Menin-MLL inhibitor for cancer treatment

Abstract

The present disclosure is directed to a menin-MLL inhibitor comprising compound A and a method of treating colorectal cancer in a subject in need thereof. Also provided by the present disclosure are methods of administering compound A for various indications.

Description

Technical Field

[0001] Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 339,635, filed May 9, 2022, the content of which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] Colorectal cancer generally results from uncontrolled cell growth in the colon or rectum (parts of the large intestine) or the appendix. Genetic analysis has essentially shown that colon and rectal tumors are genetically the same cancer, and the symptoms of colorectal cancer typically include rectal bleeding and anemia, which may in some cases be associated with weight loss and changes in bowel habits. Colorectal cancer (CRC) is a major global health problem and is the third most commonly diagnosed malignancy with an estimated worldwide incidence of over 1.8 million in 2018. CRC caused 500,000 deaths in 2018 and is the second most common cause of cancer deaths worldwide. 20% of patients have metastatic colorectal cancer (mCRC) at the time of diagnosis, and moreover, up to 50% of patients diagnosed with early disease relapse later, despite curative-intent surgery, (neo)adjuvant chemotherapy, and / or radiotherapy. At least 50% of Western populations develop colorectal tumors by the age of 70. In 10% of these individuals, the tumors progress to malignancies. In adults, colorectal cancer is the second leading cancer causing death worldwide. Thus, clinically effective treatments are notably lacking, and the present disclosure aims to meet this currently unmet clinical need.

Summary of the Invention

[0003] In some aspects, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor.

[0004] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition consisting essentially of a menin-MLL inhibitor.

[0005] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method consisting essentially of administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor.

[0006] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a single anti-cancer agent, wherein the single anti-cancer agent is a menin-MLL inhibitor.

[0007] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising Compound A at least once a day, and administering a pharmaceutical composition comprising cobicistat at least once a day.

[0008] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising Compound A at least once a day, and administering a pharmaceutical composition comprising cobicistat at least once a day, wherein administration of an EGFR inhibitor is not required.

[0009] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising Compound A at least once a day, and Administering a pharmaceutical composition comprising cobimetinib at least once a day, wherein the subject has not received an EGFR inhibitor, to a subject.

[0010] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: Administering a pharmaceutical composition comprising Compound A at least once a day, Administering a pharmaceutical composition comprising cobimetinib at least once a day, wherein the subject has not received an EGFR inhibitor, to a subject.

[0011] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: Administering a pharmaceutical composition comprising Compound A at least once a day, Administering a pharmaceutical composition comprising cobimetinib at least once a day, further comprising administering Compound A in the absence of an EGFR inhibitor, to a subject.

[0012] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A in a dose of about 25 mg to about 300 mg, wherein the subject has not received a CYP3A inhibitor, to a subject.

[0013] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A in a dose of about 25 mg to about 300 mg, wherein the subject has not received a CYP3A inhibitor, to a subject.

[0014] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 25 mg to about 300 mg, wherein the method is directed to a method that does not require administration of a CYP3A inhibitor.

[0015] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 25 mg to about 300 mg, wherein the administration of Compound A occurs in the absence of a CYP3A inhibitor.

[0016] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 25 mg to about 300 mg, wherein the administration of Compound A occurs in the absence of both a CYP3A inhibitor and an EGFR inhibitor.

[0017] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 25 mg to about 300 mg at least once a day, wherein the subject does not receive a CYP3A inhibitor.

[0018] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 25 mg to about 300 mg at least once a day, wherein the subject has not received a CYP3A inhibitor yet.

[0019] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 25 mg to about 300 mg at least once a day, wherein the method is directed to a method that does not require administration of a CYP3A inhibitor.

[0020] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 25 mg to about 300 mg at least once a day, wherein the administration of Compound A occurs in the absence of a CYP3A inhibitor.

[0021] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 25 mg to about 300 mg at least once a day, wherein the administration of Compound A occurs in the absence of both a CYP3A inhibitor and an EGFR inhibitor.

[0022] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 150 mg to about 200 mg, wherein the subject does not receive a CYP3A inhibitor.

[0023] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 150 mg to about 200 mg, wherein the subject has not received a CYP3A inhibitor yet.

[0024] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering compound A at a dose of about 150 mg to about 200 mg, wherein the method is directed to a method that does not require administration of a CYP3A inhibitor.

[0025] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering compound A at a dose of about 150 mg to about 200 mg, wherein the administration of compound A occurs in the absence of a CYP3A inhibitor.

[0026] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering compound A at a dose of about 150 mg to about 200 mg, wherein the administration of compound A occurs in the absence of both a CYP3A inhibitor and an EGFR inhibitor.

[0027] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering a pharmaceutical composition comprising compound A, wherein the administration of compound A is in the absence of a CYP3A inhibitor and the dose of compound A is about 220 to about 280 mg.

[0028] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering compound A at a dose of about 150 mg to about 200 mg at least once a day, wherein the subject does not receive a CYP3A inhibitor.

[0029] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 150 mg to about 200 mg at least once a day, wherein the subject has not received a CYP3A inhibitor.

[0030] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 150 mg to about 200 mg at least once a day, wherein administration of a CYP3A inhibitor is not required.

[0031] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 150 mg to about 200 mg at least once a day, wherein administration of Compound A occurs in the absence of a CYP3A inhibitor.

[0032] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a dose of about 150 mg to about 200 mg at least once a day, wherein administration of Compound A occurs in the absence of both a CYP3A inhibitor and an EGFR inhibitor.

[0033] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition comprising Compound A, wherein administering Compound A occurs in the absence of a CYP3A inhibitor, the dose of Compound A is about 220 to about 280 mg, and Compound A is administered at least once a day.

[0034] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A three times a day at a dose of about 150 mg to about 200 mg, wherein the subject does not receive a CYP3A inhibitor.

[0035] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A three times a day at a dose of about 150 mg to about 200 mg, wherein the subject has not received a CYP3A inhibitor yet.

[0036] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A three times a day at a dose of about 150 mg to about 200 mg, wherein no administration of a CYP3A inhibitor is required.

[0037] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A three times a day at a dose of about 150 mg to about 200 mg, wherein the administration of Compound A occurs in the absence of a CYP3A inhibitor.

[0038] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A three times a day at a dose of about 150 mg to about 200 mg, wherein the administration of Compound A occurs in the absence of both a CYP3A inhibitor and an EGFR inhibitor.

[0039] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A, wherein the subject has progressed in the pre-treatment of colorectal cancer.

[0040] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A, wherein the subject has relapsed from at least one line of prior treatment for colorectal cancer.

[0041] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A, wherein the subject has relapsed from at least two lines of prior treatment for colorectal cancer.

[0042] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A, wherein the subject has refractory colorectal cancer.

[0043] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition comprising Compound A, comprising administering Compound A in the absence of a CYP3A inhibitor, wherein the dose of Compound A is from about 220 to about 280 mg and Compound A is administered three times a day.

[0044] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a daily dose of from about 25 mg to about 900 mg, wherein the subject is not receiving a CYP3A inhibitor.

[0045] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a daily dose of from about 25 mg to about 900 mg, wherein the subject has not received a CYP3A inhibitor yet.

[0046] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a daily dose of about 25 mg to about 900 mg, wherein the method is directed to a method that does not require administration of a CYP3A inhibitor.

[0047] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a daily dose of about 25 mg to about 900 mg, wherein the administration of Compound A occurs in the absence of a CYP3A inhibitor.

[0048] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A at a daily dose of about 25 mg to about 900 mg, wherein the administration of Compound A occurs in the absence of both a CYP3A inhibitor and an EGFR inhibitor.

[0049] In some embodiments, the present disclosure is a menin-MLL inhibitor for use in the preparation of a medicament for the treatment of colorectal cancer by the method according to any one of the foregoing embodiments, wherein the medicament and / or treatment does not require the use of an EGFR inhibitor.

[0050] In some embodiments, the present disclosure is a menin-MLL inhibitor for use in the preparation of a medicament for the treatment of colorectal cancer by the method according to any one of the foregoing embodiments, wherein the medicament does not contain an EGFR inhibitor.

[0051] In some embodiments, the present disclosure is directed to a kit comprising a menin-MLL inhibitor and printed instructions for using the menin-MLL inhibitor in a subject for the treatment of colorectal cancer.

[0052] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate some embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating embodiments of the present disclosure and should not be construed as limiting the invention. Further objects, features, and advantages of the present invention will become apparent from the following detailed description in conjunction with the accompanying drawings showing exemplary embodiments of the present disclosure.

Brief Description of the Drawings

[0053]

Figure 1

Figure 2A

Figure 2B

Figure 2C

Mode for Carrying Out the Invention

[0054] The following is a detailed description provided to assist those skilled in the art in practicing the present invention. Those skilled in the art can make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0055] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering to the subject a menin-MLL inhibitor or a pharmaceutical composition thereof.

[0056] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition consisting essentially of a menin-MLL inhibitor.

[0057] In some aspects, the present disclosure is directed to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method consisting essentially of administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor.

[0058] In some aspects, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering a single anti-cancer agent to the subject, wherein the single anti-cancer agent is a menin-MLL inhibitor, and the method is targeted.

[0059] Menin-MLL inhibitor In some embodiments, the menin-MLL inhibitor is Compound B, KO-539, JNJ-75276617, Compound A, DS-1594, BMF-219, DSP-5336, Antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the menin-MLL inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0061]

Table 1-1

Table 1-2

Table 1-3

[0062] Another menin-MLL inhibitor is MI-2-2, which inhibits the interaction between menin and MLL. See Grembecka et al., 2012, Nat Chem Biol, 8: 277-284 and Shi et al., 2012, Blood, 120: 4461-4469. Yet another menin-MLL inhibitor that inhibits the interaction between the MLL enzyme and menin is N,N'-bis(4-aminophenyl)-N,N'-dimethylethylenediamine (also known as ISC-30). In some embodiments, the menin-MLL inhibitors contemplated for use in the methods of the present disclosure are known in the art and include, at least, for example, those described in WO2017 / 112768, WO2017 / 214367, WO2018 / 053267, WO2020 / 069027, WO2021 / 207335, US2021 / 0115018, US2019 / 0307750, US2016 / 0339035, and Borkin et al. Cancer Cell vol. 27,4 (2015): 589-602, the contents of each of which are incorporated by reference.

[0063] In some embodiments, the menin-MLL inhibitor is Compound A, Compound B, DSP-5336, DS-1594, KO-539, MI-503, MI-3454, MI-463, M-808, MI-136, JNJ-75276617, MI-227, BMF-219, Antibody A300-105A, MI-0202, MI-503, MI-463, MI-136, ML-227, MI-2-2, or ISC-30. In some embodiments, the menin-MLL inhibitor is Compound A or Compound B. In some embodiments, the menin-MLL inhibitor is Compound A. In some embodiments, the menin-MLL inhibitor is DSP-5336. In some embodiments, the menin-MLL inhibitor is Compound B. In some embodiments, the menin-MLL inhibitor is DS-1594. In some embodiments, the menin-MLL inhibitor is KO-539. In some embodiments, the menin-MLL inhibitor is MI-503. In some embodiments, the menin-MLL inhibitor is MI-3454. In some embodiments, the menin-MLL inhibitor is MI-463. In some embodiments, the menin-MLL inhibitor is M-808. In some embodiments, the menin-MLL inhibitor is MI-136. In some embodiments, the menin-MLL inhibitor is JNJ-75276617. In some embodiments, the menin-MLL inhibitor is MI-227. In some embodiments, the menin-MLL inhibitor is BMF-219. In some embodiments, the menin-MLL inhibitor is Antibody A300-105A. In some embodiments, the menin-MLL inhibitor is MI-0202. In some embodiments, the menin-MLL inhibitor is MI-503. In some embodiments, the menin-MLL inhibitor is MI-463. In some embodiments, the menin-MLL inhibitor is MI-136. In some embodiments, the menin-MLL inhibitor is ML-227. In some embodiments, the menin-MLL inhibitor is MI-2-2. In some embodiments, the menin-MLL inhibitor is ISC-30.

[0064] Treatment method Unless otherwise stated, any description of a method of treatment is understood to include the use of a compound for providing a treatment or prophylaxis as described herein, and the use of a compound for preparing a medicament for treating or preventing such a condition. Treatment includes the treatment of humans or non-human animals (including rodents and other disease models).

[0065] In some embodiments, the menin-MLL inhibitor is administered at least once a day. In some embodiments, the menin-MLL inhibitor is Compound A and is administered at least once a day.

[0066] In some embodiments, the menin-MLL inhibitor is administered twice a day. In some embodiments, the menin-MLL inhibitor is Compound A and is administered at least twice a day. In some embodiments, the menin-MLL inhibitor is Compound A and is administered twice a day.

[0067] In some embodiments, the menin-MLL inhibitor is administered three times a day. In some embodiments, the menin-MLL inhibitor is Compound A and is administered three times a day.

[0068] In some embodiments, the menin-MLL inhibitor is administered in combination with a CYP3A inhibitor.

[0069] In some embodiments, a pharmaceutical composition comprising a menin-MLL inhibitor further comprises a CYP3A inhibitor.

[0070] In some embodiments, the menin-MLL inhibitor is administered in combination with a CYP3A4 inhibitor.

[0071] In some embodiments, a pharmaceutical composition comprising a menin-MLL inhibitor further comprises a CYP3A4 inhibitor.

[0072] In some embodiments, the CYP3A4 inhibitor is a potent CYP3A4 inhibitor.

[0073] In some embodiments, potent CYP3A4 inhibitors are boceprevir, cobicistat, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole.

[0074] In some embodiments, the method further comprises administering cobicistat.

[0075] In some embodiments, the method further comprises administering cobicistat at least once a day.

[0076] In some embodiments, the method further comprises administering cobicistat once a day.

[0077] In some embodiments, the CYP3A4 inhibitor is a moderate CYP3A4 inhibitor.

[0078] In some embodiments, moderate CYP3A4 inhibitors are amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, or verapamil.

[0079] In some embodiments, the menin-MLL inhibitor is administered every 12 hours at a dosage of about 25 mg to about 276 mg.

[0080] In some embodiments, the menin-MLL inhibitor is administered every 12 hours at a dosage of about 163 mg.

[0081] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof in the absence of a CYP3A inhibitor.

[0082] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof, wherein the subject does not receive a CYP3A inhibitor.

[0083] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof in the absence of a CYP3A4 inhibitor.

[0084] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof, wherein the subject does not receive a CYP3A4 inhibitor.

[0085] In some embodiments, the pharmaceutical composition described herein comprises a menin inhibitor (e.g., Compound A) and does not comprise a CYP3A4 inhibitor.

[0086] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof in an amount of about 25 mg to about 900 mg.

[0087] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dosage of about 25 mg to about 276 mg.

[0088] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at least once a day, wherein the total amount of the menin-MLL inhibitor administered per day is about 25 mg to about 900 mg.

[0089] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof once a day, and the total amount of the menin-MLL inhibitor administered per day is about 25 mg to about 900 mg.

[0090] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof twice a day, wherein the total amount of the menin-MLL inhibitor administered per day is about 25 mg to about 900 mg.

[0091] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof three times a day, wherein the total amount of the menin-MLL inhibitor administered per day is from about 25 mg to about 900 mg.

[0092] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof four times a day, wherein the total amount of the menin-MLL inhibitor administered per day is from about 25 mg to about 900 mg.

[0093] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dosage of from about 25 mg to about 276 mg, wherein the menin-MLL inhibitor is administered at least once a day.

[0094] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dosage of from about 25 mg to about 276 mg, wherein the menin-MLL inhibitor is administered once a day.

[0095] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dosage of from about 25 mg to about 276 mg, wherein the menin-MLL inhibitor is administered twice a day.

[0096] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dosage of from about 25 mg to about 276 mg, wherein the menin-MLL inhibitor is administered three times a day.

[0097] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dosage of about 163 mg.

[0098] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dosage of about 163 mg when the menin-MLL inhibitor is administered three times a day.

[0099] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dosage of about 25 mg to about 276 mg.

[0100] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof in the absence of a CYP3A4 inhibitor, the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg, wherein the menin-MLL inhibitor is administered three times a day.

[0101] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof in the absence of a CYP3A4 inhibitor, and the menin-MLL inhibitor is administered at a dosage of about 163 mg.

[0102] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof in the absence of a CYP3A4 inhibitor, the menin-MLL inhibitor is administered at a dosage of about 163 mg, wherein the menin-MLL inhibitor is administered three times a day.

[0103] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof in the absence of a CYP3A4 inhibitor, and the menin-MLL inhibitor is administered at a dosage of about 276 mg.

[0104] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof in the absence of a CYP3A4 inhibitor, the menin-MLL inhibitor is administered at a dosage of about 276 mg, wherein the menin-MLL inhibitor is administered three times a day.

[0105] In some embodiments, the menin-MLL inhibitor is administered three times a day to a subject in need thereof at a dosage of about 25 mg to about 276 mg, wherein the CYP3A4 inhibitor is not administered to the subject.

[0106] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dose of about 163 mg, wherein the CYP3A4 inhibitor is not administered to the subject.

[0107] In some embodiments, the menin-MLL inhibitor is administered three times a day to a subject in need thereof at a dose of about 163 mg, wherein the CYP3A4 inhibitor is not administered to the subject.

[0108] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a dose of about 276 mg, wherein the CYP3A4 inhibitor is not administered to the subject.

[0109] In some embodiments, the menin-MLL inhibitor is administered three times a day to a subject in need thereof at a dose of about 276 mg, wherein the CYP3A4 inhibitor is not administered to the subject.

[0110] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a maximum dose of about 828 mg / day.

[0111] In some embodiments, the menin-MLL inhibitor is administered to a subject in need thereof at a maximum dose of about 828 mg / day, wherein the CYP3A inhibitor is not administered to the subject.

[0112] In some embodiments, the menin inhibitor is contained in a capsule or an oral solution.

[0113] In some embodiments, the subject has not received prior treatment for colorectal cancer.

[0114] In some embodiments, the subject has previously received at least one prior treatment for colorectal cancer.

[0115] In some embodiments, the subject has previously received at least one prior treatment for colorectal cancer, wherein the subject did not respond to at least one line of prior treatment.

[0116] In some embodiments, at least 1 line of prior treatment was chemotherapy, radiotherapy, immunotherapy, targeted small molecule therapy, or biological therapy (e.g., monoclonal antibody therapy). In some embodiments, at least 1 line of prior treatment was chemotherapy. In some embodiments, at least 1 line of prior treatment was radiotherapy. In some embodiments, at least 1 line of prior treatment is immunotherapy. In some embodiments, at least 1 line of prior treatment is targeted small molecule therapy. In some embodiments, at least 1 line of prior treatment is biological therapy (e.g., monoclonal antibody therapy).

[0117] In some embodiments, the subject has previously received treatment for colorectal cancer selected from one or more of trifluridine, tipiracil, and / or regorafenib.

[0118] In some embodiments, the subject has previously received trifluridine, tipiracil, or a combination thereof for the treatment of colorectal cancer.

[0119] In some embodiments, the subject has previously received regorafenib for the treatment of colorectal cancer.

[0120] In some embodiments, the subject has previously received trifluridine, tipiracil, and / or regorafenib. In some embodiments, the subject has previously received trifluridine. In some embodiments, the subject has previously received tipiracil. In some embodiments, the subject has previously received regorafenib.

[0121] In some embodiments, the subject has not received prior treatment for colorectal cancer.

[0122] In some embodiments, the subject progressed from at least 1 line of prior treatment for colorectal cancer. In some embodiments, the subject relapsed from at least 1 line of prior treatment for colorectal cancer. In some embodiments, the subject relapsed from at least 2 prior treatments for colorectal cancer. In some embodiments, the subject has refractory colorectal cancer. In some embodiments, the subject has recurrent or refractory colorectal cancer.

[0123] In some embodiments, the colorectal cancer is recurrent / refractory colorectal cancer. In some embodiments, the colorectal cancer is metastatic recurrent / refractory colorectal cancer.

[0124] In some embodiments, the subject is being treated for microsatellite stability / proficient mismatch repair (MSS / pMMR) metastatic colorectal cancer (mCRC). In some embodiments, the colorectal cancer is microsatellite stability / proficient mismatch repair (MSS / pMMR) metastatic colorectal cancer.

[0125] In some embodiments, the menin-MLL inhibitor is administered in the absence of an EGFR inhibitor.

[0126] In some aspects, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once daily, administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once daily, and a method comprising the steps of:

[0127] In some aspects, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once daily, administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once daily, and Here, a method that does not require administration of an EGFR inhibitor is targeted.

[0128] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; and administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, wherein the subject has not received an EGFR inhibitor.

[0129] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; and administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, wherein the subject has not received an EGFR inhibitor up to that point.

[0130] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; and administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, wherein the method further comprises administering the menin-MLL inhibitor in the absence of an EGFR inhibitor.

[0131] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; and administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, Also targeted is a method further comprising administering a menin-MLL inhibitor in the absence of an EGFR inhibitor.

[0132] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; and administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, wherein the menin-MLL inhibitor is selected from the group consisting of Compound B, KO-539, JNJ-75276617, Compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; and administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, wherein no EGFR inhibitor is required, and the menin-MLL inhibitor is selected from the group consisting of Compound B, KO-539, JNJ-75276617, Compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, and wherein the subject has not received an EGFR inhibitor and the menin-MLL inhibitor is selected from the group consisting of compound B, KO-539, JNJ-75276617, compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, and wherein the subject has not received an EGFR inhibitor and the menin-MLL inhibitor is selected from the group consisting of compound B, KO-539, JNJ-75276617, compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, and Further comprising administering a menin-MLL inhibitor in the absence of an EGFR inhibitor, wherein the menin-MLL inhibitor is selected from the group consisting of Compound B, KO-539, JNJ-75276617, Compound A, DS-1594, BMF-219, DSP-5336, Antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof, and the method is directed to.

[0137] In some embodiments, the present disclosure provides a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day, administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, and the method comprises. Further comprising administering a menin-MLL inhibitor in the absence of an EGFR inhibitor, wherein the menin-MLL inhibitor is selected from the group consisting of Compound B, KO-539, JNJ-75276617, Compound A, DS-1594, BMF-219, DSP-5336, Antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof, and the method is directed to.

[0138] In some embodiments, the present disclosure provides a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day, administering a pharmaceutical composition comprising cobimetinib at least once a day, and the method comprises.

[0139] In some embodiments, the present disclosure provides a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, and wherein the method is directed to a subject who does not require administration of an EGFR inhibitor.

[0140] In some embodiments, the disclosure provides a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, and wherein the subject has not received an EGFR inhibitor.

[0141] In some embodiments, the disclosure provides a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, and wherein the subject has not received an EGFR inhibitor up to the present.

[0142] In some embodiments, the disclosure provides a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, and further comprising administering the menin-MLL inhibitor in the absence of an EGFR inhibitor.

[0143] In some embodiments, the disclosure provides a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, and further comprising administering the menin-MLL inhibitor in the absence of an EGFR inhibitor, a method.

[0144] In some embodiments, the disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, and wherein the menin-MLL inhibitor is selected from the group consisting of Compound B, KO-539, JNJ-75276617, Compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof, a method.

[0145] In some embodiments, the disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, and Here, a method is targeted, which does not require administration of an EGFR inhibitor, and the menin-MLL inhibitor is selected from the group consisting of compound B, KO-539, JNJ-75276617, compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, wherein the subject is not receiving an EGFR inhibitor, and the menin-MLL inhibitor is selected from the group consisting of compound B, KO-539, JNJ-75276617, compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, Here, the subject has not been exposed to an EGFR inhibitor yet, and the method is directed to a subject in which the menin-MLL inhibitor is selected from the group consisting of compound B, KO-539, JNJ-75276617, compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day, administering a pharmaceutical composition comprising cobicistat at least once a day, and further comprising administering the menin-MLL inhibitor in the absence of an EGFR inhibitor, wherein the menin-MLL inhibitor is selected from the group consisting of compound B, KO-539, JNJ-75276617, compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof, and the method is directed to a subject.

[0149] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day, administering a pharmaceutical composition comprising cobicistat at least once a day, and Further comprising administering a menin-MLL inhibitor in the absence of an EGFR inhibitor, wherein the menin-MLL inhibitor is selected from the group consisting of Compound B, KO-539, JNJ-75276617, Compound A, DS-1594, BMF-219, DSP-5336, antibody A300-105A (commercially available from Bethyl Laboratories), MI-0202, MI-503, MI-463, MI-136, MI-3454, M-808, and ML-227, or a pharmaceutically acceptable salt thereof, and methods are targeted.

[0150] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising: administering a pharmaceutical composition comprising Compound A at least once a day; administering a pharmaceutical composition comprising cobicistat at least once a day, and methods are targeted. Further comprising administering Compound A in the absence of an EGFR inhibitor, and methods are targeted.

[0151] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A three times a day at a dose of about 150 mg to about 300 mg, wherein the administration of Compound A is carried out in the absence of a CYP3A inhibitor and / or an EGFR inhibitor, and methods are targeted.

[0152] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A three times a day at a dose of about 150 mg to about 300 mg, wherein the subject does not receive a CYP3A inhibitor and / or an EGFR inhibitor, and methods are targeted.

[0153] In some embodiments, the colorectal cancer is characterized by dysregulation of the WNT / β-catenin signaling pathway.

[0154] In some embodiments, the subject has progressed on neoadjuvant therapy for colorectal cancer, resulting in resistance to neoadjuvant therapy for colorectal cancer.

[0155] In some embodiments, the subject has relapsed from at least one neoadjuvant therapy for colorectal cancer, resulting in resistance to neoadjuvant therapy for colorectal cancer.

[0156] In some embodiments, the subject has relapsed from at least two neoadjuvant therapies for colorectal cancer, resulting in resistance to neoadjuvant therapy for colorectal cancer.

[0157] In some aspects, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject, comprising administering a pharmaceutical composition comprising Compound A, comprising administering about 220 mg to about 280 mg of Compound A three times a day, and not administering a CYP3A inhibitor.

[0158] In some aspects, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject, comprising administering a pharmaceutical composition comprising Compound A, comprising administering about 220 mg to about 280 mg of Compound A three times a day, and the subject not receiving a CYP3A inhibitor.

[0159] In some embodiments, the cancer is leukemia.

[0160] In some embodiments, the cancer is AML leukemia.

[0161] In some embodiments, the cancer is acute lymphoblastic leukemia.

[0162] In some embodiments, the cancer is NMP1 mutant leukemia.

[0163] In some embodiments, the cancer is colorectal cancer.

[0164] In some embodiments, the cancer is microsatellite stable / proficient mismatch repair (MSS / pMMR) mCRC.

[0165] In some embodiments, the menin-MLL inhibitor is administered at a dosage of about 270 mg to about 280 mg.

[0166] In some embodiments, the menin-MLL inhibitor is administered three times a day.

[0167] In some embodiments, the menin-MLL inhibitor is administered with food or separately from food.

[0168] In some aspects, the disclosure is directed to a menin-MLL inhibitor for use in the preparation of a medicament for the treatment of colorectal cancer by the method according to any one of the preceding claims, wherein the medicament and / or treatment does not require the use of an EGFR inhibitor.

[0169] In some aspects, the disclosure is directed to a menin-MLL inhibitor for use in the preparation of a medicament for the treatment of colorectal cancer by the method according to any one of the preceding claims, wherein the medicament does not contain an EGFR inhibitor.

[0170] In some aspects, the disclosure is directed to a kit comprising a menin-MLL inhibitor and printed instructions for using the menin-MLL inhibitor in a subject for the treatment of colorectal cancer.

[0171] In some aspects, the disclosure is directed to a kit comprising a therapeutically effective amount of a menin-MLL inhibitor and printed instructions for using the menin-MLL inhibitor in a subject for the treatment of colorectal cancer.

[0172] In some embodiments, the kit provides instructions for administering the menin-MLL inhibitor at a dosage of about 270 mg to about 280 mg.

[0173] In some embodiments, the kit provides instructions for administering the menin-MLL inhibitor at least once a day.

[0174] In some embodiments, the kit provides instructions for administering the menin-MLL inhibitor once a day.

[0175] In some embodiments, the kit provides instructions for administering the menin-MLL inhibitor twice a day.

[0176] In some embodiments, the kit provides instructions for administering the menin-MLL inhibitor three times a day.

[0177] In some embodiments, the kit provides instructions for administering approximately 276 mg of the menin-MLL inhibitor three times a day.

[0178] In some embodiments, the kit provides instructions for administering approximately 276 mg of the menin-MLL inhibitor three times a day with food.

[0179] In some embodiments, the kit provides instructions for administering approximately 276 mg of the menin-MLL inhibitor three times a day without food.

[0180] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting of the invention.

[0181] When a range of values is provided, unless the context clearly indicates otherwise, each intervening value between the upper and lower limits of that range to one tenth of the unit of the lower limit (for example, in the case of a group containing a large number of carbon atoms, each number of carbon atoms included within the range is provided), and other defined values or intervening values within this defined range are to be understood as being encompassed by the present invention. The upper and lower limits of these narrower ranges may be independently included in the narrower ranges and are also encompassed by the present invention, but are subject to any specifically excluded limit values within the defined range. When the described range includes one or both of the limit values, ranges excluding one or both of those included limit values are also included in the present invention.

[0182] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or a plurality of elements.

[0183] Colorectal cancer Colorectal cancer develops in the colon or rectum. When it starts in the colon, it may be called colon cancer. When it starts in the rectum, it may be called rectal cancer. In some embodiments, the term "colorectal cancer" describes cancer of the colon. In some embodiments, the term "colorectal cancer" describes cancer of the rectum.

[0184] A common type of colorectal cancer is adenocarcinoma. Adenocarcinomas of the colon and rectum account for 95 percent of all cases of colorectal cancer. In the digestive tract, rectal and colon adenocarcinomas develop in the inner layer cells of the large intestine. These adenocarcinomas typically start as a growth of tissue called a polyp. A specific type of polyp called an adenoma can develop into cancer. Other types of tumors can develop in the colon or rectum, including primary colorectal lymphoma, gastrointestinal stromal tumor, leiomyosarcoma, carcinoid tumor, and melanoma.

[0185] Pre-treatment LONSURF (registered trademark) is a combination of trifluridine (a nucleoside metabolic inhibitor) and tipiracil (a thymidine phosphorylase inhibitor), and is indicated for the treatment of adult subjects with metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin and irinotecan-based chemotherapy, anti-VEGF biological therapy, and anti-EGFR therapy (in the case of RAS wild-type); adult subjects with gastroesophageal junction adenocarcinoma previously treated with at least two lines of chemotherapy including any of fluoropyrimidine, platinum, taxane or irinotecan, and HER2 / neu targeted therapy where appropriate.

[0186] STIVARGA (registered trademark) (regorafenib) is a kinase inhibitor indicated for the treatment of subjects with metastatic colorectal cancer (CRC) previously treated with fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy (in the case of KRAS wild-type).

[0187] In some embodiments, the subject has received at least one prior treatment. In some embodiments, the prior treatment is for the treatment of cancer. In some embodiments, the prior treatment is for colon cancer. In some embodiments, the prior treatment is for rectal cancer. In some embodiments, the prior treatment is for colorectal cancer. In some embodiments, the prior treatment is for metastatic colorectal cancer. In some embodiments, the subject has previously received LONSURF or STIVARGA. In some embodiments, the subject has previously received LONSURF. In some embodiments, the subject has previously received STIVARGA.

[0188] In some embodiments, the subject has progressed on prior treatment. In some embodiments, the subject has progressed on at least one prior treatment. In some embodiments, the subject has progressed on prior treatment with LONSURF or STIVARGA. In some embodiments, the subject has progressed on prior treatment with LONSURF. In some embodiments, the subject has progressed on prior treatment with STIVARGA.

[0189] In some embodiments, the subject has relapsed from a previous treatment line. In some embodiments, the subject has relapsed after at least one previous treatment. In some embodiments, the subject has relapsed from a previous treatment with LONSURF or STIVARGA. In some embodiments, the subject has relapsed from a previous treatment with LONSURF. In some embodiments, the subject has relapsed from a previous treatment with STIVARGA.

[0190] In some embodiments, the subject has refractory cancer and has received previous treatment. In some embodiments, the subject has refractory cancer and has received at least one previous treatment. In some embodiments, the subject has refractory cancer and has received previous treatment with LONSURF or STIVARGA. In some embodiments, the subject has refractory cancer and has received previous treatment with LONSURF. In some embodiments, the subject has refractory cancer and has received previous treatment with STIVARGA.

[0191] In some embodiments, the subject progressed on a previous treatment using one or more of fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, anti-VEGF therapy, or anti-EGFR therapy. In some embodiments, the subject progressed on a previous treatment using fluoropyrimidine-based chemotherapy. In some embodiments, the subject progressed on a previous treatment using one cycle of oxaliplatin-based chemotherapy. In some embodiments, the subject progressed on a previous treatment using irinotecan-based chemotherapy. In some embodiments, the subject progressed on a previous treatment using anti-VEGF therapy. In some embodiments, the subject progressed on a previous treatment using anti-EGFR therapy.

[0192] Other indications In some aspects, the present disclosure is a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition comprising Compound A, comprising administering Compound A three times a day, wherein the subject does not receive a CYP3A inhibitor.

[0193] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition comprising Compound A, comprising administering Compound A three times a day, wherein the subject does not receive a CYP3A4 inhibitor.

[0194] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition comprising Compound A, comprising administering Compound A in the absence of a CYP3A / CYP3A4 inhibitor, wherein the dose of Compound A is administered three times a day.

[0195] In some embodiments, the cancer is a blood cancer such as leukemia or lymphoma. Examples of leukemias and lymphomas treatable by the compounds of the present invention include mixed lineage leukemia (MLL), MLL-related leukemia, leukemia associated with MLL, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia with MLL rearrangement or rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, pediatric leukemia, acute lymphoblastic leukemia (ALL) (also referred to as acute lymphocytic leukemia or acute lymphoblastic leukemia), acute myeloid leukemia (AML: acute myeloid leukemia) (also referred to as acute myelogenous leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also referred to as chronic lymphoblastic leukemia), chronic myelogenous leukemia (CML: chronic myelogenous leukemia) (also referred to as chronic myeloid leukemia), therapy-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD) (such as primary myelofibrosis (PMF)), myeloproliferative neoplasm (MPN), plasmacytoma, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, nucleophosmin (NPM1) AML, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granuloma fungoides, Sézary syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenström macroglobulinemia. In some embodiments, acute myeloid leukemia (AML) is abstract nucleophosmin (NPMl) variant acute myeloid leukemia (i.e., NPM1 mut acute myeloid leukemia).

[0196] In some embodiments, the methods of the disclosure are used to treat leukemia with MLL rearrangement, acute lymphoblastic leukemia with MLL rearrangement, acute lymphoblastic leukemia with MLL rearrangement, acute lymphocytic leukemia with MLL rearrangement, acute myeloid leukemia with MLL rearrangement, acute myelogenous leukemia with MLL rearrangement, or acute myeloblastic leukemia with MLL rearrangement. As used herein, "MLL rearrangement" means rearrangement of the MLL gene.

[0197] Administration In some embodiments, the amount of menin-MLL inhibitor administered is from about 1 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 10 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 100 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 200 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 300 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 400 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 500 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 600 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 700 mg / day to about 1,000 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 800 mg / day to about 1,000 mg / day.

[0198] In some embodiments, the amount of menin-MLL inhibitor administered is from about 1 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 10 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 100 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 200 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 300 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 400 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 500 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 600 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 700 mg / day to about 900 mg / day. In some embodiments, the amount of menin-MLL inhibitor administered is from about 800 mg / day to about 900 mg / day.

[0199] In some embodiments, the amount of menin-MLL inhibitor administered is from about 25 mg / day to about 828 mg / day, from about 75 mg / day to about 828 mg / day, from about 100 mg / day to about 828 mg / day, from about 150 mg / day to about 828 mg / day, from about 200 mg / day to about 828 mg / day, from about 250 mg / day to about 828 mg / day, from about 300 mg / day to about 828 mg / day, from about 350 mg / day to about 828 mg / day, from about 400 mg / day to about 828 mg / day, from about 450 mg / day to about 828 mg / day, from about 500 mg / day to about 828 mg / day, from about 550 mg / day to about 828 mg / day, from about 600 mg / day to about 828 mg / day, from about 650 mg / day to about 828 mg / day, from about 700 mg / day to about 828 mg / day, or from about 750 mg / day to about 828 mg / day.

[0200] In some embodiments, the amount of Compound A administered is from about 25 mg / day to about 828 mg / day, from about 75 mg / day to about 828 mg / day, from about 100 mg / day to about 828 mg / day, from about 150 mg / day to about 828 mg / day, from about 200 mg / day to about 828 mg / day, from about 250 mg / day to about 828 mg / day, from about 300 mg / day to about 828 mg / day, from about 350 mg / day to about 828 mg / day, from about 400 mg / day to about 828 mg / day, from about 450 mg / day to about 828 mg / day, from about 500 mg / day to about 828 mg / day, from about 550 mg / day to about 828 mg / day, from about 600 mg / day to about 828 mg / day, from about 650 mg / day to about 828 mg / day, from about 700 mg / day to about 828 mg / day, or from about 750 mg / day to about 828 mg / day.

[0201] In some embodiments, the menin-MLL inhibitor is administered at an initial dose, followed by an increasing or decreasing dose.

[0202] In some embodiments, Compound A is administered at an initial dose, followed by an increasing or decreasing dose.

[0203] In some embodiments, the menin-MLL inhibitor is administered TID at an initial dose of about 163 mg, followed by an increase to about 226 mg (TID) or a decrease to 113 mg (TID).

[0204] In some embodiments, Compound A is administered TID at an initial dose of about 163 mg, followed by an increase to about 226 mg (TID) or a decrease to 113 mg (TID).

[0205] In some embodiments, the menin-MLL inhibitor is administered TID at an initial dose of about 163 mg (total daily dose of 489 mg), followed by an increase or decrease according to the dose levels provided in Table A.

[0206] [Table 2]

[0207] In some embodiments, Compound A is administered TID at an initial dose of about 163 mg (total daily dose of 489 mg), followed by an increase or decrease according to the dose levels provided in Table B.

[0208] [Table 3]

[0209] In some embodiments, the amount of Compound A administered is from about 75 mg / day to about 330 mg / day. In some embodiments, the amount of Compound A administered is from about 150 mg / day to about 330 mg / day.

[0210] In some embodiments, the amount of Compound A administered is from about 75 mg / day to about 480 mg / day. In some embodiments, the amount of Compound A administered is from about 150 mg / day to about 480 mg / day. In some embodiments, the amount of Compound A administered is from about 330 mg / day to about 480 mg / day.

[0211] In some embodiments, the amount of Compound A administered is from about 75 mg / day to about 670 mg / day. In some embodiments, the amount of Compound A administered is from about 150 mg / day to about 670 mg / day. In some embodiments, the amount of Compound A administered is from about 330 mg / day to about 670 mg / day. In some embodiments, the amount of Compound A administered is from about 480 mg / day to about 670 mg / day.

[0212] In some embodiments, the amount of Compound A administered is from about 75 mg / day to about 850 mg / day. In some embodiments, the amount of Compound A administered is from about 150 mg / day to about 850 mg / day. In some embodiments, the amount of Compound A administered is from about 330 mg / day to about 850 mg / day. In some embodiments, the amount of Compound A administered is from about 480 mg / day to about 850 mg / day. In some embodiments, the amount of Compound A administered is from about 670 mg / day to about 850 mg / day.

[0213] In some embodiments, the daily dose is divided into multiple administrations and administered once, twice, three times, or four times a day. In some embodiments, the menin-MLL inhibitor is administered once, twice, or three times a day. In some embodiments, the daily dose of the menin-MLL inhibitor is divided into multiple administrations and administered once a day. In some embodiments, the daily dose of the menin-MLL inhibitor is divided into multiple administrations and administered twice a day. In some embodiments, the daily dose of the menin-MLL inhibitor is divided into multiple administrations and administered three times a day.

[0214] In some embodiments, the menin-MLL inhibitor is administered at about 50 mg QD (once daily), about 75 mg QD, about 100 mg QD, about 113 mg QD, about 125 mg QD, about 150 mg QD, about 175 mg QD, about 200 mg QD, about 50 mg q12h, about 75 mg q12h, about 100 mg q12h, about 113 mg q12h, about 125 mg q12h, about 150 mg q12h, about 163 mg q12h, about 175 mg q12h, about 200 mg q12h, about 225 mg q12h, about 226 mg q12h, about 250 mg q12h, about 275 mg q12h, about 300 mg q12h, about 325 mg q12h, about 339 mg q12h, about 350 mg q12h, about 375 mg q12h, about 400 mg q12h, about 425 mg q12h, about 450 mg q12h, about 452 mg q12h, about 475 mg q12h, about 500 mg q12h, about 525 mg q12h, about 550 mg q12h, about 565 mg q12h, about 575 mg q12h, or about 600 mg q12h. In some embodiments, the menin-MLL inhibitor is Compound A and is administered at about 50 mg QD, about 75 mg QD, about 100 mg QD, about 113 mg QD, about 125 mg QD, about 150 mg QD, about 175 mg QD, about 200 mg QD, about 50 mg q12h, about 75 mg q12h, about 100 mg q12h, about 113 mg q12h, about 125 mg q12h, about 150 mg q12h, about 163 mg q12h, about 175 mg q12h, about 200 mg q12h, about 225 mg q12h, about 226 mg q12h, about 250 mg q12h, about 275 mg q12h, about 300 mg q12h, about 325 mg q12h, about 339 mg q12h, about 350 mg q12h, about 375 mg q12h, about 400 mg q12h, about 425 mg q12h, about 450 mg q12h, about 452 mg q12h, about 475 mg q12h, about 500 mg q12h, about 525 mg q12h, about 550 mg q12h, about 565 mg q12h, about 575 mg q12h, or about 600 mg q12h.In some embodiments, the menin-MLL inhibitor is a pharmaceutical formulation comprising Compound A and is administered at about 50 mg QD, about 75 mg QD, about 100 mg QD, about 113 mg QD, about 125 mg QD, about 150 mg QD, about 175 mg QD, about 200 mg QD, about 50 mg q12h, about 75 mg q12h, about 100 mg q12h, about 113 mg q12h, about 125 mg q12h, about 150 mg q12h, about 163 mg q12h, about 175 mg q12h, about 200 mg q12h, about 225 mg q12h, about 226 mg q12h, about 250 mg q12h, about 275 mg q12h, about 300 mg q12h, about 325 mg q12h, about 339 mg q12h, about 350 mg q12h, about 375 mg q12h, about 400 mg q12h, about 425 mg q12h, about 450 mg q12h, about 452 mg q12h, about 475 mg q12h, about 500 mg q12h, about 525 mg q12h, about 550 mg q12h, about 565 mg q12h, about 575 mg q12h, or about 600 mg q12h. In some embodiments, the menin-MLL inhibitor is a capsule comprising Compound A and is administered at about 50 mg QD, about 75 mg QD, about 100 mg QD, about 113 mg QD, about 125 mg QD, about 150 mg QD, about 175 mg QD, about 200 mg QD, about 50 mg q12h, about 75 mg q12h, about 100 mg q12h, about 113 mg q12h, about 125 mg q12h, about 150 mg q12h, about 163 mg q12h, about 175 mg q12h, about 200 mg q12h, about 225 mg q12h, about 226 mg q12h, about 250 mg q12h, about 275 mg q12h, about 300 mg q12h, about 325 mg q12h, about 339 mg q12h, about 350 mg q12h, about 375 mg q12h, about 400 mg q12h, about 425 mg q12h, about 450 mg q12h, about 452 mg q12h, about 475 mg q12h, about 500 mg q12h, about 525 mg q12h, about 550 mg q12h, about 565 mg q12h, about 575 mg q12h, or about 600 mg q12h.

[0215] In some embodiments, the menin-MLL inhibitor is a pharmaceutical formulation comprising Compound B and is administered at about 163 mg q12h. In some embodiments, the menin-MLL inhibitor is a capsule comprising Compound B and is administered at about 163 mg q12h.

[0216] In some embodiments, the menin-MLL inhibitor is administered TID at a dose of about 25 mg, TID at a dose of about 50 mg, TID at a dose of about 75 mg, TID at a dose of about 100 mg, TID at a dose of about 113 mg, TID at a dose of about 125 mg, TID at a dose of about 150 mg, TID at a dose of about 163 mg, TID at a dose of about 175 mg, TID at a dose of about 200 mg, TID at a dose of about 225 mg, TID at a dose of about 226 mg, TID at a dose of about 250 mg, TID at a dose of about 275 mg, TID at a dose of about 276 mg, or TID at a dose of about 300 mg. In some embodiments, the menin-MLL inhibitor is Compound A and is administered TID at a dose of about 25 mg, TID at a dose of about 50 mg, TID at a dose of about 75 mg, TID at a dose of about 100 mg, TID at a dose of about 113 mg, TID at a dose of about 125 mg, TID at a dose of about 150 mg, TID at a dose of about 163 mg, TID at a dose of about 175 mg, TID at a dose of about 200 mg, TID at a dose of about 225 mg, TID at a dose of about 226 mg, TID at a dose of about 250 mg, TID at a dose of about 275 mg, TID at a dose of about 276 mg, or TID at a dose of about 300 mg. In some embodiments, the menin-MLL inhibitor is in a pharmaceutical formulation comprising Compound A and is administered TID at a dose of about 25 mg, TID at a dose of about 50 mg, TID at a dose of about 75 mg, TID at a dose of about 100 mg, TID at a dose of about 113 mg, TID at a dose of about 125 mg, TID at a dose of about 150 mg, TID at a dose of about 163 mg, TID at a dose of about 175 mg, TID at a dose of about 200 mg, TID at a dose of about 225 mg, TID at a dose of about 226 mg, TID at a dose of about 250 mg, TID at a dose of about 275 mg, TID at a dose of about 276 mg, or TID at a dose of about 300 mg.In some embodiments, the Menin-MLL inhibitor is a capsule containing Compound A and is administered TID at a dose of about 25 mg, TID at a dose of about 50 mg, TID at a dose of about 75 mg, TID at a dose of about 100 mg, TID at a dose of about 113 mg, TID at a dose of about 125 mg, TID at a dose of about 150 mg, TID at a dose of about 163 mg, TID at a dose of about 175 mg, TID at a dose of about 200 mg, TID at a dose of about 225 mg, TID at a dose of about 226 mg, TID at a dose of about 250 mg, TID at a dose of about 275 mg, TID at a dose of about 276 mg, or TID at a dose of about 300 mg.

[0217] In some embodiments, the menin-MLL inhibitor is administered TID at a dose of about 25 mg, TID at a dose of about 50 mg, TID at a dose of about 75 mg, TID at a dose of about 100 mg, TID at a dose of about 113 mg, TID at a dose of about 125 mg, TID at a dose of about 150 mg, TID at a dose of about 163 mg, TID at a dose of about 175 mg, TID at a dose of about 200 mg, TID at a dose of about 225 mg, TID at a dose of about 226 mg, TID at a dose of about 250 mg, TID at a dose of about 275 mg, TID at a dose of about 276 mg, or TID at a dose of about 300 mg in the absence of a CYP3A inhibitor. In some embodiments, the menin-MLL inhibitor is Compound A and is administered TID at a dose of about 25 mg, TID at a dose of about 50 mg, TID at a dose of about 75 mg, TID at a dose of about 100 mg, TID at a dose of about 113 mg, TID at a dose of about 125 mg, TID at a dose of about 150 mg, TID at a dose of about 163 mg, TID at a dose of about 175 mg, TID at a dose of about 200 mg, TID at a dose of about 225 mg, TID at a dose of about 226 mg, TID at a dose of about 250 mg, TID at a dose of about 275 mg, TID at a dose of about 276 mg, or TID at a dose of about 300 mg in the absence of a CYP3A inhibitor. In some embodiments, the menin-MLL inhibitor is in a pharmaceutical formulation comprising Compound A and is administered TID at a dose of about 25 mg, TID at a dose of about 50 mg, TID at a dose of about 75 mg, TID at a dose of about 100 mg, TID at a dose of about 113 mg, TID at a dose of about 125 mg, TID at a dose of about 150 mg, TID at a dose of about 163 mg, TID at a dose of about 175 mg, TID at a dose of about 200 mg, TID at a dose of about 225 mg, TID at a dose of about 226 mg, TID at a dose of about 250 mg, TID at a dose of about 275 mg, TID at a dose of about 276 mg, or TID at a dose of about 300 mg in the absence of a CYP3A inhibitor.In some embodiments, the menin-MLL inhibitor is a capsule containing Compound A and is administered TID at a dose of about 25 mg, TID at a dose of about 50 mg, TID at a dose of about 75 mg, TID at a dose of about 100 mg, TID at a dose of about 113 mg, TID at a dose of about 125 mg, TID at a dose of about 150 mg, TID at a dose of about 163 mg, TID at a dose of about 175 mg, TID at a dose of about 200 mg, TID at a dose of about 225 mg, TID at a dose of about 226 mg, TID at a dose of about 250 mg, TID at a dose of about 275 mg, TID at a dose of about 276 mg, or TID at a dose of about 300 mg in the absence of a CYP3A inhibitor.

[0218] In some embodiments, the menin-MLL inhibitor is administered at a dose of about 163 mg every 12 hours. In some embodiments, the menin-MLL inhibitor is Compound B and is administered at a dose of about 163 mg every 12 hours. In some embodiments, the menin-MLL inhibitor is in a pharmaceutical formulation containing Compound B and is administered at a dose of about 163 mg every 12 hours. In some embodiments, the menin-MLL inhibitor is a capsule containing Compound B and is administered at a dose of about 163 mg every 12 hours.

[0219] In some embodiments, the menin-MLL inhibitor is administered at a dose of about 163 mg every 12 hours in the absence of a CYP3A inhibitor. In some embodiments, the menin-MLL inhibitor is Compound B and is administered at a dose of about 163 mg every 12 hours in the absence of a CYP3A inhibitor. In some embodiments, the menin-MLL inhibitor is in a pharmaceutical formulation containing Compound B and is administered at a dose of about 163 mg every 12 hours in the absence of a CYP3A inhibitor. In some embodiments, the menin-MLL inhibitor is a capsule containing Compound B and is administered at a dose of about 163 mg every 12 hours in the absence of a CYP3A inhibitor.

[0220] In some embodiments, the administration is performed more than 6 hours after the previous administration.

[0221] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg every 12 hours, and wherein at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of Compound A from time 0 to 24 hours is about 1,000 ng*h / mL to about 200,000 ng*h / mL, about 1,000 ng*h / mL to about 150,000 ng*h / mL, about 1,000 ng*h / mL to about 100,000 ng*h / mL, about 1,000 ng*h / mL to about 50,000 ng*h / mL, about 1,000 ng*h / mL to about 40,000 ng*h / mL, about 1,000 ng*h / mL to about 30,000 ng*h / mL, about 1,000 ng*h / mL to about 20,000 ng*h / mL, about 1,000 ng*h / mL to about 10,000 ng*h / mL, about 10,000 ng*h / mL to about 200,000 ng*h / mL, about 20,000 ng*h / mL to about 200,000 ng*h / mL, about 30,000 ng*h / mL to about 200,000 ng*h / mL, about 40,000 ng*h / mL to about 200,000 ng*h / mL, about 50,000 ng*h / mL to about 200,000 ng*h / mL, about 60,000 ng*h / mL to about 200,000 ng*h / mL, about 70,000 ng*h / mL to about 200,000 ng*h / mL, about 80,000 ng*h / mL to about 200,000 ng*h / mL, about 90,000 ng*h / mL to about 200,000 ng*h / mL, about 100,000 ng*h / mL to about 200,000 ng*h / mL, about 10,000 ng*h / mL to about 50,000 ng*h / mL, about 10,000 ng*h / mL to about 45,000 ng*h / mL, about 10,000 ng*h / mL to about 40,000 ng*h / mL, about 10,000 ng*h / mL to about 35,000 ng*h / mL, about 10,000 ng*h / mL to about 30,000 ng*h / mL, about 10,000 ng*h / mL to about 25,000 ng*h / mL, about 10,000 ng*h / mL to about 20,000 ng*h / mL, or about 10,000 ng*h / mL to about 15,000 ng*h / mL.

[0222] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of up to about 828 mg / day and, upon administration, the area under the plasma concentration-time curve (AUC (0~24)) is from about 1,000 ng*h / mL to about 200,000 ng*h / mL, from about 1,000 ng*h / mL to about 150,000 ng*h / mL, from about 1,000 ng*h / mL to about 100,000 ng*h / mL, from about 1,000 ng*h / mL to about 50,000 ng*h / mL, from about 1,000 ng*h / mL to about 40,000 ng*h / mL, from about 1,000 ng*h / mL to about 30,000 ng*h / mL, from about 1,000 ng*h / mL to about 20,000 ng*h / mL, from about 1,000 ng*h / mL to about 10,000 ng*h / mL, from about 10,000 ng*h / mL to about 200,000 ng*h / mL, from about 20,000 ng*h / mL to about 200,000 ng*h / mL, from about 30,000 ng*h / mL to about 200,000 ng*h / mL, from about 40,000 ng*h / mL to about 200,000 ng*h / mL, from about 50,000 ng*h / mL to about 200,000 ng*h / mL, from about 60,000 ng*h / mL to about 200,000 ng*h / mL, from about 70,000 ng*h / mL to about 200,000 ng*h / mL, from about 80,000 ng*h / mL to about 200,000 ng*h / mL, from about 90,000 ng*h / mL to about 200,000 ng*h / mL, from about 100,000 ng*h / mL to about 200,000 ng*h / mL, from about 10,000 ng*h / mL to about 50,000 ng*h / mL, from about 10,000 ng*h / mL to about 45,000 ng*h / mL, from about 10,000 ng*h / mL to about 40,000 ng*h / mL, from about 10,000 ng*h / mL to about 35,000 ng*h / mL, from about 10,000 ng*h / mL to about 30,000 ng*h / mL, from about 10,000 ng*h / mL to about 25,000 ng*h / mL, from about 10,000 ng*h / mL to about 20,000 ng*h / mL, or from about 10,000 ng*h / mL to about 15,000 ng*h / mL.

[0223] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor or a menin-MLL inhibitor and a CYP3A4 inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg every 12 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is about 1,000 ng*h / mL to about 200,000 ng*h / mL, about 1,000 ng*h / mL to about 150,000 ng*h / mL, about 1,000 ng*h / mL to about 100,000 ng*h / mL, about 1,000 ng*h / mL to about 50,000 ng*h / mL, about 1,000 ng*h / mL to about 40,000 ng*h / mL, about 1,000 ng*h / mL to about 30,000 ng*h / mL, about 1,000 ng*h / mL to about 20,000 ng*h / mL, about 1,000 ng*h / mL to about 10,000 ng*h / mL, about 10,000 ng*h / mL to about 200,000 ng*h / mL, about 20,000 ng*h / mL to about 200,000 ng*h / mL, about 30,000 ng*h / mL to about 200,000 ng*h / mL, about 40,000 ng*h / mL to about 200,000 ng*h / mL, about 50,000 ng*h / mL to about 200,000 ng*h / mL, about 60,000 ng*h / mL to about 200,000 ng*h / mL, about 70,000 ng*h / mL to about 200,000 ng*h / mL, about 80,000 ng*h / mL to about 200,000 ng*h / mL, about 90,000 ng*h / mL to about 200,000 ng*h / mL, about 100,000 ng*h / mL to about 200,000 ng*h / mL, about 10,000 ng*h / mL to about 50,000 ng*h / mL, about 10,000 ng*h / mL to about 45,000 ng*h / mL, about 10,000 ng*h / mL to about 40,000 ng*h / mL, about 10,000 ng*h / mL to about 35,000 ng*h / mL, about 10,000 ng*h / mL to about 30,000 ng*h / mL, about 10,000 ng*h / mL to about 25,000 ng*h / mL, about 10,000 ng*h / mL to about 20,000 ng*h / mL, or about 10,000 ng*h / mL to about 15,000 ng*h / mL.

[0224] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor or a menin-MLL inhibitor and a CYP3A4 inhibitor, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg / day, and at the time of administration, the area under the plasma concentration-time curve (AUC) of Compound A from time 0 to 24 hours (0~24)) is from about 1,000 ng*h / mL to about 200,000 ng*h / mL, from about 1,000 ng*h / mL to about 150,000 ng*h / mL, from about 1,000 ng*h / mL to about 100,000 ng*h / mL, from about 1,000 ng*h / mL to about 50,000 ng*h / mL, from about 1,000 ng*h / mL to about 40,000 ng*h / mL, from about 1,000 ng*h / mL to about 30,000 ng*h / mL, from about 1,000 ng*h / mL to about 20,000 ng*h / mL, from about 1,000 ng*h / mL to about 10,000 ng*h / mL, from about 10,000 ng*h / mL to about 200,000 ng*h / mL, from about 20,000 ng*h / mL to about 200,000 ng*h / mL, from about 30,000 ng*h / mL to about 200,000 ng*h / mL, from about 40,000 ng*h / mL to about 200,000 ng*h / mL, from about 50,000 ng*h / mL to about 200,000 ng*h / mL, from about 60,000 ng*h / mL to about 200,000 ng*h / mL, from about 70,000 ng*h / mL to about 200,000 ng*h / mL, from about 80,000 ng*h / mL to about 200,000 ng*h / mL, from about 90,000 ng*h / mL to about 200,000 ng*h / mL, from about 100,000 ng*h / mL to about 200,000 ng*h / mL, from about 10,000 ng*h / mL to about 50,000 ng*h / mL, from about 10,000 ng*h / mL to about 45,000 ng*h / mL, from about 10,000 ng*h / mL to about 40,000 ng*h / mL, from about 10,000 ng*h / mL to about 35,000 ng*h / mL, from about 10,000 ng*h / mL to about 30,000 ng*h / mL, from about 10,000 ng*h / mL to about 25,000 ng*h / mL, from about 10,000 ng*h / mL to about 20,000 ng*h / mL, or from about 10,000 ng*h / mL to about 15,000 ng*h / mL.

[0225] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg every 12 hours, and at the time of administration, the minimum observed concentration (Cmin ) is from about 100 ng / mL to about 5,000 ng / mL, from about 100 ng / mL to about 4,000 ng / mL, from about 100 ng / mL to about 3,000 ng / mL, from about 100 ng / mL to about 2,000 ng / mL, from about 100 ng / mL to about 2,000 ng / mL, from about 100 ng / mL to about 1,000 ng / mL, from about 100 ng / mL to about 900 ng / mL, from about 100 ng / mL to about 800 ng / mL, from about 100 ng / mL to about 700 ng / mL, from about 100 ng / mL to about 600 ng / mL, from about 100 ng / mL to about 500 ng / mL, from about 100 ng / mL to about 400 ng / mL, from about 100 ng / mL to about 300 ng / mL, from about 100 ng / mL to about 200 ng / mL, from about 200 ng / mL to about 2,000 ng / mL, from about 200 ng / mL to about 1,000 ng / mL, from about 300,000 ng / mL to about 1,000 ng / mL, from about 300 ng / mL to about 1,000 ng / mL, from about 400 ng / mL to about 1,000 ng / mL, from about 500 ng / mL to about 1,000 ng / mL, from about 600 ng / mL to about 1,000 ng / mL, from about 700 ng / mL to about 1,000 ng / mL, from about 800 ng / mL to about 1,000 ng / mL, from about 900 ng / mL to about 1,000 ng / mL.

[0226] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg / day, and at the time of administration, the minimum observed concentration (C of compound A min) is from about 100 ng / mL to about 5,000 ng / mL, from about 100 ng / mL to about 4,000 ng / mL, from about 100 ng / mL to about 3,000 ng / mL, from about 100 ng / mL to about 2,000 ng / mL, from about 100 ng / mL to about 2,000 ng / mL, from about 100 ng / mL to about 1,000 ng / mL, from about 100 ng / mL to about 900 ng / mL, from about 100 ng / mL to about 800 ng / mL, from about 100 ng / mL to about 700 ng / mL, from about 100 ng / mL to about 600 ng / mL, from about 100 ng / mL to about 500 ng / mL, from about 100 ng / mL to about 400 ng / mL, from about 100 ng / mL to about 300 ng / mL, from about 100 ng / mL to about 200 ng / mL, from about 200 ng / mL to about 2,000 ng / mL, from about 200 ng / mL to about 1,000 ng / mL, from about 300,000 ng / mL to about 1,000 ng / mL, from about 300 ng / mL to about 1,000 ng / mL, from about 400 ng / mL to about 1,000 ng / mL, from about 500 ng / mL to about 1,000 ng / mL, from about 600 ng / mL to about 1,000 ng / mL, from about 700 ng / mL to about 1,000 ng / mL, from about 800 ng / mL to about 1,000 ng / mL, from about 900 ng / mL to about 1,000 ng / mL.

[0227] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor or a menin-MLL inhibitor and a CYP3A4 inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg every 12 hours, and at the time of administration, the minimum observed concentration (C of compound A min) is from about 100 ng / mL to about 5,000 ng / mL, from about 100 ng / mL to about 4,000 ng / mL, from about 100 ng / mL to about 3,000 ng / mL, from about 100 ng / mL to about 2,000 ng / mL, from about 100 ng / mL to about 2,000 ng / mL, from about 100 ng / mL to about 1,000 ng / mL, from about 100 ng / mL to about 900 ng / mL, from about 100 ng / mL to about 800 ng / mL, from about 100 ng / mL to about 700 ng / mL, from about 100 ng / mL to about 600 ng / mL, from about 100 ng / mL to about 500 ng / mL, from about 100 ng / mL to about 400 ng / mL, from about 100 ng / mL to about 300 ng / mL, from about 100 ng / mL to about 200 ng / mL, from about 200 ng / mL to about 2,000 ng / mL, from about 200 ng / mL to about 1,000 ng / mL, from about 300,000 ng / mL to about 1,000 ng / mL, from about 300 ng / mL to about 1,000 ng / mL, from about 400 ng / mL to about 1,000 ng / mL, from about 500 ng / mL to about 1,000 ng / mL, from about 600 ng / mL to about 1,000 ng / mL, from about 700 ng / mL to about 1,000 ng / mL, from about 800 ng / mL to about 1,000 ng / mL, from about 900 ng / mL to about 1,000 ng / mL.

[0228] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor or a menin-MLL inhibitor and a CYP3A4 inhibitor, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg / day and, at the time of administration, the minimum observed concentration (C min) is from about 100 ng / mL to about 5,000 ng / mL, from about 100 ng / mL to about 4,000 ng / mL, from about 100 ng / mL to about 3,000 ng / mL, from about 100 ng / mL to about 2,000 ng / mL, from about 100 ng / mL to about 2,000 ng / mL, from about 100 ng / mL to about 1,000 ng / mL, from about 100 ng / mL to about 900 ng / mL, from about 100 ng / mL to about 800 ng / mL, from about 100 ng / mL to about 700 ng / mL, from about 100 ng / mL to about 600 ng / mL, from about 100 ng / mL to about 500 ng / mL, from about 100 ng / mL to about 400 ng / mL, from about 100 ng / mL to about 300 ng / mL, from about 100 ng / mL to about 200 ng / mL, from about 200 ng / mL to about 2,000 ng / mL, from about 200 ng / mL to about 1,000 ng / mL, from about 300,000 ng / mL to about 1,000 ng / mL, from about 300 ng / mL to about 1,000 ng / mL, from about 400 ng / mL to about 1,000 ng / mL, from about 500 ng / mL to about 1,000 ng / mL, from about 600 ng / mL to about 1,000 ng / mL, from about 700 ng / mL to about 1,000 ng / mL, from about 800 ng / mL to about 1,000 ng / mL, from about 900 ng / mL to about 1,000 ng / mL.

[0229] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg every 12 hours, and at the time of administration, the maximum observed concentration (C of compound A max) is from about 1,000 ng / mL to about 200,000 ng / mL, from about 1,000 ng / mL to about 150,000 ng / mL, from about 1,000 ng / mL to about 100,000 ng / mL, from about 1,000 ng / mL to about 50,000 ng / mL, from about 1,000 ng / mL to about 40,000 ng / mL, from about 1,000 ng / mL to about 30,000 ng / mL, from about 1,000 ng / mL to about 20,000 ng / mL, from about 1,000 ng / mL to about 10,000 ng / mL, from about 10,000 ng / mL to about 200,000 ng / mL, from about 20,000 ng / mL to about 200,000 ng / mL, from about 30,000 ng / mL to about 200,000 ng / mL, from about 40,000 ng / mL to about 200,000 ng / mL, from about 50,000 ng / mL to about 200,000 ng / mL, from about 60,000 ng / mL to about 200,000 ng / mL, from about 70,000 ng / mL to about 200,000 ng / mL, from about 80,000 ng / mL to about 200,000 ng / mL, from about 90,000 ng / mL to about 200,000 ng / mL, from about 100,000 ng / mL to about 200,000 ng / mL, from about 10,000 ng / mL to about 50,000 ng / mL, from about 10,000 ng / mL to about 45,000 ng / mL, from about 10,000 ng / mL to about 40,000 ng / mL, from about 10,000 ng / mL to about 35,000 ng / mL, from about 10,000 ng / mL to about 30,000 ng / mL, from about 10,000 ng / mL to about 25,000 ng / mL, from about 10,000 ng / mL to about 20,000 ng / mL, or from about 10,000 ng / mL to about 15,000 ng / mL.

[0230] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of up to about 828 mg / day, and at the time of administration, the maximum observed concentration (C of compound A max) is from about 1,000 ng / mL to about 200,000 ng / mL, from about 1,000 ng / mL to about 150,000 ng / mL, from about 1,000 ng / mL to about 100,000 ng / mL, from about 1,000 ng / mL to about 50,000 ng / mL, from about 1,000 ng / mL to about 40,000 ng / mL, from about 1,000 ng / mL to about 30,000 ng / mL, from about 1,000 ng / mL to about 20,000 ng / mL, from about 1,000 ng / mL to about 10,000 ng / mL, from about 10,000 ng / mL to about 200,000 ng / mL, from about 20,000 ng / mL to about 200,000 ng / mL, from about 30,000 ng / mL to about 200,000 ng / mL, from about 40,000 ng / mL to about 200,000 ng / mL, from about 50,000 ng / mL to about 200,000 ng / mL, from about 60,000 ng / mL to about 200,000 ng / mL, from about 70,000 ng / mL to about 200,000 ng / mL, from about 80,000 ng / mL to about 200,000 ng / mL, from about 90,000 ng / mL to about 200,000 ng / mL, from about 100,000 ng / mL to about 200,000 ng / mL, from about 10,000 ng / mL to about 50,000 ng / mL, from about 10,000 ng / mL to about 45,000 ng / mL, from about 10,000 ng / mL to about 40,000 ng / mL, from about 10,000 ng / mL to about 35,000 ng / mL, from about 10,000 ng / mL to about 30,000 ng / mL, from about 10,000 ng / mL to about 25,000 ng / mL, from about 10,000 ng / mL to about 20,000 ng / mL, or from about 10,000 ng / mL to about 15,000 ng / mL.

[0231] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor or a menin-MLL inhibitor and a CYP3A4 inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg every 12 hours, and at the time of administration, the maximum observed concentration (C of compound A max) is from about 1,000 ng / mL to about 200,000 ng / mL, from about 1,000 ng / mL to about 150,000 ng / mL, from about 1,000 ng / mL to about 100,000 ng / mL, from about 1,000 ng / mL to about 50,000 ng / mL, from about 1,000 ng / mL to about 40,000 ng / mL, from about 1,000 ng / mL to about 30,000 ng / mL, from about 1,000 ng / mL to about 20,000 ng / mL, from about 1,000 ng / mL to about 10,000 ng / mL, from about 10,000 ng / mL to about 200,000 ng / mL, from about 20,000 ng / mL to about 200,000 ng / mL, from about 30,000 ng / mL to about 200,000 ng / mL, from about 40,000 ng / mL to about 200,000 ng / mL, from about 50,000 ng / mL to about 200,000 ng / mL, from about 60,000 ng / mL to about 200,000 ng / mL, from about 70,000 ng / mL to about 200,000 ng / mL, from about 80,000 ng / mL to about 200,000 ng / mL, from about 90,000 ng / mL to about 200,000 ng / mL, from about 100,000 ng / mL to about 200,000 ng / mL, from about 10,000 ng / mL to about 50,000 ng / mL, from about 10,000 ng / mL to about 45,000 ng / mL, from about 10,000 ng / mL to about 40,000 ng / mL, from about 10,000 ng / mL to about 35,000 ng / mL, from about 10,000 ng / mL to about 30,000 ng / mL, from about 10,000 ng / mL to about 25,000 ng / mL, from about 10,000 ng / mL to about 20,000 ng / mL, or from about 10,000 ng / mL to about 15,000 ng / mL.

[0232] In some embodiments, a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof comprises administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor or a menin-MLL inhibitor and a CYP3A4 inhibitor, wherein the menin-MLL inhibitor is administered at a dosage of up to about 828 mg / day, and at the time of administration, the maximum observed concentration (C of compound A max) is from about 1,000 ng / mL to about 200,000 ng / mL, from about 1,000 ng / mL to about 150,000 ng / mL, from about 1,000 ng / mL to about 100,000 ng / mL, from about 1,000 ng / mL to about 50,000 ng / mL, from about 1,000 ng / mL to about 40,000 ng / mL, from about 1,000 ng / mL to about 30,000 ng / mL, from about 1,000 ng / mL to about 20,000 ng / mL, from about 1,000 ng / mL to about 10,000 ng / mL, from about 10,000 ng / mL to about 200,000 ng / mL, from about 20,000 ng / mL to about 200,000 ng / mL, from about 30,000 ng / mL to about 200,000 ng / mL, from about 40,000 ng / mL to about 200,000 ng / mL, from about 50,000 ng / mL to about 200,000 ng / mL, from about 60,000 ng / mL to about 200,000 ng / mL, from about 70,000 ng / mL to about 200,000 ng / mL, from about 80,000 ng / mL to about 200,000 ng / mL, from about 90,000 ng / mL to about 200,000 ng / mL, from about 100,000 ng / mL to about 200,000 ng / mL, from about 10,000 ng / mL to about 50,000 ng / mL, from about 10,000 ng / mL to about 45,000 ng / mL, from about 10,000 ng / mL to about 40,000 ng / mL, from about 10,000 ng / mL to about 35,000 ng / mL, from about 10,000 ng / mL to about 30,000 ng / mL, from about 10,000 ng / mL to about 25,000 ng / mL, from about 10,000 ng / mL to about 20,000 ng / mL, or from about 10,000 ng / mL to about 15,000 ng / mL.

[0233] In some embodiments, the present disclosure is directed to a method of administering Compound A without a CPY3A inhibitor (e.g., a CYP3A4 inhibitor), yet achieving equivalent Cmax, Cmin, and AUC as achieved by administering with a CPY3A inhibitor (e.g., a CYP3A4 inhibitor). In some embodiments, this method improves patient compliance by reducing the number of agents administered.

[0234] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A is administered at a dose of about 163 mg to about 276 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is about 1,000 ng*h / mL to about 100,000 ng*h / mL.

[0235] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is about 10,000 ng*h / mL to about 60,000 ng*h / mL.

[0236] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is about 14,000 ng*h / mL to about 65,000 ng*h / mL.

[0237] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is from about 17,000 ng*h / mL to about 90,000 ng*h / mL.

[0238] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is about 22,000 ng*h / mL.

[0239] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is about 30,500 ng*h / mL.

[0240] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is about 41,000 ng*h / mL.

[0241] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A is administered at a dose of about 163 mg to about 276 mg every 8 hours, and at the time of administration, the minimum observed concentration (C min ) of compound A is from about 100 ng / mL to about 2,400 ng / mL.

[0242] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the minimum observed concentration (C min ) of compound A is from about 100 ng / mL to about 1,400 ng / mL.

[0243] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the minimum observed concentration (C min ) of compound A is from about 100 ng / mL to about 1,600 ng / mL.

[0244] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the minimum observed concentration (C min ) of compound A is from about 100 ng / mL to about 2,400 ng / mL.

[0245] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the minimum observed concentration (C min ) of compound A is about 400 ng / mL.

[0246] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein the compound A or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising compound A is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the minimum observed concentration (C min ) of compound A is about 500 ng / mL.

[0247] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein the compound A or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising compound A is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the minimum observed concentration (C min ) of compound A is about 800 ng / mL.

[0248] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A is administered at a dose of about 163 mg to about 276 mg every 8 hours, and at the time of administration, the maximum observed concentration (C max ) of compound A is about 1,000 ng / mL to about 6,000 ng / mL.

[0249] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein the compound A or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising compound A is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the maximum observed concentration (C max) is from about 1,000 ng / mL to about 3,400 ng / mL, and the method is targeted.

[0250] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein the compound A or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising compound A is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the maximum observed concentration (C max ) is from about 1,300 ng / mL to about 4,400 ng / mL, and the method is targeted.

[0251] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein the compound A or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising compound A is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the maximum observed concentration (C max ) is from about 1,700 ng / mL to about 5,400 ng / mL, and the method is targeted.

[0252] In some embodiments, the present disclosure is a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein the compound A or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising compound A is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the maximum observed concentration (C max ) is about 1700 ng / mL, and the method is targeted.

[0253] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the maximum observed concentration (C max ) of compound A is about 2400 ng / mL.

[0254] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the maximum observed concentration (C max ) of compound A is about 3,100 ng / mL.

[0255] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A and a CYP3A4 inhibitor, wherein compound A is administered at a dose of about 163 mg every 12 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of compound A from time 0 to 24 hours is about 19,000 ng*h / mL to about 110,000 ng*h / mL.

[0256] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or Compound A and a CYP3A4 inhibitor, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC (0~24) ) of Compound A from time 0 to 24 hours is about 43,000 ng*h / mL.

[0257] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or Compound A and a CYP3A4 inhibitor, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and at the time of administration, the minimum observed concentration (C min ) of Compound A is from about 200 ng / mL to about 2,800 ng / mL.

[0258] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or Compound A and a CYP3A4 inhibitor, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and at the time of administration, the minimum observed concentration (C min ) of Compound A is about 900 ng / mL.

[0259] In some embodiments, the present disclosure provides a method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or Compound A and a CYP3A4 inhibitor, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and at the time of administration, the maximum observed concentration (C max) is from about 1,700 ng / mL to about 6,200 ng / mL. The method is targeted.

[0260] In some embodiments, the present disclosure is a method of treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or Compound A and a CYP3A4 inhibitor, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and at the time of administration, the maximum observed concentration (C max ) is about 3,200 ng / mL. The method is targeted.

[0261] In some aspects, the present disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising a menin-MLL inhibitor at least once a day; and administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once a day, wherein the subject has the following characteristics: (a) Myeloid reserve capacity defined by an absolute neutrophil count (ANC) ≥ 1,500 / μL, platelet count ≥ 100,000 / μL, and hemoglobin ≥ 9 g / dL; (b) Liver function defined by total bilirubin ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN if reasonably attributable to the presence of metastatic disease in the liver); (c) Renal function defined by an estimated glomerular filtration rate ≥ 50 mL / min based on the Cockcroft-Gault formula for adults; (d) Except when the patient is receiving anticoagulant therapy, the international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN, as long as the partial thromboplastin time (PTT) is within the intended therapeutic range of the anticoagulant, meets the coagulation function threshold; (e) Unless the patient is on anticoagulant therapy, activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, and provided that PT or PTT is within the therapeutic range of the intended use of the anticoagulant, and (f) A method is targeted that has at least one of potassium maintained at ≥ 4.0 mEq / L and magnesium ≥ 2.0 mg / dL.

[0262] In some embodiments, the disclosure is a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising Compound A at least once daily, and administering a pharmaceutical composition comprising a CYP3A4 inhibitor at least once daily, wherein the subject has the following characteristics: (a) Myeloid reserve capacity defined by an absolute neutrophil count (ANC) ≥ 1,500 / μL, platelet count ≥ 100,000 / μL, and hemoglobin ≥ 9 g / dL, (b) Liver function defined by total bilirubin ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN if reasonably attributable to the presence of metastatic disease in the liver), (c) Renal function defined by an estimated glomerular filtration rate ≥ 50 mL / min based on the Cockcroft-Gault formula for adults, (d) Unless the patient is on anticoagulant therapy, international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN, provided that PT or partial thromboplastin time (PTT) is within the therapeutic range of the intended use of the anticoagulant, thereby meeting the coagulation function threshold, (e) Unless the patient is on anticoagulant therapy, activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, and provided that PT or PTT is within the therapeutic range of the intended use of the anticoagulant, and (f) A method is targeted that has at least one of potassium maintained at ≥ 4.0 mEq / L and magnesium ≥ 2.0 mg / dL.

[0263] In some embodiments, administration reduces the tumor volume in the subject by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%.

[0264] In some embodiments, administration of the menin-MLL inhibitor contemplated for use in the methods of the present disclosure is known in the art and is described in, at least, for example, WO2017 / 112768, WO2017 / 214367, WO2018 / 053267, WO2020 / 069027, WO2021 / 207335, US2021 / 0115018, US2019 / 0307750, US2016 / 0339035, and Borkin et al. Cancer Cell vol. 27,4 (2015): 589-602, the contents of each of which are incorporated by reference.

[0265] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in unit dosage form. As used herein, unit dosage form refers to physically discrete units suitable as unitary dosages for the subjects to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the unit dosage forms of the present disclosure are determined by and directly depend on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0266] It should be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0267] For the compounds of the present disclosure that can further form salts, it should be understood that all of these forms are also contemplated within the scope of the claimed present disclosure.

[0268] The techniques of formulating and administering the disclosed compounds of the present disclosure can be verified in Remington: The Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

[0269] Unless otherwise indicated, any description of a method of treatment includes the use of a compound for providing treatment or prophylaxis as described herein, and the use of a compound for preparing a medicament for treating or preventing such a condition. Treatment includes the treatment of humans or non-human animals (including rodents and other disease models).

[0270] Throughout the description where a composition is described as having, including, or containing a particular component, it should be understood that the composition is also contemplated as consisting essentially of, or consisting of, the recited components. Similarly, where a method or process is described as having, including, or containing a particular process step, the process is also contemplated as consisting essentially of, or consisting of, the recited process steps. Furthermore, it should be understood that the order of steps or the order for performing certain actions is not important as long as the invention remains operable. Moreover, two or more steps or actions can be performed simultaneously.

[0271] Definitions As used herein, the term "subject" includes humans and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be, for example, a human or a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig, or other suitable non-human mammal. The subject can also be a bird or poultry. In some embodiments, the subject is a human.

[0272] As used herein, the term "subject in need thereof" refers to a subject having a disease or at high risk of developing a disease. The subject in need thereof can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. The subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, the subject in need thereof can be a subject at high risk of developing such a disease or disorder (i.e., a subject having a tendency to develop such a disorder as compared to the population as a whole). The subject in need thereof can be refractory or resistant to a disease or disorder disclosed herein (i.e., the disease or disorder disclosed herein does not respond or has not yet responded to treatment). The subject can be resistant at the start of treatment or can become resistant during treatment. In some embodiments, the subject in need thereof has received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof has received at least one prior treatment.

[0273] As used herein, the term "treating" or "treatment" describes the management and care of a subject for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to reduce the symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treating" can also include the treatment of cell or animal models in vitro.

[0274] As used herein, the terms "preventing", "to prevent", or "protecting from" describe reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0275] As used herein, the term "pharmaceutically acceptable excipient" generally means an excipient that is safe, non-toxic, not biologically undesirable, and useful in the preparation of pharmaceutical compositions containing excipients acceptable for veterinary use as well as for pharmaceutical use in humans. "Pharmaceutically acceptable excipient" as used herein and in the claims includes both one and two or more such excipients.

[0276] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent for treating, ameliorating, or preventing a specified disease or condition or for showing a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject depends on the subject's weight, size, and health status, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0277] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the disclosure are apparent from the different examples. The examples provided show different components and methods useful in the practice of the disclosure. The examples do not limit the claimed disclosure. Based on the disclosure, one of ordinary skill in the art can identify and employ other components and methods useful in practicing the disclosure.

[0278] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form can be in any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps of aerosol inhalers, or vials. The amount of the active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose of the composition is an effective amount and varies according to the particular treatment involved. One of ordinary skill in the art will understand that it may be necessary to routinely vary the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed, under sterile conditions, with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as required.

[0279] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, corresponding to a reasonable benefit / risk ratio.

[0280] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapy treatment. For example, the compounds of the present disclosure may be injected into the bloodstream or body cavity, or may be ingested orally, or may be applied through the skin using a patch. The dosage selected should be sufficient to effect a therapeutic treatment but not so high as to cause unacceptable side effects. The condition of the disease state (e.g., the diseases or disorders disclosed herein) and the health condition of the patient should preferably be closely monitored during and for an appropriate period after treatment.

[0281] Dosage and administration are adjusted to provide a sufficient level of the active agent(s) or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, diet, time and frequency of administration, drug combinations (if any), responsiveness, and tolerance / response to treatment.

[0282] As used herein in the specification and claims, the phrase "and / or" is to be understood to mean "either or both" of the elements so conjoined, i.e., elements that in some instances coexist and in other instances separate. Multiple elements listed with "and / or" are to be construed in the same manner, i.e., as "one or more" of the elements so conjoined. Other elements may optionally exist separately from those specifically identified by the "and / or" clause, whether or not they are related to those specifically identified elements. Thus, by way of non-limiting example, reference to "A and / or B" when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to only A (optionally including elements other than B), in another embodiment, to only B (optionally including elements other than A), and in yet another embodiment, to both A and B (optionally including other elements), and so forth.

[0283] In this specification and the claims, as used herein, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" is inclusive, i.e., it should be construed to include at least one of the elements or items in the list, but also two or more, and optionally, additional unlisted items. Only terms that clearly indicate the opposite intention, such as "only one of" or "exactly one of", or when used in the claims, terms such as "consisting of", refer to the inclusion of exactly one element out of a number of elements or a list of elements. Generally, as used herein, the term "or" should be construed to indicate only exclusive alternatives (i.e., "one or the other but not both") when preceded by exclusive terms such as "either", "only one of", or "exactly one of".

[0284] When used herein in connection with a numerical value or range, terms such as "about" reflect the fact that there is a certain level of variation recognized and tolerated in the art due to practical and / or theoretical limitations. For example, slight variations are tolerated due to the inherent differences in the way a particular device operates and / or measurements are taken. According to the above, the phrase "about" is typically used to encompass values within one standard deviation or standard error.

[0285] In the claims and the above specification, all transitional phrases such as "comprising", "including", "carrying", "having", "containing", "requiring", "holding", "consisting of", etc. are open-ended, i.e., they should be understood to mean including but not limited to the following. As described in Section 2111.03 of the Manual of Patent Examining Procedure of the United States Patent and Trademark Office, only the transitional phrases "consisting of" and "consisting essentially of" are closed or semi-closed transitional phrases, respectively.

[0286] In this specification and the claims, as used herein, with respect to a list of one or more elements, the phrase "at least one" means at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of each and every element specifically recited in the list of elements, and is not to be construed as excluding any combination of elements in the list of elements. This definition also allows for elements to optionally exist in addition to those specifically identified in the list of elements referred to by the phrase "at least one", whether or not they are related to the specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently, "at least one of A and / or B") can, in one embodiment, refer to at least one (optionally including two or more) A, where B is absent (and optionally including elements other than B), in another embodiment, refer to at least one (optionally including two or more) B, where A is absent (and optionally including elements other than A), and in yet another embodiment, refer to at least one (optionally including two or more) A and at least one (optionally including two or more) B (and optionally including other elements), and so on.

[0287] It should also be understood that in a particular method described herein that includes a plurality of steps or acts, the order of the method steps or acts is not necessarily limited to the order in which the method steps or acts are recited, unless the context dictates otherwise.

[0288] All publications and patent documents cited in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended to admit that any is prior art relevant hereto, nor does it constitute any admission as to the content or date thereof. The invention has been described herein by way of written description, but those skilled in the art will recognize that the invention can be practiced in various embodiments and that the foregoing description and the following examples are for illustrative purposes only and are not intended to limit the scope of the following claims.

Example

[0289] The following examples are provided to those skilled in the art to provide a complete disclosure and description of the methods of making and using the invention and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be expected. Standard abbreviations may be used, for example, according to those set forth in Table 2 below.

[0290]

Table 4-1

Table 4-2

[0291] Example 1. Treatment of Colorectal Cancer with Compound A Test Design: This Phase 1 / 2 trial evaluates Compound A in patients with colorectal cancer (CRC) who have failed at least 1 line of prior therapy. This includes a dose escalation and signal finding part (Phase 1a) of Compound A using a Rolling 6 design, and a randomized signal confirmation part (Phase 2) of 2:1 (Compound A: trifluridine / tipiracil (LONSURF®) or Compound A: regorafenib (STIVASIP®)).

[0292] Patients enrolled in the Compound A groups in Phase 1 and Phase 2 receive Compound A continuously, 3 times a day (TID), with food, in 28-day cycles. Patients enrolled in the investigator-selected group in the Phase 2 part of this trial receive either trifluridine / tipiracil (LONSURF®) or regorafenib (STIVARGA®) at the dose and schedule of their respective drug labels.

[0293] Rationale for the trial design The starting dose level and subsequent dose levels are evaluated using a Rolling 6 dose evaluation model (Phase 1a). Doses identified as safe and tolerable are evaluated in a small number of patients for anti-tumor activity in the indication (Phase 1b) prior to initiating the randomized evaluation of Compound A against either LONSURF® or STIVARGA® (Phase 2). The two-step evaluation of anti-tumor activity (Phase 1b and Phase 2) is a means intended to limit exposure of patients to Compound A in the absence of early signs of anti-tumor activity.

[0294] Phase 1 Dose escalation (Phase 1a) The dose escalation part of the trial employs a Rolling 6 trial design. Initially, up to 3 dose levels are evaluated during dose escalation.

[0295] A maximum of 6 patients will be enrolled in a dose cohort. Depending on (1) the number of patients already enrolled in that cohort, (2) the number of patients who experienced dose-limiting toxicity (DLT) at the dose being evaluated in that cohort, and (3) the number of patients enrolled in that cohort for whom tolerability data is pending, 2 - 6 patients can be enrolled in the cohort simultaneously. When 6 cohorts are enrolled or when the study evaluation criteria are met, the escalation is interrupted.

[0296] For example, when 3 participants are enrolled in a dose cohort, toxicity data is available for all 3 when the 4th participant is enrolled. If there is no DLT, the 4th participant is enrolled at the next highest dose level. If data is not yet available for one or more of the first 3 participants and no DLT has been observed, or if 1 DLT has been observed, the new participant is enrolled at the same dose level. Finally, if 2 or more DLTs are observed, the dose level is de-escalated. This process is repeated for participants 5 and 6.

[0297] Patients for whom toxicity cannot be evaluated are replaced by the next available patient if the dose de-escalation rule is not met when the next available patient is enrolled in the study.

[0298] For the dose of Compound A evaluated in Phase 1b, a total of 6 patients had to be treated at the dose of evaluable patients who experienced ≤1 DLT. Based on safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy data, intermediate doses, as well as doses <113 mg (TID) may be explored. The dose is confirmed after consideration of the safety, tolerability, and PK data of patients for whom both DLT and PK are evaluable.

[0299] Signal Exploration (Phase 1b) Once the dosage is confirmed, the signal exploration segment of the first 1b phase of the trial is initiated. Twenty evaluable patients are enrolled at the confirmed dosage level (6 from the first 1a phase and 14 from the first 1b phase), and the antitumor activity of Compound A in CRC patients is investigated by evaluating the disease control rate (DCR) and the overall response rate (ORR). Once all patients have received 6 cycles of the selected dosage of Compound A, the DCR is calculated. (DCR 6 ).

[0300] The first 1b phase has boundaries for both superiority and futility. The superiority boundary is based on the ORR, and the futility boundary is based on the DCR 6 . If the post - hoc probability of ORR > 10% is greater than 70%, the trial proceeds to the second - phase segment. If the superiority boundary is not met (i.e., the post - hoc probability of ORR > 10% is 70% or less), the futility boundary is evaluated. If the post - hoc probability of DCR 6 ≤ 30% exceeds 80%, the trial does not proceed to the second - phase segment. If the post - hoc probability of DCR 6 ≤ 30% is 80% or less, the trial proceeds to the second - phase segment.

[0301] Second phase One hundred and two patients are enrolled in the signal confirmation segment of the second phase of the trial and are randomized 2:1 to either Compound A or LONSURF® or STIVARGA®. The patients' response to treatment is evaluated by blinded radiological examinations, and the patients are followed up for progression - free survival (PFS).

[0302] Purpose and evaluation items of the trial First phase The main purposes of the first phase are as follows: 1) To determine the safety, tolerability, MTD, and RP2D of Compound A in CRC patients, and 2) To evaluate the antitumor effect of Compound A by the assessment of the principal investigator. The secondary purpose of the first phase is to characterize the PK parameters of Compound A. The exploratory purpose of the first phase is to evaluate the antitumor effect of Compound A.

[0303] The primary evaluation items for the first phase include: 1) the occurrence of dose-limiting toxicity (DLT), 2) the frequency, duration, and severity of adverse events (TEAE), treatment-related TEAE (TRAE), and serious adverse events (SAE) occurring during treatment, 3) the occurrence and shift of clinically significant abnormalities in clinical laboratory findings, 4) changes from baseline in other observations related to safety, including electrocardiogram (ECG) and vital signs, 5) DCR 6 , and 6) ORR. The secondary evaluation items include the following PK parameters: maximum plasma concentration (C max ), time to reach maximum plasma concentration (T max ), area under the plasma concentration-time curve from time 0 to t (AUC 0~t ), AUC from time 0 to 24 hours (AUC 0~24 ), apparent oral clearance (CL / F), apparent volume of distribution (Vz / F), and half-life (t 1 / 2 ). The exploratory evaluation items are for evaluating changes in the reduction of circulating tumor DNA via the Guardant360 assay.

[0304] Phase 2 The main objective of Phase 2 is to evaluate the antitumor effect of Compound A by blinded X-ray examination. The secondary objectives include: 1) evaluating short-term and long-term safety, 2) characterizing the PK parameters of Compound A, 3) evaluating overall survival, 4) evaluating the antitumor effect of Compound A by blinded X-ray examination, and 5) evaluating the antitumor effect of Compound A by the assessment of the principal investigator. The exploratory objective is to evaluate the antitumor effect of Compound A.

[0305] The primary evaluation item for Phase 2 is progression-free survival (PFS). The secondary evaluation items for Phase 2 include the following: 1) the frequency, duration, and severity of TEAE, TRAE, and SAE, 2) the occurrence and shift of clinically significant abnormalities in clinical laboratory findings, 3) changes from baseline in other observations related to safety, including ECG and vital signs, 4) maximum plasma concentration (C max ), time to reach maximum plasma concentration ( Tmax) Area under the plasma concentration-time curve (AUC) from time 0 to t (AUC 0~t ) AUC from time 0 to 24 hours (AUC 0~24 ) PK parameters including apparent oral clearance (CL / F), apparent volume of distribution (Vz / F), and half-life (t 1 / 2 ), 5) Overall survival (OS), 6) DCR 6 , 7) Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, and 8) Duration of response (DOR). The evaluation items for the Phase 2 exploration are for evaluating changes in the reduction of circulating tumor DNA via the Guardant360 assay.

[0306] Dose of Compound A and administration of Compound A (administered with food) Dose of Compound A The dosing strategy is intended to maximize AUC and C max while limiting C min . The starting dose of Compound A is 163 mg (TID), with a gradual increase to 226 mg (TID) or a gradual decrease to 113 mg (TID) as needed.

[0307] The rationale for these doses is based on PK data from 53 treated patients in Groups A (without a potent cytochrome P450 CYP3A4 inhibitor) and B (with a potent CYP3A4 inhibitor) of test Compound A analyzed in a preliminary population PK model. The model was a one-compartment PK model with first-order absorption (ka) and lag time (Tlag) describing individual PK data. The data confirmed the expected effect of co-administration of a potent CYP3A4 inhibitor in Group B (for the purpose of reducing side effects) on the drug elimination rate (k) and apparent volume of distribution (Vz / F).

[0308] Using this model, the estimated PK of multiple administrations of Compound A (TID) without a CYP3A4 inhibitor was compared with the estimated PK when 163 mg of Compound A, the recommended Phase 2 dose (RP2D) of the test compound A, was administered every 12 hours (q12h) with a potent CYP3A inhibitor. These data are shown in Figures 2A - C and Table 3A. The starting dose of 163 mg (TID) of Compound A alone was selected because, as shown in Figures 2A - B, C max C min , as shown in Figure 2C, an AUC approximately half that of 163 mg (q12h) and a potent CYP3A4 inhibitor was achieved, and if CRC patients are more sensitive to the effect of Compound A than AML patients, lower exposure provides a safety margin. A dose of 276 mg (TID) is predicted to show exposure similar to that of 163 mg (q12h) and a potent CYP3A inhibitor based on the three main PK parameters (C 0~24 C max C min , and AUC 0~24 ) shown in Figures 2A - C and Table 3A.

[0309]

Table 5

[0310] Administration of Compound A (administered with food) When Compound A is administered TID, it is not practical to administer it consistently under fasting conditions, and considering the available data, it does not appear necessary to administer Compound A under fasting conditions. Furthermore, administering Compound A with food in this study provides information regarding the effect of food.

[0311] The doses of LONSURF (registered trademark) and STIVARGA (registered trademark) are used according to their respective labels incorporated herein by reference.

[0312]

Table 6

[0313]

Table 7

[0314] Definition of the test period and end of the test The "screening period" is up to 21 days before the first dosing of the test intervention. During the "treatment period", the patient can continue to receive Compound A until the disease progresses or until unacceptable toxicity is experienced. The "safety follow-up period" is up to 30 days after the last dose of the test intervention, and if necessary, until resolution or until the principal investigator determines that it is chronic or stable, for any further follow-up of ongoing serious adverse events (SAEs) and / or non-serious adverse events (AEs) considered to be reasonably or potentially related to the investigational medicinal product. "Survival follow-up" is up to 5 years from the end of the safety follow-up period. The "end of the test" is the final contact with the last patient for survival follow-up.

[0315] Number of patients Thirty-two patients were enrolled. In Phase 1a, 6 patients participated in up to 3 dose level cohorts, and in the signal discovery segment of Phase 1b, an additional 14 patients participated at doses considered safe and tolerable in Phase 1a. With a flat prior beta (0.5, 0.5), the sample size of 20 evaluable patients (6 from Phase 1a and 14 from Phase 1b) for signal discovery provides the following operating characteristics based on the specified superiority and futility boundaries: When the true ORR is 20% and 5% respectively, the probability of proceeding to the Phase 2 segment due to superiority in ORR is 79% and 8%, while 6 when the true DCR 6 is 20% and 40% respectively, the probability of not proceeding to the Phase 2 segment due to futility in DCR is 63% and 5%.

[0316] Patients who discontinue treatment before the first post-baseline disease assessment for reasons other than progression, TEAE, or death will be replaced.

[0317] In the second phase, assuming that compound A improves the treatment effect at a PFS of 3 to 5 months (hazard ratio = 0.6) with a randomization ratio of 2:1, 78 PFS events are required to provide 80% power at a one-sided alpha of 0.1. A total of 102 patients are enrolled at 12 months and followed for 4 months for PFS analysis.

[0318] Test intervention administered Patients enrolled in the compound A group in the first phase of the trial and the second phase of the trial receive compound A. Compound A is a small molecule formulated as a capsule (strength 25 mg or 113 mg) or an oral solution. Patients in the compound A groups in the first and second phases receive compound A throughout the trial at a dose and schedule determined by the assigned dose level, continuously in 28-day cycles starting on day 1 of cycle 1. Based on new data, intermediate doses, as well as doses less than 113 mg (TID), may be explored. Administration of compound A continues until receipt of prohibited concomitant medications, occurrence of progressive disease, or unacceptable toxicity. Compound A is administered with food. Patients taking capsules ingest the calculated number of capsules with water. Patients taking the oral solution ingest the calculated volume of solution, followed by a water rinse, both drawn into an oral syringe. Administration should be at least 6 hours after the previous dose.

[0319] Dose of compound A The starting dose of compound A is 163 mg (TID) (total daily dose 489 mg). The starting dose of compound A is increased or decreased gradually according to the dose levels described in Table 5.

[0320]

Table 8

[0321] Chemotherapy Patients enrolled in the chemotherapy group in the second part of the trial receive one of two different chemotherapeutic agents, namely either LONSURF® or STIVARGA®. Dosage, supportive care / hydration, and modifications to dosage follow the product label.

[0322] Administration of Compound A based on serum electrolytes Potassium should be maintained at ≥ 4.0 mEq / L and magnesium should be maintained at ≥ 2.0 mEq / L. For patients with potassium and magnesium levels below these thresholds, oral maintenance supplementation should be initiated and the dosing instructions for Compound A provided should be followed.

[0323] Definition of DLT DLT is defined as any of the following events, which are at least potentially related to the investigational drug, as evaluated by the principal investigator of the trial. The DLT observation period for dose escalation is the first cycle of treatment (28 days).

[0324] "Hematologic toxicity" events include any of the following: 1) Grade 2 (ANC > 1500 cells / mm 3 ) or Grade 4 neutropenia not recovered to baseline (ANC < 500 cells / mm 3 ) for more than 8 consecutive days in the absence of growth factor support, 2) Grade 3 or greater neutropenia (ANC < 1000 cells / mm 3 ) with a single temperature > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour, 3) Grade 4 thrombocytopenia for any period, 4) Grade 3 or greater thrombocytopenia (< 50,000 / mm 3 ) with clinically significant bleeding, or 5) Grade 4 anemia.

[0325] "Non-hematologic toxicity" events include any of the following: 1) Any clinically significant Grade 3 or greater non-hematologic toxicity as defined in CTCAE, version 5.0, or 2) Any Grade 3 QTcF prolongation (mean of triplicate ECGs ≥ 501 ms).

[0326] "General" DLT includes any of the following: 1) Any hematologic or non-hematologic toxicity that results in discontinuation of Compound A for >7 consecutive days, interruption of Compound A, or receipt of <75% of the planned dose intensity, regardless of NCI CTCAE grade, or 2) Any patient who requires a delay of >2 weeks prior to the start of Cycle 2 due to TRAE is considered to have experienced DLT.

[0327] The following events are not considered DLT: 1) Grade 2 allergic reactions that require discontinuation of the investigational drug are not considered DLT and the patient is replaced, or 2) Rapidly progressive diseases that require discontinuation of Compound A during the DLT period are not considered DLT and the patient is replaced.

[0328] Combination therapy with Compound A Record all prior therapies and concomitant medications from 56 days prior to the visit for safety follow-up on Day 1 of Cycle 1 (C1D1) until the visit.

[0329] Prohibited combination therapies and medications with Compound A Radiation therapy is prohibited during the study, and the following medications and treatments are also prohibited during the study: 1) Any over-the-counter drug or investigational CRC therapy other than Compound A, 2) Systemic immunosuppressive therapy (equivalent to ≤10 mg / day of prednisone for patients ≥18 years old or ≤10 mg / m 2 / day for patients <18 years old) excluding glucocorticoids for physiological replacement. Short-term use of glucocorticoids is permitted for the prevention or treatment of allergic reactions and transfusion reactions or complications resulting from other progressive medical conditions, 3) Moderate or strong CYP3A4 inhibitors or inducers shown in Tables 3B and 4, or 4) Drugs known or suspected to prolong the QT interval / QTc other than drugs with a low risk of QT interval / QTc prolongation used as standard supportive therapy (e.g., diphenhydramine, famotidine, ondansetron).

[0330] Any drugs and treatments other than those listed above, including palliative care and supportive care for disease-related symptoms, are permitted during the trial. Patients are closely monitored and, if appropriate, treatment for disease-related symptoms is initiated.

[0331] Antiemetic treatment is used according to the judgment of the guidelines of the American Society of Clinical Oncology or equivalent after recorded nausea or vomiting occurs when the drug has not been used.

[0332] Combination therapy with LONSURF or STIVARGA Patients receiving LONSURF or STIVARGA need to follow their respective USPIs for prohibited and permitted concomitant medications.

[0333] Dose modification For patients who require dose tapering, the step decrease occurs at a single dose level reduction and up to two dose tapering is permitted. Dose tapering below dose level -3 is not permitted and, if necessary, Compound A should be discontinued. An interruption of Compound A for more than 28 days requires consultation before resuming therapy. In Cycle 1, dosing may be withheld but dose tapering cannot be done unless the patient experiences DLT. Patients can start a new cycle only when ANC is ≥1,000 and platelets are ≥50,000. Any non-hematological toxicity clearly attributable to Compound A is graded and managed as outlined in Table 6A. The rules for the management of dose modification for hematological toxicity are outlined in Table 6B. Dose escalation beyond the patient's initial dose assignment is not permitted and no intervention after completion of trial participation is planned.

[0334] Tables 6A and 6B show the changes in the dose of Compound A for toxicity management.

[0335]

Table 9

[0336]

Table 10

[0337] Test population Selection criteria Patients with R / R CRC are enrolled in this trial. Patients who meet all of the following criteria are eligible for this trial.

[0338] Diagnosis Patients with microsatellite stable / proficient mismatch repair (MSS / pMMR) mCRC (which can be detected using immunohistochemistry, polymerase chain reaction, or next-generation sequencing) are measurable on X-ray images according to RECIST v1.1.

[0339] Disease status Evidence of localized recurrent disease or metastatic disease based on an imaging study (e.g., computed tomography [CT], magnetic resonance imaging [MRI]) within 28 days prior to administration of the first investigational drug. At least one measurable lesion of ≧20 mm by conventional techniques or ≧10 mm by spiral CT scan or MRI (the last imaging was performed within 28 days prior to administration of the first investigational drug). If there is only one measurable lesion and it is located within a previously irradiated area, it should show clear progression. Patients must have received at least one line of standard therapy and must be in a progressive / metastatic setting and have progressed on or be refractory to or unable to receive oxaliplatin, irinotecan, and bevacizumab. If the patient has a left-sided primary tumor that is RAS wild-type, the patient must have received anti-EGFR therapy. The patient must have experienced clear progressive disease as recorded by either RECIST v1.1 or clinical evaluation.

[0340] Age Male and female patients must be ≧18 years old.

[0341] Performance level The score of the performance status of the Eastern Cooperative Oncology Group (ECOG) in the United States is 0 to 1.

[0342] Previous treatment If the patient has received radiotherapy, the patient shall have a two-week washout period after the completion of treatment before receiving the first investigational drug, and the patient shall continue to have at least one measurable lesion in accordance with the above criteria. For patients who have received immunotherapy, at least 42 days shall have elapsed since the previous immunotherapy including tumor vaccines and checkpoint inhibitors, and at least 21 days shall have elapsed before receiving chimeric antigen receptor therapy or other modified T cell therapies. At least 7 days or the longer of 5 half-lives shall have elapsed since the completion of treatment with biological agents.

[0343] Appropriate organ function requirements Patients must have a bone marrow reserve capacity defined by an absolute neutrophil count (ANC) ≥ 1,500 / μL, a platelet count ≥ 100,000 / μL, and a hemoglobin ≥ 9 g / dL. Patients must have liver function defined by a total bilirubin ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN if the elevation can be reasonably attributed to the presence of metastatic disease in the liver). Patients must have renal function defined by an estimated glomerular filtration rate ≥ 50 mL / min based on the Cockcroft - Gault formula for adults. Except when the patient is receiving anticoagulant therapy, as long as the PT or partial thromboplastin time (PTT) is within the intended therapeutic range of the anticoagulant, the patient must meet the coagulation function threshold defined by an international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN. Except when the patient is receiving anticoagulant therapy, as long as the PT or PTT is within the intended therapeutic range of the anticoagulant, the patient must have an activated PTT (aPTT) ≤ 1.5 × ULN. Patients must have a potassium maintained at ≥ 4.0 mEq / L and a magnesium ≥ 2.0 mg / dL.

[0344] Contraception Women of childbearing potential must use an effective contraceptive method or a double - barrier method from the time of study registration until the endpoint defined by the registered treatment group. The endpoint for each treatment is defined as 120 days after the final study drug administration of Compound A, 2 months after the final study drug administration of STIVARGA, and at least 6 months after the final study drug administration of LONSURF. Fertile males consent to use a barrier contraceptive method from the time of registration until 120 days after the final dose of the study drug.

[0345] Exclusion Criteria Patients with a known history of HIV 1 / 2 antibodies must undergo a viral load test before trial registration. Patients who met any of the following criteria were not eligible to participate in this trial: 1) having a known high microsatellite instability (MSI-H) CRC, 2) having a history of malignant bowel obstruction requiring hospitalization within 6 months before registration, 3) having a history of poorly controlled ascites defined as symptomatic ascites and / or having repeated paracentesis for symptom control in the past 3 months, 4) having a detectable HIV viral load within the past 6 months, 5) the patient being hepatitis B (defined as hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive, with positive HBV DNA, or HBV positive core antibody (alone) with positive HBV DNA), or 6) the patient being hepatitis C (defined as positive hepatitis C [HCV] antibody with reflexivity to positive HCV RNA).

[0346] Patients could not have any of the following within 6 months before trial registration: myocardial infarction, poorly controlled / unstable angina, congestive heart failure (New York Heart Association classification class ≥ II), life-threatening poorly controlled arrhythmia, cerebrovascular accident, or transient ischemic attack.

[0347] Patients were excluded if they had any GI problems in the upper digestive tract that were likely to affect the absorption or administration of oral medications (e.g., gastric bypass, gastroparesis), or if they had cirrhosis with a Child-Pugh score of B or C.

[0348] Patients were excluded if they had brain metastases (except for patients who had completed definitive treatment), were not receiving steroids, had a stable neurological status for at least 4 weeks after completion of definitive treatment and steroids, and did not have neurological dysfunction that would complicate the assessment of neurological and other AEs. Patients were excluded if they had concurrent conditions, therapies, laboratory findings abnormalities, or allergies to excipients (see formulation details in the investigational drug protocol) that would complicate the results of the trial, interfere with the patient's ability to participate throughout the trial period, or potentially prevent the patient from obtaining the best benefit from participation.

[0349] Patients who had received pre-chemotherapy, targeted small molecule therapy, or radiotherapy within 2 weeks prior to baseline of the trial or had not recovered from AEs related to previously administered agents (i.e., ≤ Grade 1 or baseline) were excluded from the trial.

[0350] Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia were exceptions to this criterion and could be eligible for the trial. If the patient had undergone major surgery, they must have recovered sufficiently from the toxicity and / or complications of the intervention prior to treatment initiation.

[0351] Patients who had received a blood product transfusion (including platelets or red blood cells) or administration of a colony-stimulating factor (including granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 4 weeks of the first administration of the investigational drug were excluded.

[0352] Patients who had an additional known malignancy, either progressive or requiring immediate treatment (except for appropriately treated basal cell carcinoma, cutaneous squamous cell, cervical intraepithelial neoplasia [CIN] / cervical cancer in situ or melanoma in situ or ductal carcinoma in situ of the breast) were excluded. A history of other cancers was acceptable as long as there had been no active disease within the past 5 years.

[0353] To prevent patient exclusion, co - administration of moderate and strong inhibitors or inducers of CYP3A4 should be discontinued at least 7 days before enrollment.

[0354] Patients who participated in another therapeutic - intervention clinical trial in which the investigational drug was administered within 30 days before the start of Compound A were excluded. Patients can continue non - intervention follow - up of the preceding clinical trial.

[0355] Statistical Considerations In Phase 1, there is no formal statistical hypothesis testing. The Phase 2 portion tests the following primary and secondary hypotheses: 1) H a : The hazard ratio for PFS (Compound A vs. control) is less than 1, versus H 0 : The hazard ratio for PFS is 1 or more, 2) H a : The hazard ratio for OS (Compound A vs. control) is less than 1, versus H 0 : The hazard ratio for OS is 1 or more.

[0356] Sample - Size Determination The actual number of patients enrolled in Phase 1 depends on the number of dose levels (if any) at which toxicity is seen and the number of dose levels evaluated in dose escalation. Up to 32 patients are enrolled in Phase 1. In Phase 1a, up to 6 patients participate in each of up to 3 dose - level cohorts, and in the signal - seeking portion of Phase 1b, an additional 14 patients participate at the dose level considered safe and tolerable in Phase 1a.

[0357] With a flat prior beta (0.5, 0.5), the sample size of 20 evaluable patients (6 from Phase 1a and 14 from Phase 1b) for signal - seeking provides the following operating characteristics based on the superiority and futility boundaries.

[0358] When the true ORR is 20% and 5% respectively, the probability of proceeding to the Phase 2 portion due to superiority in ORR is 79% and 8%.

[0359] When the true DCR6 is 20% and 40% respectively, the probabilities of not progressing to the second phase due to futility for DCR6 are 63% and 5%. Patients who had treatment discontinued before the first post-baseline disease assessment for reasons other than progression, TEAE, or death are replaced.

[0360] In the second phase, assuming that Compound A improves the treatment effect at a PFS of 3 to 5 months (hazard ratio = 0.6) with a randomization ratio of 2:1, 78 PFS events are required to provide 80% power at a one-sided alpha of 0.1. A total of 102 patients are enrolled at 12 months and followed for 4 months for PFS analysis.

[0361] Efficacy Analysis In the first phase, the efficacy analysis is conducted in the evaluable population, and this analysis is essentially descriptive and graphical. No formal statistical hypothesis testing is performed. Point estimates and 95% exact binomial confidence intervals for ORR and DCR6 are provided. DOR is summarized using the Kaplan-Meier method.

[0362] In the second phase, the efficacy analysis is based on the ITT population. PFS and OS are tested sequentially. If the treatment effect in PFS is statistically significant, the treatment effect in OS is tested. The log-rank test is used to test the PFS and OS effects. The chi-square test is used to test ORR and DCR6. The populations for analysis are summarized in Table 6C.

[0363]

Table 11

[0364] Statistical Analysis Safety and efficacy analyses are presented by study phase. Where appropriate, summary tables are presented showing the number of observations, mean, standard deviation, median, minimum, and maximum of continuous variables, and the number and percentage per category of categorical data. Time-to-event evaluations are analyzed using the Kaplan-Meier method.

[0365] Patient Disposition The number of patients included in each analysis population is summarized along with any reasons for exclusion. Reasons for discontinuation of study treatment and / or withdrawal from study participation are summarized.

[0366] Demographic and Baseline Characteristics Descriptive summaries of demographic and baseline characteristics are tabulated.

[0367] Exposure The total duration of administration of study treatment and the number of cycles initiated are summarized. For each patient, the relative dose intensity of the investigational drug is calculated. These data are further summarized for all patients at the dose selected for Phase 1b by calculating the mean, standard deviation, median, and range of these values. The number and percentage of patients who had one or more dose modifications (i.e., dose reductions) are tabulated along with the reasons for the modification.

[0368] Efficacy Analysis In Phase 1, efficacy analyses are conducted in evaluable populations and are essentially descriptive and graphical. Point estimates and 95% exact binomial confidence intervals for ORR and DCR6 are provided. DOR is summarized using the Kaplan-Meier method. In Phase 2, efficacy analyses are based on the ITT population. PFS and OS are tested sequentially. If the treatment effect in PFS is statistically significant, the treatment effect in OS is tested. The log-rank test is used to test PFS and OS effects. The chi-square test is used to test ORR and DCR6.

[0369] Safety Analysis All safety analyses are performed on the safety analysis population. Safety evaluations are based on the frequency of AEs, the observation of clinically significant abnormalities in clinical laboratory values, the use of concomitant medications, vital signs, ECG, ECOG performance status, and physical examination data in the safety analysis population.

[0370] AEs are coded and graded using the Standard Medical Dictionary for Regulatory Activities, version 19.0 or higher. The analysis of AEs is based on the principle of occurrence during treatment. An AE occurring during treatment is defined as a sign, symptom, or diagnosis that develops or worsens after administration of the investigational drug. Whenever the analysis or summary of AEs is mentioned, it is intended to refer to TEAEs unless otherwise stated.

[0371] TEAEs are summarized based on the number and percentage of patients experiencing the event by organ system major classification and preferred term. The causal relationship between the occurrence of an AE and the investigational drug (i.e., related, probably related, possibly related, unlikely to be related, and not related) is determined. When a patient experiences repeated episodes of the same AE, the event with the highest severity grade and the strongest causal relationship to the investigational drug is used for the purpose of tabulating the incidence.

[0372] Tabular summaries or listings are provided for 1) all TEAEs, 2) TEAEs by relationship to the investigational drug and highest severity grade, 3) TEAEs for which measures of interruption or dose reduction of the investigational drug were taken, 4) TEAEs for which measures of discontinuation of the investigational drug were taken, 5) particularly notable adverse events (AESIs), and 6) SAEs.

[0373] Hematology and serum chemistry are summarized in a descriptive manner by calculating the mean, standard deviation, median, and range. The directional shift in the test toxicity grade (comparison between the baseline grade and the worst post-baseline grade) is analyzed using a standard shift table, presenting the number and percentage of patients, as well as their maximum grade shift. For analytes without a toxicity grade scale, the shift table indicates the directional shift above or below the test standard normal range from baseline using the maximum increase and / or decrease observed throughout the study. Vital signs are summarized in a descriptive manner by calculating the mean, standard deviation, median, and range in the same manner as described for clinical laboratory values. Frequency statistics are presented for the ECOG performance status.

[0374] Descriptive statistics of the actual values of the ECG and the changes from baseline are tabulated for each time point.

[0375] QTc is calculated using the Fridericia correction (QTcF). The formula is as follows: QTcF = QT / (RR0.33) (where RR = 60 / heart rate (beats / min)). A categorical analysis of the maximum QTcF and the maximum change from baseline is performed by summarizing the number and percentage of patients in each QTcF category (<450 ms, 450 - 480 ms, 481 - 500 ms, and ≥500 ms) and the category of change from baseline (≥30 ms and ≥60 ms).

[0376] Pharmacokinetic analysis The plasma concentration of Compound A is determined using a validated bioanalytical assay. The following PK parameters (where applicable) are calculated using standard non-compartmental methods.

[0377] Whenever possible, the following parameters are calculated for each patient based on the plasma concentration of Compound A (and any relevant metabolites): 1) AUC 0~inf (Area under the plasma concentration-time curve extrapolated from time 0 to infinity, calculated as follows: AUC0~inf =AUC 0~t +(C last ÷λz)(where C last is the last quantifiable concentration and λz is the apparent terminal phase elimination rate constant)), 2) AUC 0~t : (area under the plasma concentration-time curve from time 0 to the last measurable concentration, calculated using the linear trapezoidal formula to increase and decrease the concentration), 3) AUC 0~24 (area under the plasma concentration-time curve from time 0 to 24 hours, estimated to be three times that of AUC 0~t in the case of TID dosing), 4) C max (maximum observed concentration), 5) T max (time to maximum observed concentration), 6) t 1 / 2 (apparent terminal phase elimination half-life (if possible), where t 1 / 2 = ln(2) / λz), 7) CL / F (apparent oral clearance), and 8) Vz / F: apparent volume of distribution in the terminal phase. Summarize the plasma concentration and PK parameter summary statistics as needed. Summarize the PK parameters for each dose.

[0378] Adverse event An AE is any adverse medical event in a patient or clinical trial participant that is temporally associated with the use of an investigational medicinal product, whether or not it is considered related to the medicinal product under investigation. Events that meet the definition of an AE may include: 1) Abnormalities in the results of laboratory findings (blood tests, clinical chemistry, or urinalysis) or other safety evaluations (e.g., ECG, radiological scans, vital sign measurements) that are considered clinically significant in medical and scientific judgment (however, in other words, not related to the progression of the underlying disease), including those that have deteriorated from baseline; 2) Worsening of an existing chronic or intermittent condition, including an increase in either the frequency and / or intensity of the condition; 3) A new condition that is detected or diagnosed after the administration of the investigational medicinal product, even if it may have been present prior to the start of the trial; 4) Signs, symptoms, or clinical sequelae of a suspected drug interaction; 5) Signs, symptoms, or clinical sequelae of an overdose of either the suspected investigational medicinal product or concomitant medication. Overdose itself is not reported as an AE / SAE, unless it is an intentional overdose with the potential for suicidal / self-harm intent. Such an overdose should be reported regardless of sequelae, or 6) "Lack of efficacy" or "failure of an expected pharmacological effect" is not reported as an AE or SAE. Such examples are incorporated into the efficacy evaluation. However, signs, symptoms, and / or clinical sequelae resulting from lack of efficacy are reported as an AE or SAE if they meet the definition of an AE or SAE. Events that do not meet the definition of an AE may include: 1) Any clinically significant abnormalities in laboratory findings or other safety evaluations related to the underlying disease, unless determined by the trial physician to be more severe than expected for the participant's condition; 2) The disease / disorder under investigation or its progression, signs, or symptoms, unless more severe than expected for the participant's condition; 3) Medical or surgical procedures (e.g., endoscopy, appendectomy): The condition resulting from the procedure is an AE; 4) Situations where no adverse medical event occurred (social and / or convenience hospitalization) or 5) Expected daily fluctuations of existing disease(s).

[0379] If an event is not an AE according to the above definition, even if severe criteria (e.g., hospitalization due to signs / symptoms of the disease during the trial, death due to disease progression) are met, it cannot be considered an SAE. An SAE, regardless of the dose, is defined as any adverse medical event where: 1) death occurs; 2) the event is life-threatening (the term "life-threatening" in the definition of severe refers to an event where there was a risk of the participant dying at the time of the event. This does not refer to an event that hypothetically could have caused death if it had been more severe); 3) hospitalization of the participant or an extension of an existing hospitalization is required (generally, hospitalization means that the participant was confined to a hospital or emergency department for observation and / or treatment that is not appropriate in a clinic or outpatient setting (usually requiring at least one overnight stay)). Complications that occur during hospitalization are AEs. If the complication extends the hospitalization or meets any other severe criterion, the event is severe. If it is unclear whether "hospitalization" occurred or was required, the AE should be considered severe. Hospitalizations for PD, events caused by PD, and elective treatment of existing conditions that did not worsen from baseline are not considered AEs); 4) the event results in a persistent disability / incapacity (the term "disability" means a substantial interference with the ability of an individual to perform normal life functions. This definition is not intended to include relatively minor medically significant experiences such as headaches, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., ankle sprain) that may interfere with or disrupt daily life functions but do not cause substantial disruption or complications); or 5) it is a congenital anomaly / birth defect. Other situations may include: important medical events that do not immediately threaten life or lead to death or hospitalization but may put the participant at risk or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. In other situations, a medical or scientific judgment should be made to determine whether SAE reporting is appropriate. These events should generally be considered severe.Examples of such events include invasive or malignant cancer, emergency room or home intensive treatment for allergic bronchial convulsions, blood diseases or convulsions that do not require hospitalization, or the onset of drug dependence or drug abuse.

[0380] Prolonged QTc An increase in QTcF of CTCAE grade 2 or higher (average of triplicate ECG) is classified as an AESI. Prolonged QTc was observed in dogs treated with Compound A. Common supportive medications used in cancer patients can also cause QT interval prolongation, such as fluoroquinolones, azole antifungals, and 5-HT3 antagonists (see Section 6.6.1 for prohibited combinations). Patients may be at risk of QT interval prolongation if such treatments are combined. It is recommended to obtain an ECG before and after the start of any new drug therapy, and after dose escalation of concomitant medications known to prolong QTc in patients presenting with vomiting and / or diarrhea.

[0381] For any QTcF prolongation of ≧481 ms, treatment should be withheld. QTc is calculated using the Fridericia correction, and the reported QTcF is the average of three separate values from the patient's sequential ECGs. Further management is guided by the degree of prolongation. Address any underlying causes of other QT prolongations, including identification and discontinuation of other precipitating medications and aggressive correction of electrolyte abnormalities. The causal relationship with Compound A should be evaluated in the context of concomitant medications and electrolyte imbalances.

[0382] Assessment of intensity The intensity of TEAE is determined according to the NCI CTCAE, version 5.0. TEAEs not listed in the NCI CTCAE are reported during the trial and evaluated according to the intensity of each AE and SAE assigned to one of the following categories: 1) Grade 1 (mild): asymptomatic or mild symptoms, clinical or diagnostic observations only, no indication for intervention; 2) Grade 2 (moderate): minimal, local, or non-invasive intervention indicated, limitation of instrumental activities of daily living appropriate for age; 3) Grade 3 (severe or medically significant but not immediately life-threatening): indication for hospitalization or prolongation of hospitalization, inability to carry out anything, limitation of self-care activities of daily living; 4) Grade 4 (life-threatening outcome): indication for urgent intervention; 5) Grade 5: death related to the AE. An event is defined as serious if it meets at least one of the predefined outcomes described in the definition of SAE and is not evaluated as severe.

[0383] Assessment of Causality The relationship between the investigational drug and each occurrence of each AE / SAE is evaluated. The relationship is determined using clinical judgment. A "reasonable possibility" of a relationship conveys that there are facts, evidence, and / or arguments suggesting a causal relationship and that the relationship cannot be excluded. Alternative causes such as underlying disease(s), concomitant therapy, and other risk factors, as well as the temporal relationship between the event and the administration of the investigational drug, are examined and investigated. For each AE / SAE, the review of the AE / SAE and the assessment of causality are recorded. The assessment of causality is one of the criteria used in determining reporting requirements to regulatory authorities.

[0384] Genetic Nature Genetic variations may affect the response of participants to investigational drugs, susceptibility to diseases, as well as the severity and progression of diseases. Variable responses to investigational drugs may be due to genetic determinants that affect drug absorption, distribution, metabolism, and excretion, the mechanism of action of the drug, disease etiology, and / or the molecular subtypes of the diseases being treated. Tissue samples are taken for mutation status. Genetic studies can consist of the analysis of one or more candidate genes or, as appropriate, the analysis of gene markers across the entire genome. Tumor tissue is analyzed for mutation status. If it is hypothesized that this can help in the further understanding of clinical data, additional analyses may be performed. Samples can be analyzed as part of a multiplex test assessment of genetic factors involved in the response to Compound A or investigational drugs of this class to understand the test disease or related conditions.

[0385] Benefit-Risk Assessment The off-target screening assay did not show cross-reactivity of Compound A against >125 molecular targets, so treatment-related adverse events (TRAEs) are expected to be due to on-target effects. The main potential target organs of toxicity identified in 28-day rat and dog toxicity studies conducted in accordance with extremely important Good Laboratory Practice were the heart (ECG changes in dogs), eyes (cataracts in rats only), liver, bone marrow, lymphoid tissue, male genital system, and female genital system.

[0386] Safety measures are implemented to monitor these effects and protect patients from them. Patients receive regular ECG evaluations throughout the trial. Liver function and endocrine function are evaluated regularly and frequently. Conservative drug retention and modification parameters are clearly outlined for events of QT prolongation or elevated liver enzymes.

[0387] Evaluation and Procedures of the Trial Efficacy Evaluation For tumor measurement, all sites of disease, target, and non-target lesions are evaluated at baseline. The objective disease status is recorded at each evaluation. The same evaluation methods and the same techniques used for the test screening (CT scan or MRI) are used for each subsequent post-screening evaluation to characterize each lesion. Table 7 shows the disease response criteria for target and non-target lesions.

[0388] All patients in this study had measurable disease recorded radiographically within 28 days prior to the start of treatment with the investigational drug, which was defined as at least one measurable lesion with the following characteristics: 1) longest diameter ≥ 10 mm on axial images by CT scan or MRI with a reconstruction interval ≤ 5 mm. If the slice thickness is ≤ 5 mm, the longest diameter must be at least twice that thickness, 2) longest diameter ≤ 20 mm by chest X-ray (clearly defined and surrounded by aerated lung), CT is preferred even without contrast, or 3) lymph node ≥ 15 mm on the short axis on CT scan (CT slice thickness ≤ 5 mm). If there is only one measurable lesion and it is located in a previously irradiated area, progression had to be demonstrated according to RECIST v1.1.

[0389] The following are considered non-measurable lesions and are included: 1) mass < 10 mm, 2) lymph node 10 - 14 mm on the short axis, 3) leptomeningeal disease, 4) ascites, pleural or pericardial effusion, 5) lymphatic infiltration of the skin or lung, 6) peritonitis (abdominal mases) or organomegaly identified by physical examination that cannot be measured by reproducible imaging techniques, 7) blastemic bone lesions, and 8) should not include both benign and indeterminate ("not excluded") findings.

[0390] Target lesions vs. non-target lesions Lesions are characterized as either "target" or "non-target". All measurable lesions are a maximum of two lesions per organ and a total of five lesions (representing all lesioned organs), which are identified as "target" lesions and measured and recorded at screening. Target lesions are selected based on their size (i.e., size by longest diameter) and suitability for accurate repeated measurements. The sum of the diameters of all target lesions is calculated and recorded as the baseline total diameter. All other lesions not classified as target lesions (or disease sites) are identified as "non-target" lesions.

[0391] Scanning Procedure Contrast-enhanced CT scans of the chest, abdomen, and clinically indicated pelvis are preferred for the assessment of the disease state, but if the patient has an allergy to or develops an allergy to iodine contrast agents, contrast-enhanced MRI can be performed. Positron emission tomography (PET) alone is not permitted as part of the imaging performed for this trial. When PET is performed, PET alone should not be the basis for withdrawal of a patient from the trial because of the potential for false positives. The progression of PET must be confirmed by CT / MRI. If a combined 18F-fluorodeoxyglucose (FDG) PET-CT scan is performed, the CT portion of that examination should not be replaced by a dedicated CT examination for tumor measurement unless the CT performed as part of the FDG PET-CT is documented to be of the same diagnostic quality as a diagnostic CT using intravenous (IV) and oral contrast agents.

[0392] CT Scanning Procedure CT scans are acquired and submitted using consistent scan parameters (spacing, thickness, field of view, etc.) for all evaluations, along with a description of alternative imaging or parameter variations. If a patient develops an allergy to iodinated contrast agents during the test, performing a chest CT scan without contrast is permitted and a contrast-enhanced MRI scan as described herein must be performed on the remaining necessary anatomical structures. To adequately opacify the bowel, an oral contrast agent (either a positive [e.g., barium or Gastrografin] or negative [e.g., water or saline] contrast agent according to the standard of care for the site) should be administered to the patient prior to the examination. A non-ionic iodine IV contrast agent with a minimum of 320 mg iodine / mL should be used and the volume of the contrast agent should follow the package insert. The same contrast agent at the same concentration is used.

[0393] MRI Scanning Procedures If an IV contrast agent is medically contraindicated during the test, dynamic contrast-enhanced MRI is an acceptable alternative to CT scans of the abdomen and pelvis. MRI must be performed using either a 1.5T or 3.0T scanner. For an individual patient during the test, a change in the electric field strength of the scanner is not permitted (e.g., if a patient undergoes a C2 MRI scan at 3.0T, all subsequent scans must be performed at 3.0T). MRI scans should be performed using optimized parameters to reduce motion artifacts and maximize the signal-to-noise ratio and resolution. Breath-hold imaging, fast-scanning techniques, and gadolinium should be used to best utilize lesion characterization. Non-contrast CT scans of the chest or digital chest x-rays must be acquired in addition to MRI of the abdomen and pelvis as needed. Patients must be scanned only with an approved extracellular contrast agent (e.g., Magnevist, Dataram, Omniscan). For all examinations acquired for a given patient during the course of this study, both pre- and post-contrast, the same equipment, electric field strength, sequence, scan parameters, positioning, angulation, timing, field of view, and slice thickness should be utilized.

[0394] Evaluation of disease response Evaluate the disease and assess disease response every 8 weeks. In Phase 1 and Phase 2, the response is evaluated, and in Phase 2, the evaluation is confirmed by blinded X-ray examination. Partial or complete response is confirmed by repeated tumor imaging evaluation more than 4 weeks after the day when the response was first recorded. Tumor imaging for confirmation of response may be performed 4 weeks after the earliest time point when the first indication of response is shown at the earliest time point of the first indication of response, or at any clinically indicated time point of the next scheduled scan (i.e., 8 weeks later). If clinically stable, participants should not be discontinued until progression is confirmed.

[0395]

Table 12

[0396] Tumor tissue In the case of patients where the lesion accessible only for biopsy is an isolated target lesion, it should be suitable for core biopsy without compromising the evaluation of tumor measurement. If the patient has only one measurable lesion, the biopsy specimen should be obtained from a non-target lesion, and the lesion should not be within the pre-irradiated area unless progression of the lesion is confirmed.

[0397] ctDNA Analyze the samples taken at screening and during treatment for the topography of mutations and evaluate the changes in circulating tumor DNA (ctDNA) levels for their association with antitumor effect.

[0398] Medical history including cancer history, and genotyping The complete medical history is recorded during screening and updated at baseline prior to administration of the first compound A. The medical history includes the patient's primary diagnosis, date of diagnosis, method of diagnosis, and all prior treatments including radiation therapy, as well as the CRC history including response to said treatments. As part of the patient's cancer history, the study center submits, if available, a local histology or cytology report obtained prior to enrollment. Record the HIV history. Record the mutation status from archival tests. Archival flow cytometry reports are requested from and collected by the patient's local institution if possible.

[0399] Physical examination At screening and at each visit for safety follow-up, a detailed physical examination is performed on all patients. The detailed physical examination includes a general physical appearance, head / ear / eye / nose / throat, lung / chest, heart, abdomen, lymph nodes, musculoskeletal, extremities, and neurological examinations.

[0400] Electrocardiogram All ECGs are performed in three parts, each separated by two minutes. If necessary, QTc is calculated using Fridericia correction (QTcF). The average of three ECGs is used to calculate QTcF. If a patient experiences a QTcF prolongation of ≥ Grade 2, clinical chemistry samples (for magnesium, potassium, and calcium) are obtained, and for a QTcF prolongation of ≥ Grade 3 (based on the average of triplicate ECGs), a single simultaneous PK sample is obtained as soon as possible and the time of the last dose of the investigational drug is recorded.

[0401] Patients experiencing vomiting or diarrhea are recommended to have their electrolytes checked and to have more frequent ECGs. ECGs should be obtained before and after the start of any new dosing, and after dose escalation of concomitant medications known to prolong QTc.

[0402] All collected ECGs should initially be read locally to enable real-time treatment decisions.

[0403] Period and frequency for collecting AE and SAE information All AEs, including SAEs, are collected from the time of informed consent until the hospital visit for safety follow-up 30 days after the last administration of Compound A. Medical events that begin before Compound A but after informed consent is obtained are recorded.

[0404] All SAEs are recorded and reported. At any time after a participant withdraws from the study, any SAE, including death related to the investigational drug or study participation, is reported.

[0405] Pharmacokinetics of Compound A Blood samples are taken for measurement of the plasma concentration (PK) of Compound A. The blood samples are centrifuged to prepare plasma. Samples taken for analysis of the concentration of Compound A can also be used to evaluate aspects of safety or efficacy related to concerns that arise during or after the study.

[0406] Survival follow-up All patients receive contact for survival follow-up: This is done monthly for 11 months after the hospital visit for safety follow-up, after which the frequency is changed to every 3 months. The follow-up dates are recorded. Patient status is collected until the patient becomes untraceable, until consent is withdrawn, or until death. The date of death is recorded. Additionally, any new cancer treatment initiated by the patient after the end of the study treatment is recorded.

[0407] End of study When a patient's participation in the study ends, the end date of the study and the reason are recorded.

[0408] Equivalents Details of one or more embodiments of the present disclosure are set forth in the foregoing accompanying description. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from this specification and the claims. In this specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0409] The foregoing description is presented for purposes of illustration only and is not intended to limit the disclosure to the precise form disclosed. The disclosure is limited only by the claims appended hereto.

Claims

**Claim 1** A method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering to the subject a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor. **Claim 2** A method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition consisting essentially of a menin-MLL inhibitor. **Claim 3** A method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method consisting essentially of administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor. **Claim 4** A method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering to the subject a single anti-cancer agent, wherein the single anti-cancer agent is a menin-MLL inhibitor. **Claim 5** The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is Compound A, Compound B, DSP-5336, DS-1594, KO-539, MI-503, MI-3454, MI-463, M-808, MI-136, JNJ-75276617, MI-227, BMF-219, Antibody A300-105A, MI-0202, MI-503, MI-463, MI-136, ML-227, MI-2-2, or ISC-30. **Claim 6** The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is Compound A or Compound B. **Claim 7** The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is Compound A. **Claim 8** The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered at least once a day. **Claim 9** The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered twice a day. **Claim 10** The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered three times a day. **Claim 11** The method according to any one of the preceding claims, further comprising administering a CYP3A inhibitor. **Claim 12** The method according to any one of the preceding claims, further comprising administering a CYP3A4 inhibitor. **Claim 13** The method according to claim 12, wherein the CYP3A4 inhibitor is a potent CYP3A4 inhibitor.

14. The method according to claim 13, wherein the potent CYP3A4 inhibitor is boceprevir, cobicistat, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole.

15. The method according to any one of claims 1 to 10, further comprising administering cobicistat.

16. The method according to any one of claims 1 to 10, further comprising administering cobicistat at least once a day.

17. The method according to any one of claims 1 to 10, further comprising administering cobicistat once a day.

18. The method according to claim 12, wherein the CYP3A4 inhibitor is a moderate CYP3A4 inhibitor.

19. The method according to claim 18, wherein the moderate CYP3A4 inhibitor is amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, or verapamil.

20. The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg every 12 hours.

21. The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered at a dosage of about 163 mg every 12 hours.

22. The method according to any one of claims 1 to 10, wherein the subject does not receive a CYP3A inhibitor.

23. The method according to any one of claims 1 to 10, wherein the pharmaceutical composition does not contain a CYP3A inhibitor.

24. The method according to claim 22 or 23, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg.

25. The method according to claim 22 or 23, wherein the menin-MLL inhibitor is administered at a dosage of about 25 mg to about 276 mg, and wherein the menin-MLL inhibitor is administered three times a day.

26. The method according to claim 22 or 23, wherein the menin-MLL inhibitor is administered at a dosage of about 276 mg.

27. The method according to any one of claims 22 or 23, wherein the menin-MLL inhibitor is administered at a dose of about 276 mg, wherein the menin-MLL inhibitor is administered three times a day.

28. The method according to any one of claims 1 to 19, 22 to 25, and 27, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg / day.

29. The method according to any one of the preceding claims, wherein the menin inhibitor is contained in a capsule or an oral liquid.

30. The method according to any one of the preceding claims, wherein the subject has previously received at least one line of prior treatment for colorectal cancer.

31. The method according to any one of the preceding claims, wherein the subject has previously received at least one line of prior treatment for colorectal cancer, but the subject did not respond to the prior treatment.

32. The method according to any one of claims 30 or 31, wherein the at least one line of prior treatment was chemotherapy, radiotherapy, immunotherapy, targeted small molecule therapy, or biological therapy (e.g., monoclonal antibody therapy).

33. The method according to any one of the preceding claims, wherein the subject has previously received treatment for colorectal cancer selected from trifluridine, tipiracil, and / or regorafenib.

34. The method according to any one of the preceding claims, wherein the subject has previously received trifluridine, tipiracil, or a combination thereof.

35. The method according to any one of the preceding claims, wherein the subject has previously received regorafenib.

36. The method according to any one of the preceding claims, wherein the subject progressed on at least one line of prior treatment for colorectal cancer.

37. The method according to any one of the preceding claims, wherein the subject is being treated for microsatellite stability / proficient mismatch repair (MSS / pMMR) mCRC.

38. The method according to any one of the preceding claims, wherein the subject has not received an EGFR inhibitor.

39. A method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, administering a pharmaceutical composition comprising Compound A at least once a day, administering a pharmaceutical composition comprising cobimetinib at least once a day, and the subject has not received an EGFR inhibitor.

40. A method for treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, comprising administering Compound A three times a day at a dose of 150 mg to 200 mg, wherein the subject has not received a CYP3A inhibitor and an EGFR inhibitor.

41. The method according to any one of the preceding claims, wherein the colorectal cancer is characterized by dysregulation of the WNT / β-catenin signaling pathway.

42. The method according to any one of the preceding claims, wherein the subject has developed resistance to a prior treatment for colorectal cancer and has progressed on a prior treatment for colorectal cancer.

43. A method for treating, preventing, or reducing the severity of cancer in a subject, comprising administering a pharmaceutical composition comprising Compound A, comprising administering about 220 to about 280 mg of Compound A three times a day, wherein the subject does not receive a CYP3A inhibitor.

44. The method according to claim 43, wherein the cancer is leukemia.

45. The method according to claim 44, wherein the cancer is AML leukemia.

46. The method according to claim 44, wherein the cancer is acute lymphoblastic leukemia.

47. The method according to claim 44, wherein the cancer is NMP1-mutant leukemia.

48. The method according to claim 43, wherein the cancer is colorectal cancer.

49. The method according to claim 43, wherein the cancer is microsatellite stable / proficient mismatch repair (MSS / pMMR) mCRC.

50. The method according to any one of claims 43 to 49, wherein the menin-MLL inhibitor is administered at a dose of about 270 mg to about 280 mg.

51. The method according to any one of claims 43 to 50, wherein the menin-MLL inhibitor is administered three times a day.

52. The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered with food.

53. Use of a menin-MLL inhibitor for the preparation of a medicament for the treatment of colorectal cancer by the method according to any one of the preceding claims, wherein the medicament and / or treatment does not require the use of an EGFR inhibitor.

54. Use of a menin-MLL inhibitor for the preparation of a medicament for the treatment of colorectal cancer by the method according to any one of the preceding claims, wherein the medicament does not contain an EGFR inhibitor.

55. A kit comprising a menin-MLL inhibitor and a printed instruction manual for using the menin-MLL inhibitor in a subject for the treatment of colorectal cancer.

56. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt, or a pharmaceutical composition comprising compound A, wherein compound A is administered at a dose of about 163 mg to about 276 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） ) is from about 1,000 ng*h / mL to about 100,000 ng*h / mL.

57. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） ) from time 0 to 24 hours of Compound A is from about 10,000 ng*h / mL to about 60,000 ng*h / mL, the method according to claim 56.

58. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） ) from time 0 to 24 hours of Compound A is from about 14,000 ng*h / mL to about 65,000 ng*h / mL, the method according to claim 56.

59. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） ) is from about 17,000 ng*h / mL to about 90,000 ng*h / mL, the method according to claim 56.

60. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） ) from time 0 to 24 hours of Compound A is about 22,000 ng*h / mL, the method according to claim 56.

61. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） ) from time 0 to 24 hours of Compound A is about 30,500 ng*h / mL, the method according to claim 56.

62. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） ) from time 0 to 24 hours of Compound A is about 41,000 ng*h / mL, the method according to claim 56.

63. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A is administered at a dosage of about 163 mg to about 276 mg every 8 hours, and at the time of administration, the minimum observed concentration (C ｍｉｎ ) is from about 100 ng / mL to about 2,400 ng / mL.

64. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the minimum observed concentration (C ｍｉｎ ) is from about 100 ng / mL to about 1,400 ng / mL, the method according to claim 63.

65. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the minimum observed concentration (C ｍｉｎ ) is from about 100 ng / mL to about 1,600 ng / mL, the method according to claim 63.

66. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the minimum observed concentration (C ｍｉｎ ) is from about 100 ng / mL to about 2,400 ng / mL, the method according to claim 63.

67. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the minimum observed concentration (C ｍｉｎ ) is about 400 ng / mL, the method according to claim 63.

68. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the minimum observed concentration (C ｍｉｎ ) is about 500 ng / mL, the method according to claim 63.

69. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the minimum observed concentration (C ｍｉｎ ) is about 800 ng / mL, the method according to claim 63.

70. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A, wherein compound A is administered at a dosage of about 163 mg to about 276 mg every 8 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) of compound A is from about 1,000 ng / mL to about 6,000 ng / mL.

71. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) is from about 1,000 ng / mL to about 3,400 ng / mL, the method according to claim 70.

72. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) is from about 1,300 ng / mL to about 4,400 ng / mL, the method according to claim 70.

73. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) is from about 1,700 ng / mL to about 5,400 ng / mL, the method according to claim 70.

74. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 163 mg every 8 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) is about 1700 ng / mL, the method according to claim 70.

75. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 226 mg every 8 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) is about 2400 ng / mL, the method according to claim 70.

76. Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, is administered at a dose of about 276 mg every 8 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) is about 3,100 ng / mL, the method according to claim 70.

77. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or Compound A and a CYP3A4 inhibitor, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） from time 0 to 24 hours) of Compound A is from about 19,000 ng*h / mL to about 110,000 ng*h / mL.

78. Compound A is administered at a dosage of about 163 mg every 12 hours, and at the time of administration, the area under the plasma concentration-time curve (AUC （０～２４） ) for compound A from time 0 to 24 hours is about 43,000 ng*h / mL, the method according to claim 77.

79. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or Compound A and a CYP3A4 inhibitor, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and the minimum observed concentration (C ｍｉｎ ) of Compound A at the time of administration is from about 200 ng / mL to about 2,800 ng / mL.

80. Compound A is administered at a dosage of about 163 mg every 12 hours, and at the time of administration, the minimum observed concentration (C ｍｉｎ ) is about 900 ng / mL, the method according to claim 79.

81. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof, or Compound A and a CYP3A4 inhibitor, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) is from about 1,700 ng / mL to about 6,200 ng / mL.

82. Compound A is administered at a dosage of about 163 mg every 12 hours, and at the time of administration, the maximum observed concentration (C ｍａｘ ) is about 3,200 ng / mL, the method according to claim 81.

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