Therapies for treating cancers

Abstract

Described herein are methods of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at total daily dose of about 15 mg or about 30 mg; and (b) Compound B about 10 mg / kg on Day 1 and Day 8 of 21-day dosing cycles or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle.

Description

IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PCTHERAPIES FOR TREATING CANCERSRELATED APPLICATIONSThis application claims priority to U.S. Provisional Application No. 63 / 708,021 filed October 16, 2024, U.S. Provisional Application No. 63 / 774,457 filed March 19, 2025, and U.S. Provisional Application No. 63 / 875,634 filed September 4, 2025, the content of each of which is incorporated in its entirety.BACKGROUND

[0001] Cancer is a leading cause of death throughout the world. A limitation of prevailing therapeutic approaches, e.g., chemotherapy and immunotherapy, is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are needed to better target cancer cells.

[0002] Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The concept of synthetic lethality originates from studies in drosophila model systems in which a combination of mutations in two or more separate genes leads to cell death (in contrast to viability, which occurs when only one of the genes is mutated or deleted). More recently, a multitude of studies have explored maladaptive genetic changes in cancer cells that render them vulnerable to synthetic-lethality approaches. These tumor-specific genetic defects lead to the use of targeted agents that induce the death of tumor cells while sparing normal cells.

[0003] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosyl methionine (SAM). SAM is a primary methyl donor in cells used to methylate several substrates including DNA, RNA and proteins. One methylase that utilizes SAM as a methyl donor is protein arginine N- methyltransferase 5 (PRMT5). While SAM is required for PRMT5 activity, PRMT5 is competitively inhibited by 5 ’methylthioadenosine (MTA). Because MTA is part of the methionine salvage pathway, cellular MTA levels stay low in a process initiated by methylthioadenosine phosphorylase (MTAP).

[0004] MTAP is in a locus on chromosome 9 that is often deleted in cells of patients with cancers from several tissues of origin including the central nervous system, pancreas, esophageal, bladder and lung (cBioPortal database). Loss of MTAP results in the accumulation of MTA making MTAP-deleted cells more dependent on SAM production, and181235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC thus MAT2A activity, compared to cells that express MTAP. In an shRNA cell-line screen across approximately 400 cancer cell lines, MAT2A knockdown resulted in the loss of viability in a larger percentage of MTAP-deleted cells compared to MTAP WT cells (see McDonald et. al. 2017 Cell 170, 577-592). Furthermore, inducible knockdown of MAT2A protein decreased tumor growth in vivo (see Marjon et. al., 2016 Cell Reports 15(3), 574- 587). These results indicate that MAT2A inhibitors may provide a useful therapy for cancer patients including those with MTAP-deleted tumors.

[0005] DNA-topoisom erases are enzymes that are present in the nuclei of cells where they catalyze the breaking and rejoining of DNA strands, which control the topological state of DNA. Recent studies also suggest that topoisomerases are also involved in regulating template supercoiling during RNA transcription. There are two major classes of mammalian topoisomerase. DNA-topoisomerase-I catalyzes changes in the topological state of duplex DNA by performing transient single-strand breakage-union cycles. In contrast, mammalian topoisomerase II alters the topology of DNA by causing a transient enzyme bridged doublestrand break, followed by strand passing and resealing. The antitumor activity associated with agents that are topoisomerase poisons is associated with their ability to stabilize the enzyme- DNA cleavable complex. This drug-induced stabilization of the enzyme-DNA cleavable complex effectively converts the enzyme into a cellular poison.

[0006] Despite many recent advances in cancer therapies, there remains a need for more effective and / or enhanced treatment for those individuals suffering the effects of cancer.BRIEF SUMMARYProvided herein is a method of treating an MTAP-null cancer in a patient in need thereof comprising administering a MAT2A inhibitor and an anti-TROP2 antibody drug conjugate (ADC) to the patient at particular doses on a particular dosing schedule. As such, provided herein is a method of treating an MTAP-null cancer in a patient in need thereof comprising administering to the patient (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.DETAILED DESCRIPTION

[0007] The disclosure provides methods of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a281235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle. Thus, as recognized by those skilled in the art, Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof is administered daily, and Compound B is administered on days 1 and 8 of a 21 -day dosing cycle.

[0008] The term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, and the like, the term “about” is meant to encompass variations of ±5%, including ±4%, ±3%, ±2%, and ±1%, from the specified value, as such variations are appropriate to perform the disclosed methods.

[0009] A “patient” or “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)). The terms “patient” and “subject” are used interchangeably herein.

[0010] The terms “combination,” “therapeutic combination,” “pharmaceutical combination,” or “combination product” as used herein refer to either a fixed or non-fixed combination in separate dosage forms, where two or more therapeutic agents may be administered independently, at the same time, or separately within time intervals.

[0011] The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in separate formulations (e.g., capsules and / or intravenous formulations) for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential or separate manner, either at approximately the same time or at different times. The drugs are administered to the same patient as part of the same course of therapy. The treatment regimen will provide beneficial effects in treating the conditions or disorders described herein.

[0012] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one active compound with at least one or more pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the composition to a patient or subject. Multiple techniques of administering a compound exist in381235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0013] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound disclosed herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0014] As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of a compound disclosed herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. Other additional ingredients that may be included in the pharmaceutical compositions are known in the art and described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0015] As used herein, “dosing cycle” refers to a schedule of dosing regimens of administration of Compound A and Compound B. For example, an exemplary dosing cycle is (a) Compound A at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.481235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PCThe dosing cycle can be repeated over successive administrations, e.g., a patient can be administered Compound A and Compound B over multiple, successive, 21 -day dosing cycles.

[0016] As used herein, the term “treating” or “treatment” refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease. In some embodiments, the term “treating” or “treatment” refers to inhibiting or ameliorating the disease.

[0017] As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0018] In one aspect, the present disclosure provides a method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle. In another aspect, the present disclosure provides a method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle.

[0019] In another aspect, the present disclosure provides a method of treating an MTAP- null cancer in a patient in need thereof comprising administering (a) Compound A at a total daily dose of 15 mg or 30 mg; and (b) Compound B at 10 mg / kg on Day 1 and Day 8 of a 21- day dosing cycle. In another aspect, the present disclosure provides a method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A at581235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC a total daily dose of 15 mg or 30 mg; and (b) Compound B at a dose of 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.

[0020] In another aspect, the present disclosure provides a use of Compound A at a total daily dose of about 15 mg or about 30 mg, and Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer. In another aspect, the present disclosure provides a use of Compound A at a total daily dose of about 15 mg or about 30 mg, and Compound B at a dose of about 10 mg / kg or 7.5 mg. kg on Day 1 and Day 8 of a 21 -day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer. In some embodiments, Compound A is administered orally, and Compound B is administered intravenously.

[0021] In another aspect, the present disclosure provides a combination therapy comprising (a) Compound A at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle. In another aspect, the present disclosure provides a combination therapy comprising (a) Compound A at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.

[0022] In another aspect, the present disclosure provides a combination therapy comprising (a) a pharmaceutical composition comprising Compound A at a total daily dose of about 15 mg or about 30 mg, and a pharmaceutically acceptable carrier; and (b) a pharmaceutical composition comprising Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides a combination therapy comprising (a) a pharmaceutical composition comprising Compound A at a total daily dose of about 15 mg or about 30 mg, and a pharmaceutically acceptable carrier; and (b) a pharmaceutical composition comprising Compound B at about 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle, and a pharmaceutically acceptable carrier.

[0023] In an embodiment, the total daily dose of Compound A is 15 mg. In an embodiment, the total daily dose of Compound A is 30 mg.Compound A is aMAT2A inhibitor

[0024] Compound A is a MAT2A inhibitor that has a chemical name 4-amino-l-(2- chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(U7)-one and has the following structure.681235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PCCompound A.Compound A, and methods of making Compound A are disclosed in International Application No. PCT / US2019 / 065260 (published as WO 2020 / 123395), which is incorporated by reference in its entirety.

[0025] In the methods disclosed herein, Compound A can be administered as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and p- toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection and Use; 2002. In various embodiments, Compound A or salt thereof is administered orally.Compound B is Anti-TROP2 ADC: Sacitzumab govitecan (“SG ”)

[0026] SG is a pharmaceutical composition comprising an antibody-drug conjugate (“ADC”) comprised of (1) a drug (“SN-38”), a topoisomerase 1 inhibitor that is an active metabolite of irinotecan; (2) a linker (“CL2A”); and (3) a humanized monoclonal antibody (“hRS7 IgGk” or “sacituzumab”). CL2A couples SN-38 to hRS7, which binds to Trop-2, a cell surface protein.781235349. v1IDY Ref. 2024-012-D-PCT LGPM Ref. 770807: 086087-033PC

[0027] In certain embodiments, hRS7 is described, e.g., in International Application No. PCT / GB03 / 00885, published as WO 2003 / 074566, Figures 3 and 4, incorporated by reference in its entirety.

[0028] In certain embodiments, SG is represented by Formula I as shown below.Formula I.

[0029] In certain embodiments, the ADC comprises drug molecules linked to the antibody moieties in various stoichiometric molar ratios depending on the configuration of the antibody and, at least in part, the method used to effect configuration. In certain embodiments, the drug-antibody ratio (“DAR”) is about 7.6.

[0030] Table 1 discloses SEQ ID NOS 1-2, respectively, in order of appearance.

[0031] Table 1. Amino Acid Sequences of hRS7 antibody881235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC

[0032] In certain embodiments, the hRS7 antibody in SG comprises the heavy chain as shown in SEQ ID NO.: 1 and light chain as shown in SEQ ID NO.: 2, and as shown in Table 1. In certain embodiments, the hRS7 antibody in SG comprises two heavy chains each having the sequence as shown in SEQ ID NO.: 1, and two light chains each having the sequence as shown in SEQ ID NO.: 2.

[0033] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described, for example, in U.S. Patent No. 7,999,083 and U.S. Patent No. 9,028,833, which are hereby incorporated herein by reference in their entireties.Methods of Administration

[0034] In some embodiments, the method comprises administering to the patient a total daily dose of about 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof and about 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of about 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof and about 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt981235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC thereof and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.

[0035] In some embodiments, the method comprises administering to the patient a total daily dose of about 15 mg Compound A and about 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of about 30 mg Compound A and about 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of 15 mg Compound A and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of 30 mg Compound A and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.

[0036] In some embodiments, the method comprises administering to the patient a total daily dose of about 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof and about 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of about 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof and about 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle.

[0037] In some embodiments, the method comprises administering to the patient a total daily dose of about 15 mg Compound A and about 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of about 30 mg Compound A and about 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle. In some embodiments, the method comprises administering to the patient a total daily dose of 15 mg Compound A and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle. In some1081235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC embodiments, the method comprises administering to the patient a total daily dose of 30 mg Compound A and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.

[0038] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, Compound B is administered intravenously. In some embodiments, Compound A is administered orally, and Compound B is administered intravenously.

[0039] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered once daily (QD). In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is administered once daily (QD) of continuous 21 -day treatment cycles. In some embodiments, Compound B is administered on Day 1 and Day 8 of a 21 -day dosing cycle. In some embodiments, Compound A is administered once daily (QD) and Compound B is administered on Day 1 and Day 8 of a 21 -day dosing cycle.

[0040] In some embodiments, Compound A is administered once daily (QD). In some embodiments, Compound A is administered once daily (QD) of continuous 21 -day treatment cycles.

[0041] In some embodiments, Compound A or a pharmaceutically acceptable thereof and Compound B are administered concurrently. In some embodiments, Compound A and Compound B are administered concurrently. In some embodiments, Compound A or a pharmaceutically acceptable thereof and Compound B are administered sequentially. In some embodiments, Compound A and Compound B are administered sequentially.

[0042] In some embodiments, Compound A or a pharmaceutically acceptable thereof and Compound B are administered in separate dosage forms. In some embodiments, Compound A and Compound B are administered in separate dosage forms.

[0043] In some embodiments, Compound A or a pharmaceutically acceptable thereof and Compound B are administered in separate dosage forms, wherein Compound A or a pharmaceutically acceptable thereof is administered orally, and Compound B is administered intravenously.

[0044] In some embodiments, Compound A and Compound B are administered in separate dosage forms, wherein Compound A is administered orally, and Compound B is administered intravenously.1181235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PCCancer

[0045] An 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. Terms “MTAP- null” and “MTAP-deleted” are used interchangeably herein.

[0046] A “MTAP-deficiency-related” or “MTAP-deficiency” or “MTAP deficient” disease (for example, a proliferating disease, e.g., a cancer) or a disease (for example, a proliferating disease, e.g., a cancer) “associated with MTAP deficiency” or a disease (for example, a proliferating disease, e.g., a cancer) “characterized by MTAP deficiency” and the like refer to an ailment (for example, a proliferating disease, e.g., a cancer) wherein a significant number of cells are MTAP-deficient. For example, in an 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 is not limited to, cancers, including but not limited to bladder cancer (e.g., bladder urothelial carcinoma). Another non-limiting example of MTAP- deficient cancer is non-small cell lung cancer (NSCLC). Some types of NSCLC include, but are not limited to, squamous cell carcinoma, large cell carcinoma, and adenocarcinoma.

[0047] The efficacy of a given treatment for cancer can be determined by the skilled clinician. However, a treatment is considered “effective treatment,” as the term is used herein, if any one or all of the signs or symptoms of, e.g., a tumor are altered in a beneficial manner or other clinically accepted symptoms are improved, or even ameliorated, e.g., by at least 10% following treatment with an agent as described herein. Efficacy can also be assessed by a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of assessing these indicators are known to those of skill in the art and / or described herein.

[0048] In some embodiments, the therapy described herein exhibits a combination benefit. The term “combination benefit” refers to an observed efficacy with a dual therapy that is higher than treatment with either individual therapy alone. In some embodiments, the dual therapy described herein exhibits a combination benefit compared to Compound A monotherapy. In some embodiments, the dual therapy described herein exhibits a combination benefit compared to Compound B monotherapy.1281235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC

[0049] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. These and other changes can be made to the disclosure in light of the detailed description.

[0050] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[0051] All patents and other publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present invention, except for any definitions, subject matter disclaimers or disavowals, and except to the extent that the incorporated material is inconsistent with the express disclosure herein, in which case the language in this disclosure controls. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these documents.Non-limiting Exemplary Embodiments:1. A method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle.1381235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC2. A method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.3. A method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of 15 mg or 30 mg; and (b) Compound B at 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.4. A method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of 15 mg or 30 mg; and (b) Compound B at 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.5. The method of any one of embodiments 1 to 4, wherein the MTAP-null cancer is a solid tumor.6. The method of embodiment 5, wherein the tumor is malignant.7. The method of any one of embodiments 1 to 6, wherein the MTAP-null cancer is bladder cancer.8. The method of any one of embodiments 1 to 7, wherein the MTAP-null cancer is urothelial carcinoma.9. The method of any one of embodiments 1 to 6, wherein the MTAP-null cancer is nonsmall cell lung cancer (NSCLC).10. The method of embodiment 9, wherein the NSCLC is adenocarcinoma, giant cell carcinoma, or squamous cell carcinoma.11. The method of any one of embodiments 1 to 10, wherein Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound B are administered concurrently.12. The method of any one of embodiments 1 to 11, wherein Compound A and Compound B are administered concurrently.1481235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC13. The method of any one of embodiments 1 to 10, wherein Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound B are administered sequentially.14. The method of any one of embodiments 1 to 10 and 13, wherein Compound A and Compound B are administered sequentially.15. The method of any one of embodiments 1 to 14, comprising administering to the patient a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and a total daily dose of 10 mg / kg Compound B.16. The method of any one of embodiments 1 to 14, comprising administering to the patient a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and a total daily dose of 10 mg / kg Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.17. The method of embodiment 16, comprising administering to the patient a total daily dose of 15 mg Compound A and a total daily dose of 10 mg / kg Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.18. The method of any one of embodiments 1 to 14, comprising administering to the patient a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and a total daily dose of 10 mg / kg Compound B.19. The method of any one of embodiments 1 to 14, comprising administering to the patient a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and a total daily dose of 10 mg / kg Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.20. The method of embodiment 19, comprising administering to the patient a total daily dose of 30 mg Compound A and a total daily dose of 10 mg / kg Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.21. The method of any one of embodiments 1, 3, and 5 to 14, comprising administering to the patient a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.1581235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC22. The method of embodiment 21, comprising administering to the patient a total daily dose of 30 mg Compound A and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle.23. The method of any one of embodiments 1, 3, and 5 to 14, comprising administering to the patient a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle.24. The method of embodiment 23, comprising administering to the patient a total daily dose of 15 mg Compound A and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle.25. A use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg, and Compound B at about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle for the treatment of an MTAP-null cancer.26. A use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg; and Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle for the treatment of an MTAP-null cancer.27. A use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of 15 mg or 30 mg, and Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle for the treatment of an MTAP-null cancer.28. A use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of 15 mg or 30 mg, and Compound B at 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle for the treatment of an MTAP-null cancer.29. Use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg, and Compound B at about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer.30. Use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg, and Compound B at about 101681235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer.31. Use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of 15 mg or 30 mg, and Compound B atlO mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer.32. Use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of 15 mg or 30 mg; and Compound B atlO mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer.33. The use of any one of embodiments 25 to 32, wherein the MTAP-null cancer is a solid tumor.34. The use of embodiment 33, wherein the tumor is malignant.35. The use of any one of embodiments 25 to 34, wherein the MTAP-null cancer is bladder cancer.36. The use of any one of embodiments 25 to 34, wherein the MTAP-null cancer is urothelial carcinoma.37. The use of any one of embodiments 25 to 34, wherein the MTAP-null cancer is nonsmall cell lung cancer (NSCLC).38. The use of any one of embodiments 25 to 37, wherein Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound B are administered concurrently.39. The use of embodiment 38, wherein Compound A and Compound B are administered concurrently.40. The use of any one of embodiments 25 to 37, wherein Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound B are administered sequentially.41. The use of embodiment 40, wherein Compound A and Compound B are administered sequentially.1781235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC42. The use of any one of embodiments 25 to 41, comprising administering a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and about 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.43. The use of embodiment 42, comprising administering a total daily dose of 15 mg Compound A and about 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.44. The use of any one of embodiments 25 to 41, comprising administering a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and about 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.45. The use of embodiment 44, comprising administering a total daily dose of 30 mg Compound A and about 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.46. The use of any one of embodiments 25, 28, 29, and 32 to 41, comprising administering a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.47. The use of embodiment 46, comprising administering a total daily dose of 30 mg Compound A and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.48. The use of any one of embodiments 25, 28, 29, and 32 to 41, comprising administering a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.49. The use of embodiment 48, comprising administering a total daily dose of 15 mg Compound A and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.50. The methods or uses of the preceding embodiments, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof.51. The methods or uses of the preceding embodiments, wherein the cancer is a MTA- accumulating cancer.1881235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC52. The methods or uses of the preceding embodiments, wherein the cancer is deficient in CDKN2A.53. The methods or uses of the preceding embodiments, wherein Compound A and Compound B are in separate dosage forms.54. The method of use of embodiment 53, wherein the separate dosage forms are a pharmaceutical composition comprising Compound A and one or more pharmaceutically acceptable excipients; and a pharmaceutical composition comprising Compound B and one or more pharmaceutically acceptable excipients.55. The method or use of embodiment 54, wherein the pharmaceutical composition comprising Compound A and one or more pharmaceutically acceptable excipients is administered orally.56. The method or use of embodiment 54 or 55, wherein the pharmaceutical composition comprising Compound B and one or more pharmaceutically acceptable excipients is administered intravenously.57. The method or use of any one of embodiments 53 to 56, wherein the separate dosage forms are for sequential administration.58. The method or use of any one of embodiments 53 to 56, wherein the separate dosage forms are for simultaneous administration.59. Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of about 15 mg or about 30 mg, for use in a method of treating MTAP-null cancer, wherein said Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof is coadministered with Compound B at a dose of about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.60. Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of 15 mg or 30 mg, for use in a method of treating MTAP-null cancer, wherein said Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof is coadministered with Compound B at a dose of 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.61. Compound A at a total daily dose of about 15 mg or about 30 mg, for use in a method of treating MTAP-null cancer, wherein said Compound A is coadministered with Compound1981235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PCB at a dose of about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle.62. Compound A at a total daily dose of 15 mg or 30 mg, for use in a method of treating MTAP-null cancer, wherein said Compound A is coadministered with Compound B at a dose of 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle.63. Compound B at a dose of about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle, for use in a method of treating MTAP-null cancer, wherein said Compound B is coadministered with Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of about 15 mg or about 30 mg.64. Compound B at a dose of 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle, for use in a method of treating MTAP-null cancer, wherein said Compound B is coadministered with Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of 15 mg or 30 mg.65. Compound B at a dose of about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle, for use in a method of treating MTAP-null cancer, wherein said Compound B is coadministered with Compound A at a total daily dose of about 15 mg or about 30 mg.66. Compound B at a dose of 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle, for use in a method of treating MTAP-null cancer, wherein said Compound B is coadministered with Compound A at a total daily dose of about 15 mg or about 30 mg.67. The Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of 15 mg or 30 mg for use as defined in any one of embodiments 59 to 62, or Compound B at a dose of about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle for use as defined in any one of embodiments 61 to 64, wherein said Compound A and said Compound B are coadministered in a separate, simultaneous, or sequential manner.68. The compound for use according to any one of embodiments 59 to 67, wherein the MTAP-null cancer is a solid tumor.69. The compound for use according to embodiment 68, wherein the tumor is malignant.70. The compound for use according to any one of embodiments 59 to 69, wherein the MTAP-null cancer is bladder cancer.2081235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC71. The compound for use according to any one of embodiments 59 to 69, wherein the MTAP-null cancer is urothelial carcinoma.72. The compound for use according to any one of embodiments 59 to 69, wherein the MTAP-null cancer is non-small cell lung cancer (NSCLC).73. The compound for use according to embodiment 72, wherein the NSCLC is adenocarcinoma, giant cell carcinoma, or squamous cell carcinoma.74. The compound for use according to any one of embodiments 59 to 76, comprising administering to the patient a total daily dose of 15 mg Compound A, and a total daily dose of 10 mg / kg Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.75. The compound for use according to any one of embodiments 59 to 73, comprising administering to the patient a total daily dose of 30 mg Compound A, and a total daily dose of 10 mg / kg Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.76. The compound for use according to any one of embodiments 59 to 73, comprising administering to the patient a total daily dose of 30 mg Compound A, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.77. The compound for use according to any one of embodiments 59 to 73, comprising administering to the patient a total daily dose of 15 mg Compound A, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.78. The compound for use according to any one of embodiments 59 to 77, wherein Compound A is administered orally.79. The compound for use according to any one of embodiments 59 to 78, wherein Compound B is administered intravenously.EXAMPLES

[0052] The following Example describes the protocol for a phase 1, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Compound A in combination with Compound B in adult subjects with advanced urothelial carcinoma with MTAP-null urothelial carcinoma. Compound A (at 15 mg or 30 mg) will be administered orally once daily, and Compound B (at 10 mg / kg or 7.5 mg / kg) will be administered on Day 1 and Day 8 intravenously for cycles of 21 days.Dosing will be in the following cohorts:2181235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PCCohort 1 : 15 mg of Compound A once daily and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.Cohort 2: 30 mg of Compound A once daily and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycleCohort 2B: 30 mg of Compound A once daily and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycleExemplary Inclusion Criteria:- Age > 18 years- Advanced or metastatic urothelial carcinoma that has progressed on at least one prior line of treatment or is intolerant to additional effective standard therapy- Have evidence of homozygous loss of MTAP or MTAP deletion or MTAP loss of expression by IHC- Measurable disease as defined by RECIST v.1.1- ECOG performance status <= 1- Adequate organ function- Able to swallow and retain orally administered study treatment- Recovery from acute effects of prior therapy- Able to comply with contraceptive / barrier requirements- Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of < 1.Exemplary Exclusion Criteria:- Known symptomatic brain metastases- Known primary CNS malignancy- Current active liver or biliary disease- Impairment of gastrointestinal (GI) function- Active uncontrolled infection- Clinically significant cardiac abnormalities- Previous treatment with a MAT2A inhibitor or Compound A and / or Compound B or other Topoisomerase I inhibitors- Systemic anti-cancer therapy or major surgery within 4 weeks prior to study entry- Radiation therapy within 2 weeks prior to study entry- Prior irradiation to >25% of the bone marrow2281235349. v1IDY Ref. 2024-012-D-PCT LGPM Ref. 770807: 086087-033PC- Current use or anticipated need for food or drugs that are known strong CYP3A4 / 5 inhibitors or inducers, or interfere with UGT1 Al function- Currently receiving another investigational study drug.- Known or suspected hypersensitivity to Compound A / excipients or components- Do not have active chronic inflammatory bowel disease or GI perforation within 6 months of enrollmentPreliminary data as of October 10, 2024:Preliminary data as of February 3, 2025:Data as of August 20, 20252381235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PCData as of August 29, 2025*uPR was subsequently confirmed after the data dateThe most common Grade 3 or greater adverse events seen in Cohort 1 were anemia and neutropenia, and in cohort 2B were anemia, asthenia, and diarrhea.

[0053] As of 29 August 2025, the most common (> 15%) all grade treatment related adverse events (related either to Compound A, Compound B, or both) seen in Cohort 1 were anemia (50%; Grade > 3: 41.7%), diarrhea (41.7%; > Grade 3: None), peripheral neuropathy (25%; Grade > 3 : None) neutropenia, neutrophil count decreased, white count decreased, hypotension, hyponatremia and alopecia (16.7% each; Grade > 3 neutropenia: 16.7%; > Grade 3 white count decreased and neutrophil count decreased: 8.3% each, others: None).As of 29 August 2025, the most common (> 15%) all grade treatment related adverse events in Cohort 2B were alopecia (57.1%, Grade > 3: None) and anemia (42.9%; Grade > 3: 14.3 %).Dose escalation proceeded from Cohort 1 to Cohort 2. Cohort 1 was cleared without any dose limiting toxi cities (DLTs). 2 DLTs experienced by 1 participant each out of 6 DLT evaluable participants were observed in Cohort 2. No DLTs were observed in Cohort 2B. Based on overall safety profile during and after the DLT observation period and the delivered dose intensity across the 3 dose levels, Cohort 1 and Cohort 2B were selected as the recommended expansion doses.2481235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC

[0054] 15 mg of Compound A once daily and 10 mg / kg of Compound B on Day 1 and Day8 of a 21-day dosing cycle and 30 mg of Compound A once daily and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle were selected as expansion dose.

[0055] For Cohort 1 (15 mg of Compound A once daily and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle), the ORR (Overall Response Rate) was 33% (3 / 9) and DCR (Disease Control Rate) was 100% (9 / 9).For Cohort 2B (30 mg of Compound A once daily and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle), the ORR was 60% (3 / 5) and DCR was 60% (3 / 5).As of 29 August 2025, for Cohort 2B (30 mg of Compound A once daily and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21-day dosing cycle), the ORR was 57% (4 / 7) and DCR was 71% (5 / 7).

[0056] “Partial response (PR)” in a patient is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Additionally, for PR status, changes in tumor measurements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met.

[0057] “Stable Disease (SD)” in a patient is defined as neither sufficient shrinkage to qualify for a partial response (PR) nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study.

[0058] “Progressive disease (PD)” in a patient is defined as at least a 20% increase and an absolute increase of at least 5 mm in the sum of the longest diameters of target lesions, taking as reference the smallest sum of longest diameters recorded since the treatment started or the appearance of one or more new lesions2581235349. v1

Claims

IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PCWhat is claimed is:

1. A method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.

2. A method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of about 15 mg or about 30 mg; and (b) Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.

3. A method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at a total daily dose of 15 mg or 30 mg; and (b) Compound B at 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.

4. A method of treating an MTAP-null cancer in a patient in need thereof comprising administering (a) Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, at total daily dose of 15 mg or 30 mg; and (b) Compound B at 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle.

5. The method of any one of claims 1 to 4, wherein the MTAP-null cancer is a solid tumor.

6. The method of claim 5, wherein the tumor is malignant.

7. The method of any one of claims 1 to 6, wherein the MTAP-null cancer is bladder cancer.

8. The method of any one of claims 1 to 7, wherein the MTAP-null cancer is urothelial carcinoma.

9. The method of any one of claims 1 to 6, wherein the MTAP-null cancer is non-small cell lung cancer (NSCLC).

10. The method of any one of claims 1 to 9, wherein Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound B are administered concurrently.2681235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC11. The method of any one of claims 1 to 9, wherein Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound B are administered sequentially.

12. The method of any one of claims 1 to 11, comprising administering to the patient a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.

13. The method of any one of claims 1 to 11, comprising administering to the patient a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.

14. The method of any one of claims 1, 3, and 5 to 11, comprising administering to the patient a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.

15. The method of any one of claims 1, 3, and 5 to 11, comprising administering to the patient a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycle.

16. A use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg, and Compound B at about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle for the treatment of an MTAP-null cancer.

17. A use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg, and Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle for the treatment of an MTAP-null cancer.

18. A use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of 15 mg or 30 mg, and Compound B atlO mg / kg on Day 1 and Day 8 of a 21-day dosing cycle for the treatment of an MTAP-null cancer.2781235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC19. A use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of 15 mg or 30 mg, and Compound B at 10 mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle for the treatment of an MT AP -null cancer.

20. Use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg, and Compound B at about 10 mg / kg or about 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle in the manufacture of a medicament for the treatment of an MT AP -null cancer.

21. Use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of about 15 mg or about 30 mg, and Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer.

22. Use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of 15 mg or 30 mg; and Compound B atlO mg / kg on Day 1 and Day 8 of a 21-day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer.

23. Use of Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof at a total daily dose of 15 mg or 30 mg; and Compound B atlO mg / kg or 7.5 mg / kg on Day 1 and Day 8 of a 21-day dosing cycle in the manufacture of a medicament for the treatment of an MTAP-null cancer.

24. The use of any one of claims 16 to 23, wherein the MTAP-null cancer is a solid tumor.

25. The use of claim 24, wherein the tumor is malignant.

26. The use of any one of claims 16 to 25, wherein the MTAP-null cancer is bladder cancer.

27. The use of any one of claims 16 to 26, wherein the MTAP-null cancer is urothelial carcinoma.

28. The use of any one of claims 16 to 25, wherein the MTAP-null cancer is NSCLC.2881235349. v1IDY Ref. 2024-012-D-PCTLGPM Ref. 770807: 086087-033PC29. The use of any one of claims 16 to 28, wherein Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound B are administered concurrently.

30. The use of any one of claims 16 to 28, wherein Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and Compound B are administered sequentially.

31. The use of any one of claims 16 to 30, comprising administering a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycles.

32. The use of any one of claims 16 to 30, comprising administering a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 10 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycles.

33. The use of any one of claims 16, 19, 20, 23, 24 to 30, comprising administering a total daily dose of 30 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycles.

34. The use of any one of claims 16, 19, 20, 23, 24 to 30, comprising administering a total daily dose of 15 mg Compound A or an equivalent dose of a pharmaceutically acceptable salt thereof, and 7.5 mg / kg of Compound B on Day 1 and Day 8 of a 21 -day dosing cycles.

35. A combination therapy comprising (a) a pharmaceutical composition comprising Compound A at a total daily dose of about 15 mg or about 30 mg, and a pharmaceutically acceptable carrier; and (b) a pharmaceutical composition comprising Compound B at about 10 mg / kg on Day 1 and Day 8 of a 21 -day dosing cycle, and a pharmaceutically acceptable carrier.2981235349. v1

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