How to treat MAT2A-related diseases

Abstract

This disclosure relates to the use of MAT2A inhibitors in the treatment and prevention of MAT2A-related diseases, such as proliferative disorders including cancer. This disclosure also relates to corresponding pharmaceutical formulations, uses, methods, compositions, and related disclosed embodiments.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims, under Section 119(e) of the United States Patent Act, the benefit of priority from U.S. Provisional Application No. 63 / 583,058 filed on 15 September 2023, U.S. Provisional Application No. 63 / 605,124 filed on 1 December 2023, and U.S. Provisional Application No. 63 / 665,869 filed on 28 June 2024, the contents of which are incorporated herein by reference in their entirety for all purposes. Statement regarding rights to inventions made under federally funded research and development.

[0002] Not applicable References to the "sequence listings," tables, or computer program listing appendices submitted on compact disc.

[0003] Not applicable [Background technology]

[0004] Cancer is a leading cause of death worldwide. The limitations of conventional treatment approaches, such as chemotherapy and immunotherapy, are that their cytotoxic effects are not limited to cancer cells, and harmful side effects can occur in normal tissues. Therefore, novel strategies are needed to better target cancer cells.

[0005] Synthetic lethality arises when the combined deletion of two or more genes leads to cell death, whereas the deletion of only one of these genes does not. The concept of synthetic lethality originates from studies in Drosophila model systems where a combination of mutations in two or more separate genes leads to cell death (as opposed to the viability that results from the mutation or deletion of only one gene). More recently, numerous studies have sought maladaptive genetic changes in cancer cells that make them vulnerable to synthetic lethal approaches. These tumor-specific genetic defects have led to the use of targeted agents that induce tumor cell death while preserving normal cells.

[0006] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that uses methionine (Met) and adenosine triphosphate (ATP) to produce s-adenosylmethionine (SAM). SAM is a major 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). SAM is required for PRMT5 activity, but PRMT5 is competitively inhibited by 5'-methylthioadenosine (MTA). Since MTA is part of the methionine salvage pathway, intracellular MTA levels are kept low in a process initiated by methylthioadenosine phosphorylase (MTAP).

[0007] MTAP is located at a locus on chromosome 9 that is frequently deleted in cells from patients with cancers originating from several tissues, including the central nervous system, pancreas, esophagus, bladder, and lung (cBioPortal database). Loss of MTAP leads to the accumulation of MTA, making MTAP-deficient cells more dependent on SAM production and, consequently, MAT2A activity, compared to cells expressing MTAP. In shRNA cell line screening across approximately 400 cancer cell lines, MAT2A knockdown resulted in a higher percentage of MTAP-deficient cell viability loss compared to MTAP WT cells (see McDonald et.al. 2017 Cell 170, 577-592). Furthermore, inducible knockdown of the MAT2A protein reduced tumor growth in vivo (see Marjon et.al., 2016 Cell Reports 15(3), 574-587). These results suggest that MAT2A inhibitors may offer a useful therapy for cancer patients, including those with MTAP-deficient tumors.

[0008] Therefore, there is a need in the art to provide methods for treating MAT2A-related diseases. This disclosure addresses these needs and also provides related advantages. [Overview of the project]

[0009] In one embodiment, the present disclosure features a method for treating or preventing a proliferative disorder, such as cancer, in a subject requiring treatment. The method involves administering a therapeutically effective dose of a methionine adenosyltransferase 2A inhibitor (MAT2Ai) to the subject. The methods described herein may include one or more of the following features:

[0010] In certain embodiments, the MAT2A inhibitor is 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 1) or a pharmaceutically acceptable salt thereof.

[0011] In certain embodiments, the MAT2A inhibitor is administered orally.

[0012] In some embodiments, the Specified herein provides a method for treating a MAT2A-related disease, comprising administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the Specified provides a method for treating cancer in a subject of interest, comprising administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the method comprises administering to the subject of interest a therapeutically effective amount of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 1) or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is approximately 5 mg to approximately 100 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 is administered in the form of a free base.

[0015] In some embodiments, the methods described herein include administering a therapeutically effective dose of compound 1 to the subject in question in a total daily dose of about 50 mg to about 75 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is a total daily dose of about 25 mg to about 50 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is a total daily dose of about 5 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is a total daily dose of about 10 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is a total daily dose of about 15 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 30 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 45 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 60 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 80 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 100 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0016] In certain embodiments, compound 1 in the form of a free base is administered in doses ranging from about 5 mg QD once daily to about 60 mg QD (e.g., 5 mg QD, 10 mg QD, 15 mg QD, 30 mg QD, 45 mg, or 60 mg QD), or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered.

[0017] In certain embodiments, compound 1 in the form of a free base is administered in a dose of about 60 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered. In certain embodiments, compound 1 in the form of a free base is administered in a dose of about 30 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered. In certain embodiments, compound 1 in the form of a free base is administered in a dose of about 15 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered.

[0018] In certain embodiments, compound 1 in the form of a free base is administered in a dose of approximately 60 mg QD. In certain embodiments, compound 1 in the form of a free base is administered in a dose of approximately 45 mg QD. In certain embodiments, compound 1 in the form of a free base is administered in a dose of approximately 30 mg QD. In certain embodiments, compound 1 in the form of a free base is administered in a dose of approximately 15 mg QD. In certain embodiments, compound 1 in the form of a free base is administered in a dose of approximately 10 mg QD. In certain embodiments, compound 1 in the form of a free base is administered in a dose of approximately 5 mg QD.

[0019] In some embodiments, the MAT2A inhibitor is administered with food (i.e., the MAT2A inhibitor is administered within one hour before a meal or within two hours after a meal). In some embodiments, the MAT2A inhibitor is administered without food (i.e., the MAT2A inhibitor is administered more than one hour before a meal or more than two hours after a meal).

[0020] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0021] In certain embodiments, the subject is a human. In some embodiments, the human is an adult patient 18 years of age or older.

[0022] In some embodiments, the cancer is non-small cell lung cancer (squamous cell carcinoma and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, or gastric cancer. In some embodiments, the cancer is non-small cell lung cancer (squamous cell carcinoma). In some embodiments, the cancer is non-small cell lung cancer (adenocarcinoma). In some embodiments, the cancer is urothelial carcinoma (bladder). In some embodiments, the cancer is urothelial carcinoma (upper urinary tract).

[0023] In some embodiments, the subject suffers from non-small cell lung cancer (e.g., squamous cell carcinoma or adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, or gastric cancer. In some embodiments, the subject suffers from squamous cell carcinoma and adenocarcinoma among esophageal cancers, gastric adenocarcinoma, or gastroesophageal junction cancer.

[0024] In some embodiments, the cancer has an MTAP gene deletion.

[0025] In some embodiments, the cancer is therapeutically resistant to at least one anti-cancer agent.

[0026] In some embodiments, subjects administered compound 1 or a pharmaceutically acceptable salt thereof for at least 21 days do not exhibit grade 3 or grade 4 adverse events related to compound 1 therapy. In some embodiments, subjects administered compound 1 or a pharmaceutically acceptable salt thereof for at least 42 days do not exhibit grade 3 or grade 4 adverse events related to compound 1 therapy. In some embodiments, subjects administered compound 1 or a pharmaceutically acceptable salt thereof for at least 63 days do not exhibit grade 3 or grade 4 adverse events related to compound 1 therapy. In some embodiments, subjects exhibit at least a stable disease after administration of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects exhibit at least a partial response after administration of compound 1 or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the methods described herein include administering at least one additional therapeutic agent. In some embodiments, the methods described herein include administering at least one additional therapeutic agent or diagnostic agent. In some embodiments, the at least one additional therapeutic agent is a signal transduction inhibitor (STI). In some embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the at least one additional therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the at least one additional therapeutic agent is a PRMT5 inhibitor.

[0028] In some embodiments, unit dosage forms are provided herein that comprise about 5 mg to about 100 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0029] In some embodiments, kits comprising one or more unit dosage forms described herein are provided herein. In some embodiments, the kit further comprises at least one additional therapeutic agent.

[0030] Any of the above embodiments and aspects can be combined with any other embodiments or aspects.

[0031] Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following detailed description and drawings. [Brief explanation of the drawing]

[0032] Not applicable [Modes for carrying out the invention]

[0033] I. General Overexpression of the enzyme MAT2A has been shown to mediate certain cancers. MAT2A has also been identified as a synthetic lethal target in cancers characterized by reduced or absent methylthioadenosine phosphorylase (MTAP) gene expression, absence of the MTAP gene, impaired MTAP protein function, reduced levels of MTAP protein, absence of MTAP protein, MTA accumulation, or a combination thereof.

[0034] A method for treating MAT2A-related disorders in subjects is described herein. This method includes a specific drug regimen that is highly effective in treating subjects and is well tolerated by the subjects. II. Definition

[0035] While various embodiments and aspects of the present invention are shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided merely as examples. Those skilled in the art will immediately recall numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternative forms to the embodiments of the present invention described herein may be used in carrying out the present invention.

[0036] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein. All documents or parts of documents cited herein, including but not limited to patents, patent applications, articles, books, manuals, and professional works, are expressly incorporated herein by reference in whole for any purpose.

[0037] Unless otherwise defined, technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd ed., J. Wiley & Sons (New York, NY 1994) and Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, apparatus, and materials similar or equivalent to those described herein may be used in the practice of the present invention. The following definitions are provided to facilitate the understanding of certain terms that are frequently used herein and are not intended to limit the scope of this disclosure.

[0038] Compound 1 is given by the formula: [ka] This refers to the chemical substance 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one, which has the characteristic [characteristic]. In some embodiments, compound 1 is in the form of a pharmaceutically acceptable salt. Both compound 1 and the pharmaceutically acceptable salt are described in International Publication Nos. 2020 / 123395 and 2024 / 118070. The contents of International Publication Nos. 2020 / 123395 and 2024 / 118070 are incorporated herein by reference in their entirety for all purposes.

[0039] "Pharmaceutically acceptable salt" refers to a derivative of Compound 1, wherein the parent compound is modified by converting an existing basic moiety thereof into its salt form. Examples of pharmaceutically acceptable salts include salts of mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 23rd Edition, 2020, which is incorporated herein by reference.

[0040] Compound 1 can exist as a pharmaceutically acceptable isotopically-labeled form, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into Compound 1 include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, for example, respectively, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, and 18 F. These radiolabeled compounds may be useful, for example, in helping to determine or measure the efficacy of Compound 1 by characterizing the site or mode of action, or the binding affinity to a pharmacologically important site of action. Certain isotopically-labeled forms of Compound 1, for example those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and easy detection means.

[0041] When referring to a specific amount of compound 1 administered to a patient, this application refers to the amount of compound 1 free base. Those skilled in the art will recognize that to administer the same amount of compound 1 in different salt forms, the total amount administered needs to be slightly adjusted.

[0042] As used herein, the terms "a" or "an" mean one or more.

[0043] The terms “comprise,” “include,” and “have,” as well as their derivatives, are used interchangeably as comprehensive open-ended terms herein. For example, the use of “comprising,” “including,” or “having” means that any element, whether it is included, has, or contains, is not the only element encompassed by the subject of the clause containing this verb.

[0044] As used herein, the term “approximately” means a range of values ​​including the specified value that a person skilled in the art would consider reasonably similar to the specified value. In some embodiments, the term “approximately” means within a standard deviation using generally acceptable measurements in the art. In some embodiments, “approximately” means a range extending to + / - 10% of the specified value. In some embodiments, “approximately” means the specified value.

[0045] As used herein, “treatment,” “to treat,” “to alleviate,” and “to improve” are interchangeable herein. These terms refer to methods for obtaining beneficial or desired outcomes, which include, but are not limited to, therapeutic benefits. In the context of treating cancer, therapeutic benefits include eradication, improvement, and suppression of cancer. Therapeutic benefits are also achieved by the eradication, improvement, or suppression of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the subject, even though the subject may still be suffering from the underlying disease. Treatment includes slowing the progression of the clinical symptoms of the disease by administration of a composition, suppressing the disease, i.e., causing a reduction in the clinical symptoms of the disease; inhibiting the disease, i.e., preventing the onset of clinical symptoms by administration of a composition after the initial appearance of symptoms, and / or mitigating the disease, i.e., causing the resolution of clinical symptoms by administration of a composition after the initial appearance of symptoms.

[0046] An "effective dose" or "therapeutic effective dose" is a quantity sufficient to achieve the stated objective (e.g., to achieve the effect intended by the administration, to treat a disease, to reduce enzyme activity, or to reduce one or more symptoms of a disease or condition). An example of an "effective dose" is a quantity sufficient to contribute to the treatment or reduction of one or more symptoms of a disease, which may also be called a "therapeutic effective dose." "Reduction" (and its grammatical equivalent) of one or more symptoms means reducing the severity or frequency of a symptom, or eliminating the symptom. Effectiveness can also be expressed as a "--times" increase or decrease. For example, a therapeutic effective dose may have at least 1.2 times, 1.5 times, 2 times, 5 times, or more of the effect compared to a control. When treating cancer, an effective dose may result in tumor suppression, tumor reduction, reduced progression, tumor eradication, or improved overall survival.

[0047] "Patient," "subject," or "subject requiring treatment" refers to an organism that is suffering from or susceptible to a disease or condition that can be treated by using the methods provided herein. This term does not necessarily imply that the subject has been diagnosed with a specific disease, but typically refers to an individual under medical supervision. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient, subject, or subject requiring treatment is human.

[0048] A "partial response" or "PR (partial response)" refers to a clinical outcome in which the size of the target lesion in the subject is reduced, but still present, after treatment with compound 1 or a pharmaceutically acceptable salt thereof. A partial response is defined as a reduction of at least 30% in the total target lesion diameter in the subject after treatment with compound 1 or a pharmaceutically acceptable salt thereof, compared to the baseline total target lesion diameter before treatment.

[0049] "Complete response" or "CR (complete response)" refers to a clinical outcome in which, after treatment with compound 1 or a pharmaceutically acceptable salt thereof, all target lesions disappear in the subject and the short axis of any pathological lymph node decreases to less than 10 mm.

[0050] "Progressive disease" or "PD (progressive disease)" refers to a clinical outcome in which the size of the target lesions increases after treatment with compound 1 or a pharmaceutically acceptable salt thereof. Progressive disease is defined as an increase of at least 20% in the total diameter of the target lesions relative to the minimum total in the study (including the baseline total, if the minimum in the study), and in addition to this 20% relative increase, there is an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression.)

[0051] "Stable disease" or "SD (stable disease)" is a clinical outcome in which the target lesion does not shrink sufficiently to qualify as a partial response (PR) or increase sufficiently to qualify as a progressive disease (PD) after treatment with compound 1 or a pharmaceutically acceptable salt thereof.

[0052] A "controlled disease state" refers to a situation where the subject can alternate between stable disease and partial response.

[0053] As used herein, "CAAP1" refers to one gene that inhibits caspase activity and apoptosis.

[0054] As used herein, "CDKN2A" refers to the cyclin-dependent kinase inhibitor 2A gene. III. Modes for Carrying Out the Invention method

[0055] MAT2A has been found to play a role in certain disorders in humans or animals. This disclosure relates to compounds, such as MAT2A inhibitors, that exhibit antiproliferative activity when used alone or in combination, preferably in cancer patients. Preferably, this method relates to a method for treating proliferative disorders by administration or co-administration of such compounds.

[0056] In some embodiments, the MAT2A inhibitor used herein is given by formula: [ka] This is 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 1), which has the following properties.

[0057] In some embodiments, the MAT2A inhibitor used herein is a pharmaceutically acceptable salt of compound 1.

[0058] In certain embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered, for example, orally, in a daily dose of about 5 mg to about 100 mg of compound 1 in the form of a free base, or in an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0059] In some embodiments, the Specified Information provides a method for treating MAT2A-related disease, comprising administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0060] In some embodiments, this specification provides a method for treating a disease mediated by MAT2A, wherein a therapeutically effective amount of compound 1, A method is provided which includes administering a pharmaceutically acceptable salt thereof, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0061] In some embodiments, the Specified Information provides a method for treating cancer, comprising administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0062] In some embodiments, subjects administered compound 1 or a pharmaceutically acceptable salt thereof for at least 21 days do not exhibit grade 3 or grade 4 adverse events related to compound 1 therapy. In some embodiments, subjects administered compound 1 or a pharmaceutically acceptable salt thereof for at least 42 days do not exhibit grade 3 or grade 4 adverse events related to compound 1 therapy. In some embodiments, subjects administered compound 1 or a pharmaceutically acceptable salt thereof for at least 63 days do not exhibit grade 3 or grade 4 adverse events related to compound 1 therapy. In some embodiments, subjects exhibit at least a stable disease after administration of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects exhibit at least a partial response after administration of compound 1 or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, cancer is characterized by decreased or absent methylthioadenosine phosphorylase (MTAP) gene expression, absence of the MTAP gene, impaired MTAP protein function, decreased levels of MTAP protein, absence of MTAP protein, MTA accumulation, or a combination thereof.

[0064] In some embodiments, the Specified Provisions provide a method for treating cancer in a subject, comprising administering to a patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt, wherein the cancer is characterized by decreased or absent methylthioadenosine phosphorylase (MTAP) gene expression, absence of the MTAP gene, impaired function of the MTAP protein, decreased levels of the MTAP protein, absence of the MTAP protein, MTA accumulation, or a combination thereof.

[0065] In some embodiments, the Specified herein provides a method for treating MTAP-deficient cancer in a subject, comprising administering to a patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0066] In some embodiments, the Specified Provisions Provide a method for treating cancer in a subject having an MTAP gene deletion, comprising administering to the patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0067] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered once daily (QD).

[0068] In some embodiments, the therapeutically effective dose of compound 1 is a total daily dose of compound 1 in the form of a free base of about 50 mg to about 75 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is a total daily dose of compound 1 in the form of a free base of about 25 mg to about 50 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0069] In some embodiments, the therapeutically effective dose of compound 1 is approximately 5 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 10 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 15 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 30 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is approximately 45 mg of the total daily dose of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is a total daily dose of compound 1 in the form of a free base of about 60 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutically effective dose of compound 1 is a total daily dose of compound 1 in the form of a free base of about 80 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the therapeutic effect of compound 1 is a total daily dose of compound 1 in the form of a free base of about 100 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0070] In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered in a dose of approximately 50 mg once daily (QD) to approximately 75 mg once daily (QD), or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered. In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered in a dose of approximately 25 mg QD to approximately 50 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered.

[0071] In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered at a dose of about 5 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered at a dose of about 10 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered at a dose of about 15 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered at a dose of about 30 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered at a dose of about 45 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered in a dose of about 60 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered. In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered in a dose of about 80 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered. In some embodiments, a therapeutically effective dose of compound 1 in the form of a free base is administered in a dose of about 100 mg QD, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered.

[0072] In some embodiments, cancer is a solid tumor. In some embodiments, cancer is a solid malignant tumor.

[0073] In some embodiments, cancers include neuroblastoma, intestinal cancer (e.g., rectal cancer, colorectal cancer, familial adenomatous polyposis cancer, and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, pharyngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (ALL) These include leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminomas, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0074] In some embodiments, cancers include lung cancer, non-small cell lung cancer (NSLC), bronchioloalveolar cell carcinoma, osteosarcoma, pancreatic cancer, skin cancer, cancer of the head or neck, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, vaginal cancer, vulvar cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, mesothelioma, hepatocellular carcinoma, biliary tract cancer, chronic or acute leukemia, lymphocytic lymphoma, and central nervous system cancer. Neoplasms of the system (CNS), spinal axial tumors, brainstem gliomas, glioblastoma multiforme, astrocytoma, schwannoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, pituitary adenoma (including treatment-resistant forms of any of the above cancers), or a combination of one or more of the above cancers.

[0075] In some embodiments, cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, gastroesophageal junction cancer, malignant peripheral nerve sheath tumor, and mesothelioma.

[0076] In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer (squamous cell carcinoma and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, and gastric cancer. In some embodiments, the cancer is non-small cell lung cancer (squamous cell carcinoma). In some embodiments, the cancer is non-small cell lung cancer (adenocarcinoma). In some embodiments, the cancer is urothelial carcinoma (upper urinary tract). In some embodiments, the cancer is urothelial carcinoma (bladder). In some embodiments, the cancer is urothelial carcinoma (upper urinary tract). In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is squamous cell carcinoma and adenocarcinoma of the esophagus, gastric adenocarcinoma, or gastroesophageal junction cancer.

[0077] In some embodiments, the Specified Provisions provide a method for treating cancer in a subject characterized by reduced or absent MTAP expression, or absence of the MTAP gene, reduced levels of MTAP protein, impaired function of MTAP protein, absence of MTAP protein, MTA accumulation, or a combination thereof, compared to cancer in which the MTAP gene is present and fully functional, wherein the method comprises administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof to the subject as needed, the therapeutically effective amount being a total daily dose of compound 1 in the form of a free base of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. In one embodiment, MTAP-deficient cancers are leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma. In another embodiment, the MTAP-deficient cancer is pancreatic cancer. In yet another embodiment, the MTAP-deficient cancer is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B-cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), or mantle cell lymphoma (MCL). In yet another embodiment, the MTAP-deficient cancer is gastric cancer. In yet another embodiment, the cancer is colon cancer. In yet another embodiment, the MTAP-deficient cancer is liver cancer. In yet another embodiment, the MTAP-deficient cancer is glioblastoma multiforme (GBM). In yet another embodiment, the MTAP-deficient cancer is bladder cancer. In yet another embodiment, the MTAP-deficient cancer is esophageal cancer. In yet another embodiment, the MTAP-deficient cancer is breast cancer. In yet another embodiment, MTAP-deficient cancer is NSLCC. In yet another embodiment, MTAP-deficient cancer is MCL. In yet another embodiment, MTAP-deficient cancer is DLBCL. In yet another embodiment, MTAP-deficient cancer is ALL.In some embodiments, MTAP-deficient cancer is selected from the group consisting of non-small cell lung cancer (squamous cell carcinoma and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, and gastric cancer. In some embodiments, MTAP-deficient cancer is squamous cell carcinoma and adenocarcinoma of the esophagus, gastric adenocarcinoma, or gastroesophageal junction cancer.

[0078] In yet another embodiment, the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, anal cancer, gastric cancer, colon cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin lymphoma, gastric cancer, esophagogastric junction cancer, esophageal cancer, malignant peripheral nerve sheath tumor, and mesothelioma. In one embodiment, the cancer is mesothelioma. In one embodiment, the cancer is non-small cell lung cancer. In another embodiment, the cancer is non-squamous non-small cell lung cancer. In one embodiment, the cancer is cancer of the colon or rectum. In one embodiment, the cancer is adenocarcinoma of the colon or rectum. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is mammary gland cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is gastric adenocarcinoma. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is pancreatic adenocarcinoma. In one embodiment, the cancer is bladder cancer. In one embodiment, the cancer is characterized by MTAP deficiency. In one embodiment, the cancer is characterized by MTAP deficiency. In one embodiment, the cancer is characterized by CAAP1 deficiency. In one embodiment, the cancer is characterized by CAAP1 deficiency. In one embodiment, the cancer is characterized by CDKN2A deficiency. In yet another embodiment, the cancer is a solid tumor. In yet another embodiment, the cancer is an MTAP-deficient solid tumor. In yet another embodiment, the cancer is a metastatic MTAP-deficient solid tumor. In yet another embodiment, the cancer is metastatic. In yet another embodiment, the cancer is a solid malignant tumor. In yet another embodiment, the cancer is an MTAP-deficient lung cancer or MTAP-deficient pancreatic cancer, including MTAP-deficient NSCLC or MTAP-deficient pancreatic ductal adenocarcinoma (PDAC) or MTAP-deficient esophageal cancer. In another embodiment, the cancer is a tumor having an MTAP gene deletion. In any one of the embodiments herein, the cancer is a solid tumor or a hematological cancer. In one embodiment, the tumor is deficient in MTAP. In another embodiment, the tumor has normal expression of MTAP. In yet another embodiment, the cancer is NSCLC, mesothelioma, squamous cell carcinoma of the head and neck, salivary gland tumor, urothelial carcinoma, sarcoma, or ovarian cancer. In yet another embodiment, the cancer is NSCLC, esophageal and gastric cancer, and pancreatic cancer.In yet another embodiment, cancer is characterized by reduced or absent MTAP gene expression. In yet another embodiment, cancer is characterized by impaired MTAP protein function. In yet another embodiment, cancer is characterized by reduced or absent levels of MTAP protein. In yet another embodiment, cancer is characterized by MTA accumulation.

[0079] Genomic analysis of MTAP-deficient cell lines showed that cell lines incorporating KRAS mutations or p53 mutations were sensitive to MAT2A inhibition.

[0080] In some embodiments, a method is provided for treating cancer in a subject, wherein the cancer is characterized by reduced or absent MTAP expression, or absence of the MTAP gene, reduced levels of MTAP protein, impaired function of MTAP protein, absence of MTAP protein, or a combination thereof, and further characterized by the presence of mutant KRAS and / or mutant p53, wherein the method comprises administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dose of compound 1 in the form of free bases of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the cancer is MTAP-deficient and KRAS-mutant. In some embodiments, the cancer is MTAP-deficient and p53-mutant. In some embodiments, the cancer is MTAP-deficient, KRAS-mutant, and p53-mutant.

[0081] The term "mutant KRAS" or "KRAS mutation" refers to the KRAS protein (or the gene encoding the protein) that incorporates an activating mutation that alters its normal function. For example, a mutant KRAS protein may incorporate a single amino acid substitution at position 12 or 13. In certain embodiments, a KRAS mutant incorporates a G12X or G13X substitution, where X represents any amino acid change at the indicated position. In certain embodiments, the substitution is G12V, G12R, G12C, or G13D. In another embodiment, the substitution is G13D. "Mutant p53" or "p53 mutation" means the p53 protein (or the gene encoding the protein) that incorporates a mutation that inhibits or eliminates its tumor suppressor function. In one embodiment, the p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R282W, A159V, or R280K. In one embodiment, the cancer is non-small cell lung cancer (NSLCC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer.

[0082] In some embodiments, cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, and mesothelioma.

[0083] In some embodiments, the cancer is resistant to at least one anticancer drug. That is, the patient being treated has been administered the aforementioned anticancer drug, and either the patient did not respond to this treatment, or the healthcare professional managing the patient's care deemed the response to be insufficient. In some embodiments, the patient, who is resistant to at least one anticancer drug, is administered a MAT2A inhibitor in combination with at least one anticancer drug. In some embodiments, the patient, who is resistant to at least one anticancer drug, is no longer administered that at least one anticancer drug.

[0084] In certain embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered in a dose that has little or no adverse effects but is therapeutically effective.

[0085] In some embodiments, the MAT2A inhibitor is administered with food (i.e., the MAT2A inhibitor is administered within one hour before a meal or within two hours after a meal). In some embodiments, the MAT2A inhibitor is administered without food (i.e., the MAT2A inhibitor is administered more than one hour before a meal or more than two hours after a meal).

[0086] In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which 10 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which 15 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which 30 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which 45 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is provided, in which compound 1 or a pharmaceutically acceptable salt thereof is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which 60 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily.In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer is provided, in which compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0087] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, administered daily in amounts ranging from 5 mg to 100 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, administered daily in amounts ranging from 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg, or 100 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, administered daily in amounts ranging from 5 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, administered daily in amounts ranging from 10 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, administered daily at a dose of 15 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, administered daily at a dose of 30 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, administered daily at a dose of 45 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, administered daily at a dose of 60 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, in which 100 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily.

[0088] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered as monotherapy.

[0089] Exemplary lengths of time related to the course of treatment methods disclosed herein include approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, approximately 8 weeks, approximately 9 weeks, approximately 10 weeks, approximately 11 weeks, approximately 12 weeks, approximately 13 weeks, approximately 14 weeks, approximately 15 weeks, approximately 16 weeks, approximately 17 weeks, approximately 18 weeks, approximately 19 weeks, approximately 20 weeks, approximately 21 weeks, approximately 22 weeks, approximately 23 weeks, approximately 24 weeks, approximately 4 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, and approximately 11 months. Examples include months, approximately 12 months, approximately 13 months, approximately 14 months, approximately 15 months, approximately 16 months, approximately 17 months, approximately 18 months, approximately 19 months, approximately 20 months, approximately 21 months, approximately 22 months, approximately 23 months, approximately 24 months, approximately 30 months, approximately 3 years, approximately 4 years, and approximately 5 years, or any number of days, weeks, months, or years in between. For example, a treatment cycle could be 5 months plus an additional number of weeks and / or days, or 1 year plus an additional number of months, weeks, and / or days.

[0090] The exemplary length of time associated with the treatment process may be approximately 5 years, 4 years, 3 years, 2 years, 1 year, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month.

[0091] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered together with one or more other therapeutic agents, such as anticancer agents. Pharmaceutical composition

[0092] Compound 1 or a pharmaceutically acceptable salt thereof may be in the form of a composition suitable for administration to a subject. Generally, such a composition is a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable or physiologically acceptable excipients. The pharmaceutical composition may be used in the manner disclosed herein, and therefore, for example, the pharmaceutical composition may be administered to a subject ex vivo or in vivo to carry out the therapeutic methods and uses described herein.

[0093] Pharmaceutical compositions can be formulated to suit the intended method or route of administration, exemplary routes of administration are described herein. Furthermore, pharmaceutical compositions may be used in combination with other therapeutic agents or compounds described herein to treat the diseases, disorders, and conditions envisioned by this disclosure.

[0094] A pharmaceutical composition containing an active ingredient (e.g., compound 1, or a pharmaceutically acceptable salt thereof) may be in a form suitable for oral use, such as tablets, capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, liquids, microbeads, or elixirs. A pharmaceutical composition intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such a composition may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically excellent and palatable preparation. Tablets, capsules, etc., contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for the manufacture of tablets, capsules, etc. These excipients may include, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulators and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0095] Tablets, capsules, etc., suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Tablets may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Further agents include biodegradable or biocompatible particles or polymers such as polyesters, polyamine acids, hydrogels, polyvinylpyrrolidone, polyanhydride, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or copolymers of lactide and glycoside, polylactide and glycoside, or copolymers of ethylene vinyl acetate, for controlling the delivery of the administered composition. For example, oral drugs may be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization, using hydroxymethylcellulose or gelatin microcapsules or poly(methyl methacrylate) microcapsules, respectively, or in colloidal drug delivery systems. Examples of colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for compounding the above formulations are known in the art.

[0096] Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0097] The aqueous suspension contains an active material mixed with excipients suitable for its preparation. Such excipients may include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives.

[0098] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners, such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners and flavorings, such as those mentioned above, may be added to provide an oral preparation with a good taste.

[0099] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified herein.

[0100] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth gum; naturally occurring phosphatides, such as esters or partial esters derived from soybeans, lecithin, and fatty acids; hexitol anhydride, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0101] A pharmaceutical composition typically comprises a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl or n-propyl, p-hydroxybenzoate), emulsifiers, suspending agents, dispersants, solvents, fillers, bulking agents, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be physiological saline or citrate-buffered physiological saline, and other materials common in pharmaceutical compositions for parenteral administration may be supplemented. Neutral-buffered physiological saline or physiological saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize the various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffering component may be water-soluble materials such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonate sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0102] After a pharmaceutical composition has been formulated, it can be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations may be stored in any of the following forms: ready-to-use, lyophilized, requiring reconstitution before use, liquid, requiring dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or auto-injector (e.g., similar to EpiPen®)), while in other embodiments, a multi-use container (e.g., a multi-use vial) is provided.

[0103] The pharmaceutical composition may also include carriers to protect the composition from rapid degradation or excretion from the body, such as liposomes, hydrogels, prodrugs, and controlled-release formulations including microencapsulation delivery systems. For example, time-delaying materials such as glyceryl monostearate or glyceryl stearate may be used alone or in combination with wax. Any drug delivery devices, including implants (e.g., implantable pumps) and catheter systems, slow infusion pumps and devices, can be used to deliver compound 1 or a pharmaceutically acceptable salt thereof, all of which are well known to those skilled in the art. Combination therapy

[0104] The present invention envisions the use of compound 1 or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents.

[0105] As used herein, “combination” means a combination of therapeutic agents that can be administered separately, for example, a therapeutic agent that can be formulated separately for separate administrations (for example, as can be provided in a kit), and a therapeutic agent that can be administered together in a single formulation (i.e., a “co-formulation”).

[0106] In certain embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered or applied sequentially, for example, one agent is administered before one or more other agents. In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered simultaneously, for example, two or more agents are administered simultaneously or nearly simultaneously, and the two or more agents may exist in two or more separate formulations or be combined into a single formulation (i.e., a co-formulation). Whether administered sequentially or simultaneously, the two or more agents are considered to be administered in combination for the purposes of this disclosure. In such combination therapy, the various active agents often have different complementary mechanisms of action. Such combination therapy may be particularly advantageous in that it allows for a reduction in the dose of one or more agents, thereby reducing or eliminating adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have synergistic therapeutic or preventive effects on the underlying disease, disorder, or condition.

[0107] This disclosure provides a method for treating cancer with a dosage of compound 1 or a pharmaceutically acceptable salt thereof as described herein, and at least one additional therapeutic or diagnostic agent. This disclosure also provides a method for treating cancer with a dosage of compound 1 or a pharmaceutically acceptable salt thereof as described herein, and at least one additional therapeutic agent.

[0108] In some embodiments, at least one additional therapeutic agent is an anti-CD20 therapeutic agent such as temozolomide, pemetrexed, pegylated liposomal doxorubicin (Doxil), eribulin (Halaven), ixabepirone (Exempra), protein-bound paclitaxel (Abraxane), oxaliplatin, irinotecan, venatoclax (bcl2 inhibitor), 5-azacitadine, rituxan, and obinutuzumab; a hormonal agent (anastrozole, exemestand, letrozole, zoladex, lupon eligard); a CDK4 / 6 inhibitor; palbociclib; abemaciclib; a CPI (avelumab, semiprimab-rwlc, or bevacizumab).

[0109] In some embodiments, at least one additional treatment, or, is a signaling inhibitor (STI). In some embodiments, STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) HER-2 / neu receptor inhibitors (e.g., Herceptin); (iv) Akt family kinase or Akt pathway inhibitors (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopyridol); and (vi) phosphatidylinositol kinase inhibitors.

[0110] In some embodiments, at least one additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent includes alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates, e.g., busulfan, improsulfan and piposulfan; aziricins, e.g., benzodopa, carbocon, metsuredopa and uredopa; altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime. Tyleneimine and methylamelamine; nitrogen mustards, e.g., chiorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobenbitin, fenestrine, prednimustine, trophosphamide, uracil mustard; nitrosoureas, e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, e.g. Aclacinomycin, actinomycin, autoramycin, azaserin, bleomycin, kactinomycin, calicheamicin, carabicin, caminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detrubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycopheno Folic acid, nogaramycin, olibomycin, peplomycin, potfiromycin, promycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zolubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folic acid analogs, e.g., denopterin, methotrexate, pteropterin, trimethrexate; purine analogs, e.g., fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens, e.g., carsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal substances, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., floric acid; acegraton; aldofamide glycoside; aminolevulinic acid , Amsacrin, Bestlovesil; Bisanthren, Edatraxate; Defofamine; Demecolsin; Diadiquan, Elformithine; Elliptinium acetate; Etoglucide; Gallium nitrate, Hydroxyurea, Lentinan; Ronidamin, Mitoguazone, Mitoxantrone, Mopidamol, Nitracrine; Pentostatin, Fenamet; Pirarubicin, Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Lazoxane; Schizophyllan; Spirogermanium; Te Nuazonic acid; triadicone; 2,2',2''-trichlorotriethylamine; urethane; vindesine, dacarbazine, mannomustine; mitobronitol; mitractol, pipobromane, gasitosine; arabinoside (Ara-C); cyclophosphamide, thiotepa, taxoids, e.g., paclitaxel and doxetaxel; chlorambucil, gemcitabine, 6-thioguanine; mercaptopurine, methotrexate, platinum and platinum-coordinated complexes, e.g., cisplatin or ka Ruvoplatin; vinblastine; etoposide (VP-16); ifosfamide, mitomycin C, mitoxantrone, vincristine; vinorelbine, navelbine, novantrone; teniposide, daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid, esperamicin, capecitabine; and any pharmaceutically acceptable salts, acids, or derivatives of the above, but not limited to these. In some embodiments, at least one additional therapeutic agent is cisplatin, doxorubicin, taxol, taxotere, or mitomycin C.

[0111] Other chemotherapeutic agents include anti-hormone agents that act to modulate or inhibit the hormonal effects on tumors, such as anti-estrogens including tamoxifen, raloxifene, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, onapristone, and toremifene; and anti-androgens, such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; as well as pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, at least one additional therapeutic agent is a hormone or related hormonal agent.

[0112] In some embodiments, at least one additional therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor targets CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFβ, CD73, CD39, A2AR, A2BR, IDO1, TDO2, Arginase, B7-H3, or B7-H4. In some embodiments, the immune checkpoint inhibitor is ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, or durvalumab.

[0113] In some embodiments, at least one additional therapeutic agent is radiotherapy, a monoclonal antibody against a tumor antigen, a conjugate of a monoclonal antibody and a toxin, a T-cell adjuvant, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy).

[0114] In some embodiments, at least one additional therapeutic agent is radiotherapy and / or temozolomide (TMZ), Avastin, or Lomustine.

[0115] In some embodiments, at least one additional therapeutic agent is a PRMT5 inhibitor. In some embodiments, the PRMT5 inhibitor is an MTA-cooperative PRMT5 inhibitor. In some embodiments, the PRMT5 inhibitor has the following structure: [ka] Compounds having, or a pharmaceutically acceptable salt thereof.

[0116] In one embodiment, the PRMT5 inhibitor is [ka] Alternatively, a selection is made from its pharmaceutically acceptable salts.

[0117] In one embodiment, the PRMT5 inhibitor is [ka] or a pharmaceutically acceptable salt thereof.

[0118] In one embodiment, the PRMT5 inhibitor is [ka] or a pharmaceutically acceptable salt thereof.

[0119] In one embodiment, the PRMT5 inhibitor is [ka] or a pharmaceutically acceptable salt thereof.

[0120] In one embodiment, the PRMT5 inhibitor is MRTX-1719 or a pharmaceutically acceptable salt thereof. In one embodiment, the PRMT5 inhibitor is TNG462 or a pharmaceutically acceptable salt thereof. In one embodiment, the PRMT5 inhibitor is TNG908 or a pharmaceutically acceptable salt thereof. In one embodiment, the PRMT5 inhibitor is AZD3470 or a pharmaceutically acceptable salt thereof.

[0121] Further PRMT5 inhibitors are those described in International Publication Nos. 2022 / 026892, 2021 / 086879, 2021 / 050915, and 2023 / 036974, the contents of which are incorporated herein by reference in their entirety. Pharmaceutical dosage forms

[0122] This disclosure includes Compound 1 or a pharmaceutically acceptable form thereof in a pharmaceutical dosage form. The unit dosage forms described herein are preferred for oral administration to a subject. The unit dosage forms may be, but are not limited to, capsules, tablets, or powders, and may be any form suitable for oral administration. The term "unit dosage form" refers to physically distinct units, each containing a predetermined amount of Compound 1 or a pharmaceutically acceptable form thereof, either alone or in combination with one or more additional agents, sufficient to produce the desired effect.

[0123] In some embodiments, the Disclosure provides a single unit dose capsule or tablet containing about 5 mg to 100 mg of Compound 1 in the form of a free base, or a corresponding amount of Compound 1 in the form of a pharmaceutically acceptable salt.

[0124] In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 5 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 10 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 15 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 30 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 45 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 60 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 80 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 100 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0125] In some embodiments, the unit dosage form of compound 1 or a pharmaceutically acceptable salt thereof is a tablet.

[0126] In some embodiments, the single unit dosage form of compound 1 or a pharmaceutically acceptable salt thereof is a powder.

[0127] In some embodiments, the single unit dosage form of compound 1 or a pharmaceutically acceptable salt thereof is a capsule.

[0128] In some embodiments, a single unit dosage form is a capsule of size 0, 1, 2, 3, 4, or 5. In some embodiments, a single unit dosage form is a capsule of size 0. In some embodiments, a single unit dosage form is a capsule of size 1. In some embodiments, a single unit dosage form is a capsule of size 2. In some embodiments, a single unit dosage form is a capsule of size 3. In some embodiments, a single unit dosage form is a capsule of size 4. In some embodiments, a single unit dosage form is a capsule of size 5. kit

[0129] This disclosure also encompasses kits comprising the pharmaceutical compositions and unit dosage forms of this disclosure. Kits generally take the form of physical structures containing various components, as described below, and may be used, for example, when carrying out the methods described herein.

[0130] The kit may contain one or more of Compound 1 or its pharmaceutically acceptable salts (for example, provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. Compound 1 or its pharmaceutically acceptable salt may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form that requires reconstitution or dilution before administration (e.g., powder). If Compound 1 or its pharmaceutically acceptable salt is in a form that requires reconstitution or dilution by the user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, etc., packaged together with or separately from Compound 1 or its pharmaceutically acceptable salt. If combination therapy is intended, the kit may contain several drugs separately, or several drugs may already be combined in the kit. Each component of the kit may be sealed in an individual container, or all of the various containers may be in a single package. The kit of the present invention may be designed for conditions necessary to properly maintain the components contained therein (e.g., refrigeration or freezing).

[0131] The kit may include a label or accompanying document containing identification information about its components and instructions for their use (e.g., clinical pharmacology of the active ingredient including drug parameters, mechanism of action, pharmacokinetics, and pharmacodynamics, adverse effects, contraindications, etc.). The label or document may include manufacturer information such as lot number and expiration date. The label or accompanying document may, for example, be incorporated into the physical structure containing the components, be included separately within the physical structure, or be affixed to the components of the kit (e.g., ampoules, tubes, or vials).

[0132] Labels or documents may further include, or be incorporated into, computer-readable media such as disks (e.g., hard disks, cards, memory disks), optical discs such as CDs or DVD-ROM / RAM, DVDs, MP3s, magnetic tapes, or electrical storage media such as RAM and ROM, or magneto-optical storage media, FLASH media, or hybrids thereof such as memory cards. In some embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source, for example, via the Internet.

[0133] Some of the kits described herein include a label describing a method for administering compound 1 or a pharmaceutically acceptable salt thereof. Some of the kits described herein include a label describing a method for treating cancer. In some embodiments, cancer is characterized by reduced or absent methylthioadenosine phosphorylase (MTAP) gene expression, absence of the MTAP gene, impaired MTAP protein function, reduced or absent levels of MTAP protein, MTA accumulation, or a combination thereof. In some embodiments, cancer is MTAP-deficient cancer. In some embodiments, cancer has an MTAP gene deletion.

[0134] The compositions of this disclosure include, but are not limited to, compositions containing Compound 1 or a pharmaceutically acceptable salt thereof, in a bottle, jar, vial, ampoule, tube, blister pack, or other container sealing system approved by the Food and Drug Administration (FDA) or other regulatory body, which can provide one or more unit doses containing Compound 1 or a pharmaceutically acceptable salt thereof. The package or dispenser may also be accompanied by a warning label associated with the container in a form prescribed by the government agency that regulates the manufacture, use, or sale of the drug, the warning label indicating approval by the agency. In certain embodiments, a kit may include the formulation or composition described herein, a container sealing system including the formulation or one or more unit dose forms containing the formulation, and a warning label or instructions describing the method of use described herein.

[0135] The packaging system, such as a blister pack, includes a thermoformable rigid film or PVC suitable for pharmaceutical packaging, and a push-through lid. The lid may include foil composed of a primer / aluminum / heat-seal coating, or it may be paper-based. Those skilled in the art will readily prepare a blister pack containing compound 1. The bottle system described herein may be made in various sizes (e.g., 75cc, 100cc, 200cc, etc.) and generally includes a child-resistant cap, which may be made from polypropylene. In some embodiments, a pharmaceutical dosage form of compound 1 or a pharmaceutically acceptable salt thereof is packaged in a 75cc bottle with a child-resistant cap. Those skilled in the art will readily prepare the bottle system described herein.

[0136] In some embodiments, the Disclosure provides kits for once-daily dosing. These kits provide one or more unit dosage forms, each comprising compound 1 or a pharmaceutically acceptable salt thereof for each dose.

[0137] In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 5 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 10 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 15 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 30 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 45 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 60 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 80 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the unit dosage form of compound 1 in the form of a free base is about 100 mg, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt. Non-exclusive exemplary embodiments

[0138] In the following further embodiments 1 to 92, the disclosure includes the following: 1. Embodiment 1 is a method for treating cancer in a subject of interest, comprising administering to the subject a therapeutically effective amount of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 1) or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is approximately 5 mg to approximately 100 mg of the total daily dose of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 2. Embodiment 2 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 15 mg to about 85 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 3. Embodiment 3 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 50 mg to about 75 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 4. Embodiment 4 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 25 mg to about 50 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 5. Embodiment 5 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 6. Embodiment 6 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 10 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 7. Embodiment 7 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 15 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 8. Embodiment 8 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 30 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 9. Embodiment 9 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 45 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 10. Embodiment 10 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 30 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 11. Embodiment 11 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 10 mg to about 30 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 12. Embodiment 12 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 15 mg to about 30 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 13. Embodiment 13 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 45 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 14. Embodiment 14 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 10 mg to about 45 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 15. Embodiment 15 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 15 mg to about 45 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 16. Embodiment 16 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 30 mg to about 45 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 17. Embodiment 17 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 5 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 18. Embodiment 18 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 10 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 19. Embodiment 19 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 15 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 20. Embodiment 20 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 30 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 21. Embodiment 21 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 45 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 22. Embodiment 22 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 23. Embodiment 23 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 80 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 24. Embodiment 24 is the method according to Embodiment 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 25. Embodiment 25 is the method according to any one of Embodiments 1 to 24, wherein the cancer is a solid tumor. 26. Embodiment 26 is the method according to any one of Embodiments 1 to 25, wherein the cancer is a solid malignant tumor. 27. Embodiment 27 is a method according to any one of Embodiments 1 to 26, wherein the cancer is characterized by decreased or absent methylthioadenosine phosphorylase (MTAP) gene expression, absence of the MTAP gene, impaired MTAP protein function, decreased levels of MTAP protein, absence of MTAP protein, MTA accumulation, or a combination thereof. 28. Embodiment 28 is the method according to any one of Embodiments 1 to 27, wherein the cancer is MTAP-deficient cancer. 29. Embodiment 29 is the method according to any one of Embodiments 1 to 28, wherein the cancer has an MTAP gene deletion. 30. Embodiment 30 is the method according to any one of Embodiments 1 to 29, wherein the cancer is resistant to at least one anticancer agent. 31. Embodiment 31 is the method according to any one of Embodiments 1 to 30, wherein the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, gastroesophageal junction cancer, malignant peripheral nerve sheath tumor, and mesothelioma. 32. Embodiment 32 is the method according to any one of Embodiments 1 to 30, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous cell carcinoma and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, and gastric cancer. 33. Embodiment 33 is the method according to any one of Embodiments 1 to 30, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous cell carcinoma and adenocarcinoma) and urothelial carcinoma (bladder and upper urinary tract). 34. Embodiment 34 is the method according to any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (squamous cell carcinoma and adenocarcinoma). 35. Embodiment 35 is the method according to any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (squamous cell carcinoma). 36. Embodiment 36 is the method according to any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (adenocarcinoma). 37. Embodiment 37 is the method according to any one of Embodiments 1 to 30, wherein the cancer is urothelial carcinoma (bladder and upper urinary tract). 38. Embodiment 38 is the method according to any one of Embodiments 1 to 30, wherein the cancer is urothelial carcinoma (bladder). 39. Embodiment 39 is the method according to any one of Embodiments 1 to 30, wherein the cancer is urothelial carcinoma (upper urinary tract). 40. Embodiment 40 is the method according to any one of Embodiments 1 to 30, wherein the cancer is squamous cell carcinoma and adenocarcinoma of esophageal cancer, gastric adenocarcinoma, or gastroesophageal junction cancer. 41. Embodiment 41 is the method according to any one of Embodiments 1 to 40, wherein compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt is administered orally. 42. Embodiment 42 is the method according to any one of Embodiments 1 to 41, wherein compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt is administered once daily (QD). 43. Embodiment 43 is the method according to any one of Embodiments 1 to 41, wherein Compound 1 in the form of a free base or a corresponding amount of Compound 1 in the form of a pharmaceutically acceptable salt is administered twice daily (BID). 44. Embodiment 44 is a method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt, in at least one 7-day dosing cycle, two 7-day dosing cycles, three 7-day dosing cycles, four 7-day dosing cycles, five 7-day dosing cycles, six 7-day dosing cycles, seven 7-day dosing cycles, or eight 7-day dosing cycles. 45. Embodiment 45 is the method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt, in at least three 7-day dosing cycles. 46. ​​Embodiment 46 is the method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt, in at least nine 7-day dosing cycles. 47. Embodiment 47 is a method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt, for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks. 48. Embodiment 48 is the method according to any one of Embodiments 1 to 47, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt for at least three weeks. 49. Embodiment 49 is the method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt, for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 16 months, 20 months, 24 months, 28 months, 32 months, 36 months, 40 months, 44 months, or 48 months. 50. Embodiment 50 is the method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt for at least one month. 51. Embodiment 51 is the method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt for at least three months. 52. Embodiment 52 is the method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt for at least six months. 53. Embodiment 53 is a method according to any one of Embodiments 1 to 43, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof follows a dosing schedule comprising administering compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt in two 7-day dosing cycles, followed by a 7-day period without administration, and optionally thereafter repeating the dosing schedule for at least 3, 6, 9, 12, 15, 18, 21, 24, 27, 31, 34, 37, 40, 43, 46, 49, or 52 weeks. 54. Embodiment 54 is a method according to any one of Embodiments 1 to 53, wherein the subject exhibits at least a stable disease (SD) after administration of compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 55. Embodiment 55 is a method according to any one of Embodiments 1 to 53, wherein a subject exhibits at least a partial response (PR) after administration of compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 56. Embodiment 56 is the method of Embodiment 55, wherein the partial response (PR) is characterized by a reduction of at least 30% in the total target lesion diameter compared to the baseline total of the target lesion diameters before treatment. 57. Embodiment 57 is a method according to any one of Embodiments 1 to 56, wherein the subject does not exhibit dose-limiting toxicity (DLT). 58. Embodiment 58 is the method according to any one of Embodiments 1 to 57, further comprising administering at least one additional therapeutic agent. 59. Embodiment 59 is the method according to any one of Embodiments 1 to 58, wherein compound 1 is in the form of a free base. 60. Embodiment 60 is the method according to any one of Embodiments 1 to 59, wherein compound 1 is administered as a tablet. 61. Embodiment 61 is a method according to any one of Embodiments 1 to 60, wherein the subject is an adult. 62. Embodiment 62 is a method according to any one of Embodiments 1 to 61, wherein the subject is a human. 63. Embodiment 63 is a unit dosage form comprising about 5 mg to about 100 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 64. Embodiment 64 is the unit dosage form according to Embodiment 63, wherein the unit dosage form comprises about 5 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 65. Embodiment 65 is the unit dosage form according to Embodiment 63, wherein the unit dosage form comprises about 10 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 66. Embodiment 66 is the unit dosage form according to Embodiment 63, wherein the unit dosage form comprises about 15 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 67. Embodiment 67 is the unit dosage form according to Embodiment 63, wherein the unit dosage form comprises about 30 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 68. Embodiment 68 is the unit dosage form according to Embodiment 63, wherein the unit dosage form comprises about 45 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 69. Embodiment 69 is the unit dosage form according to Embodiment 63, wherein the unit dosage form comprises about 60 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 70. Embodiment 70 is the unit dosage form according to Embodiment 63, wherein the unit dosage form comprises about 100 mg of compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt. 71. Embodiment 71 is a kit comprising one or more unit dosage forms described in any one of Embodiments 63 to 70. 72. Embodiment 72 is the kit according to Embodiment 71, further comprising a label which includes instructions for administering Compound 1 in the form of a free base, or a corresponding amount of Compound 1 in the form of a pharmaceutically acceptable salt. 73. Embodiment 73 is the kit according to Embodiment 71 or 72, further comprising at least one additional therapeutic agent. 74. Embodiment 74 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer, in which compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 75. Embodiment 75 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer, in which Compound 1 in the form of a free base, or a corresponding amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 76. Embodiment 76 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, in which compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily. 77. Embodiment 77 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer, in which compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily. 78. Embodiment 78 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, in which compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily. 79. Embodiment 79 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, wherein 30 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt thereof, is administered daily. 80. Embodiment 80 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, in which compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily. 81. Embodiment 81 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, in which compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily. 82. Embodiment 82 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer, in which compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 83. Embodiment 83 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 84. Embodiment 84 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, in which Compound 1 in the form of a free base, or a corresponding amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 85. Embodiment 85 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein Compound 1 in the form of a free base or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt is administered daily. 86. Embodiment 86 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 10 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 87. Embodiment 87 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 15 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 88. Embodiment 88 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 30 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 89. Embodiment 89 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 45 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 90. Embodiment 90 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 60 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 91. Embodiment 91 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 100 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt, is administered daily. 92. Embodiment 92 is a method, unit dosage form, kit, use, or compound according to any one of Embodiments 1 to 91, wherein compound 1 is in the form of a free base. IV. Examples

[0139] The following examples are provided for illustrative purposes only and do not limit the claimed invention. Example 1: Phase I trial of compound 1, a selective MAT2A inhibitor for the treatment of advanced solid tumors.

[0140] A Phase 1 multicenter, open-label trial of compound 1 was conducted in adult patients with advanced solid tumors with MTAP genomic deletion or loss (NCT04794699). A Bayesian logistic regression model was used to derive dose escalation and estimate the maximum tolerated dose (MTD) / recommended dose for expansion (RDE). Safety was described using the incidence of adverse events (AEs), relating to AEs and categorized by the severity of AEs graded according to the Common Terminology Criteria for AEs (CTCAE, v5.0). The overall response rate was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1) in an evaluable patient population. See Eisenhauer et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. A reduction in the patient's tumor size is defined as a reduction in tumor size measured using the RECIST 1.1 criteria.

[0141] Tumor size can be measured, for example, by radiography, MRI (Magnetic Resonance Imaging), CT scan (also called CAT scan or computed tomography scan), PET scan (Positron Emission Tomography), X-ray, ultrasound, or a combination of these.

[0142] Subjects eligible for inclusion in this study must meet all of the following important criteria: A definitive diagnosis of advanced or metastatic solid tumor that has progressed with at least one previous stage of treatment and for which further effective standard therapy is unavailable or intolerant to the participant. • Having evidence of loss of homozygosity or deletion of MTAP. • Willingness to undergo paired fresh biopsy procedures (pre-treatment and post-treatment) during the trial. A measurable disease is defined as a non-nodular lesion that can be accurately measured by at least one of the following dimensions (longest dimension): 10 mm or more by MRI or CT when the scan slice thickness is 5 mm or less; 10 mm or more by caliper / ruler measurement by clinical examination or medical photography; or 20 mm or more by chest X-ray. • Must have a Performance Status (PS) of 1 or less in an Eastern Cooperative Oncology Group (ECOG) clinical trial group. • Appropriate organ function. • The patient must be able to swallow and retain the orally administered test drug. • Recovery from the acute effects of previous therapies. • Must be able to comply with contraception / barrier requirements.

[0143] The following individuals are not eligible to participate in the examination: Symptomatic brain metastases requiring hyperphysiological doses of systemic corticosteroids or anticonvulsants. Primary CNS malignant tumor. • Currently active liver or bile duct disease. Having a gastrointestinal (GI) disorder or GI disease (e.g., any unresolved nausea, vomiting, or diarrhea with a grade greater than 1 on the National Cancer Institute (NCI) CTCAE version 5.0) that could significantly alter the absorption of compound 1. • Uncontrolled active infection. • Clinically significant cardiac abnormalities. • Previously treated with MAT2A inhibitors and / or PRMT inhibitors. • Systemic anti-cancer therapy or major surgery within 4 weeks prior to exam entry. • Radiation therapy within two weeks prior to exam entry. • Previously, more than 25% of the bone marrow was irradiated. • Current use or anticipated need for foods or drugs known as potent CYP3A4 / 5 inhibitors or inducers. • Currently receiving treatment with another experimental drug in research. • Known or suspected hypersensitivity to compound 1 / excipient or component.

[0144] Safety Summary: As of the data cut on August 15, 2023, 40 patients received compound 1 as a free base once daily (QD) at doses ranging from 5 mg to 100 mg. The most common adverse events (AEs, all grades, related and unrelated, reported in ≥20% of subjects) during treatment were nausea (47%), decreased appetite (37%), constipation (32%), hypoglycemia (22%), vomiting (30%), diarrhea (22%), dehydration (20%), and hearing loss (37%). The majority of AEs were grade 1 and grade 2. Three subjects experienced dose-limiting toxicity (DLT) at the 100 mg QT dose level, which included myalgia, hypocalcemia, and maculopapular rash in one subject each. DLTs were managed by discontinuing compound 1 administration, resulting in improvement of the grade of DLT events in subjects with hypocalcemia and rash. Based on overall tolerability, 60 mg per day is considered the tolerable dose (MTD) and expanded recommended dose (RDE).

[0145] Pharmacokinetic data show a dose-proportional increase in exposure as the dose increases from 5 mg to 100 mg QD. The median Tmax range over doses of compound 1 was 2–5 hours post-administration. The half-life is estimated to be approximately 4 days.

[0146] Exposure at doses of 15 mg QD or higher is within the acceptable range based on preclinical predictions. Plasma SAM levels were evaluated across the tested dose range (5 mg to 100 mg QD). All cohorts showed target engagement with a significant decrease in plasma SAM levels after treatment with compound 1 compared to pre-treatment levels.

[0147] Of the 32 evaluable subjects with measurable disease at baseline and at least one trial-dependent tumor assessment, 15 had stable disease (SD) as the best overall response across the range of dose levels tested (5 mg to 100 mg QD). Of these 15 subjects with SD, 3 were treated with a 10 mg QD dose, 1 with a 15 mg QD dose, 2 with a 30 mg QD dose, 5 with a 60 mg QD dose, and 4 with a 100 mg QD dose.

[0148] Furthermore, a cfDNA reduction of 50% or more (molecular response) was observed in nine subjects, including four subjects with NSCLC (three at the 60 mg QD dose and one at the 10 mg QD dose) and one subject with bladder cancer at the 100 mg QD dose. Additional tumor types showing a molecular response included two subjects with pancreatic cancer and one with esophageal cancer at the 60 mg QD dose, and one subject with phyllodes tumor at the 100 mg QD dose.

[0149] Furthermore, one patient demonstrated a partial response (PR) with approximately 47% tumor reduction, as measured by RECIST v1.1 criteria, after dose reduction from an initial dose of 100 mg QD to 60 mg QD.

[0150] Compound 1, as monotherapy, is well-tolerated with manageable toxicity and exhibits pharmacodynamic activity at an expanded dose of 60 mg per day, along with early signs of clinical efficacy in patients with advanced solid tumors. Example 1A: Update to Example 1

[0151] Safety Summary: As of the data cut on November 21, 2023, 47 patients received compound 1 as a free base once daily (QD) at doses ranging from 5 mg to 100 mg. The most common adverse events (AEs, all grades, related and unrelated, reported in ≥20% of subjects) during treatment were decreased appetite (40%), nausea (40%), constipation (38%), hearing loss (36%), peripheral neuropathy (30%), increased serum creatinine (23%), hypocalcemia (23%), diarrhea (21%), and vomiting (21%). The majority of AEs were grade 1 and grade 2. Three subjects experienced dose-limiting toxicity (DLT) at the 100 mg QD dose level, which included myalgia, hypocalcemia, and maculopapular rash in one subject each. DLTs were managed by discontinuing compound 1 administration, resulting in improvement of the grade of DLT events in subjects with hypocalcemia and rash. Based on overall tolerability, 60 mg per day is considered the tolerable dose (MTD) and expanded recommended dose (RDE).

[0152] Pharmacokinetic data show a dose-proportional increase in exposure as the dose increases from 5 mg to 100 mg QD. The median Tmax range over doses of compound 1 was 2–5 hours post-administration. The half-life is estimated to be approximately 4 days.

[0153] Of the 31 evaluable subjects with measurable disease at baseline and at least one trial-dependent tumor assessment, 17 had stable disease (SD) as the best overall response across the range of dose levels tested (5 mg to 100 mg QD). Of these 17 subjects with SD, 3 were treated with a 10 mg QD dose, 1 with a 15 mg QD dose, 1 with a 30 mg QD dose, 8 with a 60 mg QD dose, and 4 with a 100 mg QD dose.

[0154] Furthermore, a ctDNA reduction of 50% or more (molecular response) was observed in 13 subjects (out of 26 subjects with evaluable samples), including 6 subjects with NSCLC (4 subjects at the 60 mg QD dose and 2 subjects at the 100 mg QD dose) and 3 subjects with bladder cancer at the 60 and 100 mg QD doses. Additional tumor types showing a molecular response included 1 subject with pancreatic cancer, 1 with esophageal cancer, and 1 with melanoma at the 60 mg QD dose, and 1 subject with phyllodes tumor at the 100 mg QD dose. Five additional subjects showed a measurable reduction in ctDNA from baseline but did not meet the criteria for a molecular response (3 subjects with pancreatic cancer at the 5–60 mg QD doses, and 2 subjects with cholangiocarcinoma at the 60 mg QD dose).

[0155] Furthermore, one patient demonstrated confirmed complete response (CR) according to RECIST v1.1 criteria despite two dose reductions from an initial dose of 100 mg QD to 30 mg QD (target lymph node mass decreased to less than 10 mm in the short axis).

[0156] Compound 1, as monotherapy, is well-tolerated with manageable toxicity and exhibits pharmacodynamic activity at an expanded dose of 60 mg per day, along with initial signs of clinical efficacy in patients with advanced solid tumors. Example 1B: Updates to Example 1 and Example 1A

[0157] Safety Summary: As of the data cutoff date of February 2, 2024, 56 patients received compound 1 as a free base in doses ranging from 5 mg to 100 mg once daily (QD). The most common treatment-related adverse events (TEAEs, all grades, related and unrelated, reported in ≥20% of subjects) were nausea (42.9%), decreased appetite (41.1%), constipation (39.3%), hearing loss (35.7%), peripheral neuropathy (28.6%), diarrhea (23.2%), hypocalcemia (23.2%), vomiting (21.4%), elevated serum creatinine (21.4%), and weight loss (21.4%). Regardless of the relationship with the study drug / intervention, the most frequently reported grade 3 or higher TEAEs (reported in ≥5% of subjects) were peripheral neuropathy (7.1%); as well as anemia, malignant disease anemia, hypokalemia, and muscle weakness (5.4% each). Three subjects experienced dose-limiting toxicity (DLT) at the 100 mg QD dose level, which consisted of myalgia, hypocalcemia, and maculopapular rash in one subject each. DLTs were managed by discontinuing compound 1 administration, resulting in improvement of the grade of DLT events in subjects with hypocalcemia and rash. Based on overall tolerability, 60 mg per day (QD) is considered the tolerable dose (MTD).

[0158] As of June 12, 2024, 18 patients had received the starting dose of 30 mg QD. The most common TEAEs (all grades, unrelated to the study drug / intervention, reported in ≥15% of the subjects) were nausea (27.8%), decreased appetite (22.2%), asthenia, elevated serum creatinine, constipation, and peripheral neuropathy (16.7% each). The majority of these adverse events were Grade 1 and Grade 2. The most common Grade 3 or higher TEAEs (reported in ≥5% of the subjects, unrelated to the study drug / intervention) were asthenia, anemia, and hypokalemia (5.6% each). Two patients (11.1%) each experienced one serious adverse event, none of which were related to compound 1. Based on the overall safety profile of 30 mg QD, this dose is the expanded recommended dose (RDE).

[0159] Of the 18 subjects treated with compound 1 for at least one cycle (21 days) of 30 mg QD and who underwent post-baseline scans available for tumor evaluation, six subjects experienced a partial response (PR) as the best overall response, and one subject experienced a complete response (CR) as the best overall response. In subjects with urothelial carcinoma, two subjects experienced a partial response and one a complete response, with four of the partial responders having NSCLC. Furthermore, 10 patients with NSCLC or urothelial carcinoma experienced stable disease (SD) as the best overall response to treatment with compound 1.

[0160] Furthermore, among subjects treated with compound 1 (30 mg QD), a ctDNA reduction of 50% or more (molecular response) was observed in 9 out of 12 evaluable subjects who had either NSCLC (N=5) or urothelial carcinoma (N=4). Example 1C: Updates to Example 1, Example 1A, and Example 1B

[0161] Additional incorporation criteria between the tests described in this embodiment and the tests in Examples 1, 1A, and 1B above include the following: • At the time of enrollment, any acute effects from any prior therapy (including surgery, chemotherapy, and radiotherapy) have recovered to baseline severity or grade 1 or less (CTCAE version 5.0), excluding AEs that do not constitute a safety risk.

[0162] Additional exclusion criteria for the tests described in this embodiment compared to the tests in Examples 1, 1A, and 1B above include the following: A history of a second active malignancy or another malignancy within the past two years, excluding well-treated non-melanoma skin cancer, cervical carcinoma in situ, or breast carcinoma in situ. • Other acute or chronic medical or psychiatric conditions. • Major surgery within 4 weeks prior to exam entry. • Ongoing radiation-related toxicity or radiotherapy within two weeks prior to trial entry. • Systemic cytotoxic chemotherapy within 4 weeks prior to trial entry. • The patient had received radioimmunotherapy within 6 weeks prior to administering compound 1. • The patient had received treatment with a therapeutic antibody or small molecule within 4 weeks prior to the first dose of compound 1.

[0163] As of August 8, 2024, 24 subjects had received the starting dose of 30 mg QD. The most common TEAEs (all grades, unrelated to the study drug / intervention, reported in ≥15% of subjects) were constipation (25%), decreased appetite (25%), asthenia, elevated serum creatinine, fatigue, insomnia, and nausea (20.8% each). The majority of these adverse events were Grade 1 and Grade 2. Grade 3 or higher TEAEs (unrelated to the study drug / intervention) were rare. Asthenia, hyponatremia, chronic obstructive pulmonary disease, hypokalemia, positive human rhinovirus test, iron deficiency anemia, pernicious anemia, and muscle fatigue were each reported in one subject. Six patients (25%) each experienced one serious adverse event, none of which were related to compound 1. Based on the overall safety profile of 30 mg QD, this dose is the expanded recommended dose (RDE).

[0164] Pharmacokinetic data show a dose-proportional increase in exposure as the dose increases from 5 mg to 100 mg. The median Tmax range over doses of compound 1 was 2–8 hours post-administration. The half-life is estimated to be approximately 4 days.

[0165] Monotherapy exposure at doses exceeding 15 mg QD is considered within the effective range based on non-clinical predictions. Plasma SAM levels were evaluated across the tested dose range (5 mg to 100 mg QD).

[0166] Twenty-seven subjects were treated with compound 1 at 30 mg QD for at least 21 days, followed by baseline post-scans available for tumor assessment (subjects treated with a higher starting dose of compound 1 and then reduced to 30 mg QC were included in this analysis if they were treated with compound 1 at 30 mg QD for at least 21 days prior to the subsequent tumor assessment scan). Of these 27 subjects, eight experienced a partial response (PR) with the best overall response, and one experienced a complete response (CR) with a good overall response, resulting in an overall response rate (ORR) of approximately 33%. Among subjects with urothelial carcinoma, three experienced partial responses and one experienced a complete response, with five of the partial responders having NSCLC. Furthermore, 16 patients (59%) with NSCLC or urothelial carcinoma experienced stable disease (SD) as the best overall response to treatment with compound 1.

[0167] Furthermore, among subjects treated with compound 1 (30 mg QD), a ctDNA reduction of 50% or more (molecular response) was observed in 13 out of 16 evaluable subjects (approximately 81%) who had either NSCLC (N=8) or urothelial carcinoma (N=5).

[0168] While the above invention has been described in some detail with illustrations and examples for the purpose of clear understanding, those skilled in the art will understand that certain changes and modifications within the scope of the appended claims are implementable. Furthermore, each reference provided herein is incorporated by reference to the same extent as each individual reference is incorporated by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A method for treating cancer in a target subject, wherein the target subject is given a therapeutically effective amount of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 1): 【Chemistry 1】 A method comprising administering a pharmaceutically acceptable salt thereof, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

2. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 5 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

3. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 10 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

4. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 15 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

5. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 30 mg to about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

6. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 15 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

7. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 30 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

8. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 45 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

9. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 60 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

10. The method according to claim 1, wherein the therapeutically effective dose is a total daily dose of compound 1 in the form of a free base of about 100 mg, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt.

11. The method according to any one of claims 1 to 10, wherein the cancer is a solid tumor.

12. The method according to any one of claims 1 to 11, wherein the cancer is a solid malignant tumor.

13. The method according to any one of claims 1 to 12, wherein the cancer is characterized by decreased or absent expression of the methylthioadenosine phosphorylase (MTAP) gene, absence of the MTAP gene, impaired function of the MTAP protein, decreased level of the MTAP protein, absence of the MTAP protein, MTA accumulation, or a combination thereof.

14. The method according to any one of claims 1 to 12, wherein the cancer is MTAP-deficient cancer.

15. The method according to any one of claims 1 to 12, wherein the cancer has an MTAP gene deletion.

16. The method according to any one of claims 1 to 15, wherein the cancer is resistant to at least one anticancer agent.

17. The method according to any one of claims 1 to 16, wherein the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, esophagogastric junction cancer, malignant peripheral nerve sheath tumor, and mesothelioma.

18. The method according to any one of claims 1 to 17, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous cell carcinoma and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

19. The method according to any one of claims 1 to 18, wherein compound 1 is administered orally.

20. The method according to any one of claims 1 to 19, wherein compound 1 is administered once daily (QD).

21. The method according to any one of claims 1 to 20, further comprising administering at least one additional therapeutic agent.

22. The method according to any one of claims 1 to 21, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof is subject to a dosing schedule comprising administering compound 1 in the form of a free base, or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt, for at least one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, twenty-four weeks, forty-eight weeks, or fifty-two weeks.

23. The method according to any one of claims 1 to 21, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof is subject to a dosing schedule comprising administering compound 1 in the form of a free base or a corresponding amount of compound 1 in the form of a pharmaceutically acceptable salt for at least three weeks.

24. Compound 1 has the formula: 【Chemistry 2】 The method according to any one of claims 1 to 23, wherein the free base is represented by .

25. The use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmacopoeia for the treatment of cancer, wherein compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily.

26. Compound 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, is administered daily in an amount of 5 mg to 100 mg of free base of Compound 1, or an equivalent amount of a pharmaceutically acceptable salt of Compound 1.

Images