WO2025076500A1 - Cancer treatments using mta-cooperative prmt5 inhibitors - Google Patents

Abstract

Described herein are methods of treating a MTAP-null cancer in a patient comprising administering a PRMT5 inhibitor, optionally as a monotherapy.

Description

CANCER TREATMENTS USING MTA-COOPERATIVE PRMT5 INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/542,906, filed October 6, 2023, which is hereby incorporated by reference in its entirety, and for all purposes as if fully set forth herein.

BACKGROUND

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

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

[0004] In one aspect, described herein is a method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient a total daily dose of 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, or 200 mg Compound G or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

[0005] In another aspect, described herein is a method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient, a Compound G, or pharmaceutically acceptable salt thereof, as a monotherapy, wherein Compound G has a structure of

Compound G can be synthesized as described in WO 2023/034786.

[0006] In another aspect, described herein is a method of treating a MTAP-null cancer in a patient in need thereof comprising orally administering to the patient 800 mg Compound G, or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

[0007] In yet another aspect, described herein is a method of treating a MTAP-null cancer in a patient in need thereof comprising orally administering to the patient 1200 mg Compound G, or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

BRIEF DESCRIPTION OF THE FIGURES

[0008] Figure 1A: Preliminary Mean (±SD) Plasma Compound G Concentration-time Profiles After Once Daily Administration of Compound G in Cycle 1 Day 1.

[0009] Figure 1B: Preliminary Mean (±SD) Plasma Compound G Concentration-time Profiles After Once Daily

Administration of Compound G in Cycle 1 Day 15

[0010] Figure 2A: ELISA analysis of HCT116 MTAP WT and HCT116 MTAP-null contralateral tumor cells.

Female Athymic nude mice were dosed with Compound G or vehicle. Data represent mean ±SD, n = 3 for each group.

[0011] Figure 2B: HCT116 MTAP WT and MTAP Null global SDMA levels were assessed by an in-cell imaging assay after 4 days treatment with Compound G.

[0012] Figure 3A is a graph showing Compound G AUC versus MTAP status across all lineages, pancreatic, lung, or lymphoma. The dotted line indicates average.

[0013] Figure 3B is a graph showing Compound G AUC versus RNAi knockdown for PRMT5 with the associated Pearson correlation value and p-value.

[0014] Figure 3C is a graph showing Compound G AUC versus copy number for MTAP, CDKN2A, and CDKN2B with the associated Pearson correlation value and p-value. ****p < 0.0001.

[0015] Figures 4A and 4B are representative dose response curves WT and MTAP-null pancreatic (Figure 4A) and NSCLC (Figure 4B) cancer cells treated with a serial dilution of Compound G or DMSO-only control for 6 days. Viability was measured by CellTiter-Glo. (mean ± SD, n=3).

[0016] Figure 5 provides the results of SDMA ELISA analysis of HCT116 MTAP WT and MTAP-null bilateral tumors. Percentage of inhibition reported relative to matched vehicle.

[0017] Figure 6A-6D show that Compound G exhibits significant anti-tumor activity in MTAP-null cell line derived xenografts. Female SCID mice were implanted with DOHH-2 (Figure 6A) or BxPC-3 (Figure 6B) tumors. Female athymic nude mice were implanted with LU99 (Figure 6C) or H838 (Figure 6D) tumors. Vehicle and Compound G at various doses (10 mg/kg, 20 mg/kg, or 30 mg/kg) were administered orally (p.o.) once a day for the duration of the study. Data represent group means ± SEM, n = 10. STATS: P values were determined by Linear Mixed-Effects Model with a Dunnett's comparison to control; ****p<0.0001.

[0018] Figures 7A-7D show that Compound G exhibits significant anti-tumor activity in MTAP-null patient- derived models. Female NOD/SCID mice were implanted with PA5415 (pancreatic tumors, Figure 7A), LU5268 (NSCLC tumors, Figure 7B), ME12183 (melanoma tumors, Figure 7C) or ES11082 (esophageal tumors, Figure 7D). Vehicle and Compound G at various doses (25 mg/kg, 50 mg/kg, or 100 mg/kg) were administered orally (p.o.) once a day for the duration of the study. Data represent group means ± SEM, n = 10. for each group. STATS: P values were determined by Linear Mixed-Effects Model with a Dunnett's comparison to control; ****p<0.0001.

[0019] Figure 8A shows near complete inhibition of PRMT5-mediated SDMA modification in MTAP-null patient tumor biopsies following administration of Compound G. Pretreatment and C2D1 tumor biopsies were stained for SDMA motif expression by immunohistochemistry. SDMA motif levels represented by H-scores were determined by a pathologist review.

[0020] Figure 8B shows that plasma symmetric dimethyl arginine (SDMA, the product of PRMT5 enzymatic activity) profile of subjects from different dosing cohorts. Serum samples were collected at specific timepoints to record changes in SDMA. The results demonstrated that plasma SDMA was reduced by approximately 40-75% after C1D15, indicating target inhibition. Data represent group means ± SE, n are indicated for each cohort group..

[0021] Figure 9A provides a graph showing the best percent change in ctDNA across various doses administered. The circulating tumor fraction (cTF) was evaluated by next generation sequencing of plasma tumor-specific methylation markers before and after the treatment on C2D1 and C3D1. The results are marked based on the Best Overall Response, including PD (progressive disease), SD (stable disease), PR (partial response), and NE (non-evaluable).

[0022] Figure 9B represents the correlation between treatment response and the best of reduction of ctDNA circulating tumor fraction (cTF). The cTF reduction levels after treatment were compared with those of C1D1 in patients with PD (progressive disease), SD (stable disease), and PR (partial response). The median values are represented by black lines.

[0023] Figure 10A is a graph showing cancer antigen 19-9 (CA-19-9), circulating tumor DNA (ctDNA), serum

SDMA measured during therapy and follow-up from a gallbladder cancer subject treated with 1200 mg Compound G.

[0024] Figure 10B is a graph showing cancer antigen 19-9 (CA-19-9), circulating tumor DNA (ctDNA), serum SDMA measured during therapy and follow-up from a pancreatic cancer subject treated with 800mg Compound G. [0025] Figure 11 is a plot (preliminary data) showing the maximum change from baseline in the sum of target tumor lesion diameters from thirty-five patients enrolled in the First-ln-Human study. Compound G significantly reduced tumor burden in vivo across multiple tumor types.

[0026] Figure 12 is a graph showing the frequency of MTAP deletion (%) in various cancer types.

[0027] Figure 13 is a plot of the incidence and severity of adverse events (treatment-related occurring in ≥ 5% of patients) in the First-ln-Human dose exploration study.

[0028] Figure 14 depicts graphs showing the incidence of nausea (Figure 14A) and vomiting (Figure 14B) by worst grade and duration on treatment.

[0029] Figure 15 is Waterfall plot showing response duration and change in tumor burden from patients in the First-ln-Human Dose Exploration study.

[0030] Figure 16 shows the mean plasma concentration-time profile for Compound G, following administration of QD or BID dosing in patients from dose-exploration cohorts (cycle 1 day 15). Compound G demonstrated a dose-proportional increase in plasma exposure within the dose range of 40-1200 mg QD.

[0031] Figures 17A-17F: Biomarker analysis of target engagement (SDMA) and antitumor activity (ctDNA). Figure 17A: SDMA IHC revealed strong nuclear SDMA staining the pre-treatment samples, while a notable loss of SDMA expression in the post-treatment samples. Figure 17B: Longitudinal view of SDMA H-score in MTAP- deleted and MTAP wildtype tumor cells. Figure 17C: Serum SDMA % reduction from baseline following Compound G treatment. Reduction in serum SDMA is dose proportionate and is associated with clinical response. Figure 17D: Best % serum change by BOR following Compound G treatment. Figure 17E: Best % change in ctDNA (cTF) by dose of Compound G. Figure 17F: Best % change in ctDNA among C2D1 and C3D1 following Compound G treatment. Patients with baseline ctDNA below limit of quantification (0.01%) were excluded from longitudinal assessment.

[0032] Figure 18 is a plot of the incidence and severity of treatment-related and treatment-emergent adverse events in the First-ln-Human dose exploration and expansion (N = 167) study.

[0033] Figure 19 is a graph showing the timing and severity of nausea and vomiting in the First-ln-Human dose expansion study (n=87).

[0034] Figure 20 shows a waterfall plot that includes patients treated at active doses in dose escalation and in the ongoing expansions, and a swimmer plot extending vertically above corresponding to patients on the waterfall plot.

[0035] Figure 21 Is a swimmer plot showing the duration of treatment by dose cohort in dose Exploration.

DETAILED DESCRIPTION

[0036] The disclosure provides methods of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient a total daily dose of 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, or 200 mg Compound G or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

[0037] The disclosure also provides methods of treating a MTAP-null cancer in a patient in need thereof comprising orally administering to the patient 800 mg Compound G, or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

[0038] The disclosure also provides methods of treating a MTAP-null cancer in a patient in need thereof comprising orally administering to the patient 1200 mg Compound G, or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

[0039] The disclosure also provides methods of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient a Compound G, or pharmaceutically acceptable salt thereof, as a monotherapy, wherein G has a structure of As used herein,

a monotherapy of Compound G, or salt thereof, means the administration of Compound G to a patient in need thereof as a single therapeutic for the treatment of a MTAP-null cancer.

[0040] In the methods disclosed herein, Compound G described herein can be administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002. In various embodiments, Compound G or salt thereof is administered orally.

[0041] Dosage Regimens

[0042] In some embodiments, Compound G is administered to a patient in need thereof orally and once a day. In some embodiments, Compound G is administered to a patient in need thereof orally and twice a day. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0043] In some embodiments, the patient is administered 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg of Compound G (or salt thereof), based upon free base weight of Compound G. All weights of Compound G referred to herein are based upon a free base weight of Compound G. Thus, if 500 mg Compound G is administered to a patient in salt form, the amount of therapeutic given will be higher than 500 mg to account for the salt form molecular weight. In some embodiments, the patient is administered 40 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 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg of Compound G (or salt thereof), based upon free base weight of Compound G. 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.

[0044] In some embodiments, the patient is administered a total daily dose of 200 mg of Compound G, based upon the 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 the 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 the 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 the 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 the 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 the 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 the 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 the 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 the 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 the 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 the free base weight of Compound G.

[0045] In some embodiments, the patient is administered a total daily dose of 400 mg, 500 mg, or 600 mg Compound G, based upon the 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 the 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 the free base weight of Compound G. In some embodiments, the patient is administered a total daily dose of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg of Compound G (or salt thereof), based upon the free weight of Compound G, once daily. In some embodiments, the patient is administered a total daily dose of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg of Compound G (or salt thereof), based upon the free weight of Compound G, twice daily. In some embodiments, the patient is administered a total daily dose of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg of Compound G (or salt thereof), based upon the free weight of Compound G, once daily for 28 consecutive days. In some embodiments, the patient is administered a total daily dose of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg of Compound G (or salt thereof), based upon the free weight of Compound G, twice daily for 28 consecutive days.

[0046] In some embodiments, the patient is administered 40 mg, 120 mg, 240 mg, 480 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, or 1600 mg of Compound G, based upon free base weight of Compound G. In some embodiments, the patient is administered 40 mg, 120 mg, 240 mg, 480 mg, 800 mg, 1000 mg, 1200 mg, or 1600 mg of Compound G, based upon free base weight of Compound G, once daily for 28 consecutive days. In some embodiments, the patient is administered 600 mg, 800 mg, 1000 mg, or 1200 mg of Compound G, based upon free base weight of Compound G, twice daily for 28 consecutive days. In some embodiments, the therapy is administered in treatment cycles. In some embodiments, the treatment cycle is 28 days. In some embodiments, the cycle may be repeated. In various embodiments, the patient undergoes 1, 2, 3, or more treatment cycles. In some embodiments, the patient undergoes at least 3 treatment cycles, at least 5 treatment cycles, at least 8 treatment cycles, at least 10 treatment cycles, or at least 15 treatment cycles. [0047] In some embodiments, the patient did not receive anti-tumor therapy within 28 days of receiving the first dose of Compound G. In some embodiments, the patient did not receive anti-tumor therapy within 21 days of receiving the first dose of Compound G. Exemplary anti-tumor therapies include, chemotherapy, antibody therapy, molecular targeted therapy or hormonal therapy. In some embodiments, the patient had not previously been treated with a MAT2A inhibitor (i.e. , the patient is MAT2A inhibitor naïve). An MAT2A inhibitor is a compound that inhibits methionine adenosyltransferase II alpha. An exemplary MAT2A inhibitor for use in the methods provided herein 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).

[0048] In some embodiments, the patient had not previously been treated with a PRMT5 inhibitor (i.e., the patient is PRMT5 inhibitor naïve). A PRMT5 inhibitor is a compound that inhibits protein arginine methyltransferase 5. The term “PRMT5 inhibitor” includes MTA-cooperative PRMT5 inhibitors. Exemplary PRMT5 inhibitors for use in the methods provided herein include, but are not limited to, pemrametostat (6-[(1- acetylpiperidin-4-yl)amino]-N-[(2S)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]pyrimidine-4- carboxamide), GSK3203591 (2-(Cyclobutylamino)-N-[(2S)-3-(3,4-dihydro-2(1H)-isoquinolinyl)-2-hydropropyl]-4- pyridinecarboxamide 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, MRTX1719 (2-(4-(4-(aminomethyl)-1-oxo-1,2- dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile), GSK3326595 (GSK); SCR-6920; AZD3470 (AstraZeneca); PF-06939999 (Pfizer); JNJ-64619178 (J&J); TNG908 (Tango Therapeutics); TNG462 (Tango Therapeutics); PRT811 (Prelude Therapeutics); BGB-5807 (BeiGene); PRT543 (Prelude Therapeutics); and MRTX1719 (Mirati/BMS).

[0049] In some embodiments, the patient had not previously been treated with docetaxel (i.e., the patient is docetaxel naïve).

[0050] 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).

[0051] 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. [0052] In some embodiments, the patient has not been previously diagnosed with Congenital Short QT Syndrome.

[0053] In some embodiments, the patient has not had an arterial thrombosis within 6 months before starting Compound G therapy or a myocardial infarction or symptomatic congestive heart failure within 12 months before starting Compound G therapy, such as Compound G monotherapy. In some embodiments, the patient has not had an arterial thrombosis within 6 months before starting Compound G therapy, such as Compound G monotherapy or a myocardial infarction or symptomatic congestive heart failure within 12 months before starting Compound G therapy, such as Compound G monotherapy.

[0054] In some embodiments, the patient does not have, and has not had, interstitial lung disease or pneumonitis.

[0055] In some embodiments, the patient does not have spinal cord compression, untreated brain metastases, or leptomeningeal disease.

[0056] Cancer

[0057] 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” and “MTAP-negative” are used interchangeably.

[0058] An “MTAP-deficiency-related” or “MTAP-deficiency” or “MTAP deficient” disease (for example, a proliferating disease, such as a cancer) or a disease (for example, a proliferating disease, such as a cancer) “associated with MTAP deficiency” or a disease (for example, a proliferating disease, such as 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. Examples of MTAP-deficiency-related diseases include, but are not limited to, cancers, including but not limited to: glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma interchangeably referred to as pancreatic ductal adenocarcinoma or PDAC), mesothelioma, melanoma, nonsmall cell lung cancer (NSCLC; such as lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiocarcinoma cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma. In some cases, the NSCLC is squamous. In other cases, the NSCLC is non-squamous. 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.

[0059] Overall, 10-15% of cancers harbor homozygous MTAP deletions, as shown in Figure 12.

[0060] In some cases, the cancer is non-small cell lung cancer (e.g., squamous or non-squamous) pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), gastric or gastroesophageal junction (GEJ) cancer, glioblastoma, biliary tract cancer (BTC), glioma, an MTAP-null solid tumor, or head and neck squamous cell carcinoma (HNSCC).

[0061] In some embodiments, the cancer is acute myeloid leukemia, cancer in adolescents, childhood adrenocortical carcinoma childhood, AIDS-related cancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC) (squamous or non-squamous NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer. In some cases, the cancer is pancreatic cancer; esophageal cancer; melanoma; lung cancer; mixed mullerian cancer; ovarian cancer; or gallbladder cancer.

[0062] In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma, squamous or non-squamous NSCLC), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0063] In some embodiments, the MTAP-null cancer is lung cancer, biliary tract cancer, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, gallbladder cancer, or mesothelioma.

[0064] In some embodiments, the MTAP-null cancer is a solid tumor. Exemplary MTAP-null solid tumors include, but are not limited to, MTAP-null brain cancer (including, but not limited to, MTAP-null glioma, MTAP-null oligodendroglioma, MTAP-null glioblastoma multiforme, MTAP-null astrocytoma, MTAP-null medulloblastoma, MTAP-null ependymoma, and MTAP-null meningioma), MTAP-null head and neck cancer (including, but not limited to, MTAP-null salivary gland (parotid) tumors, MTAP-null head and neck squamous cell carcinoma, and MTAP-null thyroid cancer), MTAP-null breast cancer (including, but not limited to, invasive ductal breast cancer, mixed mucinous breast cancer and lobular carcinoma), MTAP-null mesothelioma, MTAP-null gastrointestinal tract cancer (including but not limited to, MTAP-null esophageal cancer (including, but not limited to, adenocarcinoma and squamous cell carcinoma), MTAP-null gastro-esophageal junction cancer, MTAP-null stomach cancer (including, but not limited to, adenocarcinoma and signet ring cell carcinoma), MTAP-null small bowel cancer, MTAP-null colon cancer, MTAP-null rectal cancer and MTAP-null gastrointestinal stromal tumor), MTAP-null neuroendocrine tumor, MTAP-null hepatobiliary cancer (including, but not limited to, MTAP-null biliary tract cancer (including cholangiocarcinoma, gallbladder cancer and ampullary cancer) and MTAP-null hepatocellular carcinoma), MTAP-null pancreatic cancer (including pancreatic adenocarcinoma), MTAP-null kidney cancer (including, but not limited to, MTAP-null renal cell carcinoma), MTAP-null adrenocortical carcinoma, MTAP-null bladder cancer (including, but not limited to, MTAP-null urothelial carcinoma), MTAP-null adrenocortical carcinoma, MTAP-null endometrial cancer, MTAP-null uterine cancer, MTAP-null testicular cancer, MTAP-null germ cell tumor, or MTAP-null prostate cancer, MTAP-null sarcoma or MTAP-null bone cancer (including, but not limited to, MTAP-null osteosarcoma, MTAP-null chondrosarcoma, MTAP-null soft tissue sarcoma, MTAP-null Ewing sarcoma, MTAP-null liposarcoma, MTAP-null leiomyosarcoma, and MTAP-null myxofibrosarcoma), MTAP-null cutaneous tumors (MTAP-null cutaneous squamous cell carcinoma and MTAP- null melanoma), MTAP-null nerve sheath tumor and MTAP-null cancer of unknown primary (CUP).

[0065] In some embodiments, the MTAP-null cancer is a hematologic tumor. Exemplary hematologic tumors include, but are not limited to, MTAP-null leukemia (including, but not limited to, MTAP-null acute lymphocytic leukemia, MTAP-null acute myeloid leukemia), MTAP-null lymphoma (including, but not limited to, MTAP-null mantle cell lymphoma, MTAP-null follicular lymphoma, MTAP-null diffuse large B cell lymphoma, and MTAP-null mycosis fungoides).

[0066] In some cases, the MTAP-null cancer is lung cancer, biliary tract cancer, head and neck squamous cell carcinoma, pancreatic cancer, gallbladder cancer, mesothelioma, not a primary brain tumor or lymphoma, esophageal/gastric cancer, or glioma. In some cases, the MTAP-null cancer is lung cancer. In some cases, the MTAP-null lung cancer is non-small cell lung cancer (NSCLC). In some cases, the NSCLC is squamous. In some cases, the NSCLC is non-squamous. In some cases, the MTAP-null cancer is biliary tract cancer. In some cases, the MTAP-null cancer is head and neck squamous cell carcinoma. In some cases, the MTAP-null cancer is pancreatic cancer. In some cases, the MTAP-null pancreatic cancer is pancreatic adenocarcinoma. In some cases, the MTAP-null pancreatic adenocarcinoma is pancreatic ductal adenocarcinoma. In some cases, the MTAP-null cancer is gallbladder cancer. In some cases, the MTAP-null cancer is mesothelioma. In some cases, the MTAP-null cancer is not a primary brain tumor or lymphoma. In some cases, the MTAP-null cancer is esophageal/gastric cancer. In some cases, the MTAP-null cancer is glioma.

[0067] MTAP-null cancers can be identified by any suitable diagnostic test. Exemplary diagnostic tests include immunohistochemistry (IHC) and next generation sequencing (NGS).

[0068] In some embodiments, the patient does not have a tumor harboring the following mutations and genetic aberrations amenable to targeted therapies: epidermal growth factor receptor (EGFR) / ALK receptor tyrosine kinase (ALK) / ROS proto-oncogene 1 (ROS1) I neurotrophic tyrosine receptor kinase (NTRK) / MET proto-oncogene (MET) I B-Raf proto-oncogene (BRAF)/ RET proto-oncogene (RET) / Human epidermal growth factor receptor 2 (HER2 or ERBB2) / KRAS proto-oncogene (KRAS).

[0069] In some embodiments, the patient does not have a tumor harboring a CDKN2A mutation.

[0070] Monitoring Efficacy of Treatment

[0071] The efficacy of a given treatment for cancer can be determined by the skilled clinician. However, a treatment is considered "effective treatment," as the term is used herein, if any one or all of the signs or symptoms of e.g., a tumor are altered in a beneficial manner or other clinically accepted symptoms are improved, or even ameliorated, e.g., by at least 10% following treatment with an agent as described herein. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and/or described herein.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] Embodiments

[0076] 11.. A method of treating a MTAP-null cancer comprising administering to the patient a Compound

G, or pharmaceutically acceptable salt thereof, as a monotherapy, wherein Compound G has a structure of

[0077] 2. The method of embodiment 1, wherein the MTAP-null cancer is lung cancer.

[0078] 3. The method of embodiment 2, wherein the lung cancer is non-squamous cell lung cancer

(NSCLC).

[0079] 4. The method of embodiment 1 , wherein the MTAP-null cancer is biliary tract cancer. [0080] 5. The method of embodiment 1 , wherein the MTAP-null cancer is head and neck squamous cell carcinoma.

[0081] 6. The method of embodiment 1, wherein the MTAP-null cancer is pancreatic adenocarcinoma.

[0082] 7. The method of embodiment 1 , wherein the MTAP-null cancer is gallbladder cancer.

[0083] 8. The method of embodiment 1 , wherein the MTAP-null cancer is mesothelioma.

[0084] 9. The method of any one of embodiments 1 -8, comprising administering 40 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

[0085] 10. The method of any one of embodiments 1-8, comprising administering 120 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

[0086] 11. The method of any one of embodiments 1 -8, comprising administering 240 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

[0087] 12. The method of any one of embodiments 1-8, comprising administering 480 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

[0088] 13. The method of any one of embodiments 1-8, comprising administering 800 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

[0089] 14. The method of any one of embodiments 1-8, comprising administering 1200 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

[0090] 15. The method of any one of embodiments 1-8, comprising administering 1600 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

[0091] 16. The method of any one of embodiments 1-8, comprising administering 600 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

[0092] 17. The method of any one of embodiments 1-8, comprising administering 800 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

[0093] 18. The method of any one of embodiments 1-8, comprising administering 1200 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

[0094] 19. The method of any one of embodiments 1-18, wherein Compound G is administered as a free base.

[0095] 20. The method of any one of embodiments 1-19, wherein the patient has not previously been treated with a PRMT5 inhibitor.

[0096] 21. The method of any one of embodiments 1 -20, wherein the patient has not previously been treated with a MAT2A inhibitor. [0097] 22. The method of any one of embodiments 1 -21 , wherein the patient is not being treated with a compound that is a strong inducer of CYP3A4.

[0098] 23. The method of embodiment 22, wherein the compound that is a strong inducer of CYP3A4 is rifampin, mitotane, avasimibe, rifapentine, apalutamide, ivosidenib, phenytoin, carbamazepine, enzalutamide, St John's wort extract, lumacaftor and phenobarbital.

[0099] 2244.. The method of any one of embodiments 1 -23, wherein the patient is not being treated with a compound that is a strong inhibitor of CYP3A4.

[0100] 25. The method of embodiment 24, wherein the compound that is a strong inhibitor of CYP3A4 is 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, or boceprevir.

[0101] 2266.. The method of any one of embodiments 1 -25, wherein the patient has not been previously diagnosed with Congenital Short QT Syndrome.

[0102] 2277.. The method of any one of embodiments 1 -26, wherein the patient has not had an arterial thrombosis within 6 months before starting Compound G monotherapy or a myocardial infarction or symptomatic congestive heart failure within 12 months before staring Compound G monotherapy.

[0103] 28. The method of any one of embodiments 1-27, wherein the patient does not have, and has not had, interstitial lung disease or pneumonitis.

[0104] 29. The method of any one of embodiments 1 -28, wherein the patient does not have spinal cord compression, untreated brain metastases, or leptomeningeal disease.

[0105] Additional Embodiments

1A. A method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient a total daily dose of 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, or 200 mg Compound G or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

2A. The method of embodiment 1A, comprising administering a total daily dose of 1200 mg

Compound G.

3A. The method of embodiment 1A, comprising administering a total daily dose of 1100 mg

Compound G.

4A. The method of embodiment 1A, comprising administering a total daily dose of 1000 mg

Compound G.

5A. The method of embodiment 1A, comprising administering a total daily dose of 900 mg

Compound G.

6A. The method of embodiment 1A, comprising administering a total daily dose of 800 mg

Compound G.

7A. The method of embodiment 1A, comprising administering a total daily dose of 700 mg of

Compound G.

8A. The method of embodiment 1A, comprising administering a total daily dose of 600 mg of

Compound G.

9A. The method of embodiment 1A, comprising administering a total daily dose of 500 mg of

Compound G.

10A. The method of embodiment 1A, comprising administering a total daily dose of 400 mg of

Compound G.

11A. The method of embodiment 1A, comprising administering a total daily dose of 300 mg of

Compound G.

12A. The method of embodiment 1A, comprising administering a total daily dose of 200 mg of

Compound G.

13A. The method of any one of embodiments 2A-12A, wherein Compound G is administered once daily.

14A. The method of any one of embodiments 2A-12A, wherein Compound G is administered twice daily.

15A. The method of any one of embodiments 2A-14A, wherein the MTAP-null cancer is lung cancer.

16A. The method of embodiment 15A, wherein the lung cancer is non-small cell lung cancer

(NSCLC).

17A. The method of embodiment 16A, wherein the NSCLC is squamous.

18A. The method of embodiment 16A, wherein the NSCLC is non-squamous. 19A. The method of any one of embodiments 2A-14A, wherein the MTAP-null cancer is biliary tract cancer.

20A. The method of any one of embodiments 2A-14A, wherein the MTAP-null cancer is head and neck squamous cell carcinoma.

21A. The method of any one of embodiments 2A-14A, wherein the MTAP-null cancer is pancreatic adenocarcinoma.

22A. The method of any one of embodiments 2A-14A, wherein the MTAP-null cancer is gallbladder cancer.

23A. The method of any one of embodiments 2A-14A, wherein the MTAP-null cancer is mesothelioma.

24A. The method of any one of embodiments 2A-14A, wherein the MTAP-null cancer is not a primary brain tumor or lymphoma.

25A. The method of any one of embodiments 2-14, wherein the MTAP-null cancer is esophageal or gastric cancer.

26A. The method of any one of embodiments 2A-14A, wherein the MTAP-null cancer is glioma.

27A. The method of any one of embodiments 1A-26A, wherein Compound G is administered as a monotherapy.

28A. A method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient a Compound G, or pharmaceutically acceptable salt thereof, as a monotherapy, wherein Compound G has a structure of

29A. The method of embodiment 28A wherein the MTAP-null cancer is lung cancer.

30A. The method of embodiment 29A, wherein the lung cancer is non-small cell lung cancer

(NSCLC).

31A. The method of embodiment 30A, wherein the NSCLC is squamous.

32A. The method of embodiment 30A, wherein the NSCLC is non-squamous.

33A. The method of embodiment 28A, wherein the MTAP-null cancer is biliary tract cancer. 34A. The method of embodiment 28A, wherein the MTAP-null cancer is head and neck squamous cell carcinoma.

35A. The method of embodiment 28A, wherein the MTAP-null cancer is pancreatic adenocarcinoma.

36A. The method of embodiment 28A, wherein the MTAP-null cancer is gallbladder cancer.

37A. The method of embodiment 28A, wherein the MTAP-null cancer is mesothelioma.

38A. The method of embodiment 28A, wherein the cancer is not a primary brain tumor or lymphoma.

39A. The method of embodiment 28A, wherein the MTAP-null cancer is esophageal/gastric cancer.

40A. The method of embodiment 28A, wherein the MTAP-null cancer is glioma.

41A. The method of any one of embodiments 28A-40A, comprising administering 40 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

42A. The method of any one of embodiments 28A-40A, comprising administering 120 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

43A. The method of any one of embodiments 28A-40A, comprising administering 200 mg Compound G based upon free base weight of Compound G, to the patient once daily.

44A. The method of any one of embodiments 28A-40A, comprising administering 240 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

45A. The method of any one of embodiments 28A-40A, comprising administering 300 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

46A. The method of any one of embodiments 28A-40A, comprising administering 400 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

47A. The method of any one of embodiments 28A-40A, comprising administering 480 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

48A. The method of any one of embodiments 28A-40A, comprising administering 500 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

49A. The method of any one of embodiments 28A-40A, comprising administering 600 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

50A. The method of any one of embodiments 28A-40A, comprising administering 700 mg Compound G, based upon free base weight of Compound G, to the patient once daily. 51A. The method of any one of embodiments 28A-40A, comprising administering 800 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

52A. The method of any one of embodiments 28A-40A, comprising administering 900 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

53A. The method of any one of embodiments 28A-40A, comprising administering 1000 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

54A. The method of any one of embodiments 28A-40A, comprising administering 1100 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

55A. The method of any one of embodiments 28A-40A, comprising administering 1200 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

56A. The method of any one of embodiments 28A-40A, comprising administering 1600 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

57A. The method of any one of embodiments 28A-40A, comprising administering 200 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

58A. The method of any one of embodiments 28A-40A, comprising administering 300 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

59A. The method of any one of embodiments 28A-40A, comprising administering 400 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

GOA. The method of any one of embodiments 28A-40A, comprising administering 500 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

61 A. The method of any one of embodiments 28A-40A, comprising administering 600 mg

Compound G, based upon free base weight of Compound G, to the patient twice daily.

62A. The method of any one of embodiments 28A-40A, comprising administering 800 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

63A. The method of any one of embodiments 28A-40A, comprising administering 1200 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

64A. The method of any one of embodiments 1A-63A, wherein Compound G is administered orally.

65A. The method of embodiment 64A, wherein Compound G or salt thereof is administered as a tablet formulation.

66A. A method of treating a MTAP-null cancer in a patient in need thereof comprising orally administering to the patient 800 mg Compound G, or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

67A. The method of embodiment 66A, wherein Compound G or salt thereof is administered in a tablet formulation.

68A. The method of embodiment 66A or 67A, wherein the MTAP-null cancer is pancreatic ductal adenocarcinoma.

69A. The method of embodiment 66A or 67A, wherein the MTAP-null cancer is biliary tract cancer.

70A. The method of embodiment 66A or 67A, wherein the MTAP-null cancer is non-small cell lung cancer.

71A. A method of treating a MTAP-null cancer in a patient in need thereof comprising orally administering to the patient 1200 mg Compound G, or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

72A. The method of embodiment 71A, wherein Compound G or salt thereof is administered in a tablet formulation.

73A. The method of embodiment 71A or 72A, wherein the MTAP-null cancer is pancreatic ductal adenocarcinoma.

74A. The method of embodiment 71A or 72A, wherein the MTAP-null cancer is biliary tract cancer.

75A. The method of embodiment 71A or 72A, wherein the MTAP-null cancer is non-small cell lung cancer.

EXAMPLES

Example 1 - Methylthioadenosine (MTA)-cooperative PRMT5 inhibitor monotherapy in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors [0106] This is a first in human (FIH), multicenter, open-label, phase 1/1 b/2 study evaluating the safety, tolerability, pharmacokinetics (PK), PD, and efficacy of Compound G in adult subjects with advanced MTAP-null solid tumors. Compound G is an MTA-cooperative PRMT5 inhibitor (PRMT5i) that preferentially targets the MTA- bound state of PRMT5 that is enriched in MTAP-null tumors and thus represents a novel strategy to enhance the therapeutic margin of this class of inhibitors.

[0107] Compound G is administered orally (PO) once daily (QD) or twice daily (BID), continuously.

[0108] Part 1a - Compound G monotherapy exploration/escalation

[0109] Compound G is administered continuously in cycles of 28 days (QD or BID). Compound G is administered in a fasted state (no food or liquids, except water, 2 hours before dosing and no food until at least 1 hour after dosing).

[0110] Dose exploration cohorts evaluate the safety, tolerability, PK, and PD of escalating doses of Compound G in subjects with solid tumors with known MTAP deletion by next-generation sequencing (NGS), known cyclin dependent kinase inhibitor 2A (CDKN2A) deletion by NGS, or MTAP loss of protein expression by immunohistochemistry (INC). Enrollment into the dose exploration cohorts are from any eligible solid tumor type.

[0111] The dose exploration part of the study estimates the MTD using a Bayesian logistic regression model (BLRM) design. At the completion of each cohort, the DLRT recommends the next dose level using the dose level recommendation from the BLRM and by evaluating available safety data, laboratory results, and PK information. A dose level of interest is identified based on emerging safety, efficacy, PK, and PD data before reaching an MTD. This will allow for further signal finding in the dose expansion cohorts (Parts 1c to 1 h) and inform selection of indication(s) for Part 1i. A minimum of 6 DLT evaluable subjects are required to be treated at the monotherapy dose level of interest in this dose exploration part of the study, before proceeding to dose expansion in Parts 1c to 1h, 1l, 1m.

[0112] In the case that 1600 mg QD is deemed as intolerable, the dose is de-escalated to 600 mg BID. If 600 mg BID is deemed to be safe and tolerable by DLRT, the dose can be escalated to 800 mg BID. Furthermore, if 800 mg BID is deemed as safe and tolerable by DLRT the next dose level of 1200 mg BID is evaluated without exploration of 2400 mg QD.

[0113] The dose levels for Compound G to be evaluated in Part 1 a of the study are 40, 120, 240, 480, 800, 1200, and 1600 mg administered PO QD or 600, 800, and 1200 mg BID for 28 consecutive days.

[0114] Planned doses and/or dosing intervals may be modified based on emerging PK, safety, tolerability, and efficacy data from prior cohorts. In Part 1, the DLT evaluation period is 28 days after the first dose of Compound G.

[0115] The dosing within each cohort in Part 1 a is staggered such that the first dose of the first subject and the first dose for the second subject in a new cohort are separated by a minimum of 48 hours.

[0116] Parts 1c to 1l - Compound G monotherapy expansion [0117] Upon identification of the dose level of interest and/or maximum tolerated dose (MTD), Compound G dose expansion commences with cohorts:

[0118] -MTAP-null non-small cell lung cancer (NSCLC) (Part 1c),

[0119] -MTAP-null biliary tract cancer (BTC) (Part 1e) ,

[0120] -MTAP-null head and neck squamous cell carcinoma (HNSCC) (Part 1f),

[0121] -MTAP-null pancreatic adenocarcinoma (Part 1g), and

[0122] -MTAP-null solid tumors, other than primary brain tumor and lymphoma (Part 1h).

[0123] -MTAP-null esophageal/gastric cancer (Part 1l)

[0124] -MTAP-null glioma (Part 1m)

[0125] Enrollment of some expansion cohorts 1c to 1h, 1l, 1m may proceed before the enrollment of other cohorts, so that all cohorts may not begin enrollment at the same time. For Part 1 h, if ≥ 5 subjects are enrolled from any single tumor type, sponsor may restrict further the enrollment from that tumor type in Part 1 h to ensure a heterogeneous population of solid tumors are included. Based on emerging PK/safety/efficacy/pharmacodynamic data sponsor may recommend a change in the dosing regimen. The recommended alternative regimen is applied prospectively to all new subjects enrolling in expansion cohorts and any subjects on treatment may have the option to transition to the alternate regimen.

[0126] The study may be amended to add or remove cohorts based on enrollment rate, prevalence of MTAP- null, preliminary efficacy and safety data, and evolving data on other potential solid tumor indications. Therefore, the sponsor reserves the right to stop recruitment/enrollment of any of the cohorts at any time.

[0127] Once monotherapy dose level of interest and/or MTD is/are identified, and depending on data obtained, dose expansion to further characterize the safety and efficacy may proceed in the following tumor types, with known MTAP deletion by NGS or MTAP loss of protein expression by IHC:

[0128] Part 1c: MTAP-null NSCLC (n = up to 40)

[0129] Part 1e: MTAP-null BTC (n = up to 40)

[0130] Part 1f: MTAP-null HNSCC (n = up to 40)

[0131] Part 1g: MTAP-null pancreatic adenocarcinoma (n = up to 40)

[0132] Part 1h: MTAP-null solid tumors, other than primary brain tumor and lymphoma (n = up to 40)

[0133] Part 1l: MTAP-null esophageal/gastric cancer (n = up to 40)

[0134] Part 1m: MTAP-null glioma (n = up to 40)

[0135] Dose optimization (Part 1i) [0136] Dose optimization may only begin upon passing the futility criteria for one of the expansion arms (Part 1c to 1h, 1l, and 1m) to minimize the exposure of subjects prior to establishing a minimum level of clinical activity. Eligibility criteria for Part 1i matches the eligibility criteria of the given expansion arm from which the indication(s) was selected. Part 1i is a randomized dose optimization evaluation for up to 3 doses and/or regimens. Randomization is with equal distribution across randomized arms. The indication of the randomized dose optimization is based on the totality of the data generated from the expansion cohorts that have enrolled.

[0137] Phase 1, Part 1J Drug substance particle size (DSPS) substudy

[0138] The DSPS assessment is being conducted in approximately 6 subjects in US only sites. Additional subjects may be added to this substudy to ensure at least 6 subjects complete all PK collection timepoints. The eligibility criteria for subjects in Part 1j matches the eligibility criteria for those in Part 1a. On cycle 2 day 1 and day 3, subjects receive their dose of Compound G (reference tablet) at the clinic. Subjects return to the clinic on cycle 2 day 2 to receive a comparator dose of Compound G (test tablet). For days 3 to 28, the subject returns to Compound G dosing with the reference tablet. Pharmacokinetic samples are collected prior to dosing and at various time points over a 24-hour period after dosing on both days.

[0139] Phase 1, part 1k Food effect substudy

[0140] A food effect substudy is being conducted in at least 12 subjects in US only sites. Additional subjects may be enrolled to replace subjects that are not evaluable for food effect, to ensure that at least 12 subjects complete food effect assessments. The eligibility criteria for subjects in Part 1k matches the eligibility criteria for those in Part 1a. On cycle 1 day 15, subjects receive their dose of Compound G with approximately 240 ml (8 ounces) of water under fasted conditions (no food or liquids, except water) for ≥ 4 hours prior to ingesting their dose of Compound G at the clinic. The subjects fast again before returning to the clinic on cycle 1 day 16 to ingest their dose of Compound G after eating a standardized high-fat, high calorie meal. Pharmacokinetic samples are collected prior to dosing and at various time points over a 24-hour period after dosing on both days.

[0141] Sample size determination:

[0142] For Part 1a dose exploration cohorts, up to 181 subjects are enrolled. For dose level of 40, 120, and 240 mg, 13 subjects are enrolled in total. The maximum number of subjects enrolled to each dose at 480, 800, 1200, and 1600 mg QD level and 600, 800, and 1200 mg BID including backfill, does not exceed 24. In addition, there are approximately up to 6 and 12 subjects in Part 1 j DSPS and Part 1 k food effect substudies, respectively.

[0143] For Part 1 c to Part 1 h, 1l and 1 m (dose expansion cohorts), up to 280 subjects are enrolled.

[0144] For Part 1i, up to 120 subjects are being enrolled. Up to 3 dose levels with maximum of 40 subjects at each dose level are enrolled.

[0145] Inclusion criteria:

[0146] -Subject has provided informed consent/assent before initiation of any study specific activities/procedures. [0147] -Age ≥ 18 years.

[0148] -Evidence of homozygous loss of CDKN2A (null) (Parts 1a, 1j, 1k) and/or MTAP (null) in the tumor tissue or blood (Parts 1a to 1k) or lost MTAP expression in the tumor tissue (Parts 1a to 1k). Subjects with known MTAP-intact status (MTAP not deleted per local NGS) are not eligible to enroll.

[0149] -Histologically confirmed metastatic or locally advanced solid tumor not amenable to curative treatment with surgery and/or radiation.

[0150] -Parts 1a, 1j, and 1k: MTAP-null and/or CDKN2A-null or lost MTAP expression solid tumor for which no standard therapy exists; or standard therapy has failed or not available/tolerated; or in the investigator’s opinion, standard therapy does not result in meaningful clinical benefit.

[0151] -Part 1c: MTAP-null or lost MTAP expression NSCLC:

[0152] -T reated with 1 to 3 prior lines of systemic therapy for metastatic/locally advanced disease. Note:

Targeted therapies for actionable mutations do not count as a line of therapy for subjects whose tumors harbor those actional mutations.

[0153] -Without actionable mutations (i.e, EGFR, ALK, MET, RET, ROS1, KRASG12C): Treated with 1 to 3 prior lines of systemic therapy for metastatic/locally advanced disease and must have received platinumbased chemotherapy and should have received anti-programmed death-ligand 1 (PD-L1) therapy unless contraindicated (e.g, autoimmune disorders) or PD-L1 expression was tested and below 1%.

[0154] -With actionable mutation mutations (i.e, EGFR, ALK, MET, RET, ROS1, KRASG12C): Subjects with actionable genomic tumor aberrations should have disease progression on approved therapy for these aberrations.

[0155] Note: Subjects with only 1 previous line of treatment may be included only if they cannot receive the standard second line therapy due to intolerance or other medically sound reasons.

[0156] Part 1e: MTAP-null or lost MTAP expression BTC treated with 1 to 2 prior lines of systemic therapy for metastatic/locally advanced disease, to include platinum-based chemotherapy and targeted therapy if fibroblast growth factor receptor fusion/rearrangement was identified.

[0157] Part 1f: MTAP-null or lost MTAP expression HNSCC, treated with 1 to 2 prior lines of systemic therapy for metastatic/locally advanced disease, to include platinum-based chemotherapy and PD-1 or PD-L1 inhibitor.

[0158] Part 1g: MTAP-null or lost MTAP expression pancreatic adenocarcinoma, treated with 1 to 2 prior lines of systemic therapy, including standard chemotherapy regimen such as mFOLFIRINOX, gemcitabine/abraxane. Progression or recurrence within 6 months of completion of neoadjuvant or adjuvant chemotherapy can be considered 1 prior line of systemic therapy. [0159] Part 1 h: MTAP-null or lost MTAP expression solid tumors (other than lymphoma or primary brain tumor), for which no standard therapy exists; or standard therapy has failed or not avai lable/tolerated; or in the investigator’s opinion, standard therapy does not result in meaningful clinical benefit.

[0160] Note: If ≥ 5 subjects are enrolled from any single tumor type, sponsor may restrict further the enrollment from that tumor type in Part 1h to ensure a heterogeneous population of solid tumors are included.

[0161] Part 1i: Enrollment criteria for Part 1i are to match the criteria of the expansion arm from which the indication was selected.

[0162] Part 1l: MTAP-null or lost MTAP expression esophageal/gastric cancer, treated with 1 to 3 prior lines of systemic therapy for metastatic/locally advanced disease, to include platinum-based chemotherapy. Subjects with human epidermal growth factor receptor 2 (HER2) positive cancer should have disease progression on or be intolerant to approved HER2 directed therapies. Progression or recurrence within 6 months of completion of neoadjuvant chemotherapy can be considered 1 prior line of systemic therapy.

[0163] Part 1m: MTAP-null or lost MTAP expression grade 3 or 4 glioma (per World Health Organization classification) treated with 1 to 2 prior lines of therapy including chemotherapy and radiation. Rechallenge with previous line of therapy does not count as a new line. Note: Subjects for whom, in the clinical judgment of the investigator, chemotherapy and/or radiotherapy is not considered standard of care may be eligible after consultation with medical monitor.

[0164] Disease measurable as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1, Eisenhauer et al., J Cancer. 2009;45(2):228-247.). Note: except subjects enrolling to Part 1m.

[0165] Eastern Cooperative Oncology Group (ECOG) (Oken et al., 1982, Am J Clin Oncol., 5(6):649-655) performance status of 0 to 1.

[0166] Adequate hematopoietic function per local laboratory, defined as:

-absolute neutrophil count ≥ 1.5 x 10⁹/L without growth factor support within 7 days (granulocyte colony stimulating factor [G-CSF]) or 14 days (pegylated G-CSF) before screening assessment; -platelet count ≥ 100 x 10⁹/L without platelet transfusion within 7 days before screening assessment;

-hemoglobin > 9 g/dL without RBC transfusion within 7 days before screening assessment.

[0167] Adequate renal function per local laboratory, defined as:

-creatine clearance ≥ 60 ml/min based on the Cockcroft-Gault glomerular filtration rate estimation or Modification of Diet in Renal Disease formula.

[0168] Adequate glucose control per local laboratory (Part 1a only), defined as: -fasting blood glucose ≤ 160 mg/dL.

[0169] Adequate liver function per local laboratory, defined as:

-Part 1: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 X upper limit of normal (ULN) (or < 5 X ULN for subjects with liver metastases);

-Part 1: total bilirubin < 1.5 X ULN (or < 2.0 X ULN for subjects with liver metastases, documented Gilbert’s syndrome).

-Part 2: AST and ALT ≤ 1.5 X ULN;

-Part 2: total bilirubin ≤ ULN (or < 1.5 X ULN for subjects with liver metastases, documented Gilbert’s syndrome).

[0170] Adequate coagulation parameters, defined as:

[0171] prothrombin time or activated partial thromboplastin time < 1.5 X ULN, and International normalized ratio (INR) < 1.5 X ULN or without target range if on prophylactic anticoagulation therapy.

[0172] Adequate pulmonary function, defined as:

[0173] no clinically significant pleural effusion (s/p indwelling catheter allowed for NSCLC and malignant pleural mesothelioma, if subject requires drainage less frequently than once every 2 weeks)

[0174] baseline oxygen saturation > 90% at rest on room air.

[0175] Adequate cardiac function, defined as:

[0176] -cardiac ejection fraction > 50% as determined by an echocardiogram or multiple-gated acquisition scan

[0177] -no evidence of clinically significant pericardial effusion

[0178] -350 msec < baseline QTc ≤ 470 msec (based on average of screening triplicates.

[0179] Minimum life expectancy of 12 weeks as per investigator judgement.

[0180] A total of 25 slides of archived tumor tissue (formalin-fixed, paraffin-embedded [FFPE] sample collected within 5 years before screening) or an archival block must be available. The archival sample must have tumor content review with at least 20% of tumor material pre-submission. Subjects without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before Compound G dosing (cycle 1 day 1).

Subjects without sufficient archived tissue available and with no medical feasibility for a new tumor biopsy may be allowed to enroll upon agreement between the investigator and the Medical Monitor.

[0181] For Part 1f (MTAP-null or lost MTAP expression HNSCC): Must be willing to undergo tumor biopsy, before start of treatment (archival sample acceptable if obtained with 6 months of enrollment and subject has not received any other treatment since sample was obtained) and again approximately 4 weeks after starting treatment.

[0182] Food Effect Substudy (Part 1 k): Specific Inclusion Criteria. Subject able and willing to eat a standardized high-fat, high-caloric meal. Subject able and willing to fast for 6 hours.

[0183] Specific Inclusion Criteria for subjects with glioma (Part 1 m only)

[0184] -Disease measurable as defined per Modified Response Assessment in Neuro-Oncology Criteria 2.0 (mRANO 2.0) as follows:

[0185] - At least 1 contrast-enhancing lesions that can accurately be measured (with clearly defined margins) bi-d i mensional ly with ≥ 10 mm longest diameter and ≥ 10 mm perpendicular diameter and noted on more than one imaging slice that are ≤ 4 mm apart with 0-mm interslice gap.

[0186] Note: Imaging must be performed within 14 days of enrollment. Stable dose of steroid medication (defined as dexamethasone ≤ 4 mg [or equivalent] per day for at least 14 days immediately before and during imaging study) may be allowed after consultation with medical monitor.

[0187] -Karnofsky Performance Status 70 (Karnofsky DA, Burchenal JH. In: Evaluation of chemotherapeutic agents. MacLeod CM, editor. New York: Columbia University Press; 1949. The clinical evaluation of chemotherapeutic agents in cancer; pp. 191-205.)

[0188] -Tumor Treating Fields (TTF) device discontinued at least 24 hours prior to initiating Compound G.

[0189] Exclusion criteria:

[0190] Disease related:

- Spinal cord compression or untreated brain metastases or leptomeningeal disease. Subjects who have had brain metastases and have been appropriately treated with radiation therapy or surgery ending at least 4 weeks before study day 1 are eligible if they meet all of the following criteria: a) stable or improving residual neurological symptoms grade ≤ 2; and b) on stable doses of dexamethasone, if applicable.

[0191] Other Medical Conditions:

-History of other malignancy within the past 2 years, with the following exceptions:

-Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician.

-Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.

-Adequately treated cervical carcinoma in situ without evidence of disease.

-Adequately treated breast ductal carcinoma in situ without evidence of disease.

-Prostatic intraepithelial neoplasia without evidence of prostate cancer.

-Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ.

-Adequately treated prostate cancer with a Gleason score of ≤ 6. (Gleason, Cancer

Chemother Rep. 1966 Mar;50(3): 125-8).

[0192] -Any evidence of current interstitial lung disease or pneumonitis or a prior history of interstitial lung disease or non-infectious pneumonitis within 12 months before first dose of Compound G.

[0193] -Active infection requiring systemic therapy.

[0194] -Evidence of active SARS-COV2 infection. If known or suspected recent SARS-COV2 infection, a minimum of 10 days after symptom onset, if any, must have elapsed.

[0195] -History of arterial thrombosis (e.g., stroke or transient ischemic attack) within 6 months before first dose of Compound G.

[0196] -Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication within 12 months before first dose of Compound G.

[0197] -Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis). Note: subjects with a nasogastric tube may be exempt from this exclusion, in consultation with the sponsor Medical Monitor.

[0198] -History of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of study entry unless approved by the principal investigator and the Medical Monitor or history of gastrointestinal procedure(s) that result in malabsorption.

[0199] -History of solid organ transplant.

[0200] -Diagnosis of Congenital Short QT Syndrome.

[0201] Prior Concomitant Therapy

[0202] - Major surgery before 28 days of first dose of Compound G.

[0203] -Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, hormonal therapy, or investigational agent) before 28 days of study day 1 , unless anti-tumor therapy is a therapy with 5 times the half-life being shorter than 28 days (in this case, enrollment may be allowed with washout from prior therapy of D 28 days, in consultation with the Medical Monitor).

[0204] - Bisphosphonate or denosumab for skeletal related events is permitted [0205] - Prior treatment with an MAT2A inhibitor or a PRMT5 inhibitor.

[0206] - Prior irradiation to > 25% of the bone marrow.

[0207] - Therapeutic or palliative radiation therapy within 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity. Note: subjects enrolling in Part 1m may not have any therapeutic or palliative radiation within 3 months before study day 1.

[0208] - Live vaccine therapy within 4 weeks before study drug administration.

[0209] - Use of therapeutic anti-coagulation for treatment of active thromboembolic events. Subjects receiving a stable dose of anti-coagulation therapy for thromboembolic events for a duration ≥ 3 months may be eligible upon approval of principal investigator. For subjects receiving anti-coagulation and undergoing biopsies, safety precautions such as a drug holiday may be considered if deemed necessary and safe by the investigator.

[0210] - Use of prescription medications that are known strong inducers (including rifampin, mitotane, avasimibe, rifapentine, apalutamide, ivosidenib, phenytoin, carbamazepine, enzalutamide, St John's wort extract, lumacaftor and phenobarbital) or inhibitors (including 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) 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.

[0211] - Unresolved 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. Grade 2 or 3 toxicities from prior anti-cancer therapy that are considered irreversible (defined as having been present and stable for

months), such as endocrinopathies controlled with hormone replacement therapy may be allowed if they are not otherwise described in the exclusion criteria and there is agreement to allow by both the investigator and the sponsor.

[0212] Prior/Concurrent Clinical Study Experience

[0213] - Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.

[0214] Other exclusions:

[0215] - Female subjects of childbearing potential unwilling to use contraception during treatment and for an additional 30 days after the last dose of Compound G. [0216] - Female subjects who are breastfeeding or who plan to breastfeed while on study through 30 days after the last dose of Compound G.

[0217] - Female subjects planning to become pregnant while on study through 30 days after the last dose of Compound G.

[0218] -Female subjects of childbearing potential with a positive pregnancy test assessed at screening and on day 1 by a highly sensitive urine or serum pregnancy test.

[0219] - Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 21 days after the last dose of Compound G.

[0220] - Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 30 days after the last dose of Compound G

[0221] - Male subjects unwilling to abstain from donating sperm during treatment and for an additional 30 days after the last dose of Compound G

[0222] - Subject has known sensitivity to any of the products to be administered during dosing.

[0223] - For Parts 1c to 1h, 1l, and 1m subject unable to receive both iodinated contrast for computed tomography (CT) scans and gadolinium contrast for magnetic resonance imaging (MRI) scans.

[0224] - Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (e.g., Clinical Outcome Assessments) to the best of the subject and investigator’s knowledge.

[0225] - History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or sponsor physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.

[0226] Specific Exclusion Criteria for subjects with glioma (Part 1 m only)

[0227] -Treatment with non-topical systemic corticosteroids within 28 days before enrollment (cycle 1 day 1) (exemption: stable prophylactic or therapeutic dexamethasone at doses of ≤ 4 mg [or equivalent] per day may be allowed after consultation with medical monitor).

[0228] -Evidence of acute intracranial/intratumoral hemorrhage, except for subjects with stable grade 1 hemorrhage or fresh biopsy.

[0229] -Prior therapy with bevacizumab of other antiangiogenic therapy within 3 months before study.

[0230] -Evidence of extensive leptomeningeal disease or brainstem involvement.

[0231] -Rapid worsening in neurological symptoms severity indicative of rapid tumor progression.

[0232] Dose modification: [0233] A minimum of 6 DLT evaluable subjects will be required to determine the dose level of interest/MTD at the associated dose level. A recommendation to escalate to a higher dose cohort will only occur when the previous dose regimens have been found to be reasonably tolerated based on available study data through study day 28/21 for all DLT-evaluable subjects enrolled in the dose cohort and upon unanimous agreement of the DIRT members. Available data from previous cohorts will also be considered. Dose level recommendations will be made on a treatment cohort basis (not on an individual basis).

[0234] A DLT is defined as any adverse event meeting the criteria listed below occurring during the first treatment cycle of Compound G (day 1 through day 28 for Part 1a), excluding toxicities clearly related to disease progression or intercurrent illness. The DLT window may also be extended to assess events starting within the window in case the DLT definition is time dependent (e.g., thrombocytopenia). The grading of adverse events will be based on the guidelines provided in the CTCAE version 5.0. A DLT is defined as any of the following events during the first treatment cycle:

[0235] -Grade 5 toxicity

[0236] - Failure to receive at least 80% of the planned dose for cycle 1 because of dose adjustments or dose withholding caused by treatment-related adverse events

[0237] -Unresolved adverse event grade 2 that results in prolonged delay (> 14 days) in initiating cycle 2

[0238] -Any grade ≥ 2 toxicity that causes the subject to permanently discontinue treatment during cycle 1 and deemed by the investigator to be clinically significant

[0239] -Hematological toxicity

[0240] - Febrile neutropenia

[0241] - Grade 4 neutropenia

[0242] - Grade ≥ 3 thrombocytopenia for > 7 days

[0243] - Grade 3 thrombocytopenia with grade ≥ 2 bleeding

[0244] - Grade 4 thrombocytopenia

[0245] - Grade ≥ 3 anemia requiring transfusion

[0246] - Grade 4 anemia

[0247] -Non-hematological toxicity

[0248] - Grade ≥ 2 pneumonitis

[0249] - Grade ≥ 2 encephalopathy, or grade ≥ 2 motor or sensory neuropathy that lasts > 7 days

[0250] - AST or ALT > 5 X ULN (grade ≥ 3) without liver metastases

[0251] - AST or ALT > 8 X ULN in subjects with liver metastases [0252] - AST or ALT > 3 X ULN and total bilirubin > 2 X ULN (in subjects with Gilbert syndrome: AST or

ALT > 3 X ULN and direct bilirubin > 1.5 X ULN)

[0253] - Total bilirubin > 3 X ULN (grade ≥ 3)

[0254] - Gul Iain-Barre syndrome or myasthenic syndrome/myasthenia gravis

[0255] - Liver function test elevations lasting > 7 days that are considered to be clinically significant

[0256] - Grade 4 fatigue and anorexia of any duration and grade 3 fatigue or anorexia with duration > 7 consecutive days

[0257] - Grade 4 vomiting or diarrhea

[0258] - Grade 3 diarrhea or grade 3 vomiting lasting more than 3 days

[0259] - Grade 3 nausea for 3 days or more

[0260] - Any subject meeting the criteria for Hy’s Law case (ie, severe drug-induced liver injury) will be considered a DLT

[0261] - Any other grade 3 adverse event

[0262] The following adverse events will NOT be adjudicated as DLT:

[0263] - Laboratory parameters of grade 3 which resolved to baseline or grade ≤ 1 within 72 hours without intervention, grade 3 electrolyte abnormalities deemed not clinically significant by the investigator and respond to conventional medical intervention within 72 hours will not be adjudicated as DLT.

[0264] Dose limiting toxicity (DLT)-evaluable is defined as completion of 80% of planned Compound G doses within the first treatment cycle (i.e., 28 days in Part 1a). A subject who experiences a DLT within the first cycle is DLT evaluable regardless of number of doses taken. If a subject is withdrawn from study for any reason other than a DLT before completion of the 28-day safety observation period, a replacement subject may be needed and will be assigned the same dose as the replaced subject.

[0265] Intra-subject Dose Escalation

[0266] Intra-subject dose escalations are allowed on this study in Parts 1 a, 1 j, and 1 k.Subjects who have completed the DLT period may proceed to a higher dose level in a subsequent treatment cycle once this higher dose level has been assessed as safe by the DIRT and after consultation with the Medical Monitor if no DLT has been reported for this subject during or after completion of the DLT period or the subject has not experienced any grade ≥ 2 adverse events (deemed treatment related by the investigator) during treatment. In addition, intra- subject dose escalation is not allowed for subjects enrolled in the DSPS and food effect sub-studies until after completion of cycle 2 day 3.

[0267] Dose expansion study stopping criteria [0268] At any point during dose expansion, enrollment will be paused at the occurrence of ≥ 2 grade 4 or ≥ 1 grade 5 adverse events unless the events are clearly attributed to causes other than Compound G.

[0269] Guidance for Nausea and Vomiting

[0270] - Subjects are required to take one dose of oral antiemetic (5-hydroxytryptamine 3 [5-HT3] receptor agonist [e.g., ondansetron] or dopamine receptor antagonist [eg, prochlorperazine]) at least 30 minutes before each Compound G dose starting cycle 1 day 1 until cycle 1 day 15.

[0271] - Starting cycle 1 day 16, subjects may take Compound G once daily before bed (QHS); Note: except subjects in Part 1j and 1 k. As of cycle 1 day 16, antiemetic prophylaxis is to be stopped and further antiemetic use is per investigator’s clinical assessment.

[0272] Conditions for withholding and/or permanent discontinuation of Compound G

[0273] Resumption criteria

[0274] Compound G dosing can be resumed at a lower dose or different dosing schedule if subject meets all the following criteria: For nausea and vomiting, subjects may resume dose at same dose level and follow guidance in the Table entitled: Compound G Dose Modification and Management Guidelines for Nausea and Vomiting. Subjects who undergo dose reductions may escalate back to their initial planned dose with approval of investigator after consultation with medical monitor. (Note: The lowest dose level permitted for reduction is 480 mg. Dose reductions to an intermediate dose between 2 dose levels previously cleared by DLRT are permitted):

[0275] -If subject meets the following hematological requirements: absolute neutrophil count ≥ 1.5 x 10⁹/L, platelet count ≥ 100 x 10⁹/L, and hemoglobin > 9 g/dl.

[0276] -If non-hematological toxicities resolve to grade ≤ 1 or return to subjects’ baseline value

[0277] -Once restarting of therapy is deemed safe by the investigator

[0278] -A subject must not have growth factor support, RBC and/or platelet transfusion for at least 7 days before assessing if re-exposure to Compound G can occur.

[0279] In the event of QTc shortening (defined as QTc < 320 msec or a decrease of 80 msec from baseline [Shah, 2010]), the following guidance is recommended:

[0280] -If the subject has no cardiac symptoms, no new onset arrhythmia, and average of triplicate ECGs demonstrates QTc shortening, then interrupt Compound G administration must be delayed, and triplicate ECGs repeated between 15 and 30 minutes later. If asymptomatic QTc shortening persists, then hold Compound G to allow: 1 ) correction of any abnormal electrolytes (calcium, potassium); 2) cardiology consult; and 3) review of the case with the Medical Monitor.

[0281] -If the subject has cardiac symptoms or new onset arrhythmia in the presence of QTc shortening, hold Compound G provide standard of care for the cardiac sign/symptoms, consult cardiology, and discuss the case with the Medical Monitor.

[0282] -If the QTc shortening is not persistent, and not clinically relevant per cardiology consultation, the subject may resume Compound G after consultation with the Medical Monitor.

[0283] A subject should not be re-challenged with Compound G if any of the following Compound G related adverse events occur:

[0284] -Any life-threatening adverse events

[0285] -Subject meets all the conditions of Hy’s Law

[0286] -Persistent grade 3 adverse events that do not recover to baseline or grade 1 within 4 weeks of last dose

[0287] -Any treatment-related adverse events meeting DLT criteria that recurs RESULTS

[0288] In a review of data from an 8 Aug 2023 data cutoff, 47 patients with MTAP-null cancer (PDAC n = 10; NSCLC n = 6; CCA = 5; MESO n = 3; others n = 23) were enrolled in seven dose-escalating (QD) cohorts of Compound G (i.e., 40 mg, 120 mg, 240 mg, 480 mg, 800 mg, 1200 mg or 1600 mg). Five patients had dose limiting toxicities (DLTs). The most common treatment related adverse events (TRAEs) were nausea (45%), fatigue (26%), decreased appetite (17%), and vomiting (17%). Preliminary PK analyses showed doseproportional systemic exposure with a half-life of 7-11 hours. Among 31 subjects who had at least one postbaseline scan, there were 5 with confirmed partial responses (PRs) [ pancreatic ductal adenocarcinoma (PDAC) (-100%), ovarian Sertoli-Leydig (-59%), RCC (-58%), esophageal (-46%), and gallbladder cancer (-63%), 1 each], 14 with stable disease [including 9 with some degree of tumor shrinkage], and 12 with disease progression. All PRs were ongoing at the data cutoff with treatment durations of 140-275 days. Progressive disease (PD) effects demonstrated dose-dependent reduction in serum total SDMA levels and complete PRMT5 inhibition was confirmed in five patients with on-treatment biopsies spanning multiple dose levels. Exploratory analysis of changes in variant allele frequency by circulating tumor deoxyribonucleic acid (ctDNA) demonstrated rapid treatment effects that was predictive and correlated with response. Prolonged disease stabilization was observed at ≥480 mg. 10 patients treated longer than 16 weeks showed no evidence of cumulative toxicity.

Responses occurred as early as 16 weeks (800 mg) and 8 weeks (1200 mg). 3 out of 5 responders remained on treatment. At 1200 mg, 4 of 9 patients remain on treatment.

[0289] Accordingly, Compound G was demonstrated to represent a class of targeted therapeutics designed to induce synthetic lethality in MTAP-null solid tumors while sparing hematologic toxicity. No evidence of clinically significant myelosuppression was observed consistent with proof of mechanism, demonstrating both a favorable therapeutic window and an opportunity for combination therapy. Dose-limiting adverse events and treatment discontinuations were typically due to Gl events. PK/PD effects confirmed robust target engagement with once daily dosing.

DOSE EXPLORATION - 23 May 2024 Data Cutoff

[0290] As of 23 May 2024, 80 patients in dose exploration received Compound G at doses 40-1600 mg QD or 600 mg BID. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). DLTs were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The MTD was determined to be 1200 mg QD. Mean exposure of Compound G increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-evaluable patients treated at the active and tolerable doses of 800 mg QD, 1200 mg QD, or 600 mg BID (n=42), objective response rate (ORR) was 21.4% (95% Cl: 10.3-36.8). Responses were observed across eight different tumor types, including squamous/nonsquamous non-small cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating-tumor DNA [ctDNA] clearance) were observed. These results are described in further detail, below.

[0291] Baseline characteristics

[0292] At the data cutoff date of 23 May 2024, 80 patients received Compound G in dose exploration (cohort 1 : 40 mg QD [N=4]; cohort 2: 120 mg QD [N=2]; cohort 3: 240 mg QD [N=7]; cohort 4: 480 mg QD [N=17]; cohort 5: 800 mg QD [N=18]; cohort 6: 1200 mg QD [N=18]; cohort 7: 1600 mg QD [N=4]; and 600 mg BID cohort [N=10]). Baseline patient characteristics are shown in Table 1.

Table 1. Baseline demographics and disease characteristics for dose exploration

[0293] Overall, 52.5% of patients were male; the median age was 61.5 years (range: 36-83), and 58.8% of patients had an ECOG PS of 1. Patients received a median of two prior lines of therapy (range: 1-8), and 23 patients (28.8%) received ≥4 prior lines of therapy. The most common tumor types were pancreatic duct adenocarcinoma (PDAC) (19; 23.8%), non-small cell lung cancer (NSCLC) (14; 17.5%), biliary tract cancer (BTC) (7; 8.8%), GBM (5; 6.3%), and gastric/esophageal cancer (2; 2.5%). In six of the 80 patients (7.5%), tumors were CDKN2A-deleted but MTAP-intact per central IHC. Therefore, these patients were excluded from the efficacy analysis. All other patients had MTAP deletion by local NGS (55.4%) or central IHC (85.1%) or both (41.3%).

[0294] T reatment was discontinued in 68 patients (85.0%). The primary reason for discontinuation was progressive disease (n=50; 62.5%) followed by patient request (n=9; 11.3%), AEs (n=5; 6.3%), death, and other (n=2; 2.5% each). As shown in Figure 21 , antitumor activity was durable: Median DOR: 8.3 months (95% Cl: 2.7-NE). Median DoDC: 9.2 months (95% Cl: 4.9-11.8). Twelve patients continued on treatment at the time of data cutoff.

[0295] Safety

[0296] Patients received a median of two cycles of treatment. DLTs were reported in eight patients, all at doses ≥240 mg (Table 2), and were vomiting (n=2), nausea, fatigue, hypersensitivity reaction, hypokalemia, encephalopathy, and palpitations (n=1 each; Table 3). The MTD was determined to be 1200 mg QD (11.1% of patients experienced DLTs at this dose level). Safety findings are summarized in the Table 2 and Figure 13. Any- grade TRAEs were reported in 68 patients (85.0%; Table 4) and grade ≥3 in 11 patients (13.8%; Table 5). The most common any-grade TRAEs were nausea (48.8%), fatigue (31.3%) and vomiting (30.0%) occurring mostly at the beginning of treatment and being uncommon past 2 weeks (Figure 14). Serious TRAEs were reported in eight patients (10.0%). There were no fatal TRAEs. TRAEs led to treatment interruption in 22 patients (27.5%), dose reduction in 14 patients (17.5%), and treatment discontinuation in two patients (2.5%; Table 2).

Table 2. Summary of AEs

Table 3. Incidence of DLTs by dose cohort

Table 4 Incidence of TRAEs of any grade in ≥5% of patients by dose cohort

Table 5. Grade ≥3 TRAEs

[0297] Because first-generation non-MTA-cooperative PRMT5 inhibitors were associated with myelosuppression, cytopenias as TEAEs of interest were evaluated. These events (any grade; grade ≥3) were anemia (15.0%; 6.3%), lymphopenia (6.3%; 3.8%), neutropenia (3.8%; 2.5%), and leukopenia (3.8%; 1.3%). Thrombocytopenia was reported in one patient (any grade 1.3%; grade ≥3 none). None of the cytopenia events were dose limiting, and none led to treatment discontinuation.

[0298] Efficacy

[0299] Nine ORs were observed at 800 mg QD, 1200 mg QD, and 600 mg BID across eight tumor types, namely NSCLC (squamous and nonsquamous), PDAC, cholangiocarcinoma, gallbladder cancer, esophageal cancer, melanoma, renal cell carcinoma (RCC), and ovarian Sertoli-Leydig cell tumor (SLCT; Figure 15). The objective response rate (ORR) in these patients at active dose levels (n=42) was 21.4% (95% confidence interval [Cl]: 10.3-36.8), and the disease control rate (DCR) was 54.8% (95% Cl: 38.7-70.2) (Table 6). Median TTR was 3.6 months (range: 3.6— 3.7) and 1.8 months (range: 1.7-3.5) at 800 mg QD and 1200 mg QD, respectively, suggesting shorter TTR at higher doses. Median DOR was 8.3 months (95% Cl: 2.7— NE), and median DoDC was 9.2 months (95% Cl: 4.9-11.8) across all dose exploration cohorts. The longest DOR reported was 12.9 months for a patient with RCC and 11.0 months for a patient with an ovarian SLCT. At data cutoff, responses were ongoing at data cutoff, and five of the nine responders remained on treatment. Table 6. Overview of efficacy

Discussion of Dose Exploration Safety and Efficacy Results

[0300] This phase 1 study determined the MTD of Compound G to be 1200 mg QD. Nausea, vomiting, and fatigue were the predominant DLTs, while hematological toxicity was rare and not dose-limiting. Overall, the tolerability of Compound G was favorable based on the low rate of TRAEs resulting in treatment modification or discontinuation. Consistent with the MTA-cooperative mechanism of action, complete intratumoral inhibition of PRMT5 function in MTAP-deleted tumors was observed across several dose levels (≥480 mg).

[0301] Compound G was well tolerated, and treatment related AEs more commonly encountered, at a frequency of 15% or more, were nausea, fatigue, decreased appetite and vomiting. These AEs were manageable and typically reversible either with standard anti-emetic prophylaxis (e.g. odansetron for nausea and vomiting) or reversed promptly with dose-reduction. Tolerability typically improved with time on therapy beyond 2 weeks and was rarely cumulative in nature. A fractionated dosing schedule was explored to determine if lowering the peak drug exposure could improve the rate of safety events, however no appreciable difference was observed in the safety profile between twice daily dosing and once daily dosing.

[0302] Antitumor activity based on imaging (RECIST) and molecular (ctDNA) responses was observed across a variety of solid tumors, including NSCLC (squamous and nonsquamous), PDAC, BTC, and esophageal cancer at total daily doses of ≥800 mg. Among patients with stable disease, the observation of robust ctDNA reductions following treatment supports the likelihood that Compound G truly mediated anti-tumor activity, rather than confounded by pre-existing indolent disease. Preliminary DOR and DoDC results suggest a sustained treatment effect mediated by Compound G on MTAP-deleted tumors, and mechanisms of resistance are likely to be intrinsic or acquired with time.

[0303] Consistent with the tumor-selective mechanism of action of Compound G conferred by MTA cooperativity, near complete intratumoral reduction in SDMA in MTAP-deleted tumors was confirmed at well- tolerated doses, while an MTAP wildtype tumor showed persistent SDMA as evidence of incomplete intratumoral PRMT5 inhibition. Furthermore, PRMT5 activity was more strongly inhibited within the tumor compared with nontumor based on the degree of SDMA reduction in paired tumor biopsy tissue samples versus peripheral blood. In tumor tissue, there was near complete SDMA loss in all samples while the highest degree of SDMA reduction in the blood did not exceed 80% from baseline.

[0304] Compound G monotherapy had a manageable safety profile and was tolerable at doses up to 1200 mg QD, with no dose-limiting cytopenia events reported. Encouraging anti-tumor activity across multiple MTAP- deleted tumors was observed between 800 mg and 1200 mg.

DOSE EXPANSION STUDY (23 May 2024 Data Cutoff)

[0305] As of 23 May 2024, 87 patients in dose expansion received Compound G at 1200 mg QD. Baseline characteristics are shown in Table 7. Overall, 48.3% of patients were male; the median age was 63 years (range: 28-81), and 66.7% of patients had an ECOG PS of 1. Patients received a median of two prior lines of therapy (range: 1-9), and 17 patients (19.5%) received ≥4 prior lines of therapy. The most common tumor types were pancreatic duct adenocarcinoma (PDAC) (29; 33.3%), non-small cell lung cancer (NSCLC) (15; 17.2%), biliary tract cancer (BTC) (17; 19.5%), and gastric/esophageal cancer (5; 5.7%).

[0306] Safety Profile: As shown in Figure 18, Table 7, and Table 8, Compound G demonstrated an acceptable safety profile, with nausea, vomiting, and fatigue being the three most common TRAEs. In dose expansion, Grade 3 treatment-related adverse events occurred in approximately 18% of patients. No Grade 4 or Grade 5 treatment-related adverse events were reported. Consistent with a tumor-selective mechanism of action, there was no clinically significant myelosuppression and none led to treatment discontinuation.

[0307] In the fasted state, nausea and vomiting was manageable and typically reversible with standard antiemetic management (e.g., ondansetron). Incidence of treatment-related nausea or vomiting at 1200 mg QD reduced from 78% in dose exploration (14/18 patients) to 64% in dose expansion (56/87 patients) following the institution of prophylactic anti-emetic regimens. The median follow-up duration was as follows: dose expansion 3.1 months (95% Cl: 2 3-3.8). Cl, confidence interval; QD, once daily. Nausea and vomiting typically resolved with continued dosing and within 2-4 weeks. See Figure 19.

Table 7. Baseline demographics and disease characteristics for dose exploration and expansion

Table 8. Related Adverse Events in Dose Expansion with 1200 mg QD (N = 87)

[0309] Change in Tumor Burden in Dose Exploration and Expansion: Compound G demonstrated anti-tumor activity across multiple solid tumor types in heavily pretreated patients. Figure 20 (bottom) shows a waterfall plot that includes patients treated at active doses in dose escalation and the ongoing expansion. At active dose levels, responses were observed in multiple tumor types including non-small cell lung cancer, pancreas cancer, biliary tract cancer, esophageal and gastric cancer. Figure 20 (top) shows a swimmer plot extending vertically above corresponding patients on the waterfall plot. Across all tumor types, 6 responses lasted greater than 6 months. Many patients were ongoing on treatment at the time of the data cutoff, including 13 subjects with ongoing partial responses. In addition, 5 subjects with a best response of stable disease were treated for a minimum of 6 months, suggesting that patients with disease stabilization derived clinical benefit.

[0310] The best overall response in the dose exploration and expansion studies at active doses is summarized in Table 9.

Table 9. Best Overall Response in Dose Exploration and Expansion at Active Doses

[0311] As shown in Table 9, responses were observed in 5 of 17 patients with non-small cell lung cancer, 5 of 23 patients with pancreatic ductal adenocarcinoma, 2 of 19 patients with biliary tract cancer, and 2 of 6 patients with esophagogastric cancer. Most patients were ongoing on treatment at the time of the data cutoff, including 13 subjects with ongoing partial responses. In addition, 5 subjects with a best response of stable disease were treated for a minimum of 6 months.

Example 2 - Preliminary Pharmacokinetic profile of Compound G

[0312] Preliminary PK data (data cutoff of 1 September 2023) for Compound G were available in 44 subjects. Mean Compound G observed plasma concentration-time profiles after QD dosing for cycle 1 day 1 and cycle 1 day 15 are provided in Figure 1A and Figure 1B, respectively. Compound G non-compartmental analysis PK parameters for cycle 1 day 1 and cycle 1 day 15 are presented in Table 10 and Table 11, respectively. Overall, the preliminary PK data suggest exposures from 40 mg to 1200 mg PO QD increased in an approximate doseproportional manner. Exposure at 1600 mg resulted in less than dose proportional changes in exposure. Time of maximum absorption (T_max) was within 3 hours, minimal accumulation resulted from multiple PO QD dosing for 15 days, and the estimated terminal elimination half-life was approximately 7 to 11 hours. [0313] Table 10. Preliminary Compound G Noncompartmental Pharmacokinetic Parameter Estimates After Once Daily Administration of Compound G in Cycle 1 Day 1.

Table 11. Preliminary Compound G Noncompartmental Pharmacokinetic Parameter Estimates After Once Daily Administration of Compound G in Cycle 1 Day 15.

[0314] PK data (data cutoff of 10 May 2024) for Compound G were available for 80 patients on cycle 1 day 1 and 67 patients on cycle 1 day 15. The mean (standard deviation) plasma concentration-time profile of Compound G is shown in Figure 16. Compound G demonstrated a dose-proportional increase in plasma exposure within the dose range of 40-1200 mg QD. The plasma concentration with 1600 mg QD was below the mean concentration observed at 1200 mg, possibly due to reduced absorption. Steady-state plasma concentrations were achieved within 2 weeks with QD dosing, with minimal accumulation. The PK parameter estimates are provided in Table 12.

Table 12. Compound G PK parameter estimates using noncompartmental analysis (cycle 1 day 15)

Example 3 - Effect of PRMT5 inhibitors in MTAP-null and Wild-type (WT) H116 cell lines

[0315] The following Example assessed the effect of Compound G in wild-type (WT) and MTAP-null H116 cell lines.

[0316] Plated cells were at optimized cell density in 96-well black walled, clear bottom tissue culture plates in 90μL of growth media. Cells were incubated at room temperature for 30 minutes prior to placing in incubator at 37°C and 5% CO₂ overnight. The next day, Compound G was serially in DMSO with a 1 :3 dilution factor in 96- well V-Bottom plates. Secondary compound dilutions (1:100) in media were done in the 96-well V-Bottom plate by adding 3μL of the primary dilution to 297μL of culture media. Finally, 10μL from the secondary compound dilutions were added to cells in triplicate (1:10 dilution; final DMSO concentration 0.1%). Once addition was complete, plates were incubated at 37°C and 5% CO₂. Cell viability was measured by the CellTiter-Glo Luminescence assay after 6 days of treatment. Percent of Control (POC) values were calculated as follows: POC = 100 * (Treatment I Vehicle). Mean POC values were then calculated for each treatment condition and used to fit dose response curves applying a four parameter logistic curve in GraphPad Prism 7.

[0317] HCT11 WT and MTAP-null global symmetrical dimethylarginine (SDMA) levels were assessed by an ELISA assay after 4 days treatment. As shown in Figure 2A and Figure 2B, Compound G preferentially inhibits viability and SDMA signaling in HCT116 wild-type MTAP-null cells.

Example 4 - Compound G Sensitivity Profile

[0318] Compound G sensitivity profile shown by area under the curve (AUC) across a panel of barcoded cancer cell lines after 5 days of treatment with DMSO or Compound G (8-point concentration range). Cell viability was determined by relative abundance of each cell line barcode. Figure 3A: Compound G AUC versus MTAP status across all lineages, pancreatic, lung, or lymphoma. Dotted red line indicates average. Figure 3B: Compound G AUC versus RNAi knockdown for PRMT5 with the associated Pearson correlation value and p- value. Figure 3C: Compound G AUC versus copy number for MTAP, CDKN2A, and CDKN2B with the associated Pearson correlation value and p-value. ****p < 0.0001.

[0319] The sensitivity profile across all cell lines demonstrated a specific sensitivity to Compound G in a subset of cell lines. The sensitivity profile was generated by the Broad on their PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) platform. Over 850 barcoded cancer cell lines were treated with an 8-point dose response of Compound G for 5 days and relative barcode abundance (compared to vehicle control) was used to generate the cell line sensitivity profile.

Example 5 - Compound G Preferentially Inhibits Cell Viability in Endogenous MTAP Null vs WT Cancer cell Lines

[0320] The following Example assessed the effect of Compound G in wild-type (WT) and MTAP-null pancreatic (AsPC-1, CFPAC-a, PSN-1 and BxPC-3) and NSCLC (CALU, SKMES1, LU99 and H838) cancer cell lines. [0321] Plated cells were at optimized cell density in 96-well black walled, clear bottom tissue culture plates in 90μL of growth media. Cells were incubated at room temperature for 30 minutes prior to placing in incubator at 37°C and 5% CO₂ overnight. The next day, Compound G was serially in DMSO with a 1 :3 dilution factor in 96- well V-Bottom plates. Secondary compound dilutions (1:100) in media were done in the 96-well V-Bottom plate by adding 3μL of the primary dilution to 297μL of culture media. Finally, 10μL from the secondary compound dilutions were added to cells in triplicate (1:10 dilution; final DMSO concentration 0.1%). Once addition was complete, plates were incubated at 37°C and 5% CO₂. Cell viability was measured by the CellTiter-Glo Luminescence assay after 6 days of treatment. Percent of Control (POC) values were calculated as follows: POC = 100 * (Treatment / Vehicle). Mean POC values were then calculated for each treatment condition and used to fit dose response curves applying a four-parameter logistic curve in GraphPad Prism 7.

[0322] Results are shown in Tables 13 and 14 and Figure 4A and Figure 4B.

Table 13.

Table 14.

Example 6 - Compound G demonstrates in vivo MTA cooperative inhibition of PRMT5 in HCT116 MTAP WT versus MTAP-null Bilateral tumor Xenografts

[0323] The following Example described SDMA ELISA analysis of HCT116 MTAP WT and MTAP-Null bilateral tumors. Female Athymic nude mice were dosed with Vehicle or Compound G at various doses (i.e. , 3 mg/kg, 10 mg/kg, 30 mg/kg or 100 mg/kg). Mice were given a total of 4 doses and tumors were collected 4 hours post last dose. Percentage of inhibition reported relative to matched vehicle. Results are shown in Figure 5

Example 7 - Compound G exhibits significant anti-tumor activity in MTAP null cancer cell line derived xenografts. [0324] Female SCID mice were implanted with DOHH-2 (Figure 6A) or BxPC-3 (Figure 6B) tumors. Female athymic nude mice were implanted with LU99 (Figure 6C) or H838 (Figure 6D) tumors. Vehicle and Compound G at various doses (10 mg/kg, 20 mg/kg, or 30 mg/kg) were administered orally (p.o.) once a day for the duration of the study. Data represent group means ± SEM, n = 10. STATS: P values were determined by Linear Mixed- Effects Model with a Dunnett's comparison to control; ****p<0.0001. As shown in Figures 6A-6D, Compound G exhibited significantly reduced tumor volume in all treated xenografts.

Example 8 - Compound G exhibits significant anti-tumor activity in MTAP-null patient-derived models.

[0325] Female NOD/SCID mice were implanted with PA5415 (pancreatic tumors, Figure 7A), LU5268 (NSCLC tumors, Figure 7B), ME12183 (melanoma tumors, Figure 7C) or ES11082 (esophageal tumors, Figure 7D). Vehicle and Compound G at various doses (25 mg/kg, 50 mg/kg, or 100 mg/kg) were administered orally (p.o.) once a day for the duration of the study. Data represent group means ± SEM, n = 10. for each group. STATS: P values were determined by Linear Mixed-Effects Model with a Dunnett's comparison to control; ****p<0.0001. As shown in Figures 7A-7D, Compound G exhibited significantly reduced tumor volume in all patient-derived tumor models.

Example 9 - Biomarkers

[0326] Symmetrical dimethylarginine (SDMA) is a stable, catabolic product of PRMT5 enzymatic activity, which is reduced after PRMT5 inhibition. SDMA reduction is a pharmacodynamic biomarker of PRMT5 inhibition.

[0327] Based on preliminary data (data cutoff of 1 September 2023) and as shown in Figure 8A, paired tumor biopsies at pre-treatment and approximately 1 month after the start of treatment (pretreatment and on treatment) were collected on subjects that received either 480 mg Compound G or 800 mg Compound G to characterize pharmacodynamic response. The level of cellular protein arginine methyltransferase 5 (PRMTS)-mediated symmetric dimethylarginine (SDMA) histone represent PRMT5 enzymatic activity was evaluated through immunohistochemistry (IHC). The SDMA was stained and assessed through a semi-quantitative scale by an external pathologist in pretreatment and cycle 2, day 1 (C2D1). An H-score (analytical range: 0-300) was calculated using the equation (3 x % of “3+” cells) + (2 x % of “2+” cells) + (1 x % of “1+” cells) based on the cells that were stained at each intensity. Near complete inhibition was observed in all four paired tumor tissues (gastrointestinal stromal tumor 480 mg, cholangiocarcinoma 480 mg and 800 mg, and small intestine cancer 800 mg) across 480mg and 800mg dose levels.

[0328] Next, subjects were treated Compound G (i.e., 40mg, 120 mg, 240 mg, 480 mg, 800 mg, 1200 mg, or 1600 mg) and serum was collected at various timepoints (i.e., C1D1, C1D8, C1D15, C2D1, C3D1, C4D1, and C5D1) to characterize pharmacodynamic changes. The level of serum total SDMA were evaluated through liquid chromatography-mass spectrometry (LC-MS). Serum SDMA levels were compared to the pre-treatment levels and the percentage of reduction was computed. As shown in Figure 8B, there is a dose-dependent reduction in serum SDMA observed from 40 mg -1600 mg once daily. [0329] Circulating tumor DNA (ctDNA) level and change in ctDNA level on-treatment are common tools for predicting response to therapy. Advancements in methods have recently enabled use of circulating tumor specific methylation markers measured by next generation sequencing to quantify circulating tumor fraction (cTF), which has enhanced the sensitivity of this global measurement of molecular tumor burden. As shown in Figure 9A, Compound G decreased circulating tumor fraction in the blood of subjects at various doses (40 mg, 120 mg, 240 mg, 480 mg, 800 mg, and 1200 mg). As shown in in Figure 9B, more robust reductions in cTF were observed in patients with clinical response.

[0330] As shown in Figure 10A and 10B, rapid SDMA inhibition, CA19-9 and circulating tumor fraction reduction correlated with significant tumor shrinkage in several patients.

23 May 2024 Data Cutoff

[0331] Paired tumor biopsies at pre-treatment and approximately 1 month after the start of treatment (pretreatment and on treatment) were collected on subjects that received either 480 mg, 800 mg, or 1200 mg Compound G to characterize pharmacodynamic response. The level of cellular protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (SDMA) histone represent PRMT5 enzymatic activity was evaluated through immunohistochemistry (IHC). The SDMA was stained and assessed through a semi-quantitative scale by an external pathologist in pretreatment and cycle 2, day 1 (C2D1). An Hscore (analytical range: 0-300) was calculated using the equation (3 x % of “3+” cells) + (2 x % of “2+” cells) + (1 x % of “1+” cells) based on the cells that were stained at each intensity. While pretreated biopsy samples had high SDMA expression, posttreatment tumor biopsies from nine MTAP-deleted patients were observed to have near complete elimination of SDMA levels at dose levels of 480 mg, 800 mg, and 1200 mg (Figures 17A), confirming robust intratumoral target engagement. In serum, Compound G once daily dosing resulted in doseproportional reduction in SDMA from 40 mg to 1600 mg. Strongest serum SDMA reduction was achieved at doses ≥ 800 mg, confirming a greater pharmacodynamic activity at high doses. Patients with disease control (partial Response or stable disease) showed a significantly greater average serum SDMA reduction versus those with progressive disease (Figure 17B). One MTAP wild type subject had persistent SDMA staining posttreatment as evidence of incomplete PRMT5 inhibition, consistent with the MTA-cooperative mechanism of action selective in MTAP-deleted tumors.

[0332] Next, subjects were treated Compound G (i.e. , 40mg, 120 mg, 240 mg, 480 mg, 800 mg, 1200 mg, or 1600 mg) and serum was collected at various timepoints (i.e., C1D1, C1D8, C1D15, C2D1, C3D1, C4D1, and C5D1) to characterize pharmacodynamic changes. The level of serum total SDMA were evaluated through liquid chromatography-mass spectrometry (LC-MS). Serum SDMA levels were compared to the pre-treatment levels and the percentage of reduction was computed. The dose-response relationship for SDMA reduction was evaluated by grouping cohorts into low (40 mg to 120 mg), medium (240 mg to 480 mg), and high (≥ 800 mg total dose) groups. Figure 17C provides a linear mixed model for SDMA levels at time points throughout the first 5 treatment cycles. The modeling demonstrates a significant dose-response relationship when evaluating the totality of SDMA data across these three dose groups. Strongest serum SDMA reduction was achieved at doses ≥ 800 mg, which confirms greater pharmacodynamic activity at high doses. Patients with disease control (partial response or stable disease) showed a significantly greater average serum SDMA reduction versus those with progressive disease (Figure 17D). These data demonstrate that reduction in serum SDMA is dose proportionate and is associated with clinical response.

[0333] Complete ctDNA clearance (-100% ctDNA change from baseline) was observed at doses ≥480 mg (Figure 17E). The degree of ctDNA reduction correlates with RECIST response. Of the 40 patients with stable disease (SD), 33 patients (83%) had >50% reduction from baseline in ctDNA, and nine patients with partial response (PR) had >90% ctDNA reduction (Figure 17F). The degree of reduction in ctDNA levels for patients with progressive disease was significantly less than that observed in patients with SD or PR (Figure 17F), indicating an association between the degree of ctDNA reduction and RECIST response, and that disease stabilization was a result of Compound G antitumor activity rather than indolent disease.

[0334] Consistent with the tumor-selective mechanism of action of Compound G conferred by MTA cooperativity, near complete intratumoral reduction in SDMA in MTAP-deleted tumors was confirmed at well- tolerated doses, while an MTAP wildtype tumor showed persistent SDMA as evidence of incomplete intratumoral PRMT5 inhibition. Furthermore, PRMT5 activity was more strongly inhibited within the tumor compared with nontumor based on the degree of SDMA reduction in paired tumor biopsy tissue samples versus peripheral blood. In tumor tissue, there was near complete SDMA loss in all samples while the highest degree of SDMA reduction in the blood did not exceed 80% from baseline.

Example 10- Compound G significantly reduced tumor burden in vivo - Preliminary Results

[0335] As of September 1 , 2023, thirty-five subjects enrolled in the ongoing First-in-Human study with at least 1 measured tumor assessment after starting treatment with Compound G are shown in Figure 11. The Y-axis shows the maximum change from baseline in the sum of target lesions diameters. These 35 subjects were enrolled based on either local NGS MTAP/CDKNA-loss/del or prescreened with central IHC assay and were determined to have lost expression of MTAP in the tumor tissues. Patients were enrolled across 7 cohorts to receive dose of 40 mg, 120 mg, 240 mg, 480 mg, 800 mg, 1200 mg and 1600 mg once daily. Tumor assessments were made by the investigator/site radiologist per RECISIT v1.1. Partial responses were observed in 5 subjects treated at dose levels 800 mg (n=2), and 1200 mg (n=3). Additionally, 13 subjects had some degree of tumor shrinkage after receiving Compound G.

Example 11 - Methylthioadenosine (MTA)-cooperative PRMT5 inhibitor treatment in patients with advanced methylthioadenosine phosphorylase (MTAP)-null Non-Small Cell Lung Cancer (NSCLC)

[0336] This is a phase 2, open-label study evaluating efficacy, safety, tolerability, and PK of Compound G in subjects with metastatic or locally advanced MTAP-deleted NSCLC who have previously received at least one line of treatment. [0337] This study will be conducted in 2 parts. The study is planned to enroll, up to approximately 200 subjects, randomized 1 :1 to 2 active dose levels of Compound G (up to approximately 100 subjects per arm). Randomization will be stratified by histology (squamous vs non-squamous) and prior lines of therapy (≤ 2 vs ≥ 2).

[0338] Part 1 will evaluate 2 active dose levels of Compound G, at 800 mg and 1200 mg oral daily (QD) in 28 day cycles. Data from approximately the first 60 subjects enrolled will be analyzed to potentially determine the RP2D. Part 2 will be a dose expansion phase for 1 or both dose levels. Part 2 will continue to enroll up to approximately 100 subjects per dose level (with Part 1 and Part 2 combined). Amendments to the study may include additional active dose levels of Compound G, such as 400 mg, 500 mg, 600 mg, 700 mg, 900 mg, 1000 mg, and 1100 mg oral QD in 28 day cycles. Contemplated herein is an amendment to the study that includes the additional active dose level of 900 mg Compound G.

[0339] Up to approximately 200 subjects will be randomized 1 :1 to the 2 dose levels (up to approximately 100 subjects per arm). In Part 1 , data from approximately the first 60 subjects enrolled will be analyzed to potentially determine the RP2D dose. Part 2 will be a dose expansion phase for 1 or both doses. Part 2 will continue to enroll up to approximately 100 subjects per dose level (with Part 1 and Part 2 combined).

[0340] Radiographic assessments will be assessed per RECIST 1.1 every 6 weeks (± 1 week) by investigator and BICR for the first 48 weeks after first dose of Compound G (cycle 1 day 1). Thereafter, radiographic assessments will be assessed per RECIST 1.1 every 12 weeks (± 1 week) by investigator and by BICR. A confirmation of response is required by a repeat scan no earlier than 4 weeks per RECIST 1.1. Magnetic resonance imaging/computerized tomography (MRI/CT) of the brain should be performed for all subjects at screening. For subjects with untreated or treated brain metastases at baseline, the RECIST 1.1 tumor assessment schedule will be followed.

[0341] Treatments

[0342] Part 1 , subjects will be randomized to either the target dose of 800 mg or 1200 mg of Compound G administered oral daily continuously in 28-day cycles. Subjects may be randomized to additional target doses of Compound G administered oral daily continuously in 28-day cycles, such as 400 mg, 500 mg, 600 mg, 700 mg, 900 mg, 1000 mg, and 1100 mg of Compound G. Contemplated herein is the randomization of subjects to an additional target dose 900 mg of Compound G administered oral daily continuously in 28-day cycles.

[0343] Objectives and Endpoints

[0344] Inclusion Criteria

[0345] Subjects are included in the study only if all the following criteria apply:

[0346] Subject has provided informed consent before initiation of any study-specific activities/procedures.

[0347] Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).

[0348] Histologically or cytologically confirmed metastatic or unresectable locally advanced MTAP-deleted (Homozygous deletion of MTAP in the tumor tissue) non-small cell lung cancer identified through F1CDx.

[0349] Subjects will have received and progressed or experienced disease recurrence on or after receiving at least 1 prior systemic therapy for locally advanced and unresectable or metastatic disease. Prior treatment must include a platinum-based doublet chemotherapy and checkpoint inhibitor, either given as one line of therapy or as individual lines of therapy unless the subject has a medical contraindication to one of the required therapies. If the subject has a medical contraindication to a required therapy, the subject may be enrolled only after the investigator discusses and obtains approval from the medical monitor.

[0350] Adjuvant therapy counts as a line of therapy if the subject progressed on or within 6 months of adjuvant therapy administration.

[0351] In locally advanced and unresectable NSCLC, disease progression on or within 6 months of end of prior curatively intended multimodal therapy will count as a line of therapy. If chemoradiation is followed by planned systemic therapy without documented progression between chemoradiation and systemic therapy, the entire treatment course counts as one line of therapy.

[0352] Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate line of therapy.

[0353] Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 1.

[0354] Either an archival tissue sample or an archival block must be available (formalin fixed, paraffin- embedded [FFPE] sample collected ≤ 5 years). The sample must have tumor content review with at least 20% of tumor material pre submission. Subjects without archival tissue available may be allowed to enroll by undergoing tumor biopsy before Compound G dosing (cycle 1 day 1).

[0355] Able to swallow and retain orally (PO) administered study treatment and willing to record daily adherence to investigational product regimen.

[0356] Disease measurable as defined by RECIST 1.1.

[0357] Life expectancy of > 3 months, in the opinion of the investigator.

[0358] Adequate hematological laboratory assessments, defined as:

[0359] Absolute neutrophil count (ANC) ≥ 1500 cells/ L without growth factor support within 7 days (granulocyte colony stimulating factor [GCSF]) or 14 days (pegylated GCSF) from screening assessment.

[0360] Hemoglobin ≥ 9.0 g/dl without RBC transfusion within 7 days from screening assessment.

[0361] Platelet count 75000/ L without platelet transfusion within 7 days from screening assessment.

[0362] Adequate renal function per local laboratory, defined as:

[0363] Estimated creatinine clearance ≥ 40 mL/min based on the Cockcroft Gault formula or estimated glomerular filtration rate based on the Modification of Diet in Renal Disease formula.

[0364] Adequate hepatic laboratory assessments, as follows:

[0365] Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit normal (ULN) (or < 5 x ULN for subjects with liver metastases).

[0366] Total bilirubin < 1.5 x ULN (or < 2.0 x ULN for subjects with liver metastases).

[0367] Total albumin ≥ 3.0 g/dL.

[0368] No clinically significant pleural effusion (s/p indwelling catheter allowed for NSCLC, if subject requires drainage less frequently than monthly).

[0369] Subjects who have had brain metastases and have been appropriately treated with radiation therapy or surgery ending at least 14 days before study day 1 are eligible if they meet all the following criteria:

[0370] Stable or improving residual neurological symptoms grade ≤ 2.

[0371] On stable doses of corticosteroid, if applicable.

[0372] Subjects with untreated asymptomatic brain metastases smaller or equal to 2 cm in size (per lesion if more than one) and not requiring corticosteroid treatment are eligible.

[0373] Exclusion Criteria

[0374] Subjects are excluded from the study if any of the following criteria apply:

[0375] Disease Related [0376] Mixed small cell lung cancer histology.

[0377] Subjects with tumors harboring the following mutations amenable to targeted therapies: epidermal growth factor receptor (EGFR) I ALK receptor tyrosine kinase (ALK) / ROS proto-oncogene 1 (ROS1) I neurotrophic tyrosine receptor kinase (NTRK) / MET proto-oncogene (MET) I B-Raf proto-oncogene (BRAF)/ RET proto-oncogene (RET) / Human epidermal growth factor receptor 2 (HER2) I KRAS proto-oncogene (KRAS).

[0378] Other Medical Conditions

[0379] Major surgery within ≤ 28 days of study day 1.

[0380] Note: surgery to obtain a biopsy for diagnosis is allowed.

[0381] Spinal cord compression or leptomeningeal disease are excluded regardless of presence or absence of symptoms, even if treated.

[0382] Untreated symptomatic central nervous system (CNS) metastatic disease regardless of size or asymptomatic brain metastases > 2 cm per lesion.

[0383] History or presence of other malignancy unless treated with curative intent and no evidence of disease 2 years of study day 1 with the following exceptions:

[0384] Adequately treated non melanoma skin cancer or lentigo maligna without evidence of disease.

[0385] Adequately treated cervical carcinoma in situ without evidence of disease.

[0386] Adequately treated breast ductal carcinoma in situ without evidence of disease.

[0387] Prostatic intraepithelial neoplasia without evidence of prostate cancer.

[0388] Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ.

[0389] Myocardial infarction and/or, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication within 12 months of first dose of Compound G.

[0390] History of any other arterial thrombosis (e.g., stroke or transient ischemic attack) within ≤ 6 months of first dose of Compound G.

[0391] Note: For subjects receiving anti-coagulation and undergoing

[0392] biopsies, safety precautions such as a drug holiday may be considered if deemed necessary and safe by the investigator.

[0393] Uncontrolled ascites requiring recurrent drainage procedures at a frequency greater than monthly.

[0394] Gastrointestinal tract disease causing inability to take oral medication, malabsorption syndrome, requirement for intravenous (IV) alimentation, uncontrolled inflammatory gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis). [0395] History of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of study day 1, unless approved by the Medical Monitor.

[0396] History of gastrointestinal procedure(s) that result in malabsorption.

[0397] Active hepatitis C infection (subjects with detectable hepatitis C antibody [HCV Ab] and HCV RNA viral load above the limit of quantification).

[0398] Subjects with presence of HCV antibody (HCV Ab positive) and HCV RNA viral load below the limit of quantification (HCV RNA negative) with or without prior treatment are allowed.

[0399] Active hepatitis B infection (presence of hepatitis B surface antigen [HBsAg-positive] and hepatitis B virus [HBV] DNA viral load above the limit of quantification [HBV DNA positive]).

[0400] Subjects with resolved HBV infection, defined as absence of HBV surface antigen [HBsAg-negative] and presence of HBV core antibody [anti-HBc positive] followed by an HBV DNA viral load below the limit of quantification [HBV DNA negative], are allowed with a requirement for regular monitoring for reactivation for the duration of treatment on the study and assessing the need for HBV prophylaxis therapy per local or institutional guidelines.

[0401] Subjects with chronic hepatitis B virus (HBV) infection inactive carrier state, defined as presence of HBV surface antigen [HBsAg-positive] and HBV DNA viral load below the limit of quantification [HBV DNA negative], are allowed with a requirement for regular monitoring for reactivation, for the duration of treatment on the study and assessing the need for HBV prophylaxis therapy per local or institutional guideline.

[0402] History of solid organ transplant.

[0403] Diagnosis of congenital short QT syndrome.

[0404] Known positive test for human immunodeficiency virus (HIV).

[0405] Active infection within ≤ 2 weeks of study day 1 requiring therapeutic oral or intravenous antibiotics.

[0406] Evidence of active SARS COV 2 infection. If known or suspected recent SARS COV 2 infection, a minimum of 10 days after symptom onset, if any, must have elapsed.

[0407] Prior/Concomitant Therapy

[0408] Therapeutic or palliative radiation therapy within ≤ 2 weeks of study day 1. Subjects must have recovered from all radiotherapy related toxicity to grade 1 or better.

[0409] Unresolved 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 grade 1 , or to levels dictated in the eligibility criteria, except for alopecia, fatigue, and neuropathy.

[0410] Note: grade 2 or grade 3 toxicities from prior anti-cancer therapy that are considered irreversible

(defined as having been present and stable for ≥ 5 months), such as endocrinopathies controlled with hormone replacement therapy may be allowed if they are not otherwise described in the exclusion criteria and there is agreement to allow by both the investigator and sponsor.

[0411] Ant- tumor therapy (chemotherapy, antibody therapy, hormonal therapy, or investigational agent) ≤ 21 days of study cycle 1 day 1 , unless anti-tumor therapy is a therapy with 5 times the half-life being shorter than 21 days (in this case, enrollment may be allowed with washout from prior therapy of < 21 days, in consultation with the Medical Monitor).

[0412] Previous treatment with MAT2A inhibitors, or PRMT5 inhibitors, or similar class molecules.

[0413] Subject used known P glycoprotein (P-gp) substrates, with a narrow therapeutic window, within 14 days before cycle 1 day 1.

[0414] Subject used strong inducers of CYP3A4 (including herbal supplements such as St. John's wort) within 14 days before cycle 1 day 1.

[0415] Subject used proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RA) within 7 days before cycle 1 day 1.

[0416] Currently receiving treatment in another investigational device or drug study, or less than 30 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.

[0417] Other Exclusions

[0418] Female subjects of childbearing potential unwilling to use protocol-specified method of contraception during treatment and for an additional 30 days after the last dose of Compound G.

[0419] Female subjects who are breastfeeding or who plan to breastfeed while on study through 30 days after the last dose of Compound G.

[0420] Female subjects planning to become pregnant while on study through 30 days after the last dose of Compound G.

[0421] Female subjects of childbearing potential with a positive pregnancy test assessed at screening and/or day 1 by a highly sensitive urine or serum pregnancy test.

[0422] Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 30 days after the last dose of Compound G.

[0423] Male subjects unwilling to abstain from donating sperm during treatment and for an additional 30 days after the last dose of Compound G.

[0424] Subject has known sensitivity to any of the products or components to be administered during dosing. [0425] Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the subject and investigator's knowledge.

[0426] History or evidence of any other clinically significant disorder, condition, or disease (except for those outlined above) that, in the opinion of the investigator or sponsor physician, if consulted, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion.

[0427] Compound G Dose Adjustments

[0428] Subjects should continue the same dose of Compound G throughout the study except for those experiencing an intolerable Compound G-related adverse event (at least possibly related to Compound G) but showing evidence of clinical benefit. These subjects may be considered for dose modification as outlined in the table below. Each subject is allowed 2 dose reductions of Compound G. Subjects who experience an adverse event requiring dose reduction greater than dose level 2 of Compound G should be permanently discontinued from Compound G treatment.

[0429] Note for dose Re-escalation: It is recommended that if the reason for the dose reduction is resolved and/or stable for more than 3 5 days, the subject should attempt to re escalate one dose level at time until the assigned dose level is reached.

Claims

What is claimed is:

1. A method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient a total daily dose of 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, or 200 mg Compound G or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

2. The method of claim 1, comprising administering a total daily dose of 1200 mg Compound G.

3. The method of claim 1 , comprising administering a total daily dose of 1100 mg Compound G.

4. The method of claim 1, comprising administering a total daily dose of 1000 mg Compound G.

5. The method of claim 1 , comprising administering a total daily dose of 900 mg Compound G.

6. The method of claim 1, comprising administering a total daily dose of 800 mg Compound G.

7. The method of claim 1, comprising administering a total daily dose of 700 mg of Compound G.

8. The method of claim 1, comprising administering a total daily dose of 600 mg of Compound G.

9. The method of claim 1, comprising administering a total daily dose of 500 mg of Compound G.

10. The method of claim 1, comprising administering a total daily dose of 400 mg of Compound G.

11. The method of claim 1, comprising administering a total daily dose of 300 mg of Compound G.

12. The method of claim 1, comprising administering a total daily dose of 200 mg of Compound G.

13. The method of any one of claims 2-12, wherein Compound G is administered once daily.

14. The method of any one of claims 2-12, wherein Compound G is administered twice daily.

15. The method of any one of claims 2-14, wherein the MTAP-null cancer is lung cancer.

16. The method of claim 15, wherein the lung cancer is non-small cell lung cancer (NSCLC).

17. The method of claim 16, wherein the NSCLC is squamous.

18. The method of claim 16, wherein the NSCLC is non-squamous.

19. The method of any one of claims 2-14, wherein the MTAP-null cancer is biliary tract cancer.

20. The method of any one of claims 2-14, wherein the MTAP-null cancer is head and neck squamous cell carcinoma.

21. The method of any one of claims 2-14, wherein the MTAP-null cancer is pancreatic adenocarcinoma.

22. The method of any one of claims 2-14, wherein the MTAP-null cancer is gallbladder cancer.

23. The method of any one of claims 2-14, wherein the MTAP-null cancer is mesothelioma.

24. The method of any one of claims 2-14, wherein the MTAP-null cancer is not a primary brain tumor or lymphoma.

25. The method of any one of claims 2-14, wherein the MTAP-null cancer is esophageal or gastric cancer.

26. The method of any one of claims 2-14, wherein the MTAP-null cancer is glioma.

27. The method of any one of claims 1-26, wherein Compound G is administered as a monotherapy.

28. A method of treating a MTAP-null cancer in a patient in need thereof comprising administering to the patient a Compound G, or pharmaceutically acceptable salt thereof, as a monotherapy, wherein Compound G has a structure of

29. The method of claim 28 wherein the MTAP-null cancer is lung cancer.

30. The method of claim 29, wherein the lung cancer is non-small cell lung cancer (NSCLC).

31. The method of claim 30, wherein the NSCLC is squamous.

32. The method of claim 30, wherein the NSCLC is non-squamous.

33. The method of claim 28, wherein the MTAP-null cancer is biliary tract cancer.

34. The method of claim 28, wherein the MTAP-null cancer is head and neck squamous cell carcinoma.

35. The method of claim 28, wherein the MTAP-null cancer is pancreatic adenocarcinoma.

36. The method of claim 28, wherein the MTAP-null cancer is gallbladder cancer.

37. The method of claim 28, wherein the MTAP-null cancer is mesothelioma.

38. The method of claim 28, wherein the cancer is not a primary brain tumor or lymphoma.

39. The method of claim 28, wherein the MTAP-null cancer is esophageal/gastric cancer.

40. The method of claim 28, wherein the MTAP-null cancer is glioma.

41. The method of any one of claims 28-40, comprising administering 40 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

42. The method of any one of claims 28-40, comprising administering 120 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

43. The method of any one of claims 28-40, comprising administering 200 mg Compound G based upon free base weight of Compound G, to the patient once daily.

44. The method of any one of claims 28-40, comprising administering 240 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

45. The method of any one of claims 28-40, comprising administering 300 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

46. The method of any one of claims 28-40, comprising administering 400 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

47. The method of any one of claims 28-40, comprising administering 480 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

48. The method of any one of claims 28-40, comprising administering 500 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

49. The method of any one of claims 28-40, comprising administering 600 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

50. The method of any one of claims 28-40, comprising administering 700 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

51. The method of any one of claims 28-40, comprising administering 800 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

52. The method of any one of claims 28-40, comprising administering 900 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

53. The method of any one of claims 28-40, comprising administering 1000 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

54. The method of any one of claims 28-40, comprising administering 1100 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

55. The method of any one of claims 28-40, comprising administering 1200 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

56. The method of any one of claims 28-40, comprising administering 1600 mg Compound G, based upon free base weight of Compound G, to the patient once daily.

57. The method of any one of claims 28-40, comprising administering 200 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

58. The method of any one of claims 28-40, comprising administering 300 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

59. The method of any one of claims 28-40, comprising administering 400 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

60. The method of any one of claims 28-40, comprising administering 500 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

61. The method of any one of claims 28-40, comprising administering 600 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

62. The method of any one of claims 28-40, comprising administering 800 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

63. The method of any one of claims 28-40, comprising administering 1200 mg Compound G, based upon free base weight of Compound G, to the patient twice daily.

64. The method of any one of claims 1-63, wherein Compound G is administered orally.

65. The method of claim 64, wherein Compound G or salt thereof is administered as a tablet formulation.

66. A method of treating a MTAP-null cancer in a patient in need thereof comprising orally administering to the patient 800 mg Compound G, or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

67. The method of claim 66, wherein Compound G or salt thereof is administered in a tablet formulation.

68. The method of claim 66 or 67, wherein the MTAP-null cancer is pancreatic ductal adenocarcinoma.

69. The method of claim 66 or 67, wherein the MTAP-null cancer is biliary tract cancer.

70. The method of claim 66 or 67, wherein the MTAP-null cancer is non-small cell lung cancer.

71. A method of treating a MTAP-null cancer in a patient in need thereof comprising orally administering to the patient 1200 mg Compound G, or pharmaceutically acceptable salt thereof, based upon free base weight of Compound G, wherein Compound G has a structure of

72. The method of claim 71 , wherein Compound G or salt thereof is administered in a tablet formulation.

73. The method of claim 71 or 72, wherein the MTAP-null cancer is pancreatic ductal adenocarcinoma.

74. The method of claim 71 or 72, wherein the MTAP-null cancer is biliary tract cancer.

75. The method of claim 71 or 72, wherein the MTAP-null cancer is non-small cell lung cancer.