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WO2025059579A1 - Méthodes de traitement de maladies associées à mat2a - Google Patents

Méthodes de traitement de maladies associées à mat2a Download PDF

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Publication number
WO2025059579A1
WO2025059579A1 PCT/US2024/046774 US2024046774W WO2025059579A1 WO 2025059579 A1 WO2025059579 A1 WO 2025059579A1 US 2024046774 W US2024046774 W US 2024046774W WO 2025059579 A1 WO2025059579 A1 WO 2025059579A1
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Prior art keywords
compound
cancer
pharmaceutically acceptable
acceptable salt
free base
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Inventor
Claire L. NEILAN
Xu ZANG
Jasgit C. SACHDEV
Darrin M. Beaupre
Matthew Anthony MAURER
Sarah Shwu-Kuan JAW-TSAI
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Ideaya Biosciences Inc
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Ideaya Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not.
  • the concept of synthetic lethality originates from studies in drosophila model systems in which a combination of mutations in two or more separate genes leads to cell death (in contrast to viability, which occurs when only one of the genes is mutated or deleted). More recently, a multitude of studies have explored maladaptive genetic changes in cancer cells that render them vulnerable to synthetic-lethality approaches. These tumor-specific genetic defects lead to the use of targeted agents that induce the death of tumor cells while sparing normal cells.
  • Methionine adenosyltransferase 2A is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosyl methionine (SAM).
  • SAM is a primary methyl donor in cells used to methylate several substrates including DNA, RNA and proteins.
  • One methylase that utilizes SAM as a methyl donor is protein arginine N- methyltransferase 5 (PRMT5). While SAM is required for PRMT5 activity, PRMT5 is competitively inhibited by 5’methylthioadenosine (MTA).
  • the MAT2A inhibitor is 4-amino-1-(2- chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1).
  • the MAT2A inhibitor is administered orally.
  • methods of treating MAT2A related diseases comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • methods of treating cancer in a subject in need thereof the method comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the methods described herein include administering to a subject in need thereof a therapeutically effective amount of Compound 1 at a total daily dosage of from about 50 mg to about 75 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the therapeutically effective amount of Compound 1 is a total daily dosage of from about 25 mg to about 50 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the therapeutically effective amount of Compound 1 is a total daily dosage of about 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • Compound 1 in free base form is administered at a dose of about 10 mg QD. In certain embodiments, Compound 1 in free base form is administered at a dose of about 5 mg QD.
  • the MAT2A inhibitor is administered with food (i.e., administration of the MAT2A inhibitor occurs within 1 hour before or 2 hours after a meal). PATENT In some embodiments, the MAT2A inhibitor is administered without food (i.e., administration of the MAT2A inhibitor occurs more than 1 hour before or 2 hours after a meal).
  • 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.
  • the subject is a human being.
  • the human being is an adult patient aged 18 years or older.
  • the cancer is non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.
  • the cancer is non-small cell lung cancer (squamous).
  • the cancer is non-small cell lung cancer (adenocarcinoma).
  • the cancer is urothelial cancer (bladder).
  • the cancer is urothelial cancer (upper urinary tract).
  • the subject suffers from non-small cell lung cancer (e.g. squamous or adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.
  • the subject suffers from squamous and adenocarcinoma of esophagus cancer, gastric adenocarcinoma, or gastro- esophageal junction cancer.
  • the cancer has an MTAP gene deletion.
  • the cancer is refractory to at least one anticancer agent.
  • a subject administered Compound 1 or a pharmaceutically acceptable salt thereof for at least 21 days does not exhibit any grade 3 or grade 4 adverse events associated with Compound 1 therapy.
  • the subject administered Compound 1 or a pharmaceutically acceptable salt thereof for at least 42 days does not exhibit any grade 3 or grade 4 adverse events associated with Compound 1 therapy.
  • the subject administered Compound 1 or a pharmaceutically acceptable salt thereof for at least 63 days does not exhibit any grade 3 or grade 4 adverse events associated with Compound 1 therapy.
  • the subject exhibits at least a stable disease after administration with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the subject exhibits at least a partial response after administration with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the methods described herein comprise administering at least one additional therapeutic agent.
  • the methods described herein comprise administering at least one additional therapeutic agent or diagnostic agent.
  • the at least one additional therapeutic agent is a signal transduction inhibitor (STI).
  • the at least one additional therapeutic agent is a chemotherapeutic agent.
  • the at least one additional therapeutic agent is an immune checkpoint inhibitor.
  • the at least one additional therapeutic agent is a PRMT5 inhibitor.
  • unit dosage forms comprising from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • kits comprising one or more unit dosage forms described herein. In some embodiments, the kits further comprise at least one additional therapeutic agent.
  • any of the above aspects and embodiments can be combined with any other aspect or embodiment.
  • Other objects, features, and advantages of the present invention will be apparent to one of skill in the art from the following detailed description and figures. BRIEF DESCRIPTION OF THE DRAWINGS [0032] NOT APPLICABLE DETAILED DESCRIPTION I.
  • MAT2A Overexpression of the enzyme MAT2A has been demonstrated to mediate certain cancers. MAT2A has also been identified as a target for synthetic lethality in cancers characterized by a reduction or an absence of methylthioadenosine phosphorylase (MTAP) gene expression, an absence of MTAP gene, a reduced function of MTAP protein, a reduced PATENT level of MTAP protein, an absence of MTAP protein, MTA accumulation, or combinations thereof.
  • MTAP methylthioadenosine phosphorylase
  • Compound 1 refers to the chemical 4-amino-1-(2-chlorophenyl)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one, having the formula: .
  • PATENT in some embodiments, Compound 1 is in a pharmaceutically acceptable salt form.
  • Compound 1, as well as pharmaceutically acceptable salts, are described in International Publication Numbers WO2020/123395 and WO2024/118070. The contents of WO 2020/123395 and WO 2024/118070 are incorporated herein by reference in their entirety for all purposes.
  • “Pharmaceutically acceptable salt” refers to derivatives of Compound 1 wherein the parent compound is modified by converting an existing base moiety to its salt form.
  • Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the 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.
  • Compound 1 can be present as a pharmaceutically acceptable isotopically-labeled version, wherein one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into Compound 1 include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, and 18 F, respectively.
  • These radio-labeled compounds could be useful to help determine or measure the effectiveness of Compound 1, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
  • isotopically-labeled versions of Compound 1, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes 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 ready means of detection.
  • this application refers to the amount of Compound 1 free base.
  • a person of skill in the art would recognize that in order to administer the same amount of Compound 1 in a different salt form, small adjustments in overall amount administered is necessary.
  • the terms “a” or “an,” as used in herein means one or more.
  • treatment means the specified value.
  • treating refers to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit.
  • therapeutic benefit is meant to include eradication, amelioration, and stasis of a cancer.
  • a therapeutic benefit is achieved with the eradication, amelioration, or stasis of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • Treatment includes causing the clinical symptoms of the disease to slow in development by administration of a composition; suppressing the disease, that is, causing a reduction in the clinical symptoms of the disease; inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a composition after the initial appearance of symptoms; and/or relieving the disease, that is, causing the regression of clinical symptoms by administration of a composition after their initial appearance.
  • An “effective amount” or a “therapeutically effective amount” is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, reduce one or more symptoms of a disease or condition).
  • an “effective amount” is an amount sufficient to contribute to the treatment, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the PATENT symptom(s), or elimination of the symptom(s ).
  • Efficacy can also be expressed as “-fold” increase or decrease.
  • a therapeutically effective amount can have at least a 1.2- fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
  • an effective amount can produce tumor stasis, tumor reduction, reduced progression, eradication of the tumor, or improved overall survival.
  • “Patient” or “subject” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by using the methods provided herein.
  • the term does not necessarily indicate that the subject has been diagnosed with a particular disease, but typically refers to an individual under medical supervision.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient, subject, or subject in need thereof is a human.
  • “Partial response” or “PR” refers to a clinical outcome where a subject’s target lesions have decreased in size but are still present after treatment with Compound 1 or a pharmaceutically acceptable salt thereof.
  • a partial response is at least a 30% decrease in the sum of target lesion diameters in a subject after treatment with Compound 1 or a pharmaceutically acceptable salt thereof, relative to a baseline sum of target lesion diameters prior to the treatment.
  • “Complete response” or “CR” refers to a clinical outcome where there is disappearance of all target lesions and any pathological lymph nodes have a reduction in short axis to less than 10 mm in a subject after treatment with Compound 1 or a pharmaceutically acceptable salt thereof.
  • Progressive disease refers to a clinical outcome where a subject’s target lesions have increased in size after treatment with Compound 1 or a pharmaceutically acceptable salt thereof.
  • a progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest on study), and there must be an absolute increase of at least 5 mm in addition to the relative increase of 20%.
  • “Stable disease” or “SD” is a clinical outcome where a subject’s target lesions have neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD after treatment with Compound 1 or a pharmaceutically acceptable salt thereof.
  • a “controlled disease state” is when a subject may alternate between exhibiting a stable disease and a partial response.
  • CAAP1 as used herein refers to caspase activity and apoptosis inhibitor 1 gene.
  • CDKN2A refers to cyclin dependent kinase inhibitor 2A gene. III.
  • MAT2A has been found to play a role in certain disorders in a human or animal subject.
  • the present disclosure relates to compounds, e.g., MAT2A inhibitors, that exhibit anti-proliferative activity when used alone and in combination, preferably in cancer patients.
  • the method relates to methods of treating a proliferative disease by administration or co-administration of said compounds.
  • the MAT2A inhibitor used herein is 4-amino-1-(2- chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1), having the formula: .
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered, e.g., orally administered at a daily dose of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • methods of treating MAT2A related diseases comprising administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • kits for treating a disease mediated by MAT2A comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • methods of treating cancer comprising administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • a subject administered Compound 1 or a pharmaceutically acceptable salt thereof for at least 21 days does not exhibit any grade 3 or grade 4 adverse events associated with Compound 1 therapy.
  • the subject administered Compound 1 or a pharmaceutically acceptable salt thereof for at least 42 days does not exhibit any grade 3 or grade 4 adverse events associated with Compound 1 therapy.
  • the subject administered Compound 1 or a pharmaceutically acceptable salt thereof for at least 63 days does not exhibit any grade 3 or grade 4 adverse events associated with Compound 1 therapy.
  • the subject exhibits at least a stable disease after administration with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the subject exhibits at least a partial response after administration with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the cancer is characterized by a reduction or an absence of methylthioadenosine phosphorylase (MTAP) gene expression, an absence of MTAP gene, a reduced function of MTAP protein, a reduced level of MTAP protein, an absence of MTAP protein, MTA accumulation, or combinations thereof.
  • MTAP methylthioadenosine phosphorylase
  • a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form, wherein the cancer is characterized by a reduction or an absence of methylthioadenosine phosphorylase (MTAP) gene expression, an absence of MTAP gene, a reduced function of MTAP protein, a PATENT reduced level of MTAP protein, an absence of MTAP protein, MTA accumulation, or combinations thereof.
  • MTAP methylthioadenosine phosphorylase
  • kits for treating an MTAP null cancer in a subject comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • kits for treating a cancer in a subject with an MTAP gene deletion comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily (QD).
  • the therapeutically effective amount of Compound 1 is a total daily dosage of from about 50 mg to about 75 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the therapeutically effective amount of Compound 1 is a total daily dosage of from about 25 mg to about 50 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. [0069] In some embodiments, the therapeutically effective amount of Compound 1 is a total daily dosage of about 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the therapeutically effective amount of Compound 1 is a total daily dosage of about 10 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the therapeutically effective amount of Compound 1 is a total daily dosage of about 15 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the therapeutically effective amount of Compound 1 is a total daily dosage of about 30 mg of Compound 1 in free base form, or an equivalent amount of PATENT Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the therapeutically effective amount of Compound 1 is a total daily dosage of about 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the therapeutically effective amount of Compound 1 is a total daily dosage of about 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the therapeutically effective amount of Compound 1 is a total daily dosage of about 80 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the therapeutically effective of Compound 1 is a total daily dosage of about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the therapeutically effective amount of Compound 1 in free base form is administered at a dose from about 50 mg once a day (QD) to about 75 mg once a day (QD), or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered. In some embodiments, the therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 25 mg QD to about 50 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered. [0071] In some embodiments, the therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 5 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered.
  • the therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 10 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered. In some embodiments, the therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 15 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered. In some embodiments, the therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 30 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered.
  • the therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 45 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered.
  • the PATENT therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 60 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered.
  • the therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 80 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered.
  • the therapeutically effective amount of Compound 1 in free base form is administered at a dose of about 100 mg QD, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered.
  • the cancer is a solid tumor. In some embodiments, the cancer is a solid malignant tumor.
  • the cancer is neuroblastoma, intestine carcinoma (such as rectum carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma, and hereditary non-polyposis colorectal cancer), esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchyma carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors), Hodgkin lymphoma, non-Hodgkin lymphoma, Burkit
  • the cancer is lung cancer, non-small cell lung (NSLC) cancer, bronchioloalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the PATENT endometrium, carcinoma of the vagina, carcinoma of the vulva, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, chronic or acute leukemia,
  • 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 cancer, malignant peripheral nerve sheath tumor, and mesothelioma.
  • the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.
  • the cancer is non-small cell lung cancer (squamous).
  • the cancer is f non-small cell lung cancer (adenocarcinoma).
  • the cancer is urothelial cancer (bladder and upper urinary tract).
  • the cancer is urothelial cancer (bladder).
  • the cancer is urothelial cancer (upper urinary tract).
  • the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is squamous and adenocarcinoma of esophagus cancer, gastric adenocarcinoma, or gastro-esophageal junction cancer.
  • a cancer in a subject wherein said cancer is characterized by a reduction or an absence of MTAP expression or an absence of the MTAP gene, a reduced level of MTAP protein, a reduced function of MTAP protein, an absence of MTAP protein, MTA accumulation, or combinations thereof, as compared to cancers where the MTAP gene is present and fully functioning, said method comprising administering to the subject in need thereof a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt PATENT thereof, wherein the therapeutically effective amount is a total daily dosage of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the MTAP null cancer is 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.
  • the MTAP null cancer is pancreatic cancer.
  • the MTAP null 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).
  • the MTAP null cancer is gastric cancer.
  • the cancer is colon cancer.
  • the MTAP null cancer is liver cancer.
  • the MTAP null cancer is glioblastoma multiforme (GBM).
  • the MTAP null cancer is bladder cancer.
  • the MTAP null cancer is squamous and adenocarcinoma of esophagus cancer, gastric adenocarcinoma, or gastro-esophageal junction cancer.
  • 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, anal cancer, stomach cancer, colon cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin lymphoma, gastric cancer, esophagogastric cancer, esophageal cancer, malignant peripheral nerve sheath tumor, and mesothelioma.
  • the cancer is mesothelioma. In an embodiment, the cancer is non-small cell lung cancer. In another embodiment, the cancer is nonsquamous non-small cell lung cancer. In one embodiment, the cancer is cancer of the colon or rectum. In an embodiment, the cancer is PATENT adenocarcinoma of the colon or rectum. In an embodiment, the cancer is breast cancer. In an embodiment, the cancer is adenocarcinoma of the breast. In an embodiment, the cancer is gastric cancer. In an embodiment, the cancer is gastric adenocarcinoma. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is pancreatic adenocarcinoma. In an embodiment, the cancer is bladder cancer.
  • the cancer is characterized as being MTAP-null. In an embodiment, the cancer is characterized as being MTAP-deficient. In an embodiment, the cancer is characterized as being CAAP1-null. In an embodiment, the cancer is characterized as being CAAP1-deficient. In an embodiment, the cancer is characterized as being CDKN2A-deficient. In still another embodiment, the cancer is a solid tumor. In still another embodiment, the cancer is a MTAP-deleted solid tumor. In still another embodiment, the cancer is a metastatic MTAP-deleted solid tumor. In still another embodiment, the cancer is metastatic. In still another embodiment, the cancer is a solid malignant tumor.
  • the cancer is MTAP-deficient lung or MTAP- deficient pancreatic cancer, including MTAP-deficient NSCLC or MTAP-deficient pancreatic ductal adenocarcinoma (PDAC) or MTAP-deficient esophageal cancer.
  • the cancer is a tumor having an MTAP gene deletion.
  • the cancer is a solid tumor or a hematological cancer.
  • the tumor is deficient in MTAP.
  • the tumor is normal in its expression of MTAP.
  • the cancer is NSCLC, mesothelioma, squamous carcinoma of the head and neck, salivary gland tumors, urothelial cancers, sarcomas, or ovarian cancer.
  • the cancer is NSCLC, esophagogastric and pancreatic cancers.
  • the cancer is characterized by a reduction or an absence of MTAP gene expression.
  • the cancer is characterized by a reduced function of MTAP protein.
  • the cancer is characterized a reduced level or an absence of MTAP protein.
  • the cancer is characterized by MTA accumulation.
  • MTAP null cell lines have shown that cell lines that also incorporate a KRAS mutation or a p53 mutation were sensitive to MAT2A inhibition.
  • a method for treating a cancer in a subject wherein said cancer is characterized by a reduction or an absence of MTAP expression or an absence of the MTAP gene, a reduced level of MTAP protein, a reduced function of MTAP protein, an absence of MTAP protein, or a combination thereof, and further characterized by the presence of mutant KRAS and/or mutant p53, said method comprising administering to PATENT the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a total daily dosage of from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the cancer is MTAP null and KRAS mutant. In some embodiments, the cancer is MTAP null and p53 mutant. In some embodiments, the cancer is MTAP null, KRAS mutant and p53 mutant.
  • mutant KRAS or “KRAS mutation” refers to KRAS protein (or gene encoding said protein) incorporating 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 a particular embodiment, the KRAS mutant incorporates a G12X or G13X substitution, wherein X represents any amino acid change at the indicated position.
  • the substitution is G12V, G12R, G12C or G13D. In another embodiment, the substitution is G13D.
  • mutant p53 or “p53 mutation” is meant p53 protein (or gene encoding said protein) incorporating a mutation that inhibits or eliminates its tumor suppressor function. In an embodiment, said 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.
  • the foregoing cancer is non-small cell lung cancer (NSLCC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer or ovarian cancer.
  • 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 and mesothelioma.
  • the cancer is refractory to at least one anticancer agent. That is, the subject being treated has been administered a prior anticancer agent and the patient either did not respond to this treatment or medical professionals managing the care of this subject considered the subject’s response insufficient.
  • the subject that is refractory to at least one anticancer agent is administered a MAT2A inhibitor in combination with the at least one anticancer agent.
  • the subject that is refractory to at least one anticancer agent is no longer administered the at least one anticancer agent.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose that is therapeutically effective while having little or no adverse effect.
  • the MAT2A inhibitor is administered with food (i.e., administration of the MAT2A inhibitor occurs within 1 hour before or 2 hours after a meal). In some embodiments the MAT2A inhibitor is administered without food (i.e., administration of the MAT2A inhibitor occurs more than 1 hour before or 2 hours after a meal). [0086] In some embodiments, the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 5 mg to 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg, or 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 10 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. In some embodiments, the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 15 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 30 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. In some embodiments, the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • the use of Compound 1 or a pharmaceutically PATENT acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. In some embodiments, the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer is provided, wherein 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer wherein 5 mg to 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer is provided, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg, or 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer wherein 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer is provided, wherein 10 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer is provided, wherein 15 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer wherein 30 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer is provided, wherein 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer is provided, wherein 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered PATENT daily.
  • Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer is provided, wherein 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily. [0088] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a monotherapy.
  • Exemplary lengths of time associated with the course of the treatment methods disclosed herein include: about one week; about two weeks; about three weeks; about four weeks; about five weeks; about six weeks; about seven weeks; about eight weeks; about nine weeks; about ten weeks; about eleven weeks; about twelve weeks; about thirteen weeks; about fourteen weeks; about fifteen weeks; about sixteen weeks; about seventeen weeks; about eighteen weeks; about nineteen weeks; about twenty weeks; about twenty-one weeks; about twenty-two weeks; about twenty-three weeks; about twenty four weeks; about 4 months; about seven months; about eight months; about nine months; about ten months; about eleven months; about twelve months; about thirteen months; about fourteen months; about fifteen months; about sixteen months; about seventeen months; about eighteen months; about nineteen months; about twenty months; about twenty one months; about twenty-two months; about twenty-three months; about twenty-four months; about thirty months; about three years; about four years and about five years and so on; or any days, weeks, months, or years in between; for example a treatment cycle
  • Exemplary lengths of time associated with the course of the treatment methods can be about 5 years, about 4 years, about 3 years, about 2 years, about 1 years, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, or about 1 month.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered with one or more other therapeutic agents, e.g., an anti-cancer agent.
  • Pharmaceutical Compositions [0092] Compound 1, or a pharmaceutically acceptable salt thereof may be in the form of compositions suitable for administration to a subject.
  • compositions are pharmaceutical compositions comprising Compound 1, or a pharmaceutically acceptable salt PATENT thereof and one or more pharmaceutically acceptable or physiologically acceptable excipients.
  • the pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.
  • the pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.
  • the pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.
  • the tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action.
  • a time-delay material such as glyceryl monostearate or glyceryl di-stearate may be employed.
  • the tablets may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release.
  • Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, PATENT carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers in order to control delivery of an administered composition.
  • a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, PATENT carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene vinyl acetate copolymers in order to control delivery of an administered composition.
  • the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethyl cellulose or gelatin-microcapsules or poly (methyl methacrylate) microcapsules, respectively, or in a colloid drug delivery system.
  • Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations are known in the art.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methyl cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., poly-oxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptdecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate).
  • dispersing or wetting agents for
  • the aqueous suspensions may also contain one or more preservatives.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.
  • the pharmaceutical compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the pharmaceutical compositions typically comprise a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient.
  • Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants.
  • a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.
  • the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
  • Acceptable buffering agents include, for example, a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), and N- tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).
  • HEPES 2-(N-Morpholino)ethanesulfonic acid
  • MES 2-(N-Morpholino)ethanesulfonic acid sodium salt
  • MOPS 3-(N-Morpholino)propanesulfonic acid
  • TAPS N- tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid
  • PATENT After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form.
  • the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.
  • a single-use container e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)
  • a multi-use container e.g., a multi-use vial
  • Pharmaceutical compositions can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems.
  • a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.
  • any drug delivery apparatus may be used to deliver Compound 1, or a pharmaceutically acceptable salt thereof, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan.
  • Combination Therapy [0104] The present invention contemplates the use of Compound 1, or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents.
  • “combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a “co-formulation”).
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present disclosure. In such combination therapy, the various active agents frequently have different, complementary PATENT mechanisms of action.
  • Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.
  • the present disclosure provides methods for treating cancer with Compound 1, or a pharmaceutically acceptable salt thereof at a dosing amount described herein and at least one additional therapeutic or diagnostic agent.
  • the present disclosure also provides methods for treating cancer with Compound 1, or a pharmaceutically acceptable salt thereof at a dosing amount described herein and at least one additional therapeutic agent.
  • the at least one additional therapeutic agent is Temozolomide, Pemetrexed, Pegylated liposomal doxorubicin (Doxil), Eribulin (Halaven), Ixabepilone (Ixempra), Protein-bound paclitaxel (Abraxane), Oxaliplatin, Irinotecan, Venatoclax (bcl2 inhibitor), 5-azacytadine, Anti-CD20 therapeutics, such as Rituxan and obinutuzumab, Hormonal agents (anastrozole, exemestand, letrozole, zoladex, lupon eligard), CDK4/6 inhibitors, Palbociclib, Abemaciclib, CPI (Avelumab, Cemiplimab-rwlc, or Bevacizumab.
  • 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) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositol kinase inhibitors.
  • GLEEVEC epidermal growth factor
  • EGF epidermal growth factor
  • her-2/neu receptor inhibitors e.g., HERCEPTIN
  • inhibitors of Akt family kinases or the Akt pathway e.g., rapamycin
  • the at least one additional therapeutic agent is a chemotherapeutic agent.
  • chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chiorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide PATENT hydrochloride, melphalan, novembichin,
  • the at least one additional therapeutic is cisplatin, doxorubicin, taxol, taxotere or mitomycin C.
  • Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti-estrogens, including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, PATENT onapristone, and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • the at least one additional therapeutic agent is a hormone or related hormonal agent.
  • the at least one additional therapeutic agent is an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor targets CTLA- 4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFb, CD73, CD39, A2AR, A2BR, IDO1, TDO2, Arginase, B7-H3, or B7-H4.
  • the immune checkpoint inhibitor is ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, or durvalumab.
  • the at least one additional therapeutic agent is radiotherapy, a monoclonal antibody against a tumor antigen, a complex of a monoclonal antibody and toxin, a T-cell adjuvant, bone marrow transplant, or antigen presenting cells (e.g., dendritic cell therapy).
  • the at least one additional therapeutic agent is radiation and/or temozolomide (TMZ), avastin or lomustine.
  • the at least one additional therapeutic agent is a PRMT5 inhibitor.
  • the PRMT5 inhibitor is an MTA-cooperative PRMT5 inhibitor.
  • the PRMT5 inhibitor is a compound having the structure: , or a pharmaceutically
  • the PRMT5 inhibitor is selected from: , PATENT or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is: a pharmaceutically acceptable salt thereof.
  • In inhibitor is: a pharmaceutically acceptable salt thereof.
  • In is: a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is TNG462 or a pharmaceutically acceptable salt thereof. In an embodiment, the PRMT5 inhibitor is TNG908 or a pharmaceutically acceptable salt thereof. In an embodiment, the PRMT5 inhibitor is AZD3470 or a pharmaceutically acceptable salt thereof.
  • Additional PRMT5 inhibitors can include those described in WO2022/026892, WO2021/086879, WO2021/050915, and WO2023/036974, the contents of each are incorporated herein by reference in their entirety.
  • Pharmaceutical Dosage Forms [0122] The present disclosure includes pharmaceutical dosage forms of Compound 1 or a pharmaceutically acceptable form thereof. The unit dosage forms described herein are PATENT suitable for oral administration to a subject.
  • the unit dosage form may be in any form suitable for oral administration, including, but not limited to, a capsule, a tablet, a powder.
  • unit dosage form refers to physically discrete units, each unit 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.
  • the present disclosure provides a single unit dosage capsule or tablet form containing about 5 mg to 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the unit dosage form of Compound 1 in free base form is about 5 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the unit dosage form of Compound 1 in free base form is about 10 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 15 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 30 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 45 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the unit dosage form of Compound 1 in free base form is about 60 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 80 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 100 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. [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.
  • the single unit dosage form of Compound 1 or a pharmaceutically acceptable salt thereof is a capsule.
  • PATENT [0128]
  • the single unit dosage form is in a capsule of size #0, #1, #2, #3, #4, or #5.
  • the single unit dosage form is in a capsule of size #0.
  • the single unit dosage form is in a capsule of size #1.
  • the single unit dosage form is in a capsule of size #2.
  • the single unit dosage form is in a capsule of size #3.
  • the single unit dosage form is in a capsule of size #4.
  • the single unit dosage form is in a capsule of size #5.
  • kits comprising pharmaceutical compositions and unit dosage forms of the disclosure.
  • the kits are generally in the form of a physical structure housing various components, as described below, and may be utilized, for example, in practicing the methods described herein.
  • a kit can include one or more of Compound 1 or a pharmaceutically acceptable salt thereof (provided in, e.g., a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject.
  • Compound 1 or a pharmaceutically acceptable salt thereof can be provided in a form that is ready for use (e.g., a tablet or capsule) or in a form requiring, for example, reconstitution or dilution (e.g., a powder) prior to administration.
  • the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from Compound 1 or a pharmaceutically acceptable salt thereof.
  • diluents e.g., sterile water
  • the kit may contain the several agents separately or they may already be combined in the kit.
  • Each component of the kit may be enclosed within an individual container, and all of the various containers may be within a single package.
  • a kit of the present invention may be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing).
  • a kit may contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). Labels or inserts can include manufacturer information such as lot numbers and expiration dates.
  • the label or packaging insert may be, e.g., integrated into the physical structure housing the components, PATENT contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, tube or vial).
  • Labels or inserts can additionally include, or be incorporated into, a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards.
  • a computer readable medium such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory-type cards.
  • the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g., via the internet, are provided.
  • Some of the kits described herein include a label describing a method of administering Compound 1 or a pharmaceutically acceptable salt thereof.
  • kits described herein include a label describing methods of treating cancer.
  • the cancer is characterized by a reduction or an absence of methylthioadenosine phosphorylase (MTAP) gene expression, an absence of MTAP gene, a reduced function of MTAP protein, a reduced level or an absence of MTAP protein, MTA accumulation, or combination thereof.
  • MTAP methylthioadenosine phosphorylase
  • the cancer is an MTAP-null cancer.
  • the subject with cancer has an MTAP gene deletion.
  • compositions of the present invention including but not limited to, compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof in a bottle, jar, vial, ampoule, tube, blister pack, or other container-closure system approved by the Food and Drug Administration (FDA) or other regulatory body, which may provide one or more unit dosages containing Compound 1 or a phamectucially acceptable salt thereof.
  • FDA Food and Drug Administration
  • the package or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, the notice indicating approval by the agency.
  • the kit may include a formulation or composition as described herein, a container closure system including the formulation or one or more unit dosage forms including the formulation, and a notice or instructions describing a method of use as described herein.
  • Packaging systems such as blister packs include a thermoformable rigid film or PVC suitable for pharmaceutical packaging and a push through type lid.
  • the lid can include a foil, made up of a primer/aluminum/heat-seal-coating, or may be paper based.
  • a person of skill in the art will readily prepare blister packs comprising Compound 1.
  • Bottle systems PATENT described herein can be made in various sizes (e.g., 75cc, 100cc, 200cc, etc), and generally include child resistant closures that can be made from polypropylene.
  • a pharmaceutical dosage form of Compound 1 or a pharmaceutically acceptable salt thereof is packaged in 75 cc bottles, with a child resistant closure.
  • a person of skill in the art can readily prepare bottle systems described herein.
  • the present disclosure provides kits for once daily dosing. These kits provide one or more unit dosage forms comprising Compound 1 or a pharmaceutically acceptable salt thereof for each administration.
  • the unit dosage form of Compound 1 in free base form is about 5 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 10 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 15 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 30 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • the unit dosage form of Compound 1 in free base form is about 45 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 60 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 80 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. In some embodiments, the unit dosage form of Compound 1 in free base form is about 100 mg, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • Embodiment 1 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 1) or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about PATENT 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 2.
  • Embodiment 2 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of from about 15 mg to about 85 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 3.
  • Embodiment 3 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of from about 50 mg to about 75 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • Embodiment 4 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of from about 25 mg to about 50 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 5.
  • Embodiment 5 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of from about 10 mg to about 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of from about 15 mg to about 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • Embodiment 8 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of from about 30 mg to about 60 mg of PATENT Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of from about 45 mg to about 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 10.
  • Embodiment 10 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 30 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of from about 10 mg to about 30 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of from about 15 mg to about 30 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • Embodiment 13 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of from about 5 mg to about 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of from about 10 mg to about 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 15.
  • Embodiment 15 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of from about 15 mg to about 45 mg of PATENT Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of from about 30 mg to about 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of about 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 18.
  • Embodiment 18 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 10 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 19. In Embodiment 19 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 15 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 20. In Embodiment 20 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 30 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 21.
  • Embodiment 21 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • 22 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 60 mg of Compound 1 in free base PATENT form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • said therapeutically effective amount is a total daily dosage of about 80 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • Embodiment 24 is the method of Embodiment 1, wherein said therapeutically effective amount is a total daily dosage of about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • 25 is the method of any one of Embodiments 1 to 24, wherein the cancer is a solid tumor.
  • 26 is the method of any one of Embodiments 1 to 25, wherein the cancer is a solid malignant tumor.
  • Embodiment 27 is the method of any one of Embodiments 1 to 26, wherein the cancer is characterized by a reduction or an absence of methylthioadenosine phosphorylase (MTAP) gene expression, an absence of MTAP gene, a reduced function of MTAP protein, a reduced level of MTAP protein, an absence of MTAP protein, MTA accumulation, or combinations thereof.
  • MTAP methylthioadenosine phosphorylase
  • Embodiment 30 is the method of any one of Embodiments 1 to 29, wherein the cancer is refractory to at least one anticancer agent.
  • 31 is the method of any one of Embodiments 1 to 30, wherein the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, PATENT osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, esophagogastric cancer, malignant peripheral nerve sheath tumor, and mesothelioma.
  • NSCLC non-small cell lung cancer
  • Embodiment 32 is the method of any one of Embodiments 1 to 30, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.
  • the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), and urothelial cancer (bladder and upper urinary tract).
  • the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), and urothelial cancer (bladder and upper urinary tract).
  • Embodiment 34 is the method of any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (squamous and adenocarcinoma).
  • 35 is the method of any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (squamous).
  • 36 is the method of any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (adenocarcinoma).
  • 37. In Embodiment 37 is the method of any one of Embodiments 1 to 30, wherein the cancer is urothelial cancer (bladder and upper urinary tract). 38.
  • Embodiment 38 is the method of any one of Embodiments 1 to 30, wherein the cancer is urothelial cancer (bladder).
  • Embodiment 39 is the method of any one of Embodiments 1 to 30, wherein the cancer is urothelial cancer (upper urinary tract).
  • Embodiment 40 is the method of any one of Embodiments 1 to 30, wherein the cancer is squamous and adenocarcinoma of esophagus cancer, gastric adenocarcinoma, or gastro-esophageal junction cancer. 41.
  • Embodiment 45 is the method of any one of Embodiments 1 to 43, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for at least three 7-day dosing cycles.
  • Embodiment 46 is the method of any one of Embodiments 1 to 43, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for at least nine 7-day dosing cycles.
  • Embodiment 47 is the method of any one of Embodiments 1 to 43, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for at least 1 week, 2 weeks, 3 weeks, 4, weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, or 52 weeks.
  • a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for at least 1 week, 2 weeks, 3 weeks, 4, weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, or 52 weeks.
  • Embodiment 48 is the method of any one of Embodiments 1 to 47, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for at least 3 weeks.
  • Embodiment 49 is the method of any one of Embodiments 1 to 43, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form 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.
  • Embodiment 50 is the method of any one of Embodiments 1 to 43, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for at least 1 month.
  • Embodiment 51 is the method of any one of Embodiments 1 to 43, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for at least 3 months.
  • Embodiment 52 is the method of any one of Embodiments 1 to 43, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for at least 6 months.
  • Embodiment 53 is the method of any one of Embodiments 1 to 43, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing schedule comprising administering Compound 1 in free base PATENT form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form for two 7-day dosing cycles followed by no dosing for 7-days, and optionally followed by repeating said dosing schedule for additional at least 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 31 weeks, 34 weeks, 37 weeks, 40 weeks, 43 weeks, 46 weeks, 49 weeks, or 52 weeks. 54.
  • Embodiment 54 is the method of any one of Embodiments 1 to 53, wherein the subject exhibits at least a stable disease (SD) after administration with Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • Embodiment 55 is the method of any one of Embodiments 1 to 53, wherein the subject exhibits at least a partial response (PR) after administration with Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • SD stable disease
  • PR partial response
  • Embodiment 56 is the method of Embodiment 55, wherein the partial response (PR) is characterized by at least a 30% decrease in the sum of target lesion diameters, relative to a baseline sum of target lesion diameters prior to the treatment.
  • 57 is the method of any one of Embodiments 1 to 56, wherein the subject does not exhibit a dose limiting toxicity (DLT).
  • 58 is the method of any one of Embodiments 1 to 57, comprising administering at least one additional therapeutic agent.
  • 59 is the method of any one of Embodiments 1 to 58, wherein Compound 1 is in free base form. 60.
  • Embodiment 60 is the method of any one of Embodiments 1 to 59, wherein the Compound 1 is administered as a tablet.
  • 61 is the method of any one of Embodiments 1 to 60, wherein the subject is an adult.
  • 62 is the method of any one of Embodiments 1 to 61, wherein the subject is a human.
  • PATENT 63 is a unit dosage form comprising from about 5 mg to about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 64.
  • Embodiment 64 is the unit dosage form of Embodiment 63, wherein the unit dosage form comprises about 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • 65 is the unit dosage form of Embodiment 63, wherein the unit dosage form comprises about 10 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • 66 is the unit dosage form of Embodiment 63, wherein the unit dosage form comprises about 15 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 67.
  • Embodiment 67 is the unit dosage form of Embodiment 63, wherein the unit dosage form comprises about 30 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • 68 is the unit dosage form of Embodiment 63, wherein the unit dosage form comprises about 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • 69 is the unit dosage form of Embodiment 63, wherein the unit dosage form comprises about 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form. 70.
  • Embodiment 70 is the unit dosage form of Embodiment 63, wherein the unit dosage form comprises about 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • 71 In Embodiment 71 is a kit comprising one or more unit dosage forms of any one of Embodiments 63 to 70.
  • PATENT 72 In Embodiment 72 is the kit of Embodiment 71 further comprising a label with instructions for administering Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form.
  • 73 is the kit of Embodiments 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 medicament for treating cancer, wherein 5 mg to 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 75 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg, or 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 76 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg, or 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 76 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 77 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 10 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 78 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 78 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 15 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 79 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 30 mg of PATENT Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form 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 treating cancer, wherein 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 81 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 82 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 82 is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 83 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 5 mg to 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 84 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 5 mg to 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 84 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg, or 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 85 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 86 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 5 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 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 free base form, or an PATENT equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 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 free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 90 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 60 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 91 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 100 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • 92 is Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein 45 mg of Compound 1 in free base form, or an equivalent amount of Compound 1 in a pharmaceutically acceptable salt form is administered daily.
  • Embodiment 92 is the method, the unit dosage form, the kit, the use, or the Compound of any one of Embodiments 1 to 91, wherein Compound 1 is in free base form.
  • PATENT Example 1 A Phase I Trial of Compound 1, a selective MAT2A Inhibitor for the treatment of Advanced Solid Tumors [0140] A phase 1, multicenter, open-label, study of Compound 1 is being conducted in adult patients with Advanced Solid Tumors that harbor MTAP genomic deletion or loss (NCT04794699).
  • a Bayesian logistic regression model was used to guide the dose escalation and to estimate the maximum tolerated dose (MTD)/recommended dose for expansion (RDE).
  • MTD maximum tolerated dose
  • RDE recommended dose for expansion
  • Safety was described using incidence of adverse events (AEs) by relation and severity of the AE graded according to the Common Terminology Criteria for AEs (CTCAE, v5.0).
  • Overall response rate was defined as per Response Evaluation Criteria in Solid Tumors (RECIST, v1.1) in the evaluable patient population. See, Eisenhauer et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. Reduction in tumor size of a patient is defined as tumor size reduction as measured using RECIST 1.1 criteria.
  • the tumor size can be measured by, for example, radiographic scan, 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 thereof.
  • Subjects eligible for inclusion in this study are required to meet all of the following key criteria: ⁇ Confirmed diagnosis of an advanced or metastatic solid tumor that has progressed on at least one prior line of treatment and for which additional effective standard therapy is not available or for which participant is intolerant. ⁇ Have evidence of homozygous loss of MTAP or MTAP deletion. ⁇ Willing to undergo paired fresh biopsy (pre- and post-treatment) procedure during the study.
  • ⁇ Measurable disease defined as at least, for example, a non-nodal lesion that can be accurately measured in at least one dimension (longest dimension) of ⁇ 10 mm with MRI or CT when the scan slice thickness is no greater than 5 mm ; ⁇ 10 mm caliper/ruler measurement by clinical exam or medical photography; or ⁇ 20 mm by chest x-ray.
  • ⁇ Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of ⁇ 1.
  • ECOG Eastern Cooperative Oncology Group
  • PS Performance Status
  • Adequate organ function ⁇ Able to swallow and retain orally administered study treatment.
  • PATENT ⁇ Recovery from acute effects of prior therapy.
  • Subjects with any of the following are not eligible for participation in the study: ⁇ Symptomatic brain metastases requiring supraphysiologic doses of systemic corticosteroids or anti-convulsant medication. ⁇ Primary CNS malignancy ⁇ Current active liver or biliary disease ⁇ Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Compound 1, (e.g. any unresolved nausea, vomiting, or diarrhea that is National Cancer Institute (NCI) CTCAE version 5.0 Grade >1).
  • NCI National Cancer Institute
  • MTD maximum tolerated dose
  • RDE recommended dose for expansion
  • Additional tumor types that showed a molecular response included 2 subjects with pancreatic cancer and 1 with esophageal cancer at the dose of 60 mg QD, and 1 subject with phyllodes tumor at the dose of 100 mg QD.
  • 1 subject showed partial response (PR) with -47% tumor reduction as measured by RECIST v1.1 criteria after dose reduction to 60 mg QD from a starting dose of 100 mg QD.
  • Compound 1 as monotherapy is well tolerated with manageable toxicities and demonstrates pharmacodynamic activity at the expansion dose of 60 mg daily, along with early signs of clinical efficacy in patients with advanced solid tumors.
  • Example 1A Updates to Example 1 [0151] Safety summary: As of the data cut of November 21st, 2023, forty-seven patients received Compound 1 as a free base at doses ranging from 5 mg to 100 mg once daily PATENT (QD). The most common treatment emergent AEs (Adverse Events, all grade, irrespective of relationship, and reported in ⁇ 20% of subjects) were decreased appetite (40%), nausea (40%), constipation (38%), hypoacusis (36%), peripheral neuropathy (30%), blood creatinine increased (23%), hypocalcaemia (23%), diarrhea (21%), and vomiting (21%). The majority of the AEs were grade 1 and 2.
  • DLT dose limiting toxicity
  • ctDNA decrease of 50% or greater was seen in 13 subjects (out of 26 subjects who had evaluable samples), including 6 subjects with NSCLC (4 subjects at the dose of 60 mg QD and 2 at the dose of 100 mg QD) and 3 subjects with bladder cancer at the doses of 60 and 100 mg QD.
  • Additional tumor types that showed a molecular response included 1 subject with pancreatic cancer, 1 with esophageal cancer and 1 with melanoma at the dose of 60 mg QD, and 1 subject with phyllodes tumor at the dose of 100 mg QD.
  • Example 1B Updates to Example 1 and Example 1A [0157]
  • Safety summary As of the data cut of February 2, 2024, fifty-six patients received Compound 1 as a free base at doses ranging from 5 mg to 100 mg once daily (QD).
  • the most common treatment-emergent adverse events were nausea (42.9%), decreased appetite (41.1%), constipation (39.3%), hypoacusis (35.7%), peripheral neuropathy (28.6%), diarrhea (23.2%), hypocalcaemia (23.2%), vomiting (21.4%), blood creatinine increased (21.4%), and weight decreased (21.4%).
  • DLT dose limiting toxicity
  • this dose is the recommended dose for expansion (RDE).
  • RDE recommended dose for expansion
  • Example 1C Updates to Example 1, Example 1A, and Example 1B [0161] Additional inclusion criteria for the studies described in this examples as well as those in above Examples 1, 1A, and 1B include: ⁇ At the time of enrollment, have resolved acute effects of any prior therapy (including surgery, chemotherapy and radiotherapy) to baseline severity or (CTCAE version 5.0) Grade ⁇ 1 except for AEs not constituting a safety risk.
  • Additional exclusion criteria for the studies described in this examples as well as those in above Examples 1, 1A, and 1B include: ⁇ Active second malignancy or history of another malignancy in the past 2 years with the exception of adequately treated non-melanoma skin cancer, cervical carcinoma in situ, or breast carcinoma in situ. ⁇ Other acute or chronic medical or psychiatric condition. ⁇ Major surgery within 4 weeks before study entry. ⁇ Current radiation-related toxicity or radiation therapy within 2 weeks before study entry. ⁇ Systemic cytotoxic chemotherapy within 4 weeks before study entry. ⁇ Have received radioimmunotherapy less than 6 weeks before Compound 1 dosing. ⁇ Have received treatment with a therapeutic antibody less than 4 weeks or received treatment with a small molecule less than 2 weeks before the first dose of Compound 1.
  • Plasma SAM levels have been assessed across the dose range tested (5 mg to 100 mg QD).
  • 27 subjects were treated with Compound 1 for at least 21 days at 30 mg QD and had a post baseline scan that was available for tumor evaluation (if subjects were treated with Compound 1 at a higher starting dose and were subsequently lowered to 30 mg QC, the subjects with this adjusted lower 30 mg QC dose were included in this analysis if they were treated with Compound 1 at 30 mg QD for at least 21 days before subsequent tumor evaluation scan).
  • PR partial response
  • CR complete response
  • ORR overall response rate

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Abstract

La présente divulgation concerne l'utilisation d'un inhibiteur de MAT2A dans le traitement et la prévention de maladies associées à MAT2A, par exemple des maladies prolifératives. L'invention concerne également des formulations pharmaceutiques correspondantes, des utilisations, des procédés, des compositions et des modes de réalisation associés.
PCT/US2024/046774 2023-09-15 2024-09-13 Méthodes de traitement de maladies associées à mat2a Pending WO2025059579A1 (fr)

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