Gastrointestinal cancer treatments using MTA-cooperative PRMT5 inhibitors

Abstract

Described herein are methods of treating MTAP-null gastrointestinal cancer in a patient comprising administering to the patient a PRMT5 inhibitor, gemcitabine, and paclitaxel (e.g., nab-paclitaxel), or a PRMT5 inhibitor and mFOLFIRINOX. Also described herein are methods of treating MTAP-null gastrointestinal cancer in a patient comprising administering to the patient a PRMT5 inhibitor, gemcitabine, cisplatin, and an anti-PD 1 antibody or an anti-PDL1 antibody.

Description

GASTROINTESTINAL CANCER TREATMENTS USING MTA-COOPERATIVE PRMT5 INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to each of U.S. Provisional Patent Application No. 63 / 575,379, filed April 5, 2024, and U.S. Provisional Patent Application No. 63 / 575,402, filed April 5, 2024.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 dropout 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.SUMMARY

[0004] In one aspect, described herein are methods of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of (a)Compoundpharmaceutically acceptable salt thereof; (b) gemcitabine, and (c) paclitaxel. In some cases, the MTAP-null gastrointestinal cancer is pancreatic adenocarcinoma (e.g., pancreatic ductal adenocarcinoma (PDAC)).

[0005] In another aspect, described herein are methods of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of (a)Compoundpharmaceutically acceptable salt thereof; and (b) a combination of (i) irinotecan, (ii) 5-fluorouracil, (ii) leucovorin, and (iv) oxaliplatin. In some cases, the MTAP-null gastrointestinal cancer is pancreatic adenocarcinoma (e.g., pancreatic ductal adenocarcinoma (PDAC)).

[0006] In another aspect, described herein are methods of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of(a) Compoundpharmaceutically acceptable salt thereof; (b) gemcitabine, (c) cisplatin; and (d) an anti-PD 1 antibody or an anti-PDL1 antibody. In some cases, the anti-PD1 antibody is pembrolizumab. In some cases, the MTAP-null gastrointestinal cancer is biliary tract cancer.DETAILED DESCRIPTION

[0007] The disclosure provides methods of treating a MTAP-null gastrointestinal cancer in a patient in need thereof. In one aspect, the disclosure provides methods of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of (a)Compoundpharmaceutically acceptable salt thereof; (b) gemcitabine, and (c) paclitaxel. In another aspect, the disclosure also provides methods of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of (a) Compoundpharmaceutically acceptable salt thereof; and (b) a combination of (I) irinotecan, (ii) 5-fluorouracil, (ii) leucovorin, and (iv) oxaliplatin. In yet another aspect, the disclosure provides methods of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of (a) Compoundpharmaceutically acceptable salt thereof;(b) gemcitabine, (c) cisplatin; and (d) an anti-PD1 antibody or an anti-PDL1 antibody. As used herein, a "therapeutically effective amount” of a compound disclosed herein, such as Compound G, means an amount effective to treat, alleviate, or stabilize the disease or symptoms of the patient being treated or to alleviate the existing symptoms of, the patient being treated.

[0008] Further provided herein are therapeutically effective amounts of each of: (a) Compound G, or pharmaceutically acceptable salt thereof; (b) gemcitabine, and (c) paclitaxel for use in the treatment of a MTAP- null gastrointestinal cancer in a patient in need thereof. Also provided herein are therapeutically effective amounts of each of: (a) Compound G, or pharmaceutically acceptable salt thereof; and (b) a combination of (I) irinotecan, (ii) 5-fluorouracil, (ii) leucovorin, and (iv) oxaliplatin for use in the treatment of a MTAP-null gastrointestinal cancer in a patient in need thereof. Further provided herein are therapeutically effective amounts of each of: (a) Compound G, or pharmaceutically acceptable salt thereof, (b) gemcitabine, (c) cisplatin; and (d) an anti-PD 1 antibody or an anti-PDL1 antibody for use in the treatment of a MTAP-null gastrointestinal cancer in a patient in need thereof. Also provided herein is the use of therapeutically effective amounts of each of: (a) Compound G, or pharmaceutically acceptable salt thereof; (b) gemcitabine, and (c) paclitaxel in the manufactureof a medicament for treating a MTAP-null gastrointestinal cancer in a patient in need thereof. Further provided herein is the use of therapeutically effective amounts of each of: (a) Compound G, or pharmaceutically acceptable salt thereof; and (b) a combination of (I) irinotecan, (ii) 5-fluorouracil, (ii) leucovorin, and (iv) oxaliplatin in the manufacture of a medicament for treating a MTAP-null gastrointestinal cancer in a patient in need thereof. Also provided herein is the use of therapeutically effective amounts of each of: (a) Compound G, or pharmaceutically acceptable salt thereof, (b) gemcitabine, (c) cisplatin; and (d) an anti-PD 1 antibody or an anti- PDL1 antibody in the manufacture of a medicament for treating a MTAP-null gastrointestinal cancer in a patient in need thereof.

[0009] 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 G is administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the compounds described herein (e.g., Compound G) 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. In various embodiments, Compound G or salt thereof is administered orally.

[0010] Pharmaceutical compositions containing Compound G can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. In various cases, Compound G is administered orally. In some cases, Compound G is administered as a tablet formulation.

[0011] In some embodiments, Compound G or pharmaceutically acceptable salt thereof is administered to a patient in need thereof orally and once a day. 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)). In some embodiments, the subject is a human. In various embodiments, the subject is a non-human animal. The terms "patient” and "subject” are used interchangeably herein.

[0012] In some embodiments, Compound G is administered orally. In some embodiments, Compound G is administered orally once a day. In some embodiments, Compound G is administered orally and twice daily. Insome embodiments, the patient is administered a total daily dose of 100 mg, 120 mg, 200 mg, 240 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg or 1600 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 120 mg, 200 mg, 240 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 500 mg, 800 mg, 900 mg, or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 500 mg, 800 mg, or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 800 mg, 900 mg, or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 800 mg or 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 120 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 240 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 300 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 400 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 480 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 500 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 600 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 700 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 800 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 900 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 1000 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 1100 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 1200 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 1600 mg of Compound G, based upon free base weight of Compound G.

[0013] In some embodiments, the patient is administered 100 mg, 120 mg, 200 mg, 240 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg or 1600 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 120mg, 200 mg, 240 mg, 300 mg, 400 mg, 480 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1200 mg, or 1600 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 500 mg, 800 mg, 900 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 500 mg, 800 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 800 mg, 900 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 800 mg or 1200 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 120 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 200 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 240 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 300 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 400 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 480 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 500 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 600 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 700 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 800 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 900 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 1000 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 1100 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 1200 mg of Compound G, based upon free base weight of Compound G, once daily. In some embodiments, the patient is administered 1600 mg of Compound G, based upon free base weight of Compound G, once daily.

[0014] When a dose or amount of Compound G is recited, unless otherwise specified, it refers to the amount of Compound G based upon the free base weight of Compound G. For example, when disclosed herein that 400 mg of Compound G or salt thereof is administered to a patient, that 400 mg is the amount of Compound G based upon the free base weight of Compound G. It is understood that if a salt of Compound G is administered to a patient, the weight of the amount of Compound G salt would be higher to compensate for the weight of the salt entity.

[0015] In some embodiments, Compound G is administered in treatment cycles. In some embodiments, the treatment cycle is 28 days. In some embodiments, the 28-day treatment cycle is repeated. In variousembodiments, the patient undergoes 1, 2, 3, or more 28-day treatment cycles. In some embodiments, the patient undergoes at least three 28-day treatment cycles, at least five 28-day treatment cycles, at least eight 28- day treatment cycles, at least ten 28-day treatment cycles, or at least fifteen 28-day treatment cycles. In some cases, the methods for treating MTAP-null pancreatic adenocarcinoma (e.g., PDAC) disclosed herein comprise administering Compound G in one or more 28-day treatment cycles.

[0016] In some embodiments, the treatment cycle is 21 days. In some embodiments, the 21 -day treatment cycle is repeated. In various embodiments, the patient undergoes 1, 2, 3, or more 21 -day treatment cycles. In some embodiments, the patient undergoes at least three 21 -day treatment cycles, at least five 21 -day treatment cycles, at least eight 21 -day treatment cycles, at least ten 21 -day treatment cycles, or at least fifteen 21 -day treatment cycles. In some cases, the methods for treating MTAP-null biliary tract cancer disclosed herein comprise administering Compound G in one or more 21 -day treatment cycles.Gemcitabine

[0017] Gemcitabine (GEMZAR®) is a nucleoside analogue that exhibits antitumor activity. See GEMZAR® US Prescribing Information, Eli Lily & Co., Indianapolis, IN 46285 (revision 5 / 2019), which is incorporated by reference herein in its entirety.

[0018] In some embodiments, the methods comprise administering 1000 mg / m2gemcitabine to the patient. In some embodiments, the gemcitabine is administered intravenously ("via IV administration”). In some embodiments, the gemcitabine is administered three times in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 1000 mg / m2gemcitabine via IV three times in every 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 1000 mg / m2gemcitabine via IV on days 1, 8, and 15 of a 28-day treatment cycle. In some cases, the methods comprise administering to the patient 1000 mg / m2gemcitabine via IV three times in one or more 28-day treatment cycles to treat MTAP-null pancreatic adenocarcinoma (e.g., PDAC). In some embodiments, the gemcitabine is administered twice in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 1000 mg / m2gemcitabine via IV twice in every 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 1000 mg / m2gemcitabine via IV on days 1 and 8 of a 21 -day treatment cycle. In some cases, the methods comprise administering to the patient 1000 mg / m2gemcitabine via IV three times in one or more 21 -day treatment cycles to treat MTAP-null biliary tract cancer.Paclitaxel

[0019] Paclitaxel is a semisynthetic taxane, a class of anticancer agents that bind to beta tubulin, thereby stabilizing microtubules and inducing cell cycle arrest and apoptosis. Paclitaxel 200 mg / m2administered intravenously over 3 hours every 3 weeks in combination with carboplatin is a standard of care option for the treatment of patients with good performance status, advanced or metastatic, previously untreated PDAC.

[0020] Complete information about paclitaxel (TAXOL®) preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g., TAXOL® (paclitaxel) INJECTION U.S. Prescribing Information, Bristol-Myers Squibb Company, Princeton, New Jersey, 08543 (revision 4 / 2011)), which is herein incorporated by reference in its entirety. In some embodiments, the paclitaxel that is administered to the patient is bound to albumin ("nab-paclitaxel”). Complete information about nab- paclitaxel (ABRAXANE®) preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g., ABRAXANE® U.S. Prescribing Information, Bristol-Myers Squibb Company, New Jersey, 08543 (revision 8 / 2020), which is herein incorporated by reference in its entirety).

[0021] In some embodiments, the methods comprise administering paclitaxel to the patient. In some embodiments, the paclitaxel is nab-paclitaxel. In some embodiments, the paclitaxel (e.g., nab-paclitaxel) is administered intravenously ("via IV”). In some embodiments, the paclitaxel (e.g., nab-paclitaxel) is administered three times in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 125 mg / m2paclitaxel (e.g., nab-paclitaxel) via IV three times in every 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 125 mg / m2paclitaxel (e.g., nab-paclitaxel) via IV on days 1, 8, and 15 of a 28-day treatment cycle. In some embodiments, the paclitaxel (e.g., nab-paclitaxel) is administered to treat MTAP-null pancreatic adenocarcinoma (e.g., PDAC).FOLFIRINOX

[0022] In some embodiments, the methods described herein comprise administering a FOLFIRINOX-based regimen to the patient. In some embodiments, the methods described herein comprise administering a modified FOLFIRINOX regimen to the patient ("mFOLFIRINOX”). FOLFIRINOX is a combination therapy including leucovorin, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin. Modified FOLFIRINOX or mFOLFIRINOX is a combination regimen that contains leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin. Compared to FOLFIRINOX, mFOLFIRINOX has no fluorouracil bolus and the irinotecan dose is reduced from 180 mg / m2to 150 mg / m2. "Leucovorin”, "leucovorin calcium”, “5-formyl-tetrahydrofoloate”, and "LV” are used interchangeably herein. "Irinotecan” and "Irinotecan hydrochloride” are used interchangeably herein. "Fluorouracil”, "5-fluorouracil”, “FU”, and "5-FU” are used interchangeably herein. See, CALCIUM FOLINATE (Leucovorin Calcium) US Prescribing Information, Bedford Laboratories, Bedford, OH 44146 (revision 11 / 2011); CAMPTOSTAR® (irinotecan), US Prescribing Information, Pfizer, Inc, New York, NY 10017 (revision 12 / 2014); ELOXATIN® (oxaliplatin), US Prescribing Information, Pfizer, New York 1017 (revision 4 / 2016); and FLUOROURACIL, US Prescribing Information, Fresenius Kabi, Lake Zurich, IL 60047 (revision 2 / 2024), the disclosures of which are incorporated herein by reference in their entireties.

[0023] In some embodiments, the methods described herein comprise administering to the patent 150 mg / m2irinotecan. In some embodiments, the irinotecan is administered via IV. In some embodiments, the irinotecan is administered twice in a 28-day treatment cycle. In some embodiments, the methods described herein compriseadministering to the patient 150 mg / m2irinotecan via IV twice in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patent 2400 mg / m25-fluorouracil. In some embodiments, the 5-fluorouracil is administered via IV. In some embodiments, the 5-fluorouracil is administered twice in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 2400 mg / m25-fluorouracil via IV twice in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patent 400 mg / m2leucovorin. In some embodiments, the leucovorin is administered via IV. In some embodiments, the leucovorin is administered twice in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 400 mg / m2leucovorin via IV in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patent 85 mg / m2oxaliplatin. In some embodiments, the oxaliplatin is administered via IV. In some embodiments, the oxaliplatin is administered twice in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 85 mg / m2oxaliplatin via IV twice in a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient irinotecan, 5-fluorouracil, leucovorin and oxaliplatin on day 1 and day 15 of a 28-day cycle.

[0024] In some embodiments, the 400 mg / m2leucovorin can be substituted with 200 mg / m2levoleucovorin (See KHAPZORY® US Prescribing Information, Spectrum Pharmaceuticals, Inc., Irvine, CA 92618 (revision IQ- 2018), which is incorporated by reference herein in its entirety.Cisplatin

[0025] Cisplatin (PLATINOL®), cisplatinum or cis-diamminedichloroplatinum(ll) (CDDP), is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumors. It was the first member of its class, which now also includes carboplatin and oxaliplatin. See also PLATINOL® US Prescribing Information, Bristol-Myers Squibb Co., Princeton, NJ 08543 (revision 12 / 2023), which is incorporated by reference herein in its entirety.

[0026] In some embodiments, the methods described herein comprise administering to the patent 25 mg / m2cisplatin. In some embodiments, the cisplatin is administered via IV. In some embodiments, the cisplatin is administered twice in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering 25 mg / m2cisplatin twice in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient 25 mg / m2cisplatin via IV day 1 and day 8 of a 21 -day treatment cycle.Anti-PD1 and Anti-PDL1 antibodies

[0027] The protein Programmed Death 1 (PD-1 or PD1) is an inhibitory member of the CD28 family of receptors, that also includes CD28, CTLA-4, ICOS and BTLA Anti-PD1 antibodies and methods of using in treatment of disease are described in U.S. Pat. Nos. 7,595,048; 8,168,179; 8,728,474; 7,722,868; 8,008,449; 7,488,802; 7,521,051; 8,088,905; 8,168,757; 8,354,509; and US Publication Nos. US20110171220;US20110171215; and US20110271358. Combinations of CTLA-4 and PD1 antibodies are described in U.S. Pat.No. 9,084,776. Some exemplary anti-PD1 antibodies include tislelizumab, dostarlimab and toripalimab.

[0028] Nivolumab (OPDIVO®) is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against PD1. Other names for nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence for nivolumab and methods of using and making are disclosed in U.S. Pat. No. 8,008,449. See also, OPDIVO® US Prescribing Information, Bristol-Myers Squibb Co., Princeton, NJ 08543 (revision 02 / 2023), which is incorporated by reference herein in its entirety.

[0029] Cemiplimab (LIBTAYO®) is an anti-PD1 antibody marketed for the treatment of cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BSC), and non-small cell lunch cancer (NSCLC) by Regeneron Pharmaceuticals. The amino acid sequences for cemiplimab are disclosed in U.S. Patent No. 11,292,842. See also LIBTAYO® US Prescribing Information, Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 (revision 04 / 2024), which is incorporated by reference herein in its entirety.

[0030] Pembrolizumab (KEYTRUDA®) is an anti-PD 1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using are disclosed in U.S. Pat. No. 8,168,757. See also KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ 07033 (revision 01 / 2025), which is incorporated by reference herein in its entirety. In some cases, the methods described herein comprise administering pembrolizumab to the patient in need thereof. In some cases, the pembrolizumab is administered once every 21 days. In some cases, the pembrolizumab is administered via IV. In some embodiments, the methods described herein comprise administering to the patient 200 mg pembrolizumab once every 21-days (once every 21 -day treatment cycle).

[0031] Exemplary anti-PDL1 antibodies are described in WO 2013 / 079174, WO 2015 / 061668, WO 2010 / 089411, WO 2007 / 005874, WO 2010 / 036959, WO 2014 / 100079, WO 2013 / 019906, WO 2010 / 077634, and U.S. Pat. Nos. 8,552,154, 8,779,108, and 8,383,796. In some embodiments, the anti-PDL1 antibody is avelumab (BAVENCIO®) or durvalumab (INFINZI®). See BAVENCIO® US Prescribing Information, EMD Serono, Inc., Rockland, MA 02370 (revision 11 / 2024), which is incorporated by reference herein in its entirety. See INFINZI® US Prescribing Information, AstraZeneca UK Ltd., Cambridge, England, CB20AA (revision 12 / 2024), which is incorporated by reference herein in its entirety. Exemplary anti-PDL1 antibodies include, but are not limited to, atezolizumab and durvalumab.Dosage Regimens

[0032] In some embodiments, the methods described herein comprise administering to the patient a therapeutically effective amount of each of (a) Compound G or pharmaceutically acceptable salt thereof, (b) gemcitabine, and (c) paclitaxel. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1, day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods describedherein comprise administering to the patient (a) 200 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28- day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 300 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab- paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1, day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 400 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 480 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28- day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 500 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab- paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1, day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 600 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 700 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28- day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 800 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab- paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1, day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 900 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1000 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28- day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient(a) 1100 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab- paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1, day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1200 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1600 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered to the patient on day 1 , day 8, and day 15 of a 28- day treatment cycle. In some cases, Compound G is administered as a free base in the dosage regimen described herein. In some cases, Compound G is administered in a tablet formulation in the dosage regimen described herein. In some cases, Compound G is administered as a film-coated tablet. In some cases, the dosage regimen is administered to treat a patient suffering from pancreatic adenocarcinoma (e.g., PDAC).

[0033] In some embodiments, the methods described herein comprise administering to the patient a therapeutically effective amount of each of (a) Compound G or salt thereof and (b) a combination of (i) irinotecan, (ii) 5-fluorouracil, (iii) leucovorin, and (iv) oxaliplatin, wherein the irinotecan, 5-fluorouracil, leucovorin and oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg Compound G or salt thereof once daily, and (b) a combination of (i) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (iii) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 200 mg Compound G or salt thereof once daily, and (b) a combination of (i) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (iii) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg Compound G or salt thereof once daily, and (b) a combination of (i) 150 mg / m2irinotecan, (ii) 2400 mg / m25- fluorouracil, (iii) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 300 mg Compound G or salt thereof once daily, and (b) a combination of (i) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (iii) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 400 mg Compound G or salt thereof once daily, and (b) a combination of (i) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (iii) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, whereinthe 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 480 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 500 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 600 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 700 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25- fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 800 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 900 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1000 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1100 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1200 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1600 mg Compound G or salt thereof once daily, and (b) a combination of (I) 150 mg / m2irinotecan, (ii) 2400 mg / m25- fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle. In some cases, Compound G is administered as a free base in the dosage regimen described herein. In some cases, Compound G is administered in a tablet formulation in the dosage regimen described herein. In some cases, Compound G is administered as a film-coated tablet. In some cases, the dosage regimen is administered to treat a patient suffering from pancreatic adenocarcinoma (e.g., PDAC).

[0034] In some embodiments, the methods described herein comprise administering to the patient a therapeutically effective amount of each of (a) Compound G or salt thereof, (b) gemcitabine, (c) cisplatin, and (d) pembrolizumab. In some embodiments, the methods described herein comprise administering to the patient (a) 120 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 200 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 240 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 300 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 400 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 480 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 500 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 600 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 700 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 800 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 900 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1000 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1100 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1200 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some embodiments, the methods described herein comprise administering to the patient (a) 1600 mg Compound G or salt thereof once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatinare administered to the patient on day 1 and day 8 of a 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle. In some cases, Compound G is administered as a free base in the dosage regimen described herein. In some cases, Compound G is administered in a tablet formulation in the dosage regimen described herein. In some cases, Compound G is administered as a film- coated tablet. In some cases, the dosage regimen is administered to treat a patient suffering from biliary tract cancer.Prior Therapeutic Regimens of Patients

[0035] In some embodiments, the patient had not previously been treated with a systemic therapy for MTAP- null gastrointestinal cancer, e.g., advanced (metastatic) or unresectable (locally advanced) adenocarcinoma of the pancreas (e.g., PDAC) or advanced (metastatic) or unresectable (locally advanced) biliary tract cancer (intra- or extra- hepatic cholangiocarcinoma or gallbladder cancer) (i.e., the patient is treatment naive for the MTAP-null gastrointestinal cancer). As such, in some cases, the methods are as a first line therapy for the MTAP-null gastrointestinal cancer. In some cases, the methods are as a first line therapy for MTAP-null pancreatic adenocarcinoma, such as PDAC. In some cases of first line therapy for MTAP-null pancreatic adenocarcinoma, such as PDAC, the patient is administered a combination of Compound G and a FOLFIRINOX-based regimen (e.g., mFOLFIRINOX) as disclosed herein. In some cases of first line therapy for MTAP-null pancreatic adenocarcinoma (e.g., PDAC), the patient is administered a combination of Compound G, gemcitabine, and paclitaxel (e.g., nab-paclitaxel), as disclosed herein. In some cases, the methods are as a first line therapy for MTAP-null biliary tract cancer. In some cases of first line therapy for MTAP-null biliary tract cancer, the patient is administered a combination of Compound G, gemcitabine, cisplatin, and an anti-PD1 antibody or an anti-PDL1 antibody as disclosed herein.

[0036] In some cases, the patient has been treated with a prior systemic therapy for gastrointestinal cancer, and the methods are as a second (or higher) line of therapy, and the patients are not treatment naive for the cancer being treated by the methods disclosed herein. In some embodiments, the patient had received at least one systemic therapy for locally advanced or metastatic disease prior to administration of Compound G. In some cases, patients have received prior systemic therapy, and the first dose of prior systemic therapy was administered within 28 days at time of signing main consent. In some cases, the prior systemic therapy is a FOLFIRINOX-based regimen. In some cases, the prior systemic therapy is a FOLFIRINOX-based regimen, and the second (or higher) line of therapy comprises administration to the patient of Compound G, gemcitabine, and nab-paclitaxel as disclosed herein. In some cases, the prior systemic therapy is a FOLFIRINOX-based regimen, and the second (or higher) line of therapy comprises administration to the patient of Compound G and mFOLFIRINOX. In some cases, the prior systemic therapy is gemcitabine and paclitaxel (e.g., nab-paclitaxel), and the second (or higher) line of therapy comprises administration to the patient of Compound G, gemcitabine, and paclitaxel (e.g., nab-paclitaxel). In some cases, the prior systemic therapy is gemcitabine and cisplatin, with or without an anti-PD1 inhibitor or an anti-PDL1 ("anti-PD(L)T') inhibitor. In some cases, the prior systemictherapy is a combination of gemcitabine and cisplatin, with or without anti-PD(L)1 inhibitor, and the second (or higher) line of therapy comprises administration to the patient of Compound G, gemcitabine, and cisplatin.

[0037] In some embodiments, the patient had not previously been treated with liver directed anticancer therapy (e.g., TACE, palliative surgery) for advanced unresectable biliary tract cancer (intra- or extra- hepatic cholangiocarcinoma or gallbladder cancer.

[0038] In some embodiments, the patient had not previously been treated with a MAT2A inhibitor (i.e., the patient is MAT2A inhibitor naive). An MAT2A inhibitor is a compound that inhibits methionine adenosyltransferase II alpha. An exemplary MAT2A inhibitor is AG 270 (3-(cyclohex-1 -en-1 -yl)-6-(4- methoxyphenyl)-2-phenyl-zetidindin-2-ylamino)pyrazolo[1 ,5-a]pyrimidin-7(4H)-one).

[0039] In some embodiments, the patient had not previously been treated with a PRMT5 inhibitor (i.e., the patient is PRMT5 inhibitor naive). A PRMT5 inhibitor is a compound that inhibits protein arginine methyltransferase 5. The term "PRMT5 inhibitor” includes MTA-cooperative PRMT5 inhibitors. Exemplary PRMT5 inhibitors include, but are not limited to, pemrametostat (6-[(1 -acetylpiperidin-4-yl)amino]-N-[(2S)-3-(3,4- dihydro-1 H-isoquinolin-2-yl)-2-hydroxypropyl]pyrimidine-4-carboxamide), GSK3203591 (2-(Cyclobutylamino)-N- [(2S)-3-(3,4-dihydro-2(1 H)-isoquinoli nyl)-2-hydropropy l]-4-pyridi necarboxamide dihydrochloride)), LLY-283 ((R)- 5'-phenyl-7-deazaadenosine; 6-amino-9-[(R)-5'-phenyl(ribofuranosyl)]-7-deazapurine, (2R,3R,4S,5R)-2-(4- Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-hydroxy (phenyl)methyl)tetrahydrofuran-3,4-diol), PRT 811, and MRTX1719 (2-(4-(4-(aminomethyl)-1 -oxo-1, 2-dihydrophthalazin-6-yl)-1-methyl-1 H-pyrazol-5-yl)-4-chloro-6- cyclopropoxy-3-fluorobenzonitrile).

[0040] In some embodiments, the patient is not being treated with a compound that is a strong inducer of CYP3A4. Exemplary strong inducers of CYP3A4 include, but are not limited to, rifampin, mitotane, avasimibe, rifapentine, apalutamide, ivosidenib, phenytoin, carbamazepine, enzalutamide, St John's wort extract, lumacaftor and phenobarbital.

[0041] In some embodiments, the patient is not being treated with a compound that is a strong inhibitor of CYP3A4. Exemplary strong inhibitors of CYP3A4 include, but are not limited to, VIEKIRA PAK , indinavir / ritonavir, tipranavir / ritonavir, ritonavir, cobicistat, ketoconazole, troleandomycin, telaprevir, danoprevir / ritonavir, elvitegravir / ritonavir, saquinavir / ritonavir, lopinavir / ritonavir, itraconazole, indinavir, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, lonafarnib, posaconazole, telithromycin, grapefruit juice, conivaptan, tucatinib, nefazodone, ceritinib, nelfinavir, saquinavir, ribociclib, idelalisib, and boceprevir.

[0042] In some embodiments, the patient does not have toxicity from prior anti-cancer therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria, with the exception of alopecia.MTAP-Null Gastrointestinal Cancers

[0043] The disclosure provides methods of treating a MTAP-null gastrointestinal cancer in a patient in need thereof. 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. Terms "MTAP-null”, "MTAP-deficient”, "MTAP-negative”, and "MTAP-deleted” are used interchangeably.

[0044] 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. In a patient afflicted with a MTAP-deficiency-related disease, it is possible that some disease cells (e.g., cancer cells) can be MTAP-deficient while others are not. Similarly, some disease cells may be MTA-accumulating while others are not. Thus, the present disclosure encompasses methods of treatment involving diseases of these tissues, or any other tissues, wherein the proliferation of MTAP-deficient and / or MTA- accumulating cells can be inhibited by administration of a PRMT5 inhibitor. Some cancer cells which are MTAP-deficient are also deficient in CDKN2A; the post-translational modification, production, expression, level, stability and / or activity of the CDKN2A gene or its product are decreased in these cells. The genes for MTAP and CDKN2A are in close proximity on chromosome 9p21; MTAP is located approximately 100 kb telomeric to CDKN2A. Many cancer cell types harbor CDKN2A / MTAP loss (loss of both genes). Thus, in some embodiments, a MTAP-deficient cell is also deficient in CDKN2A. MTAP-null cancers can be identified by any suitable diagnostic test. Exemplary diagnostic tests for MTAP-deletion or MTAP protein loss include immunohistochemistry (IHC) and local or central next generation sequencing (NGS).

[0045] 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 cases, the gastrointestinal cancer is biliary tract cancer or pancreatic cancer. In some embodiments, the MTAP-null gastrointestinal cancer is locally advanced. In some embodiments, the MTAP-null gastrointestinal cancer is metastatic.

[0046] 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 gallbladdercancer, 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.

[0047] In some embodiments, the MTAP-null gastrointestinal cancer is pancreatic cancer. In some embodiments, the MTAP-null gastrointestinal cancer is pancreatic adenocarcinoma (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the pancreatic ductal adenocarcinoma is locally advanced. In some embodiments, the pancreatic ductal adenocarcinoma is metastatic.Monitoring Efficacy of Treatment

[0048] The efficacy of a given treatment for cancer can be determined by the skilled clinician. However, a treatment is considered effective 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 measured by stabilization of disease or its symptoms or 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 measuring these indicators are known to those of skill in the art and / or described herein.

[0049] 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 .

[0050] 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.

[0051] Progression free survival (PFS) can be assessed as described in the RECIST 1.1 protocol. In various embodiments, the patient exhibits a PFS of at least 1 month. In various embodiments, the patient exhibits a PFS of at least 3 months. In some embodiments, the patient exhibits a PFS of at least 6 months.

[0052] Embodiments:1 . A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient(a) Compoundpharmaceutically acceptable salt thereof;(b) gemcitabine, and(c) paclitaxel.2. The method of embodiment 1 , wherein the MTAP-null gastrointestinal cancer is locally advanced.3. The method of embodiment 1 , wherein the MTAP-null gastrointestinal cancer is metastatic.4. The method of any one of embodiments 1-3, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.5. The method of any one of embodiments 1-3, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.6. The method of embodiment 7, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.7. The method of any one of embodiments 1-6, wherein Compound G is administered as a free base.8. The method of any one of embodiments 1-7, comprising administering to the patient 400 mg Compound G.9. The method of any one of embodiments 1-7, comprising administering to the patient 500 mg Compound G.10. The method of any one of embodiments 1-7, comprising administering to the patient 600 mg Compound G.11. The method of any one of embodiments 1-7, comprising administering to the patient 800 mg Compound G.12. The method of any one of embodiments 1-7, comprising administering to the patient 1200 mg Compound G.13. The method of any one of embodiments 1-12, wherein Compound G is administered to the patient once daily.14. The method of any one of embodiments 1-13, comprising administering to the patient 1000 mg / m2gemcitabine via IV three times in a 28-day treatment cycle.15. The method of any one of embodiments 1-14, wherein the paclitaxel is nab-paclitaxel.16. The method of any one of embodiments 1-15, comprising administering to the patient 125 mg / m2nab-paclitaxel via IV three times in a 28-day treatment cycle.17. The method of any one of embodiments 1-16, comprising administering to the patient gemcitabine and nab-paclitaxel on day 1 , day 8, and day 15 of a 28-day treatment cycle.18. The method of any one of embodiments 1-7, comprising administering to the patient (a) 400 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1 , 8, and 15 of a 28-day treatment cycle.19. The method of any one of embodiments 1-7, comprising administering to the patient (a) 500 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1 , 8, and 15 of a 28-day treatment cycle.20. The method of any one of embodiments 1-7, comprising administering to the patient (a) 600 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1 , 8, and 15 of a 28-day treatment cycle.21. The method of any one of embodiments 1-7, comprising administering to the patient (a) 800 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1 , 8, and 15 of a 28-day treatment cycle.22. The method of any one of embodiments 1-7, comprising administering to the patient (a) 1200 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1 , 8, and 15 of a 28-day treatment cycle.23. The method of any one of embodiments 1-22, wherein the patient is treatment naive for the MTAP-null gastrointestinal cancer.24. The method of any one of embodiments 1-22, wherein the patient has undergone a prior systemic therapy for the MTAP-null gastrointestinal cancer.25. The method of embodiment 24, wherein the prior systemic therapy is FOLFIRINOX.26. A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patientpharmaceutically acceptable salt thereof; and(b) a combination of (i) irinotecan, (ii) 5-fluorouracil, (ii) leucovorin, and (iv) oxaliplatin.27. The method of embodiment 26, wherein the MTAP-null gastrointestinal cancer is locally advanced.28. The method of embodiment 26, wherein the MTAP-null gastrointestinal cancer is metastatic.29. The method of any one of embodiments 26-28, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.30. The method of any one of embodiments 26-28, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.31 . The method of embodiment 30, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.32. The method of any one of embodiments 26-31 , wherein Compound G is administered as a free base.33. The method of any one of embodiments 26-32, comprising administering to the patient 400 mg Compound G.34. The method of any one of embodiments 26-32, comprising administering to the patient 500 mg Compound G.35. The method of any one of embodiments 26-32, comprising administering to the patient 600 mg Compound G.36. The method of any one of embodiments 26-32, comprising administering to the patient 800 mg Compound G.37. The method of any one of embodiments 26-32, comprising administering to the patient 1200 mg Compound G.38. The method of any one of embodiments 26-37, wherein Compound G is administered to the patient once daily.39. The method of any one of embodiments 26-38, comprising administering to the patient 150 mg / m2irinotecan via IV twice in a 28-day treatment cycle.40. The method of any one of embodiments 26-39, comprising administering to the patient 2400 mg / m25-fl uorouracil via IV twice in a 28-day treatment cycle.41 . The method of any one of embodiments 26-40, comprising administering to the patient 400 mg / m2leucovorin via IV twice in a 28-day treatment cycle.42. The method of any one of embodiments 26-41 , comprising administering to the patient 85 mg / m2oxaliplatin via IV twice in a 28-day treatment cycle.43. The methods of any one of embodiments 26-42, wherein the irinotecan, 5-fluorouracil, leucovorin and oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.44. The method of any one of embodiments 26-32, 38, and 43, comprising administering to the patient (a) 400 mg Compound G once daily, (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25- fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.45. The method of any one of embodiments 26-32, 38, and 43, comprising administering to the patient (a) 500 mg Compound G once daily, (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25- fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2, wherein the 150 mg / m2irinotecan, 2400 mg / m25- fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.46. The method of any one of embodiments 26-32, 38, and 43, comprising administering to the patient (a) 600 mg Compound G once daily, (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25- fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.47. The method of any one of embodiments 26-32, 38, and 43, comprising administering to the patient (a) 800 mg Compound G once daily, (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25- fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.48. The method of any one of embodiments 26-32, 38, and 43, comprising administering to the patient (a) 1200 mg Compound G once daily, (b) a combination of (i)150 mg / m2irinotecan, (ii) 2400 mg / m25- fluorouracil, (iii) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.49. The method of any one of embodiments 26-48, wherein the patient is treatment naive for the MTAP-null gastrointestinal cancer.

[0053] Additional embodiments:1 A. A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient(a) Compoundpharmaceutically acceptable salt thereof;(b) gemcitabine,(c) cisplatin; and(d) an anti-PD1 antibody or an anti-PDL1 antibody.2A. The method of embodiment 1 A, wherein the MTAP-null gastrointestinal cancer is locally advanced.3A. The method of embodiment 1 A, wherein the MTAP-null gastrointestinal cancer is metastatic.4A. The method of any one of embodiments 1 A-3A, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.5A. The method of any one of embodiments 1 A-3A, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.6A. The method of embodiment 5A, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.7A. The method of embodiment 1 A, wherein Compound G is administered as a free base.8A. The method of any one of embodiments 1 A-7A, wherein Compound G is administered once daily.9A. The method of any one of embodiments 1 A-8A, comprising administering to the patient 400 mg Compound G.10A. The method of any one of embodiments 1 A-8A, comprising administering to the patient 500 mg Compound G.11 A. The method of any one of embodiments 1 A-8A, comprising administering to the patient 600 mg Compound G.12A. The method of any one of embodiments 1-8, comprising administering to the patient 800 mg Compound G.13A. The method of any one of embodiments 1 A-8A, comprising administering to the patient 1200 mg Compound G.14A. The method of any one of embodiments 1 A-13A, wherein the patient is administered an anti- PDL1 antibody.15A. The method of any one of embodiments 1 A-13A, wherein the patient is administered an anti- PD1 antibody.16A. The method of embodiment 15A, wherein the anti-PD1 antibody is pembrolizumab.17A. The method of embodiment 16A, comprising administering to the patient 200 mg pembrolizumab via IV administration once in a 21 -day treatment cycle.18A. The method of any one of embodiments 1-17A, comprising administering to the patient 1000 mg / m2gemcitabine via IV on day 1 and day 8 of every 21 -day treatment cycle.19A. The method of any one of embodiments 1-18A, comprising administering to the patient 25 mg / m2cisplatin via IV on day 1 and day 8 of every 21 -day treatment cycle.20A. The method of any one of embodiments 1 A-8A, comprising administering to the patient (a) 400 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21- day treatment cycle.21 A. The method of any one of embodiments 1 A-8A, comprising administering to the patient (a) 500 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21- day treatment cycle.22A. The method of any one of embodiments 1 A-8A comprising administering to the patient (a) 600 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21- day treatment cycle.23A. The method of any one of embodiments 1 A-8A, comprising administering to the patient (a) 800 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21- day treatment cycle.24A. The method of any one of embodiments 1 A-8A, comprising administering to the patient (a) 1200 mg Compound G once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21- day treatment cycle.

[0054] Further embodiments:1 B. A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of(a) Compoundpharmaceutically acceptable salt thereof;(b) gemcitabine, and(c) paclitaxel.2B. The method of embodiment 1 B, wherein the MTAP-null gastrointestinal cancer is locally advanced.3B. The method of embodiment 1 B, wherein the MTAP-null gastrointestinal cancer is metastatic.4B. The method of any one of embodiments 1 B-3B, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.5B. The method of any one of embodiments 1 B-3B, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.6B. The method of embodiment 7B, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.7B. The method of any one of embodiments 1 B-6B, wherein Compound G is administered as a free base.8B. The method of any one of embodiments 1 B-7B, comprising administering to the patient a total daily dose of 500 mg Compound G or salt thereof, based upon free base weight of Compound G.9B. The method of any one of embodiments 1 B-7B, comprising administering to the patient a total daily dose of 600 mg Compound G or salt thereof, based upon free base weight of Compound G.10B. The method of any one of embodiments 1 B-7B, comprising administering to the patient a total daily dose of 800 mg Compound G or salt thereof, based upon free base weight of Compound G.11 B. The method of any one of embodiments 1 B-7B, comprising administering to the patient a total daily dose of 900 mg Compound G or salt thereof, based upon free base weight of Compound G.12B. The method of any one of embodiments 1 B-7B, comprising administering to the patient a total daily dose of 1200 mg Compound G or salt thereof, based upon free base weight of Compound G.13B. The method of any one of embodiments 1 B-12B, wherein Compound G is administered to the patient once daily.14B. The method of any one of embodiments 1 B-13B, wherein Compound G is administered orally.15B. The method of any one of embodiments 1 B-14B, wherein Compound G is administered as a tablet formulation.16B. The method of any one of embodiments 1 B-15B, comprising administering to the patient 1000 mg / m2gemcitabine via IV three times in a 28-day treatment cycle.17B. The method of any one of embodiments 1 B-16B, wherein the paclitaxel is nab-paclitaxel.18B. The method of any one of embodiments 1 B-17B, comprising administering to the patient 125 mg / m2nab-paclitaxel via IV three times in a 28-day treatment cycle.19B. The method of any one of embodiments 1 B-18B, comprising administering to the patient gemcitabine and nab-paclitaxel on day 1, day 8, and day 15 of a 28-day treatment cycle.20B. The method of any one of embodiments 1 B-7B, and 13B-15B, comprising administering to the patient (a) 500 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.21 B. The method of any one of embodiments 1 B-7B, and 13B-15B, comprising administering to the patient (a) 600 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.22B. The method of any one of embodiments 1 B-7B, and 13B-15B, comprising administering to the patient (a) 800 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.23B. The method of any one of embodiments 1 B-7B, and 13B-15B, comprising administering to the patient (a) 900 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.24B. The method of any one of embodiments 1 B-7B, and 13B-15B, comprising administering to the patient (a) 1200 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab-paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.25B. The method of any one of embodiments 1 B-24B, wherein the patient is treatment naive for the MTAP-null gastrointestinal cancer.26B. The method of any one of embodiments 1 B-24B, wherein the patient has undergone a prior systemic therapy for the MTAP-null gastrointestinal cancer.27B. The method of embodiment 26B, wherein the prior systemic therapy is FOLFIRINOX.28B. A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of:and(b) a combination of (I) irinotecan, (ii) 5-fluorouracil, (ii) leucovorin, and (iv) oxaliplatin.29B. The method of embodiment 28B, wherein the MTAP-null gastrointestinal cancer is locally advanced.30B. The method of embodiment 28B, wherein the MTAP-null gastrointestinal cancer is metastatic.31 B. The method of any one of embodiments 28B-30B, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.32B. The method of any one of embodiments 30B-32B, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.33B. The method of embodiment 32B, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.34B. The method of any one of embodiments 28B-33B, wherein Compound G is administered as a free base.35B. The method of any one of embodiments 28B-34B, comprising administering to the patient 500 mg Compound G or salt thereof, based upon free base weight of Compound G.36B. The method of any one of embodiments 28B-34B, comprising administering to the patient 600 mg Compound G or salt thereof, based upon free base weight of Compound G.37B. The method of any one of embodiments 28B-34B, comprising administering to the patient 800 mg Compound G or salt thereof, based upon free base weight of Compound G.38B. The method of any one of embodiments 28B-34B, comprising administering to the patient 900 mg Compound G or salt thereof, based upon free base weight of Compound G.39B. The method of any one of embodiments 28B-34B, comprising administering to the patient 1200 mg Compound G or salt thereof, based upon free base weight of Compound G.40B. The method of any one of embodiments 28B-39B, wherein Compound G is administered to the patient once daily.41 B. The method of any one of embodiments 28B-40B, wherein Compound G is administered orally.42B. The method of any one of embodiments 28B-41 B, wherein Compound G is administered as a tablet formulation.43B. The method of any one of embodiments 28B-42B, comprising administering to the patient 150 mg / m2irinotecan via IV twice in a 28-day treatment cycle.44B. The method of any one of embodiments 28B-43B, comprising administering to the patient 2400 mg / m25-fl uorouracil via IV twice in a 28-day treatment cycle.45B. The method of any one of embodiments 28B-44B, comprising administering to the patient 400 mg / m2leucovorin via IV twice in a 28-day treatment cycle.46B. The method of any one of embodiments 28B-45B, comprising administering to the patient 85 mg / m2oxaliplatin via IV twice in a 28-day treatment cycle.47B. The methods of any one of embodiments 28B-46B, wherein the irinotecan, 5-fluorouracil, leucovorin and oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.48B. The method of any one of embodiments 28B-33B, and 40B-42B, comprising administering to the patient (a) 500 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.49B. The method of any one of embodiments 28B-33B, and 40B-42B, comprising administering to the patient (a) 600 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.50B. The method of any one of embodiments 28B-33B, and 40B-42B, comprising administering to the patient (a) 800 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.51 B. The method of any one of embodiments 28B-33B, and 40B-42B, comprising administering to the patient (a) 900 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.52B. The method of any one of embodiments 28B-33B, and 40B-42B, comprising administering to the patient (a) 1200 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.53B. The method of any one of embodiments 48B-52B, wherein Compound G is administered as a free base.54B. The method of any one of embodiments 28B-53B, wherein the patient is treatment naive for the MTAP-null gastrointestinal cancer.55B. A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each ofsalt thereof;(b) gemcitabine,(c) cisplatin; and(d) an anti-PD1 antibody or an anti-PDL1 antibody.56B. The method of embodiment 55B, wherein the MTAP-null gastrointestinal cancer is locally advanced.57B. The method of embodiment 55B, wherein the MTAP-null gastrointestinal cancer is metastatic.58B. The method of any one of embodiments 55B-57B, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.59B. The method of any one of embodiments 55B-57B, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.60B. The method of embodiment 59B, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.61 B. The method of any one of embodiments 55B-60B, comprising administering to the patient 500 mg Compound G or salt thereof, based upon free base weight of Compound G.62B. The method of any one of embodiments 55B-60B, comprising administering to the patient 600 mg Compound G or salt thereof, based upon free base weight of Compound G.63B. The method of any one of embodiments 55B-60B, comprising administering to the patient 800 mg Compound G or salt thereof, based upon free base weight of Compound G.64B. The method of any one of embodiments 55B-60B, comprising administering to the patient 900 mg Compound G or salt thereof, based upon free base weight of Compound G.65B. The method of any one of embodiments 55B-60B, comprising administering to the patient 1200 mg Compound G or salt thereof, based upon free base weight of Compound G.66B. The method of any one of embodiments 55B-65B, wherein Compound G is administered as a free base.67B. The method of any one of embodiments 55B-66B, wherein Compound G is administered once daily.68B. The method of any one of embodiments 55B-67B, wherein Compound G is administered orally.69B. The method of any one of embodiments 55B-68B, wherein Compound G is administered as a tablet formulation.70B. The method of any one of embodiments 55B-69B, wherein the patient is administered an anti- PDL1 antibody.71 B. The method of any one of embodiments 55B-69B, wherein the patient is administered an anti- PD1 antibody.72B. The method of embodiment 71 B, wherein the anti-PD 1 antibody is pembrolizumab.73B. The method of embodiment 72B, comprising administering to the patient 200 mg pembrolizumab via IV administration once in a 21 -day treatment cycle.74B. The method of any one of embodiments 55B-73B, comprising administering to the patient 1000 mg / m2gemcitabine via IV on day 1 and day 8 of every 21 -day treatment cycle.75B. The method of any one of embodiments 55B-74B, comprising administering to the patient 25 mg / m2cisplatin via IV on day 1 and day 8 of every 21 -day treatment cycle.76B. The method of any one of embodiments 55B-60B, and 67B-69B, comprising administering to the patient (a) 500 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.77B. The method of any one of embodiments 55B-60B, and 67B-69B, comprising administering to the patient (a) 600 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.78B. The method of any one of embodiments 55B-60B, and 67B-69B, comprising administering to the patient (a) 800 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.79B. The method of any one of embodiments 55B-60B, and 67B-69B, comprising administering to the patient (a) 900 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.80B. The method of any one of embodiments 55B-60B, and 67B-69B, comprising administering to the patient (a) 1200 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.EXAMPLES

[0055] Example 1

[0056] This is a phase 1b multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of Compound G in combination with gemcitabine and nab-paclitaxel or in combination with mFOLFIRINOX in subjects with pancreatic ductal adenocarcinoma (PDAC) and homozygous MTAP-deletion.

[0057] The study consists of two treatment arms, Arm A and Arm B. Arm A assesses the safety of Compound G in combination with gemcitabine and nab-paclitaxel. Arm B assesses the safety of Compound G in combination mFOLFIRINOX (irinotecan, 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin). Gemcitabine and nab-paclitaxel (in Arm A) and mFOLFIRINOX (in Arm B) are administered at standard doses (see Treatments section below). The following dose levels of Compound G are explored in both Arm A and Arm B:

[0058] Dose level 2: 1200 mg QD daily

[0059] Dose level 1 : 800 mg QD daily

[0060] Dose level -1 500 mg QD daily

[0061] Arms A and B will begin with dose level 1 .

[0062] Summary of Subject Eligibility Criteria:

[0063] Adult subjects (> 18 years old), ECOG performance status of 0 or 1, with advanced PDAC with homozygous MTAP-deletion as assessed by local or central Next Generation Sequencing (NGS) testing will be eligible to participate in the study. MTAP protein loss as determined by local immunohistochemistry is also acceptable. MTAP-deletion status may be determined during pre-screening testing. Once consented to the study, subjects will provide a medical history and undergo screening safety tests to confirm all eligibility requirements of the study have been met. Subjects must have adequate hematological, renal, and hepaticfunction. Subjects must provide archived tumor tissue samples (formalin fixed paraffin embedded [FFPE] sample) collected within the past 5 years. If archived tumor tissue is not available, subjects must be willing to undergo a pre-treatment tumor biopsy if deemed safe per investigator judgement.

[0064] Treatments

[0065] Arms A and B: Compound G is administered once daily continuously for 28 days.

[0066] Arm A: Gemcitabine in combination with nab-paclitaxel, intravenously (IV) on day 1, day 8, and day 15 of every 28-day cycle (gemcitabine: 1000 mg / m2; and nab-paclitaxel: 125 mg / m2).

[0067] Arm B: mFOLFIRINOX, intravenously (IV) on day 1 and 15 of every 28-day cycle-irinotecan (150 mg / m2)-5-FU (2400 mg / m2over 46 to 48 hours)-leucovorin (400 mg / m2), and -oxaliplatin (85 mg / m2)

[0068] Exemplary Inclusion Criteria

[0069] - Age > 18 years (or > legal age within the country if it is older than 18 years).

[0070] - Histologically or cytologically confirmed diagnosis of metastatic and / or unresectable (locally advanced) adenocarcinoma of the pancreas without prior systemic therapy for metastatic or unresectable disease with the exception of 28 days of first line therapy outlined in the exemplary exclusion criteria below.

[0071] Exemplary Exclusion Criteria

[0072] Prior Concomitant Therapy:

[0073] - Prior systemic therapy for advanced (metastatic) or unresectable (locally advanced) adenocarcinoma of the pancreas. In order to enable local or central prescreening NGS testing to determine MTAP deletion, subjects that have started treatment with the standard of care first line therapy, i.e., gemcitabine and nab- paclitaxel (arm A) or mFOLFIRINOX (arm B) and have received their first dose within 28 days at time of signing main consent are eligible. (Exceptions: Arm A: a prior FOLFIRINOX-based regimen regardless of duration is allowed. Arm B: a prior Gemcitabine / Nab-paclitaxel-base regimen regardless of duration is allowed.)

[0074] Neoadjuvant / adjuvant therapy

[0075] -Dose exploration: Prior neoadjuvant / adjuvant therapy is allowed without conditions.

[0076] - Prior neoadjuvant / adjuvant therapy is allowed if completed at least 6 months prior to diagnosis of advanced and / or unresectable disease, and if subjects did not receive gemcitabine and / or nab-paclitaxel (Arm A) or any active agent of FOLFIRINOX (Arm B) in the neoadjuvant / adjuvant setting. Participants who received prior neoadjuvant / adjuvant therapy with R2 postoperative pathology of the oncologic resection are excluded. Note: Bisphosphonate or denosumab for skeletal related events per institution guideline is permitted.

[0077] - Major surgery within 28 days of first dose of study treatment. Note: surgery to obtain a biopsy for diagnosis is allowed.

[0078] - Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.

[0079] - Toxicities from prior anti-tumor therapy not having improved to at least Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, with the exception of alopecia or toxicities that are stable and well controlled.

[0080] - Prior irradiation to > 25% of the bone marrow.

[0081] - Radiation therapy within 28 days of first dose (or local or focal radiotherapy with palliative intend within 14 days of first dose). Previously treated lesion(s) are considered measurable if progression has been shown in such lesions and they meet criteria for measurable disease per RECIST 1.1.

[0082] - All radiotherapy related toxicity must have improved to < grade 1 before first dose of study treatment.

[0083] - Live vaccine therapy within 4 weeks before study drug administration.

[0084] - Use of prescription medications that are known strong inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives (whichever is longer) before study day 1 .

[0085] - Has a known sensitivity to any component of study treatment.

[0086] Disease Related

[0087] -Untreated CNS metastatic disease regardless of symptoms. Subjects with treated CNS metastases that are radiographically and neurologically stable for > 28 days and have not required corticosteroid for at least 14 days and do not require anticonvulsant prophylaxis or treatment before first dose of study treatment are eligible.

[0088] -Subjects with leptomeningeal disease are excluded regardless of presence or absence of symptoms even if treated.

[0089] -Patients with pleural effusions or ascites that require therapeutic drainage (e.g., thoracentesis or paracentesis) at a frequency greater than one time per month.

[0090] Other Medical Conditions

[0091] -History of other malignancy within the past 3 years prior to first dose except: (1) Adequately treated in situ cancer and precancerous lesions without evidence of disease; (2) Malignancy (other than in situ) treated with curative intent and with no known active disease present for > 2 years before first dose and felt to be at low risk for recurrence by the treating physician. Note: Patients with prior or concurrent malignancy may be eligible if the risk of the malignancy interfering with either safety or efficacy endpoints is deemed to be very low in the opinion of the investigator.

[0092] -Evidence of interstitial lung disease or active, noninfectious pneumonitis, or uncontrolled asthma.

[0093] -Confirmed history or current autoimmune disease requiring immunosuppressive therapy.

[0094] -History of diseases resulting in permanent immunosuppression.

[0095] -Active infection requiring systemic therapy. Subject with symptoms and / or clinical signs and / or radiographic signs that indicate an acute and / or uncontrolled active fungal, bacterial, viral, or other infection requiring anti infectious therapy within 14 days of dosing. NOTE: Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with medical monitor. Screening for chronic infectious conditions is not required unless otherwise noted in the eligibility criteria.

[0096] -History of arterial or untreated venous thrombosis: (1) Arterial thrombosis (e.g., stroke, transient ischemic attack) within 12 months of first dose; (2) Untreated venous thromboembolism (e.g., DVT, pulmonary embolism). Subjects on stable anti-coagulation > 1 month prior to first dose are eligible.

[0097] -Myocardial infarction and / or symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or history of cardiac arrest, ventricular tachycardia, known Wolf-Parkinson White syndrome or a genetic syndrome with increased risk of sudden cardiac death, e.g. long QT syndrome, short QT syndrome, hereditary hypertrophic cardiomyopathy, Brugada syndrome, arrhythmogenic right vent cardiomyopathy, or catecholaminergic polymorphic ventricular tachycardia.

[0098] -Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome (excluding compensated pancreatic exocrine insufficiency on adequate pancreatic enzymes), requirement for IV alimentation, gastric / jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis).

[0099] -History of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of first dose of Compound G.

[0100] -History or evidence of gastrointestinal disorders causing chronic nausea, vomiting, or diarrhea (defined as CTCAE grade > 2).

[0101] -Grade > 2 peripheral neuropathy.

[0102] -History of solid organ transplantation.

[0103] -Diagnosis of Congenital Short QT Syndrome.

[0104] -Arm B only: Known history of dihydropyrimidine dehydrogenase (DPD) complete deficiency.

[0105] -Arm B only: Known UGT genetic polymorphisms for homozygous UGT1A1*6 or UGT1A1*28, or compound heterozygous UGT1A1*6 and UGT1A1*28.

[0106] -Arm B only: Diagnosis of congenital long QT syndrome and / or QTc interval > 470 ms (for women) and > 450 ms (for men).

[0107] Prior / Concomitant Therapy

[0108] -Currently receiving treatment in another investigational device or drug study, or less than 21 days or 5 half-lives, whichever is shorter, since ending treatment on another investigational device or drug study(ies).Other investigational procedures and participation in observational research studies while participating in this study are excluded.

[0109] -Arm B only: Use of prescription medicines known to prolong the QT interval, including Class la, and III antiarrhythmics. Exception: anti-emetics such as ondansetron are allowed with regular QTc interval monitoring on study.

[0110] Diagnostic Assessments

[0111] -Known positive test for Human Immunodeficiency Virus (HIV) with detectable viral load and without appropriate treatment. Note: Subjects that are adequately managed with therapies that do not interact or preclude full-dose treatment with any of the therapies in the study treatments are eligible.

[0112] -Viral hepatitis infection based on the following results and / or criteria: (1) Positive for hepatitis B surface antigen (HBsAg). (2) If negative HBsAg and positive for hepatitis B core antibody then: Hepatitis B virus DNA by polymerase chain reaction is required. Subjects with detectable hepatitis B virus DNA are ineligible.

[0113] -If positive Hepatitis C virus antibody (HCVAb): Hepatitis C virus RNA by PCR is required. Subjects with detectable hepatitis C virus RNA are ineligible.

[0114] Preliminary data (February 6, 2025 data cutoff)

[0115] Example 2

[0116] This is a phase 1b multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of Compound G in combination with gemcitabine, cisplatin, and pembrolizumab in subjects with homozygous MTAP-deletion (“MTAP-null”) biliary tract cancer (BTC).

[0117] The following dose levels of Compound G are explored:

[0118] Dose level 2: 1200 mg QD daily

[0119] Dose level 1 : 800 mg QD daily

[0120] Dose level -1 : 500 mg QD daily

[0121] The study begins with dose level 1 .

[0122] Summary of Subject Eligibility Criteria:

[0123] Adult subjects (> 18 years old) with advanced BTC with homozygous MTAP deletion as assessed by local or central Next Generation Sequence (NGS) testing are eligible to participate in the study. MTAP protein loss as determined by local immunohistochemistry is also acceptable. MTAP-deletion may be determined in a pre-screening assay. Once consented to the study, subjects will provide a medical history and undergo screening safety tests to confirm all eligibility requirements of the study have been met. Subjects must have adequate hematological, renal, and hepatic function. Subjects must provide archived tumor tissue samples (formalin fixed paraffin embedded [FFPE] sample) collected within the past 5 years. If archived tumor tissue is not available, subjects must be willing to undergo a pre-treatment tumor biopsy if deemed safe per investigator judgement.

[0124] Treatments

[0125] Compound G is administered once daily continuously for 21-days.

[0126] Gemcitabine in combination with cisplatin are administered intravenously (IV) on day 1 and day 8 of every 21 -day treatment cycle (gemcitabine: 1000 mg / m2; and cisplatin (25 mg / m2; maximum of 8 cycles).

[0127] Pembrolizumab (200 mg) is administered on day 1 of every 21 -day treatment cycle (maximum 35 cycles).

[0128] Exemplary Exclusion Criteria

[0129] Prior Concomitant Therapy:

[0130] -Prior systemic therapy for advanced (metastatic) or unresectable (locally advanced) biliary tract cancer (intra- or extra- hepatic cholangiocarcinoma or gallbladder cancer). In order to enable local or central prescreening NGS testing to determine MTAP-deletion, subjects that have started treatment with the standard of care first line therapy, i.e. , gemcitabine and cisplatin with or without anti-PD(L) 1 inhibitor and have received their first dose within 28 days at time of signing main consent are eligible.

[0131] -Neoadjuvant / adjuvant therapy:

[0132] -Dose exploration: Prior neoadjuvant / adjuvant therapy is allowed without conditions.

[0133] -Dose expansion: Prior neoadjuvant / adjuvant therapy is allowed if completed at least 6 months prior to diagnosis of advanced and / or unresectable disease, and if subjects did not receive gemcitabine and / or cisplatin and / or anti PD (L) 1 antibody in the neoadjuvant / adjuvant setting. Participants who received prior neoadjuvant / adjuvant therapy with R2 postoperative pathology of the oncologic resection are excluded. NOTE: Bisphosphonate or denosumab for skeletal related events per institution guideline is permitted.

[0134] -Major surgery within 28 days of first dose of Compound G.

[0135] -Prior liver directed anticancer therapy (e.g., TACE, palliative surgery) for advanced unresectable biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder cancer), including investigational agents within 4 weeks prior to first dose of study treatment.

[0136] -Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.

[0137] -Toxicities from prior anti-tumor therapy not having improved to at least Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, with the exception of alopecia or toxicities that are stable and well controlled.

[0138] -Subjects who experienced grade 2 or higher immune-mediated adverse events (irAEs) including those that lead to permanent discontinuation with immune oncology agents. (For immune agonists including TCE). Exceptions: Endocrine disorders that are treated with replacement therapy.

[0139] -Prior irradiation to > 25% of the bone marrow.

[0140] -Radiation therapy within 28 days of first dose (or local or focal radiotherapy with palliative intend within 14 days of first dose). All radiotherapy related toxicity must have improved to < grade 1 before first dose of study treatment.

[0141] -Live vaccine therapy within 4 weeks before study drug administration.

[0142] -Use of prescription medications that are known strong inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives (whichever is longer) before study day 1 that was not reviewed and approved by the principal investigator and the medical monitor.

[0143] -Has a known sensitivity to any component of study treatment.

[0144] Disease Related

[0145] -Untreated CNS metastatic disease regardless of symptoms. Subjects with treated CNS metastases that are radiographically and neurologically stable for > 28 days and have not required corticosteroid for at least 14 days and do not require anticonvulsant prophylaxis or treatment before first dose of study treatment are eligible.

[0146] -Subjects with leptomeningeal disease are excluded regardless of presence or absence of symptoms even if treated.

[0147] -Ampullary cancer.

[0148] -Patients with pleural effusions or ascites that require therapeutic drainage (e.g., thoracentesis or paracentesis) at a frequency greater than one time per month.

[0149] Other Medical Conditions

[0150] -History of other malignancy within the past 3 years, with the following exceptions: (1) Adequately treated in situ cancer and precancerous lesions without evidence of disease. (2) Malignancy (other than in situ) treated with curative intent and with no known active disease present for > 2 years before first dose and felt to be at low risk for recurrence by the treating physician. NOTE: Patients with prior or concurrent malignancy may be eligible if the risk of the malignancy interfering with either safety or efficacy endpoints is deemed to be very low in the opinion of the investigator.

[0151] -Evidence of interstitial lung disease or active, noninfectious pneumonitis, or uncontrolled asthma.

[0152] -Confirmed history or current autoimmune disease requiring immunosuppressive therapy.

[0153] -History of diseases resulting in permanent immunosuppression.

[0154] -Active infection requiring systemic therapy. Subject with symptoms and / or clinical signs and / or radiographic signs that indicate an acute and / or uncontrolled active fungal, bacterial, viral, or other infection requiring anti infectious therapy within 14 days of dosing. NOTE: Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with medical monitor. Screening for chronic infectious conditions is not required unless otherwise noted in the eligibility criteria.

[0155] -History of arterial or venous thrombosis: (1) Arterial thrombosis (e.g., stroke, transient ischemic attack) within 12 months of first dose. (2) Untreated venous thromboembolism (e.g., DVT, pulmonary embolism). Subjects on stable anti-coagulation for > 1 month prior to first dose are eligible.

[0156] -Myocardial infarction and / or symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication within 6 months of first dose of Compound G. Patients requiring therapy must have been on stable regimen for at least 6 months.

[0157] -Gastrointestinal tract disease causing the inability to take PC medication, malabsorption syndrome, requirement for IV alimentation, gastric / jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis).

[0158] -History or evidence of gastrointestinal disorders causing chronic nausea, vomiting, or diarrhea (defined as CTCAE grade > 2).

[0159] -Grade > 2 peripheral neuropathy.

[0160] -History of solid organ transplantation.

[0161] -Diagnosis of Congenital Short QT Syndrome.

[0162] Prior / Concomitant Therapy

[0163] -Currently receiving treatment in another investigational device or drug study, or less than 21 days or 5 half-lives since ending treatment on another investigational device or drug study(ies). Other investigational procedures and participation in observational research studies while participating in this study are excluded. Participation in observational research should be discussed with the medical monitor.

[0164] Diagnostic Assessments

[0165] -Known positive test for Human Immunodeficiency Virus (HIV) with detectable viral load and without appropriate treatment.

[0166] -Viral hepatitis infection based on the following results and / or criteria:

[0167] -positive for hepatitis B surface antigen (HBsAg).

[0168] -negative HBsAg and positive for hepatitis B core antibody:

[0169] -hepatitis B virus DNA by polymerase chain reaction is required. Subjects with detectable hepatitis B virus DNA are ineligible.

[0170] -positive Hepatitis C virus antibody (HCVAb): Hepatitis C virus RNA by PCR is required. Subjects with detectable hepatitis C virus RNA are ineligible.References:ABRAXANE® U.S. Prescribing Information, Bristol-Myers Squibb Company, New Jersey, 08543 (revision 8 / 2020).CALCIUM FOLINATE (Leucovorin Calcium) US Prescribing Information, Bedford Laboratories, Bedford, OH 44146 (revision 11 / 2011).CAMPTOSTAR® (irinotecan), US Prescribing Information, Pfizer, Inc, New York, NY 10017 (revision 12 / 2014).Chen et al., Front Oncol., 2021 11:679331 .Eisenhauer, et al., Eur. J. Cancer 200945:228-247.ELOXATIN® (oxaliplatin), US Prescribing Information, Pfizer, New York 1017 (revision 4 / 2016).FLUOROURACIL, US Prescribing Information, Fresenius Kabi, Lake Zurich, IL 60047 (revision 2 / 2024).GEMZAR® US Prescribing Information, Eli Lily & Co., Indianapolis, IN 46285 (revision 5 / 2019).KEYTRUDA® US Prescribing Information, Merck & Co., Kenilworth, NJ 07033 (revision 1 / 2025).KHAPZORY® US Prescribing Information, Spectrum Pharmaceuticals, Inc., Irvine, CA 92618 (revision 10-2018).LIBTAYO® US Prescribing Information, Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 (revision 4 / 2024).National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute.OPDIVO® US Prescribing Information, Bristol-Myers Squibb Co., Princeton, NJ 08543 (revision 10 / 2024).PLATINOL® US Prescribing Information, Bristol-Myers Squibb Co., Princeton, NJ 08543 (revision 12 / 2023).TAXOL® (paclitaxel) INJECTION U.S. Prescribing Information, Bristol-Myers Squibb Company, Princeton, New Jersey, 08543 (revision 4 / 2011).

Claims

What is claimed is:1 . A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of(a) Compoundpharmaceutically acceptable salt thereof;(b) gemcitabine, and(c) paclitaxel.

2. The method of claim 1 , wherein the MTAP-null gastrointestinal cancer is locally advanced.

3. The method of claim 1 , wherein the MTAP-null gastrointestinal cancer is metastatic.

4. The method of any one of claims 1-3, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.

5. The method of any one of claims 1-3, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.

6. The method of claim 7, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

7. The method of any one of claims 1-6, wherein Compound G is administered as a free base.

8. The method of any one of claims 1-7, comprising administering to the patient a total daily dose of 500 mg Compound G or salt thereof, based upon free base weight of Compound G.

9. The method of any one of claims 1-7, comprising administering to the patient a total daily dose of 600 mg Compound G or salt thereof, based upon free base weight of Compound G.

10. The method of any one of claims 1-7, comprising administering to the patient a total daily dose of 800 mg Compound G or salt thereof, based upon free base weight of Compound G.

11. The method of any one of claims 1-7, comprising administering to the patient a total daily dose of 900 mg Compound G or salt thereof, based upon free base weight of Compound G.

12. The method of any one of claims 1-7, comprising administering to the patient a total daily dose of 1200 mg Compound G or salt thereof, based upon free base weight of Compound G.

13. The method of any one of claims 1-12, wherein Compound G is administered to the patient once daily.

14. The method of any one of claims 1-13, wherein Compound G is administered orally.

15. The method of any one of claims 1-14, wherein Compound G is administered as a tablet formulation.

16. The method of any one of claims 1-15, comprising administering to the patient 1000 mg / m2gemcitabine via IV three times in a 28-day treatment cycle.

17. The method of any one of claims 1-16, wherein the paclitaxel is nab-paclitaxel.

18. The method of any one of claims 1-17, comprising administering to the patient 125 mg / m2nab- paclitaxel via IV three times in a 28-day treatment cycle.

19. The method of any one of claims 1-18, comprising administering to the patient gemcitabine and nab-paclitaxel on day 1, day 8, and day 15 of a 28-day treatment cycle.

20. The method of any one of claims 1-7, and 13-15, comprising administering to the patient (a) 500 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.

21. The method of any one of claims 1-7, and 13-15, comprising administering to the patient (a) 600 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.

22. The method of any one of claims 1-7, and 13-15, comprising administering to the patient (a) 800 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.

23. The method of any one of claims 1-7, and 13-15, comprising administering to the patient (a) 900 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.

24. The method of any one of claims 1-7, and 13-15, comprising administering to the patient (a) 1200 mg Compound G or salt thereof, based upon free base weight of Compound G once daily, (b) 1000 mg / m2gemcitabine, and (c) 125 mg / m2nab-paclitaxel, wherein the 1000 mg / m2gemcitabine and 125 mg / m2nab- paclitaxel are administered via IV on days 1, 8, and 15 of a 28-day treatment cycle.

25. The method of any one of claims 1-24, wherein the patient is treatment naive for the MTAP- null gastrointestinal cancer.

26. The method of any one of claims 1-24, wherein the patient has undergone a prior systemic therapy for the MTAP-null gastrointestinal cancer.

27. The method of claim 26, wherein the prior systemic therapy is FOLFIRINOX.

28. A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of:(b) a combination of (i) irinotecan, (ii) 5-fluorouracil, (ii) leucovorin, and (iv) oxaliplatin.

29. The method of claim 28, wherein the MTAP-null gastrointestinal cancer is locally advanced.

30. The method of claim 28, wherein the MTAP-null gastrointestinal cancer is metastatic.31 . The method of any one of claims 28-30, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.

32. The method of any one of claims 28-30, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.

33. The method of claim 32, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

34. The method of any one of claims 28-33, wherein Compound G is administered as a free base.

35. The method of any one of claims 28-34, comprising administering to the patient 500 mgCompound G or salt thereof, based upon free base weight of Compound G.

36. The method of any one of claims 28-34, comprising administering to the patient 600 mg Compound G or salt thereof, based upon free base weight of Compound G.

37. The method of any one of claims 28-34, comprising administering to the patient 800 mg Compound G or salt thereof, based upon free base weight of Compound G.

38. The method of any one of claims 28-34, comprising administering to the patient 900 mg Compound G or salt thereof, based upon free base weight of Compound G.

39. The method of any one of claims 28-34, comprising administering to the patient 1200 mg Compound G or salt thereof, based upon free base weight of Compound G.

40. The method of any one of claims 28-39, wherein Compound G is administered to the patient once daily.41 . The method of any one of claims 28-40, wherein Compound G is administered orally.

42. The method of any one of claims 28-41 , wherein Compound G is administered as a tablet formulation.

43. The method of any one of claims 28-42, comprising administering to the patient 150 mg / m2irinotecan via IV twice in a 28-day treatment cycle.

44. The method of any one of claims 28-43, comprising administering to the patient 2400 mg / m25- fluorouracil via IV twice in a 28-day treatment cycle.

45. The method of any one of claims 28-44, comprising administering to the patient 400 mg / m2leucovorin via IV twice in a 28-day treatment cycle.

46. The method of any one of claims 28-45, comprising administering to the patient 85 mg / m2oxaliplatin via IV twice in a 28-day treatment cycle.

47. The methods of any one of claims 28-46, wherein the irinotecan, 5-fluorouracil, leucovorin and oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.

48. The method of any one of claims 28-33, and 40-42, comprising administering to the patient (a) 500 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.

49. The method of any one of claims 28-33, and 40-42, comprising administering to the patient (a) 600 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.

50. The method of any one of claims 28-33, and 40-42, comprising administering to the patient (a) 800 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.51 . The method of any one of claims 28-33, and 40-42, comprising administering to the patient (a) 900 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.

52. The method of any one of claims 28-33, and 40-42, comprising administering to the patient (a) 1200 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, and (b) a combination of (1)150 mg / m2irinotecan, (ii) 2400 mg / m25-fluorouracil, (ill) 400 mg / m2leucovorin, and (iv) 85 mg / m2oxaliplatin, wherein the 150 mg / m2irinotecan, 2400 mg / m25-fluorouracil, 400 mg / m2leucovorin and 85 mg / m2oxaliplatin are administered on day 1 and day 15 of a 28-day treatment cycle.

53. The method of any one of claims 48-52, wherein Compound G is administered as a free base.

54. The method of any one of claims 28-53, wherein the patient is treatment naive for the MTAP- null gastrointestinal cancer.

55. A method of treating a MTAP-null gastrointestinal cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of each of(a) Compoundpharmaceutically acceptable salt thereof;(b) gemcitabine,(c) cisplatin; and(d) an anti-PD1 antibody or an anti-PDL1 antibody.

56. The method of claim 55, wherein the MTAP-null gastrointestinal cancer is locally advanced.

57. The method of claim 55, wherein the MTAP-null gastrointestinal cancer is metastatic.

58. The method of any one of claims 55-57, wherein the MTAP-null gastrointestinal cancer is biliary tract cancer.

59. The method of any one of claims 55-57, wherein the MTAP-null gastrointestinal cancer is pancreatic cancer.

60. The method of claim 59, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.61 . The method of any one of claims 55-60, comprising administering to the patient 500 mg Compound G or salt thereof, based upon free base weight of Compound G.

62. The method of any one of claims 55-60, comprising administering to the patient 600 mgCompound G or salt thereof, based upon free base weight of Compound G.

63. The method of any one of claims 55-60, comprising administering to the patient 800 mg Compound G or salt thereof, based upon free base weight of Compound G.

64. The method of any one of claims 55-60, comprising administering to the patient 900 mg Compound G or salt thereof, based upon free base weight of Compound G.

65. The method of any one of claims 55-60, comprising administering to the patient 1200 mg Compound G or salt thereof, based upon free base weight of Compound G.

66. The method of any one of claims 55-65, wherein Compound G is administered as a free base.

67. The method of any one of claims 55-66, wherein Compound G is administered once daily.

68. The method of any one of claims 55-67, wherein Compound G is administered orally.

69. The method of any one of claims 55-68, wherein Compound G is administered as a tablet formulation.

70. The method of any one of claims 55-69, wherein the patient is administered an anti-PDL 1 antibody.

71. The method of any one of claims 55-69, wherein the patient is administered an anti-PD1 antibody.

72. The method of claim 71, wherein the anti-PD1 antibody is pembrolizumab.

73. The method of claim 72, comprising administering to the patient 200 mg pembrolizumab via IV administration once in a 21 -day treatment cycle.

74. The method of any one of claims 55-73, comprising administering to the patient 1000 mg / m2gemcitabine via IV on day 1 and day 8 of every 21 -day treatment cycle.

75. The method of any one of claims 55-74, comprising administering to the patient 25 mg / m2cisplatin via IV on day 1 and day 8 of every 21 -day treatment cycle.

76. The method of any one of claims 55-60, and 67-69, comprising administering to the patient (a) 500 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.

77. The method of any one of claims 55-60, and 67-69, comprising administering to the patient (a) 600 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.

78. The method of any one of claims 55-60, and 67-69, comprising administering to the patient (a) 800 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.

79. The method of any one of claims 55-60, and 67-69, comprising administering to the patient (a) 900 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.

80. The method of any one of claims 55-60, and 67-69, comprising administering to the patient (a) 1200 mg Compound G or salt thereof, based upon free base weight of Compound G, once daily, (b) 1000 mg / m2gemcitabine, (c) 25 mg / m2cisplatin, and (d) 200 mg pembrolizumab, wherein the 1000 mg / m2gemcitabine and 25 mg / m2cisplatin are administered via IV on day 1 and day 8 of every 21 -day treatment cycle, and wherein the pembrolizumab is administered via IV once in a 21 -day treatment cycle.

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