[0014] In some cases, in the methods disclosed herein, Compound G is administered as a free base. In some cases, in the methods disclosed herein, Compound A can be administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002.

[0015] In various embodiments, Compound A or salt thereof is administered orally. In various embodiments, Compound A or salt thereof is administered at a dose of 120 mg, based on the free base weight of Compound A. In various embodiments, Compound A or salt thereof is administered at a dose of 240 mg, based on the free base weight of Compound A. In various embodiments, Compound A or salt thereof is administered at a dose of 300 mg, based on the free base weight of Compound A. In various embodiments, Compound A or salt thereof is administered at a dose of 480 mg, based on the free base weight of Compound A. In various embodiments, Compound A or salt thereof is administered at a dose of 600 mg, based on the free base weight of Compound A. In various embodiments, Compound A or salt thereof is administered at a dose of 800 mg, based on the freebase weight of Compound A. In various embodiments, Compound A or salt thereof is administered at a dose of 900 mg, based on the free base weight of Compound A. In various embodiments, Compound A or salt thereof is administered at a dose of 1200 mg, based on the free base weight of Compound A. In various embodiments, Compound A or salt thereof is administered at a dose of 1600 mg, based on the free base weight of Compound A.

[0016] In some cases, Compound A is administered as a free base. In some embodiments, the free base of Compound A is administered at a dose of 120 mg. In some embodiments, the free base of Compound A is administered at a dose of 240 mg. In some embodiments, the free base of Compound A is administered at a dose of 300 mg. In some embodiments, the free base of Compound A is administered at a dose of 480 mg. In some embodiments, the free base of Compound A is administered at a dose of 600 mg. In some embodiments, the free base of Compound A is administered at a dose of 900 mg. In some embodiments, the free base of Compound A is administered at a dose of 1200 mg. In some embodiments, the free base of Compound A is administered at a dose of 1600 mg.

[0017] Compound B is a MAT2A inhibitor that has a chemical name 4-amino-1-(2-chlorophenyl)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1 H)-one and has the following structure.Compound B.Compound B, and methods of making Compound B are disclosed in International Application No. PCT / US2019 / 065260 (published as WO 2020 / 123395).

[0018] In the methods disclosed herein, Compound B can be administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Suitable salts include thosedescribed in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002.

[0019] In various embodiments, Compound B or salt thereof is administered orally. In various embodiments, Compound B or salt thereof is administered at a dose of 10 mg, based on the free base weight of Compound B. In various embodiments, Compound B or salt thereof is administered at a dose of 15 mg, based on the free base weight of Compound B. In various embodiments, Compound B or salt thereof is administered at a dose of 30 mg, based on the free base weight of Compound B. In various embodiments, Compound B or salt thereof is administered at a dose of 60 mg, based on the free base weight of Compound B. In various embodiments, Compound B or salt thereof is administered at a dose of 100 mg, based on the free base weight of Compound B.

[0020] In some embodiments, the method comprises administering to the patient a total daily dose of 120 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 120 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 120 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 120 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0021] In some embodiments, the method comprises administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0022] In some embodiments, the method comprises administering to the patient a total daily dose of 300 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 300 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 300 mg Compound A and a total daily dose of 30 mgCompound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 300 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0023] In some embodiments, the method comprises administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0024] In some embodiments, the method comprises administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0025] In some embodiments, the method comprises administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0026] In some embodiments, the method comprises administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0027] In some embodiments, the method comprises administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 1 200 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0028] In some embodiments, the method comprises administering to the patient a total daily dose of 1600 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 1600 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 1600 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively. In some embodiments, the method comprises administering to the patient a total daily dose of 1600 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

[0029] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, Compound B or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, Compound A and Compound B are each administered orally.

[0030] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered once daily (QD). In some embodiments, Compound B or a pharmaceutically acceptable salt thereof isadministered once daily (QD). In some embodiments, Compound A and Compound B are each administered once daily (QD).

[0031] In some embodiments, Compound A or a pharmaceutically acceptable thereof and Compound B or a pharmaceutically acceptable salt thereof are administered concurrently. In some embodiments, Compound A and Compound B are administered concurrently. In some embodiments, Compound A or a pharmaceutically acceptable thereof and Compound B or a pharmaceutically acceptable salt thereof are administered sequentially. In some embodiments, Compound A and Compound B are administered sequentially.Cancer

[0032] A MTAP-null cancer refers to a cancer that lacks expression of the enzyme methylthioadenosine phosphorylase (MTAP). The MTAP gene, located at chromosomal locus 9p21 is frequently co-deleted with the CDKN2A and CDKN2B genes. Selective MTAP deficiency, refers to deficiency without co-deletion of the CDKN2 genes, due either to selective deletion of the MTAP locus or to methylation of the MTAP promoter. MTAP-null cancers include MTAP-deficiency in at least 1% of disease cells, and in some cases, at least 20% of disease cells.

[0033] Terms "MTAP-null”, "MTAP-deleted”, "MTAP-deficiency”, and "MTAP-deficient” are used interchangeably herein. An "MTAP-deficiency-related” or "MTAP-deficiency” or "MTAP deficient” disease (for example, a proliferating disease, e.g., a cancer) or a disease (for example, a proliferating disease, e.g., a cancer) "associated with MTAP deficiency” or a disease (for example, a proliferating disease, e.g., a cancer) "characterized by MTAP deficiency” and the like refer to an ailment (for example, a proliferating disease, e.g., a cancer) wherein a significant number of cells are MTAP-deficient. For example, in a MTAP-deficiency-related disease, one or more disease cells can have a significantly reduced post-translational modification, production, expression, level, stability and / or activity of MTAP. MTAP-null cancers can be identified by any suitable diagnostic test. Exemplary diagnostic tests include immunohistochemistry (IHC) and next generation sequencing (NGS).

[0034] Examples of MTAP-deficiency-related diseases include, but are not limited to, cancers, including but not limited to: glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0035] In some embodiments, the cancer is acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer,brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic my leoprol iterative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer. In some cases, the cancer is pancreatic cancer; esophageal cancer; melanoma; lung cancer; mixed mullerian cancer; ovarian cancer; or gallbladder cancer.

[0036] In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0037] In some embodiments, the cancer is leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma or mesothelioma. In various embodiments, the cancer is bladder cancer, melanoma, brain cancer, lung cancer,pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL) or mantle cell lymphoma (MCL). In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is glioblastoma multiforme (GBM). In some embodiments, the cancer is bladder cancer. In various embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is MCL. In some embodiments, the cancer is DLBCL. In various embodiments, the cancer is ALL. In some embodiments, the cancer is lung cancer or pancreatic cancer.

[0038] In some embodiments, the cancer is a solid tumor. In some embodiments, the tumor is malignant.

[0039] In some embodiments, the cancer is a gastrointestinal cancer. Gastrointestinal cancers include, but are not limited to, anal cancer, appendix cancer, biliary duct cancer, biliary tract cancer, colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumors, islet cell tumors, liver cancer, gastrointestinal neuroendocrine tumor, pancreatic cancer, rectal cancer, and small intestine cancer. In some embodiments, the MTAP-null gastrointestinal cancer is locally advanced. In some embodiments, the MTAP-null gastrointestinal cancer is metastatic. In some embodiments, the cancer is gallbladder cancer.

[0040] In some cases, the gastrointestinal cancer is biliary tract cancer or pancreatic cancer. In some embodiments, the MTAP-null gastrointestinal cancer is biliary tract cancer. Biliary tract cancer, or cholangiocarcinoma, arises from the biliary epithelium of the small ducts in the periphery of the liver (intrahepatic) and the main ducts of the hilum (extrahepatic). Extrahepatic biliary tract cancers include gallbladder cancer, ampullary cancer, and cancer of the pancreatic biliary ducts. In some embodiments, the biliary tract cancer is locally advanced. In some cases, the biliary tract cancer is metastatic. In some embodiments, the MTAP-null gastrointestinal cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the pancreatic ductal adenocarcinoma is locally advanced. In some embodiments, the pancreatic ductal adenocarcinoma is metastatic.

[0041] In some embodiments, the MTAP-null cancer is lung cancer. In various embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is NSCLC wherein the NSCLC is squamous cell lung cancer. In some embodiments, the lung cancer is NSCLC wherein the NSCLC is adenocarcinoma of the lung. In some embodiments, the cancer is head and neck squamous cell.

[0042] In some embodiments, the MTAP-null cancer is adrenal carcinoma. In some embodiments, the MTAP-null cancer is soft tissue sarcoma. In some embodiments, MTAP-null cancer is melanoma. In some embodiments, the MTAP-null cancer is gastroesophageal junction (GEJ) carcinoma. In some embodiments, the MTAP-null cancer is breast cancer. In some embodiments, the MTAP-null cancer is triple-negative breast cancer (TNBC).

[0043] In some embodiments, the MTAP-null cancer is a solid tumor. In some cases, the solid tumor is malignant. In some cases, the MTAP-null cancer is gastrointestinal cancer. In some cases, the MTAP-null canceris lung cancer. In some cases, the MTAP-null lung cancer is non-small cell lung cancer (NSCLC). In some cases, the MTAP-null cancer is squamous NSCLC. In some cases, the MTAP-null cancer is non-squamous NSCLC. In some cases, the MTAP-null cancer is biliary tract cancer. In some cases, the MTAP-null cancer is pancreatic cancer. In some cases, the MTAP-null pancreatic cancer is pancreatic adenocarcinoma. In some cases, the MTAP-null cancer is gallbladder cancer. In some cases, the MTAP-null cancer is mesothelioma. In some cases, the MTAP-null cancer is primary brain tumor. In some cases, the MTAP-null cancer is lymphoma. In some cases, the MTAP-null cancer is esophageal / gastric cancer. In some cases, the MTAP-null cancer is esophageal cancer. In some cases, the MTAP-null cancer is gastric cancer. In some cases, the MTAP-null cancer is glioma.

[0044] In some embodiments, the patient does not have a tumor harboring the following mutations and genetic aberrations amenable to targeted therapies: epidermal growth factor receptor (EGFR) I ALK receptor tyrosine kinase (ALK) I ROS proto-oncogene 1 (ROS1) I neurotrophic tyrosine receptor kinase (NTRK) I MET proto-oncogene (MET) I B-Raf proto-oncogene (BRAF) / RET proto-oncogene (RET) I Human epidermal growth factor receptor 2 (HER2 or ERBB2) I KRAS proto-oncogene (KRAS).Monitoring Efficacy of Treatment

[0045] The efficacy of a given treatment for cancer can be determined by the skilled clinician. However, a treatment is considered "effective treatment," as the term is used herein, if any one or all of the signs or symptoms of e.g., a tumor are altered in a beneficial manner or other clinically accepted symptoms are improved, or even ameliorated, e.g., by at least 10% following treatment with an agent as described herein. Efficacy can also be assessed by stabilization of disease or its symptoms or a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of assessing these indicators are known to those of skill in the art and / or described herein.

[0046] The patient can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). RECIST v1 .1 is discussed in detail in the examples below. An at least stable disease is one that is a stable disease, has shown a partial response (PR) or has shown a complete response (CR) (i.e., "at least SD” = SD+PR+CR, often referred to as disease control). In various embodiments, the stable disease has neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD). In various embodiments, the patient exhibits at least a partial response (i.e., "at least PR” = PR+CR, often referred to as objective response). Additionally or alternatively, patient response can be determined by Response Assessment in Neuro-Oncology (RANG) criteria, see, e.g., Chen et al., Front Oncol., 2021 11 :679331.

[0047] Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases. In various embodiments, the progression of a patient's disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT)scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof. In some embodiments, progression of a patient's disease (e.g., progression free survival) can be assessed by measuring ctDNA reduction from baseline.

[0048] In some embodiments, the therapy described herein exhibits a combination benefit. The term "combination benefit” refers to an observed efficacy with a dual therapy that is higher than treatment with either individual therapy alone. In some embodiments, the dual therapy described herein exhibits a combination benefit compared to Compound A monotherapy. In some embodiments, the dual therapy described herein exhibits a combination benefit compared to Compound B monotherapy.

[0049] Exemplary embodiments:1 . A method of treating a MTAP-null cancer in a patient in need thereof comprising administering(a) Compound A at total daily dose of about 240 mg, about 480 mg, about 800 mg, or about 1200 mg; and (b)Compound B at a total daily dose of about 10 mg, about 15 mg, about 30 mg, or about 60 mg.2. A method of treating a MTAP-null cancer in a patient in need thereof comprising administering(a) Compound A at total daily dose of 240 mg, 480 mg, 800 mg, or 1200 mg; and (b) Compound B at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg.3. The method of embodiment 1 or embodiment 2, wherein the MTAP-null cancer is a solid tumor.4. The method of embodiment 3, wherein the tumor is malignant.5. The method of any one of embodiment 1-4, wherein the MTAP-null cancer is gastrointestinal cancer.6. The method of any one of embodiments 1-4, wherein the MTAP-null cancer is lung cancer.7. The method of embodiment 6, wherein the lung cancer is non-small cell lung cancer (NSCLC).8. The method of any one of embodiments 1-4, wherein the MTAP-null cancer is biliary tract cancer.9. The method of any one of embodiments 1-4, wherein the cancer is head and neck squamous cell carcinoma.10. The method of any one of embodiments 1-4, wherein the MTAP-null cancer is pancreatic adenocarcinoma.11. The method of any one of embodiments 1-4, wherein the MTAP-null cancer is gallbladder cancer.12. The method of any one of embodiments 1-11, wherein Compound A or salt thereof and Compound B or salt thereof are administered concurrently.13. The method of any one of embodiments 1-11 , wherein Compound A or salt thereof and Compound B or salt thereof are administered sequentially.14. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 10 mg Compound B.15. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 15 mg Compound B.16. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 30 mg Compound B.17. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 60 mg Compound B.18. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 10 mg Compound B.19. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 15 mg Compound B.20. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 30 mg Compound B.21. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 60 mg Compound B.22. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 10 mg Compound B.23. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 15 mg Compound B.24. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 30 mg Compound B.25. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 60 mg Compound B.26. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 10 mg Compound B.27. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 15 mg Compound B.28. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 30 mg Compound B.29. The method of any one of embodiments 1-13, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 60 mg Compound B.30. A use of Compound A at a total daily dose of 240 mg, 480 mg, 800 mg, or 1200 mg; and Compound B at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg for the treatment of a MTAP-null cancer.31 . Use of Compound A at a total daily dose of 240 mg, 480 mg, 800 mg, or 1200 mg; and Compound B at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg in the manufacture of a medicament for the treatment of a MTAP-null cancer.32. The use of embodiment 30 or 31 , wherein Compound A or pharmaceutically acceptable salt thereof and Compound B or pharmaceutically acceptable salt thereof are administered concurrently.33. The use of embodiment 30 or 31 , wherein Compound A or pharmaceutically acceptable salt thereof and Compound B or pharmaceutically acceptable salt thereof are administered sequentially.Additional embodiments:1 A. A method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient (a) Compound A, or a pharmaceutically acceptable salt thereof, having the structure oftotal daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg,900 mg, 1200 mg, or 1600 mg; and (b) Compound B, or pharmaceutically acceptable salt thereof, having a structuretotal daily dose of 10 mg, 15 mg, 30 mg, or 60 mg.2A. A method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient (a) Compound A, or a pharmaceutically acceptable salt thereof having the structure oftotal daily dose of 240 mg, 300 mg, 480 mg, 600, 800 mg, 900 mg, or1200 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, having the structure oftotal daily dose of 10 mg, 15 mg, 30 mg, or 60 mg.3A. The method of embodiment 1 A or embodiment 2A, wherein the MTAP-null cancer is a solid tumor.4A. The method of embodiment 3A, wherein the tumor is malignant.5A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is gastrointestinal cancer.6A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is lung cancer.7A. The method of embodiment 6A, wherein the lung cancer is non-small cell lung cancer(NSCLC).8A. The method of embodiment 7A, wherein the lung cancer is squamous NSCLC.9A. The method of embodiment 7A, wherein the lung cancer is non-squamous NSCLC.10A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is biliary tract cancer.11 A. The method of any one of embodiments 1 A-4A, wherein the cancer is head and neck squamous cell carcinoma.12A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is pancreatic adenocarcinoma.13A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is gallbladder cancer.14A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is mesothelioma.15A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is primary brain tumor.16A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is lymphoma.17A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is esophageal / gastric cancer.18A. The method of any one of embodiments 1 A-4A, wherein the MTAP-null cancer is glioma.19A. The method of any one of embodiments 1 A-18A, wherein Compound A or salt thereof and Compound B or salt thereof are administered concurrently.20A. The method of any one of embodiments 1 A-18A, wherein Compound A or salt thereof and Compound B or salt thereof are administered sequentially.21 A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 120 mg Compound A of and a total daily dose of 10 mg Compound B.22A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 120 mg Compound A and a total daily dose of 15 mg Compound B.23A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 120 mg Compound A and a total daily dose of 30 mg Compound B.24A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 120 mg Compound A and a total daily dose of 60 mg Compound B.25A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 240 mg Compound A of and a total daily dose of 10 mg Compound B.26A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 15 mg Compound B.27A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 30 mg Compound B.28A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 240 mg Compound A and a total daily dose of 60 mg Compound B.29A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 300 mg Compound A of and a total daily dose of 10 mg Compound B.30A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 300 mg Compound A and a total daily dose of 15 mg Compound B.31 A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 300 mg Compound A and a total daily dose of 30 mg Compound B.32A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 300 mg Compound A and a total daily dose of 60 mg Compound B.33A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 10 mg Compound B.34A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 15 mg Compound B.35A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 30 mg Compound B.36A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 60 mg Compound B.37A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 600 mg Compound A of and a total daily dose of 10 mg Compound B.38A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 15 mg Compound B.39A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 30 mg Compound B.40A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 60 mg Compound B.41 A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 10 mg Compound B.42A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 15 mg Compound B.43A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 30 mg Compound B.44A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 60 mg Compound B.45A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 900 mg Compound A of and a total daily dose of 10 mg Compound B.46A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 15 mg Compound B.47A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 30 mg Compound B.48A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 60 mg Compound B.49A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 10 mg Compound B.50A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 15 mg Compound B.51 A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 30 mg Compound B.52A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 60 mg Compound B.53A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 1600 mg Compound A and a total daily dose of 10 mg Compound B.54A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 1600 mg Compound A and a total daily dose of 15 mg Compound B.55A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 1600 mg Compound A and a total daily dose of 30 mg Compound B.56A. The method of any one of embodiments 1 A-20A, comprising administering to the patient a total daily dose of 1600 mg Compound A and a total daily dose of 60 mg Compound B.57A. The method of any one of embodiments 1 A-56A, comprising administering Compound A or pharmaceutically acceptable salt thereof to the patient once daily.58A. The method of any one of embodiments 1 A-56A, comprising administering Compound A or pharmaceutically acceptable salt thereof to the patient twice daily.59A. The method of any one of embodiments 1 A-56A, comprising administering Compound B or pharmaceutically acceptable salt thereof to the patient once daily.60A. A use of Compound A at a total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and Compound B at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg for the treatment of a MTAP-null cancer.61 A. Use of Compound A at a total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and Compound B at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg in the manufacture of a medicament for the treatment of a MTAP-null cancer.62A. The use of embodiment 60A or 61 A, wherein Compound A or pharmaceutically acceptable salt thereof and Compound B or pharmaceutically acceptable salt thereof are administered concurrently.63A. The use of embodiment 60A or 61 A, wherein Compound A or pharmaceutically acceptable salt thereof and Compound B or pharmaceutically acceptable salt thereof are administered sequentially.64A. The use of any one of embodiments 61 A-63A, wherein Compound A or pharmaceutically acceptable salt thereof is administered once daily.65A. The use of any one of embodiments 61 A-63A, wherein Compound A or pharmaceutically acceptable salt thereof is administered twice daily.66A. The use of any one of embodiments 61 A-63A, wherein Compound B or pharmaceutically acceptable salt thereof is administered once daily.EXAMPLES

[0050] The following Example describes the protocol for a phase 1 / 2, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Compound A in combination with Compound B in adult subjects with advanced or metastatic methyladenosine phosphorylase (MTAP)-null solid tumors. Compound A (at 120 mg, 240 mg, 480 mg, 800 mg, 1200 mg, or 1600 mg) and Compound B (at 10 mg, 15 mg, 30 mg, 60 mg, or 100 mg) will be administered orally once daily continuously for cycles of 21 days.

[0051] Dosing is in the following cohorts:

[0052] Cohort A: 120 mg Compound A and 10 mg Compound B

[0053] Cohort 1 : 240 mg Compound A and 15 mg Compound B

[0054] Cohort 2: 480 mg Compound A and 15 mg Compound B

[0055] Cohort 3: 480 mg Compound A and 30 mg Compound B

[0056] Cohort 4: 800 mg Compound A and 15 mg Compound B

[0057] Cohort 5: 240 mg Compound A and 30 mg Compound B

[0058] Cohort 6: 800 mg Compound A and 10 mg Compound B

[0059] Cohort 7: 1200 mg Compound A and 100 mg Compound B; and

[0060] Cohort 8: 1600 mg Compound A and 100 mg Compound B.

[0061] Exemplary Inclusion Criteria:

[0062] - Age > 18 years

[0063] - Evidence of homozygous loss of MTAP (null) and / or MTAP-deletion by local next-generation sequencing or central testing using IHC

[0064] Presence of advanced / metastatic solid tumor not amenable to curative treatment

[0065] Disease measurable as defined by RECIST v.1.1

[0066] Eastern Cooperative Oncology Group (ECOG) performance of 0 to 1 .

[0067] Exemplary Exclusion Criteria:

[0068] - Radiologic or clinical evidence of spinal cord compression, untreated or symptomatic brain metastases of leptomeningeal disease. Subjects who have had brain metastases and have been appropriatelytreated with radiation therapy or surgery ending at least 4 weeks prior to study Dy 1 are eligible if they meet all of the following criteria: (a) stable or improving residual neurological symptoms grade < 2; and (b) on stable or decreasing doses of corticosteroids for at least 14 days prior to enrollment, if applicable.

[0069] History of other malignancy withing the past 2 years, with the following exceptions:

[0070] -Malignancy treated with curative intent and felt to be at low risk for recurrence

[0071] -adequately treated non-melanoma skin cancer or lentigo maligna

[0072] -adequately treated cervical carcinoma in situ

[0073] -breast ductal carcinoma in situ

[0074] -urothelial papillary noninvasive carcinoma or carcinoma in situ without evidence of disease

[0075] Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, hormonal therapy) within 28 days of study day 1, unless anti-tumor therapy is a therapy with 5 times the half-life shorter than 21 days.

[0076] Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.

[0077] Preliminary data:*defined as at least 6 weeks of treatment with scan**not confirmed, subsequent scan showed PD***includes one patient with PD during cycle 1

[0078] Partial response (PR)” in a patient is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

[0079] "Stable Disease (SD)” in a patient is defined as neither sufficient shrinkage to qualify for a partial response (PR) nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study.

[0080] Data with a cutoff of January 23, 2025:

Claims

What is claimed is:1 . A method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient (a) Compound A, or a pharmaceutically acceptable salt thereof, having the structure oftotal daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg,900 mg, 1200 mg, or 1600 mg; and (b) Compound B, or pharmaceutically acceptable salt thereof, having a structuretotal daily dose of 10 mg, 15 mg, 30 mg, or 60 mg.

2. A method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient (a) Compound A, or pharmaceutically acceptable salt thereof, having the structure oftotal daily dose of 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, or 1200 mg; and (b) Compound B, or a pharmaceutically acceptable salt thereof, having the structure oftotal daily dose of 10 mg, 15 mg, 30 mg, or 60 mg.

3. The method of claim 1 or claim 2, wherein the MTAP-null cancer is a solid tumor.

4. The method of claim 3, wherein the tumor is malignant.

5. The method of any one of claims 1-4, wherein the MTAP-null cancer is gastrointestinal cancer.

6. The method of any one of claims 1-4, wherein the MTAP-null cancer is lung cancer.

7. The method of claim 6, wherein the lung cancer is non-small cell lung cancer (NSCLC).

8. The method of claim 7, wherein the lung cancer is squamous NSCLC.

9. The method of claim 7, wherein the lung cancer is non-squamous NSCLC.

10. The method of any one of claims 1-4, wherein the MTAP-null cancer is biliary tract cancer.

11. The method of any one of claims 1-4, wherein the cancer is head and neck squamous cell carcinoma.

12. The method of any one of claims 1-4, wherein the MTAP-null cancer is pancreatic cancer.

13. The method of claim 12, wherein the pancreatic cancer is pancreatic adenocarcinoma.

14. The method of any one of claims 1-4, wherein the MTAP-null cancer is gallbladder cancer.

15. The method of any one of claims 1-4, wherein the MTAP-null cancer is mesothelioma.

16. The method of any one of claims 1-4, wherein the MTAP-null cancer is primary brain tumor.

17. The method of any one of claims 1-4, wherein the MTAP-null cancer is lymphoma.

18. The method of any one of claims 1-4, wherein the MTAP-null cancer is esophageal cancer.

19. The method of any one of claims 1-4, wherein the MTAP-null cancer is gastric cancer.

20. The method of any one of claims 1-4, wherein the MTAP-null cancer is glioma.

21. The method of any one of claims 1-20, wherein Compound A or salt thereof and Compound B or salt thereof are administered concurrently.

22. The method of any one of claims 1-20, wherein Compound A or salt thereof and Compound B or salt thereof are administered sequentially.

23. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

24. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

25. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

26. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 480 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

27. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 600 mg Compound A of and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

28. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

29. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

30. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 600 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

31. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

32. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

33. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

34. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 800 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

35. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 900 mg Compound A of and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

36. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

37. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

38. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 900 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

39. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 10 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

40. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 15 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

41. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 30 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

42. The method of any one of claims 1-22, comprising administering to the patient a total daily dose of 1200 mg Compound A and a total daily dose of 60 mg Compound B, based upon the free base weight of each of Compound A and Compound B, respectively.

43. The method of any one of claims 1-42, comprising administering Compound A or pharmaceutically acceptable salt thereof to the patient once daily.

44. The method of any one of claims 1-42, comprising administering Compound A or pharmaceutically acceptable salt thereof to the patient twice daily.

45. The method of any one of claims 1-42, comprising administering Compound B or pharmaceutically acceptable salt thereof to the patient once daily.

46. A use of Compound A, or pharmaceutically acceptable salt thereof, at a total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg, based upon the free base weight of each of Compound A and Compound B, respectively, for the treatment of a MTAP-null cancer.

47. Use of Compound A, or pharmaceutically acceptable salt thereof, at a total daily dose of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg; and Compound B, or a pharmaceutically acceptable salt thereof, at a total daily dose of 10 mg, 15 mg, 30 mg, or 60 mg, based upon the free base weight of each of Compound A and Compound B, respectively, in the manufacture of a medicament for the treatment of a MTAP-null cancer.

48. The use of claim 46 or 47, wherein Compound A or pharmaceutically acceptable salt thereof and Compound B or pharmaceutically acceptable salt thereof are administered concurrently.

49. The use of claim 46 or 47, wherein Compound A or pharmaceutically acceptable salt thereof and Compound B or pharmaceutically acceptable salt thereof are administered sequentially.

50. The use of any one of claims 46-49, wherein Compound A or pharmaceutically acceptable salt thereof is administered once daily.51 . The use of any one of claims 46-49, wherein Compound A or pharmaceutically acceptable salt thereof is administered twice daily.

52. The use of any one of claims 46-51 , wherein Compound B or pharmaceutically acceptable salt thereof is administered once daily.

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