Menin-MLL inhibitors for treating cancer

Abstract

The present disclosure relates to a method of treating colorectal cancer in a subject in need thereof with a menin-MLL inhibitor, the menin-MLL inhibitor comprising Compound A. The present disclosure relates to a method of treating colorectal cancer in a subject in need thereof. The present disclosure also provides methods of administering Compound A for various indications. # imgabs0 #

Description

[0001] Related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 339,635, filed May 9, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes. Background Technology

[0003] Colorectal cancer is typically caused by uncontrolled cell growth in the colon or rectum (part of the large intestine) or appendix. Genetic analysis shows that colon and rectal tumors are essentially the same cancer genetically, and symptoms of colorectal cancer often include rectal bleeding and anemia, sometimes accompanied by weight loss and changes in bowel habits. Colorectal cancer (CRC) is a major global health problem, the third most frequently diagnosed malignancy, with an estimated global incidence of over 1.8 million in 2018. CRC is the second leading cause of cancer death worldwide, causing 500,000 deaths in 2018. Twenty percent of patients present with metastatic colorectal cancer (mCRC), and up to 50 percent of patients with early-stage disease experience recurrence despite radical surgery, (neo)adjuvant chemotherapy, and / or radiation therapy. At least 50 percent of the Western population will develop colorectal cancer before age 70. Of these individuals, 10% will develop malignancy. In adults, colorectal cancer is the second leading cause of cancer death worldwide. Therefore, there is a severe lack of clinically effective treatments, and this disclosure aims to address the currently unmet clinical needs. Summary of the Invention

[0004] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering to the subject an effective amount of a menin-MLL inhibitor or a pharmaceutical composition containing a menin-MLL inhibitor.

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

[0006] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, which essentially consists of administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor.

[0007] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering an effective amount of a single anticancer agent to the subject, wherein the single anticancer agent is a menin-MLL inhibitor.

[0008] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0009] A pharmaceutical composition containing compound A, taken at least once daily, and

[0010] A pharmaceutical composition containing cobicistat, taken at least once daily.

[0011] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0012] A pharmaceutical composition containing compound A, taken at least once daily.

[0013] A drug composition containing cobistat, taken at least once daily, and

[0014] The method described does not involve the administration of EGFR inhibitors.

[0015] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0016] A pharmaceutical composition containing compound A, taken at least once daily.

[0017] A drug composition containing cobistat, taken at least once daily, and

[0018] The subjects in question had not received EGFR inhibitors.

[0019] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0020] A pharmaceutical composition containing compound A, taken at least once daily.

[0021] A drug composition containing cobistat, taken at least once daily, and

[0022] The subjects mentioned were not also receiving EGFR inhibitors.

[0023] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0024] A pharmaceutical composition containing compound A, taken at least once daily.

[0025] A drug composition containing cobistat, taken at least once daily, and

[0026] The method also includes administering compound A in the absence of an EGFR inhibitor.

[0027] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 25 mg and about 300 mg, wherein the subject does not receive a CYP3A inhibitor.

[0028] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 25 mg and about 300 mg, wherein the subject is not also receiving a CYP3A inhibitor.

[0029] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 25 mg and about 300 mg, wherein the method does not involve the administration of a CYP3A inhibitor.

[0030] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 25 mg and about 300 mg, wherein the administration of compound A is carried out in the absence of CYP3A inhibitors.

[0031] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering compound A at a dose between about 25 mg and about 300 mg.

[0032] Compound A was administered in the absence of both CYP3A inhibitors and EGFR inhibitors.

[0033] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 25 mg and about 300 mg at least once daily, wherein the subject is not receiving a CYP3A inhibitor.

[0034] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 25 mg and about 300 mg, at least once daily, wherein said subject is not also receiving a CYP3A inhibitor.

[0035] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 25 mg and about 300 mg at least once daily, wherein said method does not involve the administration of a CYP3A inhibitor.

[0036] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 25 mg and about 300 mg at least once daily, wherein the administration of compound A is performed in the absence of CYP3A inhibitors.

[0037] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering compound A at a dose between about 25 mg and about 300 mg, at least once daily.

[0038] Compound A was administered in the absence of both CYP3A inhibitors and EGFR inhibitors.

[0039] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 150 mg and about 200 mg, wherein the subject is not receiving a CYP3A inhibitor.

[0040] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 150 mg and about 200 mg, wherein the subject is not also receiving a CYP3A inhibitor.

[0041] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 150 mg and about 200 mg, wherein the method does not involve the administration of a CYP3A inhibitor.

[0042] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 150 mg and about 200 mg, wherein the administration of compound A is carried out in the absence of CYP3A inhibitors.

[0043] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering compound A at a dose between about 150 mg and about 200 mg.

[0044] Compound A was administered in the absence of both CYP3A inhibitors and EGFR inhibitors.

[0045] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition containing compound A, wherein the method comprises administering compound A in the absence of a CYP3A inhibitor, wherein the dose of compound A is between about 220 and about 280 mg.

[0046] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 150 mg and about 200 mg at least once daily, wherein the subject is not receiving a CYP3A inhibitor.

[0047] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 150 mg and about 200 mg, at least once daily, wherein said subject is not also receiving a CYP3A inhibitor.

[0048] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 150 mg and about 200 mg at least once daily, wherein said method does not involve the administration of a CYP3A inhibitor.

[0049] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 150 mg and about 200 mg at least once daily, wherein the administration of compound A is performed in the absence of CYP3A inhibitors.

[0050] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering compound A at a dose between about 150 mg and about 200 mg, at least once daily.

[0051] Compound A was administered in the absence of both CYP3A inhibitors and EGFR inhibitors.

[0052] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition containing compound A, wherein the method comprises administering compound A in the absence of a CYP3A inhibitor, wherein the dose of compound A is between about 220 and about 280 mg, and wherein compound A is administered at least once daily.

[0053] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A at a dose between about 150 mg and about 200 mg three times daily, wherein the subject is not receiving a CYP3A inhibitor.

[0054] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A three times daily at a dose between about 150 mg and about 200 mg, wherein said subject is not also receiving a CYP3A inhibitor.

[0055] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 150 mg and about 200 mg three times daily, wherein said method does not involve the administration of a CYP3A inhibitor.

[0056] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 150 mg and about 200 mg three times daily, wherein the administration of compound A is performed in the absence of CYP3A inhibitors.

[0057] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering compound A three times daily at a dose between about 150 mg and about 200 mg.

[0058] Compound A was administered in the absence of both CYP3A inhibitors and EGFR inhibitors.

[0059] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A, wherein the subject has experienced disease progression following prior colorectal cancer therapy.

[0060] In some respects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A, wherein the subject has experienced a recurrence of disease after at least one prior line of therapy for colorectal cancer.

[0061] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A, wherein the subject has experienced disease recurrence after at least two prior lines of therapy for colorectal cancer.

[0062] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering compound A, wherein the subject has refractory colorectal cancer.

[0063] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition containing compound A, wherein the method comprises administering compound A in the absence of a CYP3A inhibitor, wherein the dose of compound A is between about 220 and about 280 mg, and wherein compound A is administered three times daily.

[0064] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a daily dose between about 25 mg and about 900 mg, wherein the subject does not receive a CYP3A inhibitor.

[0065] In some aspects, this disclosure relates to a method for treating, preventing, or reducing the severity of colorectal cancer in a subject of need, the method comprising administering compound A at a daily dose between about 25 mg and about 900 mg, wherein the subject is not also receiving a CYP3A inhibitor.

[0066] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a daily dose between about 25 mg and about 900 mg, wherein the method does not involve the administration of a CYP3A inhibitor.

[0067] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a daily dose between about 25 mg and about 900 mg, wherein the administration of compound A is carried out in the absence of CYP3A inhibitors.

[0068] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering compound A at a daily dose between about 25 mg and about 900 mg.

[0069] Compound A was administered in the absence of both CYP3A inhibitors and EGFR inhibitors.

[0070] In some aspects, this disclosure relates to a menin-MLL inhibitor for preparing an agent for treating colorectal cancer according to any of the foregoing embodiments, wherein the agent and / or treatment does not involve the use of an EGFR inhibitor.

[0071] In some aspects, this disclosure relates to a menin-MLL inhibitor for preparing an agent for treating colorectal cancer according to any of the foregoing embodiments, wherein the agent does not contain an EGFR inhibitor.

[0072] In some aspects, this disclosure relates to a kit comprising a menin-MLL inhibitor and printed instructions for treating colorectal cancer in subjects using the menin-MLL inhibitor. Attached Figure Description

[0073] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to illustrate the principles of the disclosure. The drawings are for illustrative purposes only and should not be construed as limiting the invention. Other objects, features, and advantages of the invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which illustrate illustrative embodiments of the present disclosure.

[0074] Figure 1 An overview of the clinical trial protocol for treating colorectal cancer using the menin-MLL inhibitor compound A is presented.

[0075] Figure 2A-2C The simulated median and 5-95% pharmacokinetic parameters of 163 mg compound A administered every 12 hours (q12h) with a potent CYP3A inhibitor are illustrated compared with those of 163 mg, 226 mg or 276 mg compound A administered three times daily (TID) in the absence of a CYP3A inhibitor. Figure 2A The compound AC is illustrated. max . Figure 2B The compound AC is illustrated. min . Figure 2C The AUC of compound A is plotted. 0-24 . Detailed Implementation

[0076] The following are specific embodiments provided to assist those skilled in the art in practicing the present invention. Those skilled in the art can make modifications and changes to the embodiments described herein without departing from the spirit or scope of this disclosure. All publications, patent applications, patents, drawings, and other references mentioned herein are expressly incorporated herein by reference in their entirety.

[0077] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering a menin-MLL inhibitor or a pharmaceutical composition thereof to the subject.

[0078] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering to the subject a pharmaceutical composition consisting essentially of a menin-MLL inhibitor.

[0079] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, which essentially consists of administering to the subject a pharmaceutical composition comprising a menin-MLL inhibitor.

[0080] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need, comprising administering a single anticancer agent to the subject, wherein the single anticancer agent is a menin-MLL inhibitor.

[0081] Menin-MLL inhibitors

[0082] In some implementations, 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.

[0083] In some implementations, the menin-MLL inhibitor is one of the compounds listed in Table 1.

[0084] Table 1. Menin-MLL Inhibitors

[0085]

[0086]

[0087]

[0088] Or its pharmaceutically acceptable salt.

[0089] 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; Shi et al., 2012, Blood, 120:4461-4469. Yet another menin-MLL inhibitor that inhibits the interaction between MLL enzymes and menin is N,N'-bis(4-aminophenyl)-N,N'-dimethylethylenediamine (also known as ISC-30). In some embodiments, the menin-MLL inhibitors considered for use in the methods of this disclosure are known in the art, at least for example, WO 2017 / 112768, WO 2017 / 214367, WO 2018 / 053267, WO2020 / 069027, WO 2021 / 207335, US2021 / 0115018, US2019 / 0307750, 2016 / 0339035 and Borkin et al., Cancer Cell vol.27,4(2015):589-602, the contents of each of which are incorporated herein by reference.

[0090] 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 either 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.

[0091] Treatment

[0092] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of compounds to provide such treatment or prevention as described herein, and the use of compounds to prepare pharmaceutical agents for treating or preventing such conditions. Treatment includes treatment of human or non-human animals, including rodents and other disease models.

[0093] In some embodiments, the menin-MLL inhibitor is administered at least once daily. In some embodiments, the menin-MLL inhibitor is compound A and is administered at least once daily.

[0094] In some embodiments, the menin-MLL inhibitor is administered twice daily. In some embodiments, the menin-MLL inhibitor is compound A and is administered at least twice daily. In some embodiments, the menin-MLL inhibitor is compound A and is administered twice daily.

[0095] In some embodiments, the menin-MLL inhibitor is administered three times daily. In some embodiments, the menin-MLL inhibitor is compound A and is administered three times daily.

[0096] In some implementations, menin-MLL inhibitors are administered in combination with CYP3A inhibitors.

[0097] In some embodiments, the pharmaceutical composition containing the menin-MLL inhibitor also contains a CYP3A inhibitor.

[0098] In some implementations, the menin-MLL inhibitor is administered in combination with the CYP3A4 inhibitor.

[0099] In some embodiments, the pharmaceutical composition containing the menin-MLL inhibitor also contains a CYP3A4 inhibitor.

[0100] In some implementations, the CYP3A4 inhibitor is a potent CYP3A4 inhibitor.

[0101] In some implementations, potent CYP3A4 inhibitors include boceprevir, cobistat, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole.

[0102] In some implementations, the method further includes the administration of cobistat.

[0103] In some implementations, the method also includes administering cobistat at least once a day.

[0104] In some implementations, the method also includes administering cobistat once daily.

[0105] In some implementations, the CYP3A4 inhibitor is an intermediate-acting CYP3A4 inhibitor.

[0106] In some implementation schemes, intermediate-acting CYP3A4 inhibitors are amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, or verapamil.

[0107] In some implementations, the menin-MLL inhibitor is administered every 12 hours at a dose between about 25 mg and about 276 mg.

[0108] In some implementations, the menin-MLL inhibitor is administered at a dose of approximately 163 mg every 12 hours.

[0109] In some implementations, a menin-MLL inhibitor is administered to subjects who require it in the absence of a CYP3A inhibitor.

[0110] In some implementations, a menin-MLL inhibitor is administered to the subject who requires it, wherein the subject does not receive a CYP3A inhibitor.

[0111] In some implementations, a menin-MLL inhibitor is administered to subjects in need of this treatment in the absence of a CYP3A4 inhibitor.

[0112] In some implementations, a menin-MLL inhibitor is administered to a subject who requires this, wherein the subject does not receive a CYP3A4 inhibitor.

[0113] In some embodiments, the pharmaceutical compositions described herein contain a menin inhibitor (e.g., compound A) but not a CYP3A4 inhibitor.

[0114] In some implementations, menin-MLL inhibitors are administered to subjects in need at doses between about 25 mg and about 900 mg.

[0115] In some implementations, menin-MLL inhibitors are administered to subjects in need at a dose between about 25 mg and about 276 mg.

[0116] In some implementations, the menin-MLL inhibitor is administered to the subject in need at least once a day and the total amount of menin-MLL inhibitor administered daily is between about 25 mg and about 900 mg.

[0117] In some implementations, the menin-MLL inhibitor is administered once daily to the subject in need, and the total amount of menin-MLL inhibitor administered daily is between about 25 mg and about 900 mg.

[0118] In some implementations, the menin-MLL inhibitor is administered twice daily to the subject in need, and the total daily dose of the menin-MLL inhibitor is between about 25 mg and about 900 mg.

[0119] In some implementations, the menin-MLL inhibitor is administered to the subject in need three times a day, and the total amount of menin-MLL inhibitor administered daily is between about 25 mg and about 900 mg.

[0120] In some implementations, the menin-MLL inhibitor is administered to the subject in need four times a day, and the total amount of menin-MLL inhibitor administered daily is between about 25 mg and about 900 mg.

[0121] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose between about 25 mg and about 276 mg, wherein the menin-MLL inhibitor is administered at least once daily.

[0122] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose between about 25 mg and about 276 mg, wherein the menin-MLL inhibitor is administered once daily.

[0123] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose between about 25 mg and about 276 mg, wherein the menin-MLL inhibitor is administered twice daily.

[0124] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose between about 25 mg and about 276 mg, wherein the menin-MLL inhibitor is administered three times daily.

[0125] In some implementations, the menin-MLL inhibitor is administered to subjects in need at a dose of approximately 163 mg.

[0126] In some implementations, when the menin-MLL inhibitor is administered three times daily, the menin-MLL inhibitor is given to the subject in need at a dose of approximately 163 mg.

[0127] In some implementations, menin-MLL inhibitors are administered to subjects in need at a dose between about 25 mg and about 276 mg.

[0128] In some implementations, in the absence of a CYP3A4 inhibitor, a menin-MLL inhibitor is administered to the subject in need, and the menin-MLL inhibitor is administered at a dose between about 25 mg and about 276 mg, wherein the menin-MLL inhibitor is administered three times daily.

[0129] In some implementations, in the absence of a CYP3A4 inhibitor, a menin-MLL inhibitor is administered to the subject in need, and the menin-MLL inhibitor is administered at a dose of approximately 163 mg.

[0130] In some implementations, in the absence of a CYP3A4 inhibitor, a menin-MLL inhibitor is administered to the subject in need, and the menin-MLL inhibitor is administered at a dose of approximately 163 mg, wherein the menin-MLL inhibitor is administered three times daily.

[0131] In some implementations, in the absence of a CYP3A4 inhibitor, a menin-MLL inhibitor is administered to the subject in need, and the menin-MLL inhibitor is administered at a dose of approximately 276 mg.

[0132] In some implementations, in the absence of a CYP3A4 inhibitor, a menin-MLL inhibitor is administered to the subject in need, and the menin-MLL inhibitor is administered at a dose of approximately 276 mg, wherein the menin-MLL inhibitor is administered three times daily.

[0133] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose between about 25 mg and about 276 mg, three times a day, wherein no CYP3A4 inhibitor is administered to the subject.

[0134] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose of approximately 163 mg, wherein the subject is not given a CYP3A4 inhibitor.

[0135] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose of approximately 163 mg three times daily, without the administration of a CYP3A4 inhibitor to the subject.

[0136] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose of approximately 276 mg, wherein the subject is not given a CYP3A4 inhibitor.

[0137] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose of approximately 276 mg three times daily, without the administration of a CYP3A4 inhibitor to the subject.

[0138] In some implementations, menin-MLL inhibitors are administered to subjects in need at a dose of up to approximately 828 mg per day.

[0139] In some implementations, the menin-MLL inhibitor is administered to the subject in need at a dose of up to about 828 mg per day, wherein no CYP3A inhibitor is administered to the subject.

[0140] In some implementations, the menin inhibitor is contained in a capsule or oral solution.

[0141] In some implementation schemes, the subjects had not received prior therapy for colorectal cancer.

[0142] In some implementations, the subject has previously received at least one prior therapy for colorectal cancer.

[0143] In some implementations, the subject has previously received at least one prior therapy for colorectal cancer, wherein the subject has not responded to at least one prior line of therapy.

[0144] In some embodiments, at least one prior therapy line is chemotherapy, radiotherapy, immunotherapy, targeted small molecule therapy, or a biological therapy (e.g., monoclonal antibody therapy). In some embodiments, at least one prior therapy line is chemotherapy. In some embodiments, at least one prior therapy line is radiotherapy. In some embodiments, at least one prior therapy line is immunotherapy. In some embodiments, at least one prior therapy line is targeted small molecule therapy. In some embodiments, at least one prior therapy line is a biological therapy (e.g., monoclonal antibody therapy).

[0145] In some implementations, the subject has previously received treatment for colorectal cancer with one or more of trifluridine, tipiracil, and / or regorafenib.

[0146] In some implementations, the subject has previously received trifluuridine, ticipiridine, or a combination thereof to treat colorectal cancer.

[0147] In some implementations, the subjects had previously received regorafenib for the treatment of colorectal cancer.

[0148] In some embodiments, the subject has previously received trifluuridine, ticipiridine, and / or regorafenib. In some embodiments, the subject has previously received trifluuridine. In some embodiments, the subject has previously received ticipiridine. In some embodiments, the subject has previously received regorafenib.

[0149] In some implementation schemes, the subjects had not received prior therapy for colorectal cancer.

[0150] In some implementations, the subject's disease progressed after at least one prior line of therapy for colorectal cancer. In some implementations, the subject's disease recurred after at least one prior line of therapy for colorectal cancer. In some implementations, the subject's disease recurred after at least two prior lines of therapy for colorectal cancer. In some implementations, the subject had refractory colorectal cancer. In some implementations, the subject had recurrent or refractory colorectal cancer.

[0151] In some implementations, colorectal cancer is defined as recurrent / refractory colorectal cancer. In other implementations, colorectal cancer is defined as metastatic recurrent / refractory colorectal cancer.

[0152] In some implementations, the subject is being treated with microsatellite stable / skilled mismatch repair (MSS / pMMR) metastatic colorectal cancer (mCRC). In some implementations, the colorectal cancer is microsatellite stable / skilled mismatch repair (MSS / pMMR) metastatic colorectal cancer.

[0153] In some implementations, menin-MLL inhibitors are administered in the absence of EGFR inhibitors.

[0154] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0155] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily, and

[0156] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily.

[0157] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0158] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0159] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0160] The method described does not involve the administration of EGFR inhibitors.

[0161] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0162] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0163] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0164] The subjects in question had not received EGFR inhibitors.

[0165] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0166] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0167] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0168] The subjects mentioned were not also receiving EGFR inhibitors.

[0169] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0170] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0171] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0172] The method also includes administering a menin-MLL inhibitor in the absence of an EGFR inhibitor.

[0173] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0174] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0175] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0176] The method also includes administering a menin-MLL inhibitor in the absence of an EGFR inhibitor.

[0177] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0178] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily, and

[0179] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0180] The menin-MLL inhibitors mentioned therein are selected from 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 pharmaceutically acceptable salts thereof.

[0181] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0182] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0183] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0184] The method described herein does not involve the administration of an EGFR inhibitor, and the menin-MLL inhibitor is selected from 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 pharmaceutically acceptable salts thereof.

[0185] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0186] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0187] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0188] The subjects in question had not received EGFR inhibitors, and the menin-MLL inhibitor was selected from 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 pharmaceutically acceptable salts thereof.

[0189] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0190] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0191] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0192] The subject in question was not also receiving an EGFR inhibitor, and the menin-MLL inhibitor was selected from 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 pharmaceutically acceptable salts thereof.

[0193] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0194] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0195] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0196] The method further includes administering a menin-MLL inhibitor in the absence of an EGFR inhibitor, wherein the menin-MLL inhibitor is selected from 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 pharmaceutically acceptable salts thereof.

[0197] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0198] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0199] A pharmaceutical composition containing a CYP3A4 inhibitor, taken at least once daily, and

[0200] The method further includes administering a menin-MLL inhibitor in the absence of an EGFR inhibitor, wherein the menin-MLL inhibitor is selected from 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 pharmaceutically acceptable salts thereof.

[0201] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0202] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily, and

[0203] A pharmaceutical composition containing cobicistat, taken at least once daily.

[0204] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0205] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0206] A drug composition containing cobistat, taken at least once daily, and

[0207] The method described does not involve the administration of EGFR inhibitors.

[0208] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0209] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0210] A drug composition containing cobistat, taken at least once daily, and

[0211] The subjects in question had not received EGFR inhibitors.

[0212] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0213] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0214] A drug composition containing cobistat, taken at least once daily, and

[0215] The subjects mentioned were not also receiving EGFR inhibitors.

[0216] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0217] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0218] A drug composition containing cobistat, taken at least once daily, and

[0219] The method also includes administering a menin-MLL inhibitor in the absence of an EGFR inhibitor.

[0220] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0221] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0222] A drug composition containing cobistat, taken at least once daily, and

[0223] The method also includes administering a menin-MLL inhibitor in the absence of an EGFR inhibitor.

[0224] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0225] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily, and

[0226] A drug composition containing cobistat, taken at least once daily, and

[0227] The menin-MLL inhibitors mentioned therein are selected from 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 pharmaceutically acceptable salts thereof.

[0228] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0229] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0230] A drug composition containing cobistat, taken at least once daily, and

[0231] The method described herein does not involve the administration of an EGFR inhibitor, and the menin-MLL inhibitor is selected from 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 pharmaceutically acceptable salts thereof.

[0232] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0233] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0234] A drug composition containing cobistat, taken at least once daily, and

[0235] The subjects in question had not received EGFR inhibitors, and the menin-MLL inhibitor was selected from 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 pharmaceutically acceptable salts thereof.

[0236] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0237] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0238] A drug composition containing cobistat, taken at least once daily, and

[0239] The subject in question was not also receiving an EGFR inhibitor, and the menin-MLL inhibitor was selected from 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 pharmaceutically acceptable salts thereof.

[0240] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0241] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0242] A drug composition containing cobistat, taken at least once daily, and

[0243] The method further includes administering a menin-MLL inhibitor in the absence of an EGFR inhibitor, wherein the menin-MLL inhibitor is selected from 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 pharmaceutically acceptable salts thereof.

[0244] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0245] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily.

[0246] A drug composition containing cobistat, taken at least once daily, and

[0247] The method further includes administering a menin-MLL inhibitor in the absence of an EGFR inhibitor, wherein the menin-MLL inhibitor is selected from 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 pharmaceutically acceptable salts thereof.

[0248] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0249] A pharmaceutical composition containing compound A, taken at least once daily.

[0250] A drug composition containing cobistat, taken at least once daily, and

[0251] The method also includes administering compound A in the absence of an EGFR inhibitor.

[0252] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A at a dose between about 150 mg and about 300 mg three times daily, wherein the administration of compound A is performed in the absence of CYP3A inhibitors and / or EGFR inhibitors.

[0253] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects in need, comprising administering compound A three times daily at a dose between about 150 mg and about 300 mg, wherein the subject is not receiving CYP3A inhibitors and / or EGFR inhibitors.

[0254] In some implementations, colorectal cancer is characterized by dysregulation of the WNT / β-catenin signaling pathway.

[0255] In some implementations, the subject's disease progressed after previous colorectal cancer treatment due to resistance to the previous treatment.

[0256] In some implementations, the subject has experienced a recurrence of colorectal cancer after at least one prior treatment due to resistance to previous colorectal cancer therapies.

[0257] In some implementations, the subject's disease relapsed after at least two prior colorectal cancer therapies due to resistance to previous colorectal cancer treatments.

[0258] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition comprising compound A, wherein the method comprises administering compound A three times daily, each time between about 220 mg and about 280 mg, wherein no CYP3A inhibitor is administered.

[0259] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject, comprising administering a pharmaceutical composition comprising compound A, wherein the method comprises administering compound A three times daily, each time between about 220 mg and about 280 mg, wherein the subject does not receive a CYP3A inhibitor.

[0260] In some implementation schemes, cancer is defined as leukemia.

[0261] In some implementations, the cancer is AML leukemia.

[0262] In some implementations, the cancer is acute lymphoblastic leukemia.

[0263] In some implementations, the cancer is NMP1-mutant leukemia.

[0264] In some implementations, the cancer is colorectal cancer.

[0265] In some implementations, cancer is represented as microsatellite stable / skilled mismatch repair (MSS / pMMR) mCRC.

[0266] In some implementations, the menin-MLL inhibitor is administered at a dose of about 270 mg to about 280 mg.

[0267] In some implementations, the menin-MLL inhibitor is administered three times daily.

[0268] In some implementations, the menin-MLL inhibitor may or may not be administered with food.

[0269] In some aspects, this disclosure relates to a menin-MLL inhibitor for preparing an agent for treating colorectal cancer according to any one of the preceding claims, wherein the agent and / or treatment does not involve the use of an EGFR inhibitor.

[0270] In some aspects, this disclosure relates to a menin-MLL inhibitor for preparing an agent for treating colorectal cancer according to any one of the preceding claims, wherein the agent does not contain an EGFR inhibitor.

[0271] In some aspects, this disclosure relates to a kit comprising a menin-MLL inhibitor and printed instructions for treating colorectal cancer in subjects using the menin-MLL inhibitor.

[0272] In some aspects, this disclosure relates to a kit comprising a therapeutically effective amount of a menin-MLL inhibitor and printed instructions for using the menin-MLL inhibitor to treat colorectal cancer in subjects.

[0273] In some implementations, the kit provides instructions for administering the menin-MLL inhibitor at a dose of about 270 mg to about 280 mg.

[0274] In some implementations, the kit provides instructions for administering the menin-MLL inhibitor at least once daily.

[0275] In some implementations, the kit provides instructions for administering the menin-MLL inhibitor once daily.

[0276] In some implementations, the kit provides instructions for administering the menin-MLL inhibitor twice daily.

[0277] In some implementations, the kit provides instructions for administering the menin-MLL inhibitor three times daily.

[0278] In some implementations, the kit provides instructions for administering approximately 276 mg of the menin-MLL inhibitor three times daily.

[0279] In some implementations, the kit provides instructions for administering approximately 276 mg of the menin-MLL inhibitor three times daily with food.

[0280] In some implementations, the kit provides instructions for administering approximately 276 mg of the menin-MLL inhibitor three times daily without food.

[0281] Unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0282] When a range of values ​​is provided, it should be understood that every intermediate value between the upper and lower limits of the range (unless the context explicitly specifies otherwise (e.g., in the case of a group containing many carbon atoms, in which case the number of each carbon atom falling into the range is provided), up to one-tenth of the lower limit unit), as well as any other stated value or intermediate value within the stated range, is taken into account within the invention. The upper and lower limits of these smaller ranges may be independently included in the smaller range and are also taken into account within the invention, but are subject to any specific exclusion limits within the stated range. When the stated range includes one or both of these limits, the range excluding any or both of these limits is also included in the invention.

[0283] As used herein and in the appended claims, the article “a / an” refers to one or more (i.e., at least one) grammatical object of the article, unless the context clearly indicates otherwise. For example, “an element” refers to one or more elements.

[0284] Colorectal cancer

[0285] Colorectal cancer occurs in the colon or rectum. If it originates in the colon, it may be called colon cancer. If it originates in the rectum, it may be called rectal cancer. In some implementations, the term "colorectal cancer" describes cancer of the colon. In some implementations, the term "colorectal cancer" describes cancer of the rectum.

[0286] A common type of colorectal cancer is adenocarcinoma. Adenocarcinomas of the colon and rectum account for 95% of all colorectal cancer cases. In the gastrointestinal tract, rectal and colonic adenocarcinomas occur in the cells lining the large intestine. These adenocarcinomas typically begin as growths in tissues called polyps. A specific type of polyp, called an adenoma, can develop into cancer. Other types of tumors can occur in the colon or rectum and include: primary colorectal lymphoma, gastrointestinal stromal tumor, leiomyosarcoma, carcinoid tumor, and melanoma.

[0287] Previous treatment

[0288] This combination of tetrofluridine (a nucleoside metabolism inhibitor) and tipiracil (a thymidine phosphorylase inhibitor) is indicated for the treatment of adult subjects with metastatic colorectal cancer who have previously been treated with chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan, anti-VEGF biologic therapy, and (if RAS wild-type) anti-EGFR therapy; and for metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy including fluoropyrimidine, platinum, taxanes, or irinotecan and (if appropriate) HER2 / neu-targeted therapy.

[0289] Regorafenib is a kinase inhibitor indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have previously been treated with chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan, anti-VEGF therapy, and (if KRAS wild-type) anti-EGFR therapy.

[0290] In some embodiments, the subject has received at least one prior therapy. In some embodiments, the prior therapy was for the treatment of cancer. In some embodiments, the prior therapy is for colon cancer. In some embodiments, the prior therapy is for rectal cancer. In some embodiments, the prior therapy is for colorectal cancer. In some embodiments, the prior therapy 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.

[0291] In some embodiments, the subject's condition has progressed after prior therapy. In some embodiments, the subject's condition has progressed after at least one prior therapy. In some embodiments, the subject's condition has progressed after prior therapy with LONSURF or STIVARGA. In some embodiments, the subject's condition has progressed after prior therapy with LONSURF. In some embodiments, the subject's condition has progressed after prior therapy with STIVARGA.

[0292] In some implementations, the subject's condition has relapsed after a prior line of therapy. In some implementations, the subject's condition has relapsed after at least one prior therapy. In some implementations, the subject's condition has relapsed after prior therapy with LONSURF or STIVARGA. In some implementations, the subject's condition has relapsed after prior therapy with LONSURF. In some implementations, the subject's condition has relapsed after prior therapy with STIVARGA.

[0293] In some implementations, the subject has refractory cancer and has received prior therapy. In some implementations, the subject has refractory cancer and has received at least one prior therapy. In some implementations, the subject has refractory cancer and has received prior therapy with LONSURF or STIVARGA. In some implementations, the subject has refractory cancer and has received prior therapy with LONSURF. In some implementations, the subject has refractory cancer and has received prior therapy with STIVARGA.

[0294] In some embodiments, the subject's condition progressed after prior therapy with one or more of fluoropyrimidine-based, oxaliplatin-based, and irinotecan-based chemotherapy, anti-VEGF therapy, or anti-EGFR therapy. In some embodiments, the subject's condition progressed after prior therapy with fluoropyrimidine-based chemotherapy. In some embodiments, the subject's condition progressed after prior therapy with oxaliplatin-based chemotherapy. In some embodiments, the subject's condition progressed after prior therapy with irinotecan-based chemotherapy. In some embodiments, the subject's condition progressed after prior therapy with anti-VEGF therapy. In some embodiments, the subject's condition progressed after prior therapy with anti-EGFR therapy.

[0295] Other indications

[0296] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition containing compound A, wherein the method comprises administering compound A three times daily, and the subject does not receive a CYP3A inhibitor.

[0297] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition containing compound A, wherein the method comprises administering compound A three times daily, and the subject does not receive a CYP3A4 inhibitor.

[0298] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer, comprising administering a pharmaceutical composition containing compound A, wherein the method comprises administering compound A in the absence of a CYP3A / CYP3A4 inhibitor, wherein a dose of compound A is administered three times daily.

[0299] In some implementations, the cancer is a blood cancer, such as leukemia or lymphoma. Examples of leukemias and lymphomas that can be treated with the compounds of the present invention include mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with MLL rearrangements or MLL gene rearrangements, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myeloid leukemia, childhood leukemia, acute lymphoblastic leukemia (ALL) (also known as acute lymphoblastic leukemia or acute lymphoblastic leukemia), and acute myeloid leukemia (AML) (also known as acute myeloid leukemia or acute lymphoblastic leukemia). Medulloblastic leukemia, acute myeloid leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also known as chronic lymphoblastic leukemia), chronic myeloid leukemia (CML) (also known as chronic myeloid leukemia), treatment-related leukemia, myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD) (such as primary myelofibrosis (PMF)), myeloproliferative neoplasms (MPN), plasma cell tumors, multiple myeloma, spinal dysplasia, cutaneous T-cell lymphoma, nucleolar phosphatase (NPM1) AML, lymphoid neoplasms, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides. Acute myeloid leukemia (AML) includes fungoides, Alibert-Bazin syndrome, granuloma fungoides, Sezary syndrome, hairy cell leukemia, T-cell prolymphoblastic leukemia (T-PLL), large granular lymphoblastic leukemia, meningeal leukemia, leukemic meningitis, leukemic meningitis, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenström macroglobulinemia. In some implementations, acute myeloid leukemia (AML) is defined as acute myeloid leukemia with nucleolar phosphatase (NPM1) mutation (i.e., NPM1). mut Acute myeloid leukemia.

[0300] In some embodiments, the methods disclosed herein are used to treat leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, or acute medulloblastic leukemia associated with MLL rearrangement. As used herein, “MLL rearrangement” means rearrangement of the MLL gene.

[0301] Dosage

[0302] 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.

[0303] 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.

[0304] In some implementations, the amount of menin-MLL inhibitor administered is approximately 25 mg / day to approximately 828 mg / day, approximately 75 mg / day to approximately 828 mg / day, approximately 100 mg / day to approximately 828 mg / day, approximately 150 mg / day to approximately 828 mg / day, approximately 200 mg / day to approximately 828 mg / day, approximately 250 mg / day to approximately 828 mg / day, approximately 300 mg / day to approximately 828 mg / day, and approximately 350 mg / day. / day to about 828mg / day, about 400mg / day to about 828mg / day, about 450mg / day to about 828mg / day, about 500mg / day to about 828mg / day, about 550mg / day to about 828mg / day, about 600mg / day to about 828mg / day, about 650mg / day to about 828mg / day, about 700mg / day to about 828mg / day, or about 750mg / day to about 828mg / day.

[0305] In some embodiments, the amount of compound A applied is about 25 mg / day to about 828 mg / day, about 75 mg / day to about 828 mg / day, about 100 mg / day to about 828 mg / day, about 150 mg / day to about 828 mg / day, about 200 mg / day to about 828 mg / day, about 250 mg / day to about 828 mg / day, about 300 mg / day to about 828 mg / day, about 350 mg / day to about 828 mg / day, about 400 mg / day to about 828 mg / day, about 450 mg / day to about 828 mg / day, about 500 mg / day to about 828 mg / day, about 550 mg / day to about 828 mg / day, about 600 mg / day to about 828 mg / day, about 650 mg / day to about 828 mg / day, about 700 mg / day to about 828 mg / day, or about 750 mg / day to about 828 mg / day.

[0306] In some implementations, the menin-MLL inhibitor is administered at an initial dose, followed by dose escalation or decrement.

[0307] In some implementations, compound A is administered at an initial dose, followed by dose increases or decreases.

[0308] In some implementations, the menin-MLL inhibitor is administered as a starting dose of approximately 163 mg TID, which is then increased to approximately 226 mg TID or decreased to 113 mg TID.

[0309] In some embodiments, compound A is administered as an initial dose of about 163 mg TID, which is then increased to about 226 mg TID or decreased to 113 mg TID.

[0310] In some implementations, the menin-MLL inhibitor is administered as a starting dose of approximately 163 mg TID (489 mg total daily dose), followed by escalation or decrement according to the dose levels provided in Table A. Table A. Dosing Regimens with Menin-MLL Inhibitors

[0311]

[0312]

[0313] a Starting dose; TID = 3 times daily.

[0314] In some implementations, compound A is administered as an initial dose of approximately 163 mg TID (489 mg total daily dose), followed by escalation or decrement according to the dose levels provided in Table B.

[0315] Table B. Dosing regimen using compound A

[0316] dose level dose -3 25mg TID -2 50mg TID -1 113mg TID <![CDATA[1 a ]]> 163mg TID 2 226mg TID 3 276mg TID

[0317] a Starting dose; TID = 3 times daily.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] In some embodiments, the daily dose is divided into multiple administrations and given once, twice, three times, or four times daily. In some embodiments, the menin-MLL inhibitor is given once, twice, or three times daily. In some embodiments, the daily dose of the menin-MLL inhibitor is divided into multiple administrations and given once daily. In some embodiments, the daily dose of the menin-MLL inhibitor is divided into multiple administrations and given twice daily. In some embodiments, the daily dose of the menin-MLL inhibitor is divided into multiple administrations and given three times daily.

[0323] In some implementations, menin-MLL inhibitors are administered at doses of approximately 50 mg QD (once daily), approximately 75 mg QD, approximately 100 mg QD, approximately 113 mg QD, approximately 125 mg QD, approximately 150 mg QD, approximately 175 mg QD, approximately 200 mg QD, approximately 50 mg ql2h, approximately 75 mg ql2h, approximately 100 mg ql2h, approximately 113 mg ql2h, approximately 125 mg ql2h, approximately 150 mg ql2h, approximately 163 mg ql2h, approximately 175 mg ql2h, approximately 200 mg ql2h, approximately 225 mg ql2h, approximately 226 mg ql2h, approximately 250 mg ql2h, approximately 275 mg ql2h, approximately 300 mg ql2h, approximately 325 mg ql2h, and approximately 339 mg. Administer at approximately 350 mg ql2h, approximately 375 mg ql2h, approximately 400 mg ql2h, approximately 425 mg ql2h, approximately 450 mg ql2h, approximately 452 mg ql2h, approximately 475 mg ql2h, approximately 500 mg ql2h, approximately 525 mg ql2h, approximately 550 mg ql2h, approximately 565 mg ql2h, approximately 575 mg ql2h, or approximately 600 mg ql2h. In some implementations, the menin-MLL inhibitor is compound A and is administered at doses of approximately 50 mg QD, approximately 75 mg QD, approximately 100 mg QD, approximately 113 mg QD, approximately 125 mg QD, approximately 150 mg QD, approximately 175 mg QD, approximately 200 mg QD, approximately 50 mg ql2h, approximately 75 mg ql2h, approximately 100 mg ql2h, approximately 113 mg ql2h, approximately 125 mg ql2h, approximately 150 mg ql2h, approximately 163 mg ql2h, approximately 175 mg ql2h, approximately 200 mg ql2h, approximately 225 mg ql2h, approximately 226 mg ql2h, approximately 250 mg ql2h, approximately 275 mg ql2h, approximately 300 mg ql2h, approximately 325 mg ql2h, and approximately 339 mg ql2h. Administer at approximately 350 mg ql2h, approximately 375 mg ql2h, approximately 400 mg ql2h, approximately 425 mg ql2h, approximately 450 mg ql2h, approximately 452 mg ql2h, approximately 475 mg ql2h, approximately 500 mg ql2h, approximately 525 mg ql2h, approximately 550 mg ql2h, approximately 565 mg ql2h, approximately 575 mg ql2h, or approximately 600 mg ql2h.In some implementations, the menin-MLL inhibitor is a pharmaceutical formulation comprising compound A and administered at doses of approximately 50 mg QD, approximately 75 mg QD, approximately 100 mg QD, approximately 113 mg QD, approximately 125 mg QD, approximately 150 mg QD, approximately 175 mg QD, approximately 200 mg QD, approximately 50 mg ql2h, approximately 75 mg ql2h, approximately 100 mg ql2h, approximately 113 mg ql2h, approximately 125 mg ql2h, approximately 150 mg ql2h, approximately 163 mg ql2h, approximately 175 mg ql2h, approximately 200 mg ql2h, approximately 225 mg ql2h, approximately 226 mg ql2h, approximately 250 mg ql2h, approximately 275 mg ql2h, approximately 300 mg ql2h, and approximately 325 mg. Administered at approximately 339 mg ql2h, approximately 350 mg ql2h, approximately 375 mg ql2h, approximately 400 mg ql2h, approximately 425 mg ql2h, approximately 450 mg ql2h, approximately 452 mg ql2h, approximately 475 mg ql2h, approximately 500 mg ql2h, approximately 525 mg ql2h, approximately 550 mg ql2h, approximately 565 mg ql2h, approximately 575 mg ql2h, or approximately 600 mg ql2h. In some implementations, the menin-MLL inhibitor is a capsule containing compound A and administered at doses of approximately 50 mg QD, approximately 75 mg QD, approximately 100 mg QD, approximately 113 mg QD, approximately 125 mg QD, approximately 150 mg QD, approximately 175 mg QD, approximately 200 mg QD, approximately 50 mg ql2h, approximately 75 mg ql2h, approximately 100 mg ql2h, approximately 113 mg ql2h, approximately 125 mg ql2h, approximately 150 mg ql2h, approximately 163 mg ql2h, approximately 175 mg ql2h, approximately 200 mg ql2h, approximately 225 mg ql2h, approximately 226 mg ql2h, approximately 250 mg ql2h, approximately 275 mg ql2h, approximately 300 mg ql2h, and approximately 325 mg. Administered at approximately 339 mg ql2h, approximately 350 mg ql2h, approximately 375 mg ql2h, approximately 400 mg ql2h, approximately 425 mg ql2h, approximately 450 mg ql2h, approximately 452 mg ql2h, approximately 475 mg ql2h, approximately 500 mg ql2h, approximately 525 mg ql2h, approximately 550 mg ql2h, approximately 565 mg ql2h, approximately 575 mg ql2h, or approximately 600 mg ql2h.

[0324] In some embodiments, the menin-MLL inhibitor is a pharmaceutical formulation containing compound B and is administered at approximately 163 mg every 12 hours. In some embodiments, the menin-MLL inhibitor is a capsule containing compound B and is administered at approximately 163 mg every 12 hours.

[0325] In some implementations, the menin-MLL inhibitor is administered at doses of approximately 25 mg TID, approximately 50 mg TID, approximately 75 mg TID, approximately 100 mg TID, approximately 113 mg TID, approximately 125 mg TID, approximately 150 mg TID, approximately 163 mg TID, approximately 175 mg TID, approximately 200 mg TID, approximately 225 mg TID, approximately 226 mg TID, approximately 250 mg TID, approximately 275 mg TID, approximately 276 mg TID, or approximately 300 mg TID. In some implementations, the menin-MLL inhibitor is compound A and is administered at doses of about 25 mg TID, about 50 mg TID, about 75 mg TID, about 100 mg TID, about 113 mg TID, about 125 mg TID, about 150 mg TID, about 163 mg TID, about 175 mg TID, about 200 mg TID, about 225 mg TID, about 226 mg TID, about 250 mg TID, about 275 mg TID, about 276 mg TID, or about 300 mg TID. In some implementations, the menin-MLL inhibitor is administered in a pharmaceutical formulation containing compound A at doses of about 25 mg TID, about 50 mg TID, about 75 mg TID, about 100 mg TID, about 113 mg TID, about 125 mg TID, about 150 mg TID, about 163 mg TID, about 175 mg TID, about 200 mg TID, about 225 mg TID, about 226 mg TID, about 250 mg TID, about 275 mg TID, about 276 mg TID, or about 300 mg TID. In some implementations, the menin-MLL inhibitor is a capsule containing compound A and is administered at doses of about 25 mg TID, about 50 mg TID, about 75 mg TID, about 100 mg TID, about 113 mg TID, about 125 mg TID, about 150 mg TID, about 163 mg TID, about 175 mg TID, about 200 mg TID, about 225 mg TID, about 226 mg TID, about 250 mg TID, about 275 mg TID, about 276 mg TID, or about 300 mg TID.

[0326] In some implementations, the menin-MLL inhibitor is administered in the absence of a CYP3A inhibitor at doses of approximately 25 mg TID, approximately 50 mg TID, approximately 75 mg TID, approximately 100 mg TID, approximately 113 mg TID, approximately 125 mg TID, approximately 150 mg TID, approximately 163 mg TID, approximately 175 mg TID, approximately 200 mg TID, approximately 225 mg TID, approximately 226 mg TID, approximately 250 mg TID, approximately 275 mg TID, approximately 276 mg TID, or approximately 300 mg TID. In some implementations, the menin-MLL inhibitor is compound A and is administered in the absence of a CYP3A inhibitor at doses of about 25 mg TID, about 50 mg TID, about 75 mg TID, about 100 mg TID, about 113 mg TID, about 125 mg TID, about 150 mg TID, about 163 mg TID, about 175 mg TID, about 200 mg TID, about 225 mg TID, about 226 mg TID, about 250 mg TID, about 275 mg TID, about 276 mg TID, or about 300 mg TID. In some implementations, the menin-MLL inhibitor is administered in a pharmaceutical formulation containing compound A and, in the absence of a CYP3A inhibitor, at doses of about 25 mg TID, about 50 mg TID, about 75 mg TID, about 100 mg TID, about 113 mg TID, about 125 mg TID, about 150 mg TID, about 163 mg TID, about 175 mg TID, about 200 mg TID, about 225 mg TID, about 226 mg TID, about 250 mg TID, about 275 mg TID, about 276 mg TID, or about 300 mg TID. In some implementations, the menin-MLL inhibitor is a capsule containing compound A and, in the absence of a CYP3A inhibitor, is administered at doses of about 25 mg TID, about 50 mg TID, about 75 mg TID, about 100 mg TID, about 113 mg TID, about 125 mg TID, about 150 mg TID, about 163 mg TID, about 175 mg TID, about 200 mg TID, about 225 mg TID, about 226 mg TID, about 250 mg TID, about 275 mg TID, about 276 mg TID, or about 300 mg TID.

[0327] In some embodiments, the menin-MLL inhibitor is administered at a dose of approximately 163 mg every 12 hours. In some embodiments, the menin-MLL inhibitor is compound B and is administered at a dose of approximately 163 mg every 12 hours. In some embodiments, the menin-MLL inhibitor is administered in a pharmaceutical formulation containing compound B and at a dose of approximately 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 approximately 163 mg every 12 hours.

[0328] In some embodiments, the menin-MLL inhibitor is administered at a dose of approximately 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 approximately 163 mg every 12 hours in the absence of a CYP3A inhibitor. In some embodiments, the menin-MLL inhibitor is administered in a pharmaceutical formulation containing compound B and at a dose of approximately 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 approximately 163 mg every 12 hours in the absence of a CYP3A inhibitor.

[0329] In some implementations, the dose is taken at least 6 hours after the previous dose.

[0330] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition containing a menin-MLL inhibitor to the subject, wherein the menin-MLL inhibitor is administered every 12 hours at a dose between about 25 mg and about 276 mg, and wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A is measured from time 0 to 24 hours. (0-24)The values ​​are approximately 1,000 ng*h / mL to approximately 200,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 150,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 100,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 50,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 40,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 30,000 ng*h / mL, and approximately 1,000 ng*h / mL to approximately 2... 0,000 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 The values ​​are approximately 45,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 40,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 35,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 30,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 25,000 ng*h / mL, approximately 10,000 ng*h / mL, or approximately 10,000 ng*h / mL to approximately 15,000 ng*h / mL.

[0331] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition containing a menin-MLL inhibitor to the subject, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg per day, and wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A is measured from time 0 to 24 hours. (0-24)The values ​​are approximately 1,000 ng*h / mL to approximately 200,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 150,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 100,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 50,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 40,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 30,000 ng*h / mL, and approximately 1,000 ng*h / mL to approximately 2... 0,000 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 The values ​​are approximately 45,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 40,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 35,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 30,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 25,000 ng*h / mL, approximately 10,000 ng*h / mL, or approximately 10,000 ng*h / mL to approximately 15,000 ng*h / mL.

[0332] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor and a CYP3A4 inhibitor to the subject, wherein the menin-MLL inhibitor is administered every 12 hours at a dose between about 25 mg and about 276 mg, and wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A is measured from time 0 to 24 hours.(0-24) The values ​​are approximately 1,000 ng*h / mL to approximately 200,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 150,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 100,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 50,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 40,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 30,000 ng*h / mL, and approximately 1,000 ng*h / mL to approximately 2... 0,000 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 The values ​​are approximately 45,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 40,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 35,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 30,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 25,000 ng*h / mL, approximately 10,000 ng*h / mL, or approximately 10,000 ng*h / mL to approximately 15,000 ng*h / mL.

[0333] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor and a CYP3A4 inhibitor to the subject, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg per day, and wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A is measured from time 0 to 24 hours.(0-24) The values ​​are approximately 1,000 ng*h / mL to approximately 200,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 150,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 100,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 50,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 40,000 ng*h / mL, approximately 1,000 ng*h / mL to approximately 30,000 ng*h / mL, and approximately 1,000 ng*h / mL to approximately 2... 0,000 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 The values ​​are approximately 45,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 40,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 35,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 30,000 ng*h / mL, approximately 10,000 ng*h / mL, approximately 25,000 ng*h / mL, approximately 10,000 ng*h / mL, or approximately 10,000 ng*h / mL to approximately 15,000 ng*h / mL.

[0334] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition containing a menin-MLL inhibitor to the subject, wherein the menin-MLL inhibitor is administered every 12 hours at a dose between about 25 mg and about 276 mg, and wherein, after administration, the minimum observed concentration (C0) of compound A is [not specified]. minThe values ​​are approximately 100 ng / mL to approximately 5,000 ng / mL, approximately 100 ng / mL to approximately 4,000 ng / mL, approximately 100 ng / mL to approximately 3,000 ng / mL, approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 1,000 ng / mL, approximately 100 ng / mL to approximately 900 ng / mL, approximately 100 ng / mL to approximately 800 ng / mL, approximately 100 ng / mL to approximately 700 ng / mL, approximately 100 ng / mL to approximately 600 ng / mL, approximately 100 ng / mL to approximately 500 ng / mL, approximately 100 ng / mL to approximately 400 ng / mL, and approximately 100 ng / mL. g / mL to about 300 ng / mL, about 100 ng / mL to about 200 ng / mL, about 200 ng / mL to about 2,000 ng / mL, about 200 ng / mL to about 1,000 ng / mL, about 300,000 ng / mL to about 1,000 ng / mL, about 300 ng / mL to about 1,000 ng / mL, about 400 ng / mL to about 1,000 ng / mL, about 500 ng / mL to about 1,000 ng / mL, about 600 ng / mL to about 1,000 ng / mL, about 700 ng / mL to about 1,000 ng / mL, about 800 ng / mL to about 1,000 ng / mL, about 900 ng / mL to about 1,000 ng / mL.

[0335] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition containing a menin-MLL inhibitor to the subject, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg per day, and wherein, after administration, the minimum observed concentration (C) of compound A is [not specified]. minThe values ​​are approximately 100 ng / mL to approximately 5,000 ng / mL, approximately 100 ng / mL to approximately 4,000 ng / mL, approximately 100 ng / mL to approximately 3,000 ng / mL, approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 1,000 ng / mL, approximately 100 ng / mL to approximately 900 ng / mL, approximately 100 ng / mL to approximately 800 ng / mL, approximately 100 ng / mL to approximately 700 ng / mL, approximately 100 ng / mL to approximately 600 ng / mL, approximately 100 ng / mL to approximately 500 ng / mL, approximately 100 ng / mL to approximately 400 ng / mL, and approximately 100 ng / mL. g / mL to about 300 ng / mL, about 100 ng / mL to about 200 ng / mL, about 200 ng / mL to about 2,000 ng / mL, about 200 ng / mL to about 1,000 ng / mL, about 300,000 ng / mL to about 1,000 ng / mL, about 300 ng / mL to about 1,000 ng / mL, about 400 ng / mL to about 1,000 ng / mL, about 500 ng / mL to about 1,000 ng / mL, about 600 ng / mL to about 1,000 ng / mL, about 700 ng / mL to about 1,000 ng / mL, about 800 ng / mL to about 1,000 ng / mL, about 900 ng / mL to about 1,000 ng / mL.

[0336] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor and a CYP3A4 inhibitor to the subject, wherein the menin-MLL inhibitor is administered every 12 hours at a dose between about 25 mg and about 276 mg, and wherein, after administration, the minimum observed concentration (C0) of compound A is [not specified]. minThe values ​​are approximately 100 ng / mL to approximately 5,000 ng / mL, approximately 100 ng / mL to approximately 4,000 ng / mL, approximately 100 ng / mL to approximately 3,000 ng / mL, approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 1,000 ng / mL, approximately 100 ng / mL to approximately 900 ng / mL, approximately 100 ng / mL to approximately 800 ng / mL, approximately 100 ng / mL to approximately 700 ng / mL, approximately 100 ng / mL to approximately 600 ng / mL, approximately 100 ng / mL to approximately 500 ng / mL, approximately 100 ng / mL to approximately 400 ng / mL, and approximately 100 ng / mL. g / mL to about 300 ng / mL, about 100 ng / mL to about 200 ng / mL, about 200 ng / mL to about 2,000 ng / mL, about 200 ng / mL to about 1,000 ng / mL, about 300,000 ng / mL to about 1,000 ng / mL, about 300 ng / mL to about 1,000 ng / mL, about 400 ng / mL to about 1,000 ng / mL, about 500 ng / mL to about 1,000 ng / mL, about 600 ng / mL to about 1,000 ng / mL, about 700 ng / mL to about 1,000 ng / mL, about 800 ng / mL to about 1,000 ng / mL, about 900 ng / mL to about 1,000 ng / mL.

[0337] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor and a CYP3A4 inhibitor to the subject, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg per day, and wherein, after administration, the minimum observed concentration (C0) of compound A is [not specified]. minThe values ​​are approximately 100 ng / mL to approximately 5,000 ng / mL, approximately 100 ng / mL to approximately 4,000 ng / mL, approximately 100 ng / mL to approximately 3,000 ng / mL, approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 2,000 ng / mL, approximately 100 ng / mL to approximately 1,000 ng / mL, approximately 100 ng / mL to approximately 900 ng / mL, approximately 100 ng / mL to approximately 800 ng / mL, approximately 100 ng / mL to approximately 700 ng / mL, approximately 100 ng / mL to approximately 600 ng / mL, approximately 100 ng / mL to approximately 500 ng / mL, approximately 100 ng / mL to approximately 400 ng / mL, and approximately 100 ng / mL. g / mL to about 300 ng / mL, about 100 ng / mL to about 200 ng / mL, about 200 ng / mL to about 2,000 ng / mL, about 200 ng / mL to about 1,000 ng / mL, about 300,000 ng / mL to about 1,000 ng / mL, about 300 ng / mL to about 1,000 ng / mL, about 400 ng / mL to about 1,000 ng / mL, about 500 ng / mL to about 1,000 ng / mL, about 600 ng / mL to about 1,000 ng / mL, about 700 ng / mL to about 1,000 ng / mL, about 800 ng / mL to about 1,000 ng / mL, about 900 ng / mL to about 1,000 ng / mL.

[0338] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition containing a menin-MLL inhibitor to the subject, wherein the menin-MLL inhibitor is administered every 12 hours at a dose between about 25 mg and about 276 mg, and wherein, after administration, the maximum observed concentration (C) of compound A is [not specified]. maxThe concentrations are approximately 1,000 ng / mL to approximately 200,000 ng / mL, approximately 1,000 ng / mL to approximately 150,000 ng / mL, approximately 1,000 ng / mL to approximately 100,000 ng / mL, approximately 1,000 ng / mL to approximately 50,000 ng / mL, approximately 1,000 ng / mL to approximately 40,000 ng / mL, approximately 1,000 ng / mL to approximately 30,000 ng / mL, and approximately 1,000 ng / mL to approximately 20,000 ng / mL. 000 ng / mL, about 1,000 ng / mL to about 10,000 ng / mL, about 10,000 ng / mL to about 200,000 ng / mL, about 20,000 ng / mL to about 200,000 ng / mL, about 30,000 ng / mL to about 200,000 ng / mL, about 40,000 ng / mL to about 200,000 ng / mL, about 50,000 ng / mL to about 200,000 ng / mL, about 6 0,000 ng / mL to about 200,000 ng / mL, about 70,000 ng / mL to about 200,000 ng / mL, about 80,000 ng / mL to about 200,000 ng / mL, about 90,000 ng / mL to about 200,000 ng / mL, about 100,000 ng / mL to about 200,000 ng / mL, about 10,000 ng / mL to about 50,000 ng / mL, about 10,000 ng / mL L to about 45,000 ng / mL, about 10,000 ng / mL to about 40,000 ng / mL, about 10,000 ng / mL to about 35,000 ng / mL, about 10,000 ng / mL to about 30,000 ng / mL, about 10,000 ng / mL to about 25,000 ng / mL, about 10,000 ng / mL to about 20,000 ng / mL, or about 10,000 ng / mL to about 15,000 ng / mL.

[0339] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition containing a menin-MLL inhibitor to the subject, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg per day, and wherein, after administration, the maximum observed concentration (C) of compound A is [not specified]. maxThe concentrations are approximately 1,000 ng / mL to approximately 200,000 ng / mL, approximately 1,000 ng / mL to approximately 150,000 ng / mL, approximately 1,000 ng / mL to approximately 100,000 ng / mL, approximately 1,000 ng / mL to approximately 50,000 ng / mL, approximately 1,000 ng / mL to approximately 40,000 ng / mL, approximately 1,000 ng / mL to approximately 30,000 ng / mL, and approximately 1,000 ng / mL to approximately 20,000 ng / mL. 000 ng / mL, about 1,000 ng / mL to about 10,000 ng / mL, about 10,000 ng / mL to about 200,000 ng / mL, about 20,000 ng / mL to about 200,000 ng / mL, about 30,000 ng / mL to about 200,000 ng / mL, about 40,000 ng / mL to about 200,000 ng / mL, about 50,000 ng / mL to about 200,000 ng / mL, about 6 0,000 ng / mL to about 200,000 ng / mL, about 70,000 ng / mL to about 200,000 ng / mL, about 80,000 ng / mL to about 200,000 ng / mL, about 90,000 ng / mL to about 200,000 ng / mL, about 100,000 ng / mL to about 200,000 ng / mL, about 10,000 ng / mL to about 50,000 ng / mL, about 10,000 ng / mL L to about 45,000 ng / mL, about 10,000 ng / mL to about 40,000 ng / mL, about 10,000 ng / mL to about 35,000 ng / mL, about 10,000 ng / mL to about 30,000 ng / mL, about 10,000 ng / mL to about 25,000 ng / mL, about 10,000 ng / mL to about 20,000 ng / mL, or about 10,000 ng / mL to about 15,000 ng / mL.

[0340] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor and a CYP3A4 inhibitor to the subject, wherein the menin-MLL inhibitor is administered every 12 hours at a dose between about 25 mg and about 276 mg, and wherein, after administration, the maximum observed concentration (C) of compound A is [not specified]. maxThe concentrations are approximately 1,000 ng / mL to approximately 200,000 ng / mL, approximately 1,000 ng / mL to approximately 150,000 ng / mL, approximately 1,000 ng / mL to approximately 100,000 ng / mL, approximately 1,000 ng / mL to approximately 50,000 ng / mL, approximately 1,000 ng / mL to approximately 40,000 ng / mL, approximately 1,000 ng / mL to approximately 30,000 ng / mL, and approximately 1,000 ng / mL to approximately 20,000 ng / mL. 000 ng / mL, about 1,000 ng / mL to about 10,000 ng / mL, about 10,000 ng / mL to about 200,000 ng / mL, about 20,000 ng / mL to about 200,000 ng / mL, about 30,000 ng / mL to about 200,000 ng / mL, about 40,000 ng / mL to about 200,000 ng / mL, about 50,000 ng / mL to about 200,000 ng / mL, about 6 0,000 ng / mL to about 200,000 ng / mL, about 70,000 ng / mL to about 200,000 ng / mL, about 80,000 ng / mL to about 200,000 ng / mL, about 90,000 ng / mL to about 200,000 ng / mL, about 100,000 ng / mL to about 200,000 ng / mL, about 10,000 ng / mL to about 50,000 ng / mL, about 10,000 ng / mL L to about 45,000 ng / mL, about 10,000 ng / mL to about 40,000 ng / mL, about 10,000 ng / mL to about 35,000 ng / mL, about 10,000 ng / mL to about 30,000 ng / mL, about 10,000 ng / mL to about 25,000 ng / mL, about 10,000 ng / mL to about 20,000 ng / mL, or about 10,000 ng / mL to about 15,000 ng / mL.

[0341] In some embodiments, methods for treating, preventing, or reducing the severity of colorectal cancer in subjects with this need include administering a menin-MLL inhibitor or a pharmaceutical composition comprising a menin-MLL inhibitor and a CYP3A4 inhibitor to the subject, wherein the menin-MLL inhibitor is administered at a dose of up to about 828 mg per day, and wherein, after administration, the maximum observed concentration (C) of compound A is [not specified]. maxThe concentrations are approximately 1,000 ng / mL to approximately 200,000 ng / mL, approximately 1,000 ng / mL to approximately 150,000 ng / mL, approximately 1,000 ng / mL to approximately 100,000 ng / mL, approximately 1,000 ng / mL to approximately 50,000 ng / mL, approximately 1,000 ng / mL to approximately 40,000 ng / mL, approximately 1,000 ng / mL to approximately 30,000 ng / mL, and approximately 1,000 ng / mL to approximately 20,000 ng / mL. 000 ng / mL, about 1,000 ng / mL to about 10,000 ng / mL, about 10,000 ng / mL to about 200,000 ng / mL, about 20,000 ng / mL to about 200,000 ng / mL, about 30,000 ng / mL to about 200,000 ng / mL, about 40,000 ng / mL to about 200,000 ng / mL, about 50,000 ng / mL to about 200,000 ng / mL, about 6 0,000 ng / mL to about 200,000 ng / mL, about 70,000 ng / mL to about 200,000 ng / mL, about 80,000 ng / mL to about 200,000 ng / mL, about 90,000 ng / mL to about 200,000 ng / mL, about 100,000 ng / mL to about 200,000 ng / mL, about 10,000 ng / mL to about 50,000 ng / mL, about 10,000 ng / mL L to about 45,000 ng / mL, about 10,000 ng / mL to about 40,000 ng / mL, about 10,000 ng / mL to about 35,000 ng / mL, about 10,000 ng / mL to about 30,000 ng / mL, about 10,000 ng / mL to about 25,000 ng / mL, about 10,000 ng / mL to about 20,000 ng / mL, or about 10,000 ng / mL to about 15,000 ng / mL.

[0342] In some embodiments, this disclosure relates to a method of administering compound A without a CPY3A inhibitor (e.g., a CYP3A4 inhibitor) while still achieving comparable Cmax, Cmin, and AUC as achieved by administration with a CPY3A inhibitor (e.g., a CYP3A4 inhibitor). In some embodiments, the method improves patient adherence by reducing the amount of medication administered.

[0343] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound A to said subject, wherein compound A is administered every 8 hours at a dose between about 163 mg and about 276 mg, wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A is measured from time 0 to 24 hours. (0-24) The concentration is approximately 1,000 ng*h / mL to approximately 100,000 ng*h / mL.

[0344] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 163 mg every 8 hours, wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A from time 0 to 24 hours is measured. (0-24) The concentration ranges from approximately 10,000 ng*h / mL to approximately 60,000 ng*h / mL.

[0345] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 226 mg every 8 hours, wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A from time 0 to 24 hours is measured. (0-24) The concentration ranges from approximately 14,000 ng*h / mL to approximately 65,000 ng*h / mL.

[0346] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 276 mg every 8 hours, wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A from time 0 to 24 hours is measured. (0-24) The concentration ranges from approximately 17,000 ng*h / mL to approximately 90,000 ng*h / mL.

[0347] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 163 mg every 8 hours, wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A from time 0 to 24 hours is measured. (0-24) The concentration is approximately 22,000 ng*h / mL.

[0348] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 226 mg every 8 hours, wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A from time 0 to 24 hours is measured. (0-24) The concentration is approximately 30,500 ng*h / mL.

[0349] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 276 mg every 8 hours, wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A from time 0 to 24 hours is measured. (0-24) The concentration is approximately 41,000 ng*h / mL.

[0350] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A is administered every 8 hours at a dose of about 163 mg to about 276 mg, and wherein, after administration, the minimum observed concentration (C0) of compound A is... min The concentration ranges from approximately 100 ng / mL to approximately 2,400 ng / mL.

[0351] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 163 mg every 8 hours, wherein after administration, the minimum observed concentration (C0) of compound A is... min The concentration is approximately 100 ng / mL to approximately 1,400 ng / mL.

[0352] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 226 mg every 8 hours, wherein after administration, the minimum observed concentration (C0) of compound A is... min The concentration ranges from approximately 100 ng / mL to approximately 1,600 ng / mL.

[0353] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 276 mg every 8 hours, wherein after administration, the minimum observed concentration (C0) of compound A is... min The concentration ranges from approximately 100 ng / mL to approximately 2,400 ng / mL.

[0354] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 163 mg every 8 hours, wherein after administration, the minimum observed concentration (C0) of compound A is... min The concentration was approximately 400 ng / mL.

[0355] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 226 mg every 8 hours, wherein after administration, the minimum observed concentration (C0) of compound A is...min The concentration was approximately 500 ng / mL.

[0356] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 276 mg every 8 hours, wherein after administration, the minimum observed concentration (C0) of compound A is... min The concentration was approximately 800 ng / mL.

[0357] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound A to said subject, wherein compound A is administered every 8 hours at a dose of about 163 mg to about 276 mg, and wherein, after administration, the maximum observed concentration (C0) of compound A is determined. max The concentration ranges from approximately 1,000 ng / mL to approximately 6,000 ng / mL.

[0358] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 163 mg every 8 hours, wherein, after administration, the maximum observed concentration (C0) of compound A is... max The concentration ranges from approximately 1,000 ng / mL to approximately 3,400 ng / mL.

[0359] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 226 mg every 8 hours, wherein, after administration, the maximum observed concentration (C0) of compound A is... max The concentration ranges from approximately 1,300 ng / mL to approximately 4,400 ng / mL.

[0360] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 276 mg every 8 hours, wherein, after administration, the maximum observed concentration (C0) of compound A is... max The concentration ranges from approximately 1,700 ng / mL to approximately 5,400 ng / mL.

[0361] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 163 mg every 8 hours, wherein, after administration, the maximum observed concentration (C0) of compound A is... max The concentration was approximately 1700 ng / mL.

[0362] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 226 mg every 8 hours, wherein, after administration, the maximum observed concentration (C0) of compound A is... max The concentration was approximately 2400 ng / mL.

[0363] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A to said subject, wherein compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing compound A is administered at a dose of about 276 mg every 8 hours, wherein, after administration, the maximum observed concentration (C0) of compound A is... max The concentration was approximately 3,100 ng / mL.

[0364] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound A and a CYP3A4 inhibitor to said subject, wherein compound A is administered at a dose of about 163 mg every 12 hours, and wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A from time 0 to 24 hours is measured. (0-24)The concentration was approximately 19,000 ng*h / mL to approximately 110,000 ng*h / mL.

[0365] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound A and a CYP3A4 inhibitor to said subject, wherein compound A is administered at a dose of about 163 mg every 12 hours, and wherein, following administration, the area under the plasma concentration-time curve (AUC) of compound A from time 0 to 24 hours is measured. (0-24) The concentration is approximately 43,000 ng*h / mL.

[0366] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound A and a CYP3A4 inhibitor to said subject, wherein compound A is administered at a dose of about 163 mg every 12 hours, and wherein, after administration, the minimum observed concentration (C0) of compound A is... min The concentration is approximately 200 ng / mL to approximately 2,800 ng / mL.

[0367] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound A and a CYP3A4 inhibitor to said subject, wherein compound A is administered at a dose of about 163 mg every 12 hours, and wherein, after administration, the minimum observed concentration (C0) of compound A is... min The concentration was approximately 900 ng / mL.

[0368] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound A and a CYP3A4 inhibitor to said subject, wherein compound A is administered at a dose of about 163 mg every 12 hours, and wherein, after administration, the maximum observed concentration (C0) of compound A is... max The concentration ranges from approximately 1,700 ng / mL to approximately 6,200 ng / mL.

[0369] In some embodiments, this disclosure relates to a method of treating, preventing, or reducing the severity of cancer in a subject with this need, comprising administering compound A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound A and a CYP3A4 inhibitor to said subject, wherein compound A is administered at a dose of about 163 mg every 12 hours, and wherein, after administration, the maximum observed concentration (C0) of compound A is... max The concentration was approximately 3,200 ng / mL.

[0370] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0371] A pharmaceutical composition containing a menin-MLL inhibitor, taken at least once daily, and

[0372] A pharmaceutical composition comprising a CYP3A4 inhibitor, administered at least once daily, wherein the subject has at least one of the following characteristics:

[0373] (a) Bone marrow reserve defined by the following: absolute neutrophil count (ANC) ≥1,500 / μL, platelet count ≥100,000 / μL, and hemoglobin ≥9 g / dL;

[0374] (b) Liver function defined by the following: 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);

[0375] (c) Renal function defined by: glomerular filtration rate ≥50 mL / min based on the Cockcroft-Gault formula for adults;

[0376] (d) Meets the coagulation function threshold defined by the International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN, unless the patient is receiving anticoagulation therapy, provided that PT or partial thromboplastin time (PTT) is within the therapeutic range for the intended use of the anticoagulant.

[0377] (e) Activated PTT (aPTT) ≤ 1.5 × ULN, unless the patient is receiving anticoagulation therapy, provided that PT or PTT is within the therapeutic range intended for the anticoagulant's purpose; and

[0378] (f) Potassium should be maintained at ≥4.0 mEq / L and magnesium at ≥2.0 mg / dL.

[0379] In some aspects, this disclosure relates to a method of treating, preventing, or reducing the severity of colorectal cancer in subjects with this need, comprising administering:

[0380] A pharmaceutical composition containing compound A, taken at least once daily, and

[0381] A pharmaceutical composition comprising a CYP3A4 inhibitor, administered at least once daily, wherein the subject has at least one of the following characteristics:

[0382] (a) Bone marrow reserve defined by the following: absolute neutrophil count (ANC) ≥1,500 / μL, platelet count ≥100,000 / μL, and hemoglobin ≥9 g / dL;

[0383] (b) Liver function defined by the following: 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);

[0384] (c) Renal function defined by: glomerular filtration rate ≥50 mL / min based on the Cockcroft-Gault formula for adults;

[0385] (d) Meets the coagulation function threshold defined by the International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN, unless the patient is receiving anticoagulation therapy, provided that PT or partial thromboplastin time (PTT) is within the therapeutic range for the intended use of the anticoagulant.

[0386] (e) Activated PTT (aPTT) ≤ 1.5 × ULN, unless the patient is receiving anticoagulation therapy, provided that PT or PTT is within the therapeutic range intended for the anticoagulant's purpose; and

[0387] (f) Potassium should be maintained at ≥4.0 mEq / L and magnesium at ≥2.0 mg / dL.

[0388] In some implementations, the 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%.

[0389] In some embodiments, the administration of the menin-MLL inhibitor considered for use in the methods of this disclosure is as known in the art, at least for example, WO 2017 / 112768, WO 2017 / 214367, WO 2018 / 053267, WO 2020 / 069027, WO 2021 / 207335, US 2021 / 0115018, US 2019 / 0307750, 2016 / 0339035 and Borkin et al., Cancer Cell vol.27,4(2015):589-602, the contents of each of which are incorporated herein by reference.

[0390] Particularly advantageous is the formulation of oral or parenteral compositions in easily administered and uniformly dosed unit form. As used herein, dosed unit form refers to a physically discrete unit suitable as a single dose for a subject to be treated; each unit contains a predetermined amount of the active compound (calculated to produce the desired therapeutic effect in combination with the desired drug carrier). The specifications of the dosed unit form of this disclosure are determined by and directly depend on the unique properties of the active compound and the specific therapeutic effect to be achieved.

[0391] It should be understood that the pharmaceutical composition may be included in a container, package or dispenser along with the instructions for use.

[0392] It should be understood that, since the compounds of this disclosure can further form salts, all such forms are also considered within the scope of the claimed disclosure.

[0393] Techniques for formulating and administering the disclosed compounds of this disclosure can be found in Remington: The Science and Practice of Pharmacy, 19th Edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and their pharmaceutically acceptable salts, are combined with a pharmaceutically acceptable carrier or diluent for use in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0394] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of compounds to provide such treatment or prevention as described herein, and the use of compounds to prepare pharmaceutical agents for treating or preventing such conditions. Treatment includes treatment of human or non-human animals, including rodents and other disease models.

[0395] It should be understood that throughout the description, when a composition is described as having, including, or comprising specific components, it is assumed that the composition is also substantially composed of or consisting of the described components. Similarly, when a method or process is described as having, including, or comprising specific process steps, the process is also substantially composed of or consisting of the described processing steps. Furthermore, it should be understood that the order of the steps or the order in which certain actions are performed is irrelevant as long as the invention remains operable. Moreover, two or more steps or actions can be performed simultaneously.

[0396] definition

[0397] 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. A mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject can also be a bird or poultry. In some embodiments, the subject is a human.

[0398] As used herein, the term "subject in need" refers to a subject who has a disease or has an increased risk of developing that disease. A subject in need may be a subject who has been previously diagnosed or identified with a disease or condition disclosed herein. A subject in need may also be a subject currently suffering from a disease or condition disclosed herein. Alternatively, a subject in need may be a subject with an increased risk of developing such a disease or condition relative to the general population (i.e., a subject who is susceptible to such a condition relative to the general population). A subject in need may have a treatment-resistant or drug-resistant disease or condition disclosed herein (i.e., a disease or condition disclosed herein that is unresponsive to treatment or has not yet responded to treatment). A subject may become drug-resistant at the start of treatment or may become drug-resistant during treatment. In some embodiments, a subject in need has received all known effective therapies for the disease or condition disclosed herein and has failed. In some embodiments, a subject in need has received at least one prior therapy.

[0399] As used herein, the term "treating / treat" describes the administration and care of a subject for the purpose of combating a disease, condition, or symptom, and includes the administration of the compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate or eliminate symptoms or complications of the disease, condition, or symptom. The term "treating" may also include treatment in in vitro cell or animal models.

[0400] As used in this article, the terms “preventing” or “protecting against” describe reducing or eliminating the onset of symptoms or complications of such a disease, condition, or ailment.

[0401] As used herein, the term "pharmaceuticalally acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for veterinary use as well as for human pharmaceutical use. As used in this specification and claims, "pharmaceuticalally acceptable excipient" includes one or more such excipients.

[0402] As used herein, the term "therapeutic effective amount" refers to the amount of a drug that treats, improves, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, body size, and health status; the nature and severity of the condition; and the treatment or combination of treatments chosen for administration. The therapeutic effective amount for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0403] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will become apparent from the various embodiments. The provided embodiments illustrate different components and methods for practicing this disclosure. The embodiments do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods that can be used to practice this disclosure.

[0404] 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 dose form. Unit dose form is any of a variety of forms, including, for example, capsules, IV bags, tablets, a single pump on an aerosol inhaler, or vials. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates, or isomers) in the unit dose composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that doses may sometimes need to be routinely varied according to the patient's age and condition. The dose will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal application of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. In one embodiment, the active compound is mixed with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants under aseptic conditions.

[0405] As used herein, the term “pharmaceutically acceptable” means those compounds, anionic, cationic, materials, compositions, carriers, and / or dosage forms that are suitable for use in human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and in proportion to a reasonable benefit / risk ratio.

[0406] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to a subject using many well-known methods currently used for chemotherapy. For example, the compounds of this disclosure can be injected into the bloodstream or body cavity, or administered orally or through a patch. The selected dose should be sufficient to constitute an effective treatment, but should not be high enough to cause unacceptable side effects. Close monitoring of the disease condition (e.g., the disease or symptom disclosed herein) and the patient's health status is preferred during and for a reasonable period after treatment.

[0407] Adjust the dosage and administration to provide adequate levels of the active agent or maintain the desired effect. Factors to consider include the severity of the disease state, the subject's overall health status, the subject's age, weight and sex, diet, administration time and frequency, concomitant medications, sensitivity to response, and tolerance / response to treatment.

[0408] As used herein in the specification and claims, the expression “and / or” should be understood to mean “any one or both” of the elements so combined, i.e., elements that exist together in some cases and separately in others. Multiple elements listed with “and / or” should be interpreted in the same way, i.e., “one or more” of the elements so combined. In addition to the elements specifically identified by the “and / or” clause, other elements may optionally be present, whether related to or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising,” reference to “A and / or B” may in one embodiment refer only to A (optionally including elements other than B); in another embodiment only to B (optionally including elements other than A); in yet another embodiment both A and B (optionally including other elements); and so on.

[0409] As used herein in the specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when items in a list are separated, “or” or “and / or” should be interpreted as inclusive, i.e., including multiple elements or at least one of the elements in the list, but also including more than one, and optionally including additional unlisted items. Only explicitly indicating the opposite terms, such as “only one of…” or “exact one of…”, or when used in the claims, “consisting of…” will refer to including multiple elements or exactly one element in the list of elements. In general, the term “or” as used herein, when followed by exclusive terms such as “any one of…”, “one of…”, “only one of…”, or “exact one of…”, should be interpreted only as indicating an exclusive alternative (i.e., “one or the other, but not both”).

[0410] As used herein, the term “about” and similar terms related to numerical values ​​or ranges reflect the fact that a certain level of variation exists and is accepted and tolerated in the art due to practical and / or theoretical limitations. For example, small variations tolerated due to inherent differences in how certain devices are operated and / or measurements are performed. Based on the foregoing, the expression “about” is generally used to cover values ​​within the standard deviation or standard error.

[0411] In the claims and in the description above, all conjunctions such as “comprising,” “including,” “with,” “having,” “containing,” “involving,” “holding,” “constituting,” etc., should be understood as open-ended, that is, meaning including but not limited to. As explained in Section 2111.03 of the U.S. Patent Examination Procedure Manual, only the conjunctions “constituting of” and “substantially consisting of” should be closed or semi-closed conjunctions, respectively.

[0412] As used herein in the specification and claims, when referring to a list of one or more elements, the expression "at least one" should be understood to mean at least one element selected from any one or more elements in the list, but does not necessarily include at least one of every element specifically listed in the list, nor exclude any combination of elements in the list. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by "at least one," whether related to or unrelated to those specifically identified elements. Thus, as a 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") may in one embodiment mean at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment mean at least one, optionally including more than one B, without A (and optionally including elements other than B); in yet another embodiment mean at least one, optionally including more than one A and at least one, optionally including more than one B (and optionally including elements other than B); and so on.

[0413] It should also be understood that in some methods described herein that involve more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are stated, unless the context otherwise indicates.

[0414] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended to acknowledge any of them as relevant prior art, nor does it constitute any admission of their content or dates. The invention has now been described in written form, and 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 and do not limit the scope of the appended claims.

[0415] Example

[0416] The following embodiments provide a complete disclosure and description of how those skilled in the art can implement and use the invention, and are not intended to limit the scope of what the inventors consider their invention, nor are they intended to represent all or only the experiments conducted. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but certain experimental errors and biases should be assumed. Standard abbreviations, such as those described in Table 2 below, may be used.

[0417] Table 2. Abbreviations

[0418]

[0419]

[0420]

[0421] Example 1. Treatment of colorectal cancer with compound A

[0422] Research Design:

[0423] This phase 1 / 2 study evaluated the effect of compound A in patients with colorectal cancer (CRC) who had failed at least one prior line of therapy. It included dose escalation of compound A using a rolling 6 design (phase 1a) and a signal-seeking portion (phase 1b), as well as a 2:1 (compound A: trifluuridine / tipiridine) study. Or compound A: Regorafenib Randomized signal confirmation section (Phase 2).

[0424] Patients enrolled in the Phase 1 and Phase 2 trials of the compound A arm received compound A three times daily (TID) with food for 28 consecutive days. Patients enrolled in the Phase 2 trial of the investigator-selected arm received trifluuridine / tipiridine at the dosage and schedule specified on the drug label. Or Regorafenib

[0425] Research Design Basis

[0426] The starting and subsequent dose levels were evaluated using a rolling 6-dose evaluation model (phase 1a). At the beginning, the dose levels of compound A relative to... or Prior to randomized evaluation (Phase 2), an indicator of antitumor activity at a dose determined to be safe and tolerable was evaluated in a small number of patients (Phase 1b). The two-step evaluation of antitumor activity, namely Phase 1b and Phase 2, is a method designed to limit patient exposure to compound A if no early signs of antitumor activity are found.

[0427] Phase 1

[0428] Dose escalation (Phase 1a)

[0429] The dose escalation portion of the study employed a rolling 6-dose design. Initially, up to three dose levels were evaluated during the dose escalation period.

[0430] A maximum of six patients will be enrolled in the dose cohort. Two to six patients may be enrolled in the cohort simultaneously, depending on (1) the number of patients already enrolled in the cohort; (2) the number of patients who have experienced dose-limiting toxicities (DLTs) at the doses evaluated in the cohort; and (3) the number of patients enrolled in the cohort but whose tolerability data are yet to be determined. Enrollment is paused when the six-patient cohort is full or when the study endpoint has been reached.

[0431] For example, when three participants are enrolled in the dose cohort, if all three participants have toxicity data and no DLTs are observed when the fourth participant enters, the fourth participant will be enrolled at the next highest dose level. If one or more of the first three participants have not yet obtained data and no DLTs have been observed, or if one DLT has been observed, the new participant will enter at the same dose level. Finally, if two or more DLTs have been observed, the dose level will be decreased. This process is repeated for participants 5 and 6.

[0432] If the decrement rule is not met when the next available patient is enrolled in the study, the patient whose toxicity cannot be evaluated will be replaced by the next available patient.

[0433] For a dose of compound A to be evaluated in phase 1b, a total of six patients must have received that dose, with ≤1 evaluable patient having undergone treatment-dependent leukemia (DLT). Intermediate doses and doses below 113 mg TID can be explored based on safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and efficacy data. The dose is confirmed after reviewing safety, tolerability, and PK data from patients for whom both DLT and PK are evaluable.

[0434] Signal Seeking (Phase 1b)

[0435] Once the dose was confirmed, the Phase 1b signaling phase of the study commenced. Twenty evaluable patients (6 from Phase 1a and 14 from Phase 1b) were enrolled at the confirmed dose level to investigate the antitumor activity of compound A in CRC patients by assessing disease control rate (DCR) and overall response rate (ORR). DCR was calculated once all patients had received 6 cycles of the selected compound A dose (DCR6).

[0436] Phase 1b has superiority and nullity boundaries. The superiority boundary is based on ORR, and the nullity boundary is based on DCR6. If the posterior probability of ORR > 10% is greater than 70%, the study will proceed to Phase 2. If the superiority boundary is not met (i.e., the posterior probability of ORR > 10% is not greater than 70%), the nullity boundary is evaluated. If the posterior probability of DCR6 ≤ 30% is greater than 80%, the study will not proceed to Phase 2. If the posterior probability of DCR6 ≤ 30% is not greater than 80%, the study will proceed to Phase 2.

[0437] Phase 2

[0438] One hundred and two patients were enrolled in the phase 2 signal confirmation portion of the study and were randomly assigned in a 2:1 ratio to either compound A or compound B. or The patient's response to therapy was evaluated through blinded radiological review, and the patient's progression-free survival (PFS) was followed up.

[0439] Research objectives and endpoints

[0440] Phase 1

[0441] The primary objectives of Phase I are as follows: 1) to determine the safety, tolerability, MTD, and RP2D of compound A in CRC patients; and 2) to evaluate the antitumor efficacy of compound A through investigator assessment. Secondary objectives of Phase I are to characterize the pharmacokinetic parameters of compound A. The exploratory objective of Phase I is to evaluate the antitumor efficacy of compound A.

[0442] The primary endpoints for Phase 1 included: 1) the occurrence of dose-limiting toxicities (DLTs); 2) the frequency, duration, and severity of treatment-related adverse events (TEAEs), treatment-associated TEAEs (TRAEs), and serious adverse events (SAEs); 3) the incidence and changes in clinically significant clinical laboratory abnormalities; 4) changes in other safety-related observations (including electrocardiogram (ECG) and vital signs) relative to baseline; 5) DCR; and 6) ORR. Secondary endpoints included the following pharmacokinetic parameters: maximum plasma concentration (C... max ), time to reach maximum plasma concentration (T) max ), 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 Apparent oral clearance (CL / F), apparent volume of distribution (Vz / F), and half-life (t) 1 / 2 The exploratory endpoint was to evaluate changes in the reduction of circulating tumor DNA as measured by Guardant360.

[0443] Phase 2

[0444] The primary objective of Phase 2 is to evaluate the antitumor efficacy of compound A through blinded radiological review. Secondary objectives include: 1) evaluating short-term and long-term safety; 2) characterizing the pharmacokinetic parameters of compound A; 3) assessing overall survival; 4) evaluating the antitumor efficacy of compound A through blinded radiological review; and 5) evaluating the antitumor efficacy of compound A through investigator assessment. An exploratory objective is to evaluate the antitumor efficacy of compound A.

[0445] The primary endpoint for Phase II was progression-free survival (PFS). Secondary endpoints for Phase II included: 1) the frequency, duration, and severity of TEAE, TRAE, and SAE; 2) the incidence and changes in clinically significant clinical laboratory abnormalities; 3) changes in other safety-related observations (including ECG and vital signs) relative to baseline; and 4) pharmacokinetic parameters, including: peak plasma concentration (C0.05). max ), time to reach maximum plasma concentration (T) max), 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 Apparent oral clearance (CL / F), apparent volume of distribution (Vz / F), and half-life (t) 1 / 2 5) Overall survival (OS), 6) Disease response rate (DCR), 7) Oral response rate (ORR) according to RECIST version (v) 1.1, and 8) Duration of response (DOR). The exploratory endpoint for phase 2 was the change in circulating tumor DNA reduction as measured by Guardant360.

[0446] Dosage of Compound A and its administration with food

[0447] Compound A dosage

[0448] Dosing strategies aim to maximize AUC and C min At the same time, restrict C max The starting dose of compound A is 163 mg TID, increasing to 226 mg TID, or decreasing to 113 mg TID if necessary.

[0449] These dosages are based on pharmacokinetic (PK) data from 53 patients treated in both arm A (without a potent cytochrome P450 CYP3A4 inhibitor) and arm B (with a potent CYP3A4 inhibitor) of study compound A. These data were analyzed using a preliminary population-based PK model. This model is a one-compartment PK model with first-order absorption (ka) and lag time (Tlag) describing individual PK data. The data confirmed the expected effects of combination therapy with a potent CYP3A4 inhibitor in arm B on drug elimination (k) and apparent volume of distribution (Vz / F).

[0450] This model was used to compare the predicted p-value (PK) of several doses of compound A TID in the absence of a CYP3A4 inhibitor with the predicted PK of 163 mg of compound A administered every 12 hours (q12h) in the presence of a potent CYP3A4 inhibitor (which is the recommended phase 2 dose (RP2D) for the study compound A). These data are shown in... Figure 2A -C and Table 3A. The starting dose of compound A alone, 163 mg TID, was chosen because it provides C max C min (like Figure 2A (as shown in -B) and AUC 0-24 (like Figure 2C(As shown) is approximately half that provided by 163 mg q12h in the presence of a potent CYP3A4 inhibitor; if CRC patients are more sensitive to the effects of compound A than patients with acute myeloid leukemia, the lower exposure will provide a safety margin. Based on three key PK parameters (C max C min and AUC 0-24 A dose of 276 mg TID is expected to show similar exposure to that shown with 163 mg q12h in the presence of a potent CYP3A inhibitor, such as... Figure 2A -C and as shown in Table 3A.

[0451] Table 3A. Quantitative values ​​of each of the various pharmacokinetic parameters at each dose of compound A.

[0452]

[0453]

[0454] Abbreviation: C max = Maximum observed concentration; C min =Minimum observed concentration; AUC 0-24 =Area under the plasma concentration-time curve from time 0 to 24 hours; q12h = every 12 hours; TID = 3 times a day.

[0455] Compound A is taken with food.

[0456] When compound A is administered via TID, continuous administration under fasting conditions is impractical; and given the available data, it appears unnecessary to administer compound A under fasting conditions. Furthermore, administering compound A with food in this study provides information about the effects of food.

[0457] and The dosages are used according to their respective labels, which are incorporated herein by reference.

[0458] Table 3B. Inhibitors of CYP3A4

[0459]

[0460] 1. Increase the AUC of the substrate by ≥5 times.

[0461] 2. Increases the substrate's AUC by 2 to 5 times.

[0462] Table 4. Inducers of CYP3A4

[0463]

[0464] 1. Reduce the AUC of the substrate by ≥80%.

[0465] 2. Reduces the substrate's AUC by 50%-80%.

[0466] Definitions of research period and research end

[0467] The “screening period” is up to 21 days before the first dose of the study intervention. During the “treatment period,” patients may continue to receive compound A until disease progression or until they experience unacceptable toxicity. The “safety follow-up period” is up to 30 days after the last administration of the study intervention, and, as needed, any further follow-up for persistent serious adverse events (SAEs) and / or non-serious adverse events (AEs) deemed reasonably or probably related to the study drug, until they subside or are determined by the investigator to be chronic or stable. The “survival follow-up” is up to 5 years from the end of the safety follow-up period. The “end of study” is the last contact with the last patient for survival follow-up.

[0468] Number of patients

[0469] Thirty-two patients were enrolled, with six patients enrolled in the Phase 1a cohort at up to three dose levels, and another 14 patients enrolled in the Phase 1b signal seeking portion at doses deemed safe and tolerable in Phase 1a. Under a flat prior β(0.5, 0.5) condition, for signal seeking, a sample size of 20 evaluable patients (6 from Phase 1a and 14 from Phase 1b) will provide the following operational characteristics based on the specified superiority and ineffectiveness boundaries: if the true ORR is 20% and 5%, respectively, the probability of entering the Phase 2 portion due to ORR superiority is 79% and 8%, respectively; and if the true DCR6 is 20% and 40%, respectively, the probability of not entering the Phase 2 portion due to DCR6 ineffectiveness is 63% and 5%, respectively.

[0470] Patients who discontinue treatment before the initial baseline disease assessment due to reasons other than disease progression, TEAE, or death will be replaced.

[0471] For Phase 2, 78 PFS events were required to provide 80% efficacy, with an alpha of 0.1 on one side. Compound A was assumed to improve PFS from 3 months to 5 months (hazard ratio = 0.6), and the randomization ratio was 2:1. A total of 102 patients were enrolled within 12 months and followed up for 4 months for the PFS analysis.

[0472] Research interventions applied

[0473] Patients enrolled in the Phase 1 and Phase 2 trials of the Compound A arm received Compound A. Compound A is a small molecule formulated as capsules (25 mg or 113 mg strength) or oral solution. Patients in both Phase 1 and Phase 2 trials of the Compound A arm received Compound A continuously for 28 days, starting on Day 1 of Cycle 1, with the dose and schedule determined by the assigned dose level throughout the study. Intermediate doses and doses below 113 mg TID may be explored based on emerging data. Compound A administration continued until concomitant use, progression of disease, or unacceptable toxicity occurred. Compound A was administered with food. Patients taking capsules took the calculated number of capsules with water. Patients taking the oral solution took the calculated volume of the solution and then rinsed with water, both aspirated into an oral syringe. The dose should be taken at least 6 hours after the previous dose.

[0474] Compound A dosage

[0475] The starting dose of compound A is 163 mg TID (489 mg total daily dose). The starting dose of compound A is increased or decreased according to the dose levels provided in Table 5.

[0476] Table 5. CRC Dosing Schedule Using Compound A

[0477] dose level dose -3 25mg TID -2 50mg TID -1 113mg TID <![CDATA[1 a ]]> 163mg TID 2 226mg TID 3 276mg TID

[0478] a Starting dose; TID = 3 times daily.

[0479] Chemotherapy

[0480] Patients in the chemotherapy arm of the phase 2 portion of the enrolled study received one of two different chemotherapy agents, namely or Dosage, supportive care / fluid replacement, and dosage adjustments should be performed according to the product label.

[0481] Compound A administration based on serum electrolytes

[0482] Potassium should be maintained at ≥4.0 mEq / L, and magnesium should be maintained at ≥2.0 mEq / L. For patients whose potassium and magnesium levels are below these thresholds, maintenance oral supplementation should be initiated, and the dosing instructions for Compound A provided should be followed.

[0483] DLT Definition

[0484] DLT is defined as any of the following events that, as assessed by the investigator, are at least likely to be related to the investigational drug. The DLT observation period for dose escalation purposes is the first cycle of treatment (28 days).

[0485] Hematologic toxicity events include any of the following: 1) Grade 4 neutropenia (ANC << 500 cells / mm³) for more than 7 consecutive days without growth factor support. 3 (ANC > 1500 cells / mm) did not regress to grade 2 (ANC > 1500 cells / mm) 3 1) or baseline, 2) grade 3 neutropenia (ANC < 1000 cells / mm²) 3 1) Accompanied by a single body temperature >38.3℃ (101℉) or a sustained body temperature ≥38℃ (100.4℉) for more than 1 hour; 2) Grade 4 thrombocytopenia of any duration; 3) Grade 3 thrombocytopenia (<50,000 / mm³). 3 ) Accompanied by clinically significant bleeding, or 5) Grade 4 anemia.

[0486] “Non-hematologic toxicity” includes any of the following: 1) any clinically significant grade 3 non-hematologic toxicity as defined in CTCAE version 5.0, or 2) any grade 3 QTcF prolongation (average of three ECGs ≥ 501 ms).

[0487] “General” DLT includes any of the following: 1) any hematologic or non-hematologic toxicity, regardless of the NCICTCAE grade, that leads to discontinuation of compound A or interruption of compound A for more than 7 consecutive days or receiving <75% of the planned dose intensity, or 2) any patient who needs to delay more than 2 weeks before starting cycle 2 due to TRAE is considered to have experienced DLT.

[0488] The following events are not considered DLTs: 1) Grade 2 allergic reactions requiring discontinuation of the investigational drug will not be considered DLTs and the patient will be replaced, or 2) rapidly progressive disease requiring discontinuation of compound A during a DLT will not be considered a DLT and the patient will be replaced.

[0489] Concomitant therapy with compound A

[0490] Record all previous and concomitant medications from day 1 of cycle 1 (C1D1) for 56 days until the safety follow-up visit.

[0491] Therapies and medications concomitant with compound A are prohibited.

[0492] Radiation therapy is prohibited during study participation, and the following medications and treatments are also prohibited during study participation: 1) any commercially available or investigational CRC therapy other than Compound A; 2) glucocorticoids except for physiological replacement therapy (for patients ≥18 years of age, equivalent to ≤10 mg prednisone daily, or for patients <18 years of age, equivalent to ≤10 mg / m² daily). 2Systemic immunosuppressive therapies other than ), short-term use of glucocorticoids to prevent or treat allergic and transfusion reactions or complications due to other evolving medical conditions, 3) intermediate or potent CYP3A4 inhibitors or inducers, as shown in Tables 3B and 4, or 4) medications known or suspected of prolonging the QT interval / QTc, except for medications with a low risk of QT interval / QTc prolongation when used as standard supportive therapy (e.g., diphenhydramine, famotidine, ondansetron).

[0493] During the study, any medications and treatments other than those listed above are permitted, including palliative and supportive care for disease-related symptoms. Patients should be closely monitored, and disease-related symptoms should be treated as needed.

[0494] If a documented episode of nausea or vomiting has occurred without the use of medication, antiemetic treatment may be used as appropriate and in accordance with the American Society of Clinical Oncology guidelines or equivalent guidelines.

[0495] Use LONSURF or STIVARGA as a companion therapy

[0496] Regarding prohibited and permitted concomitant medications, patients receiving LONSURF or STIVARGA should follow the relevant USPI.

[0497] Dosage adjustment

[0498] For patients requiring dose reduction, gradual reduction should be performed at single dose levels, with a maximum of two dose reductions permitted. Dose reduction is not permitted below dose level -3, and if necessary, compound A should be discontinued. Discontinuation of compound A for more than 28 days requires discussion before resuming therapy. During cycle 1, the dose may be maintained, but not reduced, unless the patient has experienced DLT. A new cycle may only begin if the patient's ANC ≥ 1,000 and platelet count ≥ 50,000. Any non-hematologic toxicities definitively caused by compound A are graded and managed as outlined in Table 6A. The management rules for dose adjustments for hematologic toxicities are outlined in Table 6B. Dose escalations beyond the patient's initial dose allocation are not permitted, and no intervention is planned after completion of study participation.

[0499] Tables 6A and 6B illustrate the dosage adjustments for compound A in response to toxicity management.

[0500] Table 6A outlines actions for non-hematologic toxicity standards.

[0501]

[0502] Table 6B outlines actions for hematological toxicity standards.

[0503]

[0504]

[0505] Abbreviations: ANC = Absolute Neutrophil Count; PLT = Platelets.

[0506] Study population

[0507] Inclusion criteria

[0508] Patients with relapsed / relapsed CRC were enrolled in this study. Patients meeting all of the following criteria were eligible for inclusion in the study:

[0509] diagnosis

[0510] Patients with microsatellite stable / skilled mismatch repair (MSS / pMMR) mCRC (which can be measured by immunohistochemistry, polymerase chain reaction or next-generation sequencing) can be radiographically measured using RECIST v1.1.

[0511] Disease status

[0512] Evidence of locally recurrent or metastatic disease based on imaging studies (e.g., computed tomography [CT], magnetic resonance imaging [MRI]) within 28 days prior to the first study drug dose. At least one measurable lesion ≥20 mm found by conventional techniques or ≥10 mm found by spiral CT or MRI, with the last imaging performed within 28 days prior to the first study drug dose. If only one measurable lesion is present and located within a previously irradiated field of view, it must have shown clear progression. The patient must have received at least one line of standard care and must have experienced disease progression following treatment with oxaliplatin, irinotecan, and bevacizumab in advanced / metastatic cases, or be intolerant to or unable to receive oxaliplatin, irinotecan, and bevacizumab. If the patient has a left-sided primary tumor of RAS wild-type, the patient must have received anti-EGFR therapy. The patient must have experienced a documented history of clearly progressive disease according to RECIST v1.1 or clinical assessment.

[0513] age

[0514] Male and female patients must be ≥18 years old.

[0515] physical fitness level

[0516] The Eastern Cooperative Oncology Group (ECOG) performance status score ranges from 0 to 1.

[0517] Previous treatments

[0518] If the patient is receiving radiation therapy, the patient must have completed a 2-week clearance period after treatment before receiving the first study drug dose, and the patient must continue to have at least one measurable lesion according to the above criteria. For patients who have received immunotherapy, at least 42 days must have passed since the previous immunotherapy (including tumor vaccines and checkpoint inhibitors), and at least 21 days must have passed before receiving chimeric antigen receptor therapy or other modified T-cell therapy. At least 7 days or 5 half-lives, whichever is longer, must have passed since completion of treatment with a biologic.

[0519] Sufficient organ function requirements

[0520] Patients must have bone marrow reserves defined by the following: an absolute neutrophil count (ANC) ≥1,500 / μL, a platelet count ≥100,000 / μL, and hemoglobin ≥9 g / dL. Patients must have liver function defined by the following: 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 the following: an estimated glomerular filtration rate ≥50 mL / min based on the Cockcroft-Gault formula for adults. Patients must meet the international normalized ratio (INR) threshold for coagulation function or a prothrombin time (PT) ≤1.5 × ULN, unless the patient is receiving anticoagulation therapy, in which case the PT or partial thromboplastin time (PTT) must be within the therapeutic range intended for the anticoagulant's purpose. Patients must have an activated PTT (aPTT) ≤1.5×ULN unless they are receiving anticoagulation therapy, in which case the PT or PTT must be within the therapeutic range intended for the anticoagulant's purpose. Patients must maintain potassium levels ≥4.0 mEq / L and magnesium levels ≥2.0 mg / dL.

[0521] contraception

[0522] From the time of study enrollment until the endpoint defined by the enrolled treatment group, women of reproductive potential must use either highly effective contraception or a dual barrier method. The endpoint for each treatment is defined as: 120 days after the last study drug dose of compound A, 2 months after the last study drug dose of Stivarga, and at least 6 months after the last study drug dose of Lonsurf. Men of reproductive age consent to use barrier contraception from the time of enrollment until 120 days after the last study drug dose.

[0523] Exclusion criteria

[0524] Patients with a known history of HIV 1 / 2 antibodies must undergo viral load testing prior to study enrollment. Patients meeting any of the following criteria are ineligible for study participation: 1) known high microsatellite instability (MSI-H) CRC; 2) history of malignant bowel obstruction requiring hospitalization within 6 months prior to enrollment; 3) history of uncontrolled ascites, defined as symptomatic ascites and / or repeated paracentesis for symptom control within the past 3 months; 4) detectable HIV viral load within the past 6 months; 5) hepatitis B (defined as positive for hepatitis B surface antigen and HBV core antibody with positive HBV DNA, or positive HBV core antibody alone with positive HBV DNA); or 6) hepatitis C (defined as positive for hepatitis C antibody and HCV RNA).

[0525] Patients must not have any of the following conditions within 6 months prior to enrollment in the study: myocardial infarction, uncontrolled / unstable angina, congestive heart failure (New York Heart Association Class II or higher), life-threatening uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.

[0526] Patients with any upper GI problems that could affect the absorption or intake of oral medications (e.g., gastric bypass surgery, gastroparesis) or cirrhosis with a Child-Pugh score of B or C are excluded.

[0527] Patients with brain metastases are excluded, except those who have completed definitive therapy, are not using steroids, have a stable neurological status for at least 4 weeks after completing definitive therapy and steroids, and have no neurological dysfunctions that would confound the evaluation of neurological and other adverse events. Patients are also excluded if they have a history or any comorbidities, treatments, laboratory abnormalities, or allergies to excipients that could confound study results, interfere with their ability to participate in the study throughout its duration, or are not in the best interests of their participation (see formulation details in the investigator's brochure).

[0528] Patients who had received prior chemotherapy, targeted small molecule therapy, or radiotherapy within 2 weeks prior to baseline, or who had not yet recovered from adverse events (AEs) associated with previously administered medications (i.e., ≤ Grade 1 or baseline), were excluded from the study.

[0529] Patients with ≤2 grade neuropathy or ≤2 grade alopecia are exceptions to this criterion and may be eligible to participate in the study. If patients have undergone major surgery, they must have fully recovered from the toxicity and / or complications of the intervention before treatment begins.

[0530] Patients who had received blood products (including platelets or red blood cells) transfusions or colony-stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 4 weeks of the first dose of the study drug were excluded.

[0531] Patients with any other known malignancy that is progressing or requires active treatment (excluding adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, cervical intraepithelial neoplasia [CIN] / cervical carcinoma in situ or melanoma in situ or ductal carcinoma in situ of the breast) are excluded. A history of other cancers is permissible, provided there has been no active disease in the past 5 years.

[0532] Patients should discontinue the use of intermediate and potent inhibitors or inducers of CYP3A4 at least 7 days prior to enrollment to avoid exclusion.

[0533] Patients who had participated in another therapeutic interventional clinical study in which they had received an investigational drug within 30 days prior to the start of Compound A were excluded. Patients may continue to receive non-interventional follow-up of their previous clinical studies.

[0534] Statistical considerations

[0535] No formal statistical hypothesis testing was conducted in Phase 1. Phase 2 will test the following primary and secondary hypotheses: 1) H0: The hazard ratio for PFS (compound A relative to the control) is greater than or equal to 1; H a 1) The risk ratio of PFS is less than 1; and 2) The risk ratio of H0:OS (compound A relative to the control) is greater than or equal to 1. a The risk ratio of OS is less than 1.

[0536] Sample size determination

[0537] The actual number of patients enrolled in Phase 1 depends on the number of dose levels at which toxicity was observed and the number of dose levels evaluated in dose escalation. Up to 32 patients were enrolled in Phase 1, with 6 patients enrolled in Phase 1a at up to 3 dose level cohorts, and an additional 14 patients enrolled in the Phase 1b signal seeking portion at doses deemed safe and tolerable in Phase 1a.

[0538] In the case of a flat prior β(0.5,0.5), for signal seeking, a sample size of 20 evaluable patients (6 from phase 1a and 14 from phase 1b) will provide the following operational characteristics based on the superiority and ineffectiveness boundaries.

[0539] • If the actual ORRs are 20% and 5%, the probabilities of entering the phase 2 portion due to ORR superiority are 79% and 8%, respectively.

[0540] • If the true DCR6 is 20% and 40%, respectively, the probability of not progressing to the stage 2 portion due to DCR6 ineffectiveness is 63% and 5%, respectively. Patients who discontinue treatment before the initial disease assessment after baseline for reasons other than disease progression, TEAE, or death will be replaced.

[0541] For Phase 2, 78 PFS events were required to provide 80% efficacy, with an alpha of 0.1 on one side. Compound A was assumed to improve PFS from 3 months to 5 months (hazard ratio = 0.6), and the randomization ratio was 2:1. A total of 102 patients were enrolled within 12 months and followed up for 4 months for the PFS analysis.

[0542] Efficacy Analysis

[0543] For Phase 1, the power analysis was performed in the evaluable population and was descriptive and graphical in nature. No formal statistical hypothesis testing was performed. Point estimates and 95% exact binomial confidence intervals for ORR and DCR6 are provided. DOR was summarized using the Kaplan-Meier method.

[0544] For Phase 2, efficacy analysis was based on the ITT population. PFS and OS were tested in a sequential manner. If treatment efficacy in PFS was statistically significant, then treatment efficacy in OS was tested. The log-rank test was used to test PFS and OS efficacy. The chi-square test was used to test ORR and DCR6. The analyzed population is summarized in Table 6C.

[0545] Table 6C. Analytical Population

[0546]

[0547] Statistical analysis

[0548] Safety and efficacy analyses are presented by study phase. Summary tables, if necessary, will be presented showing the number of observations, mean, standard deviation, median, minimum, and maximum for continuous variables, as well as the number and percentage of each category for categorical data. The Kaplan-Meier method is used to analyze the event endpoints.

[0549] Disposal

[0550] Summarize the number of patients included in each analysis set and the reasons for any exclusions. Summarize the reasons for discontinuing study treatment and / or withdrawing from study participation.

[0551] Demographic and baseline characteristics

[0552] Descriptive summaries of demographic and baseline characteristics are presented in tables.

[0553] Exposure

[0554] The total duration of treatment administration and the number of cycles initiated were summarized. For each patient, the relative dose intensity of the study drug was calculated. These data for all patients at the dose selected in phase 1b were further summarized by calculating the mean, standard deviation, median, and range of these values. The number and proportion of patients who underwent one or more dose adjustments (i.e., dose reductions) and the reasons for the adjustments were tabulated.

[0555] Efficacy Analysis

[0556] For Phase 1, the efficacy analysis was conducted in the evaluable population and was descriptive and graphical in nature. Point estimates and 95% exact binomial confidence intervals for ORR and DCR6 are provided. DOR was summarized using the Kaplan-Meier method. For Phase 2, the efficacy analysis was based on the ITT population. PFS and OS were tested in an ordinal manner. If treatment effect in PFS was statistically significant, treatment effect in OS was tested. The log-rank test was used to test PFS and OS effects. The chi-square test was used to test ORR and DCR6.

[0557] Security Analysis

[0558] All safety analyses were conducted in the safety population. Safety assessments were based on the frequency of adverse events (AEs), observation of clinically significant laboratory abnormalities, concomitant medications, vital signs, ECG, ECOG performance status, and physical examination data in the safety population.

[0559] AEs are coded and graded using the Standard Regulatory Activities Medical Dictionary version 19.0 or later. AE analysis is based on the principle of treatment-emergent AEs. A treatment-emergent AE is defined as a sign, symptom, or diagnosis that occurs or worsens after administration of the investigational drug. Whenever references are made to the analysis or summary of AEs, unless otherwise stated, they are intended to refer to treatment-emergent AEs.

[0560] TEAEs are summarized by system organ classification and preferred terminology based on the number and percentage of patients who experienced the event. A causal relationship between the occurrence of the AE and the study drug is determined (i.e., relevant, highly likely relevant, possibly relevant, unlikely to be relevant, and unrelated). If patients repeatedly experience the same AE, the event with the highest severity grade and the strongest causal relationship to the study drug is used for the purpose of incidence tabulation.

[0561] Provide a table summary or list for the following: 1) all TEAEs, 2) TEAEs classified by their relationship to the investigational drug and the highest severity level, 3) TEAEs that lead to the interruption of the investigational drug or dose reduction, 4) TEAEs that lead to the discontinuation of the investigational drug, 5) adverse events of particular concern (AESIs), and 6) SAEs.

[0562] Hematology and serology are summarized descriptively by calculating the mean, standard deviation, median, and range. Directional shifts in laboratory toxicity grades are analyzed using a standard shift table that presents the number and proportion of patients and their maximum grade shift (comparing the baseline grade to the worst post-baseline grade). For analytes without a toxicity grading scale, the shift table will use the maximum increase and / or decrease observed throughout the study to present directional shifts from baseline to above or below the laboratory standard normal range. Vital signs are summarized descriptively by calculating the mean, standard deviation, median, and range in the same manner described for laboratory values. Frequency statistics for ECOG performance status are presented.

[0563] A tabular table listing the actual values ​​in the ECG and descriptive statistics of changes relative to the baseline at specific time points.

[0564] QTc was calculated using Fridericia correction (QTcF). The formula is: QTcF = QT / (RR0.33), where RR = 60 / heart rate (heart rate per minute). Categorical analysis was performed on maximum QTcF and maximum change relative to baseline by summarizing the number and percentage of patients in each QTcF category (<450ms, 450-480ms, 481-500ms, and ≥500ms) and the change relative to baseline category (≥30ms and ≥60ms).

[0565] Pharmacokinetic analysis

[0566] Determine the plasma concentration of compound A using a validated bioanalytical assay. Calculate the following PK parameters (if applicable) using standard non-compartmental methods.

[0567] Whenever possible, calculate the following parameters for each patient based on the plasma concentration of compound A (and any related metabolites): 1) AUC 0-inf (The area under the plasma concentration-time curve, extrapolated from time 0 to infinity, is calculated as follows: AUC) 0-inf =AUC 0-t +(C last ÷λz), where C last (where λz is the final quantifiable concentration and λz is the apparent terminal 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 rule for increasing and decreasing concentration), 3) AUC 0-24 (The area under the plasma concentration-time curve from time 0 to 24 hours is estimated as the AUC of TID administration) 0-t (3 times), 4)C max (Maximum observed concentration), 5)Tmax (Time to reach maximum observed concentration), 6)t 1 / 2 ((the apparent terminal elimination half-life (where possible), where t) 1 / 2 =ln(2) / λz), 7)CL / F (apparent oral clearance), and 8)Vz / F: terminal apparent volume of distribution. Generate summary statistics of plasma concentration and PK parameters as appropriate. Summarize PK parameters by dose.

[0568] Adverse events

[0569] An AE is any adverse medical event in a patient or clinical study participant that is temporally related to the use of the investigational drug, whether or not it is considered to be related to the investigational drug. Events that meet the definition of an AE may include: 1) any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiographic scans, vital sign measurements), including those that worsen relative to baseline and are considered clinically significant in medical and scientific judgment (i.e., but not related to the progression of the underlying disease); 2) exacerbation of a chronic or intermittent pre-existing condition, including an increase in the frequency and / or intensity of the condition; 3) a new condition detected or diagnosed after administration of the investigational drug, even if it may have existed before the start of the study; 4) signs, symptoms, or clinical sequelae of suspected drug-drug interactions; and 5) signs, symptoms, or clinical sequelae of suspected overdose of the investigational drug or concomitant medication. Overdose itself is not reported as an AE / SAE unless it is an intentional overdose with possible suicidal / self-harm intent. Regardless of any sequelae, such overdose should be reported, or 6) “lack of efficacy” or “failure to achieve the expected pharmacological effect” will not be reported as AE or SAE. Such situations are documented in the efficacy assessment. However, if signs, symptoms, and / or clinical sequelae resulting from lack of efficacy meet the definition of AE or SAE, they will be reported as AE or SAE. Events that do not meet the definition of AE may include: 1) any clinically significant abnormal laboratory findings or other abnormal safety assessments related to the underlying disease, unless judged by the investigator to be more serious than expected for the participant’s condition; 2) the disease / condition under study or its progression, signs, or symptoms, unless more serious than expected for the participant’s condition; 3) medical or surgical procedures (e.g., endoscopy, appendectomy): the condition leading to the procedure is an AE; 4) situations in which no adverse medical events occurred (social and / or convenient admission); or 5) expected daily fluctuations of a pre-existing condition.

[0570] If an event is not an AE according to the definition above, it cannot be an SAE even if it meets the criteria for severity (e.g., hospitalization due to signs / symptoms of the disease under study, death due to disease progression). An SAE is defined as any adverse medical event at any dose that: 1) results in death; 2) is life-threatening (the term "life-threatening" in the definition of severity means an event in which the participant was at risk of death at the time of the event. It does not mean an event that presumably would have resulted in death if the event had been more severe); or 3) requires hospitalization or prolongs an existing hospital stay (generally, hospitalization means that the participant is held (usually involving at least an overnight stay) in a hospital or emergency room for observation and / or treatment that would be inappropriate in a physician's office or outpatient setting. Complications occurring during hospitalization are AEs. If a complication prolongs hospitalization or meets any other criteria for severity, then the SAE is considered an AE. The event is serious. An AE should be considered serious when there is doubt as to whether hospitalization has occurred or is necessary. Hospitalization due to PD, events caused by PD, and selective treatment of existing conditions that have not worsened relative to baseline are not considered AEs; 4) resulting in persistent disability / incapacity (the term disability means a substantial impairment of a person’s ability to perform normal daily activities. This definition is not intended to include experiences of relatively minor medical significance, such as simple headaches, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., an ankle sprain) that may interfere with or impair daily activities but do not constitute substantial impairment); or 5) a congenital abnormality / birth defect. Other circumstances may include: significant medical events that should be subject to medical or scientific judgment to determine whether reporting an SAE is appropriate in other circumstances, such as events that may not be immediately life-threatening or result in death or hospitalization but may endanger the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These events should generally be considered serious. Examples of such events include invasive or malignant cancer, intensive treatment for allergic bronchospasm in the emergency room or at home, blood cachexia or seizures that do not lead to hospitalization, or drug dependence or abuse.

[0571] QTc extension

[0572] CTCAE grade 2 or higher QTcF (mean of three ECGs) prolongation is classified as AESI. QTc prolongation has been observed in dogs treated with compound A. Common supportive care 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 contraindicated concomitant medications). Patients may be at risk of QT interval prolongation when combining such treatments. ECGs are recommended to be obtained before and after starting any new medication, after increasing the dose of a concomitant medication known to prolong QTc, and in patients experiencing vomiting and / or diarrhea.

[0573] For any QTcF prolongation ≥481 ms, treatment should be discontinued. QTc is calculated using Fridricia correction, and the reported QTcF is the average of three distinct values ​​from consecutive ECGs of the patient. Further management is guided by the degree of prolongation. Address any other potential causes of QT prolongation, including identifying and discontinuing other precipitating medications and actively correcting electrolyte abnormalities. Causality with compound A should be evaluated in the context of concomitant medications and electrolyte imbalances.

[0574] Strength assessment

[0575] The intensity of TEAEs was determined according to NCI CTCAE version 5.0. TEAEs not included in the NCI CTCAE were assessed based on the intensity of each AE and SAE reported during the study period and assigned to one of the following categories: 1) Grade 1 (mild): asymptomatic or mildly symptomatic; clinical or diagnostic observation only; no intervention required; 2) Grade 2 (moderate): requiring minimal, local or non-invasive intervention; limiting age-appropriate instrumental activities of daily living; 3) Grade 3 (serious or medically significant but not immediately life-threatening): requiring hospitalization or prolonged hospitalization; disabling; limiting self-care activities of daily living; 4) Grade 4 (life-threatening consequences): requiring urgent intervention; 5) Grade 5: death associated with the AE. An event was defined as serious when it met at least one of the predefined outcomes described in the definition of SAE, rather than when it was assessed as severe.

[0576] Causal relationship assessment

[0577] Assess the relationship between the investigational drug and each occurrence of each adverse event (AE) / suppressive acute injury (SAE). This relationship is determined using clinical judgment. A “reasonable probability” of a relationship indicates the presence of facts, evidence, and / or arguments suggesting a causal relationship, rather than a relationship that cannot be ruled out. Consider and investigate alternative causes such as underlying medical conditions, concomitant therapies, and other risk factors, as well as the timing of the event relative to the administration of the investigational drug. For each AE / SAE, document the review of the AE / SAE and the causality assessment. Causality assessment is one of the criteria used when determining regulatory reporting requirements.

[0578] Genetics

[0579] Genetic variations can influence a participant's response to an investigational drug, susceptibility to disease, and the severity and progression of the disease. Different responses to an investigational drug may be due to genetic determinants affecting drug absorption, distribution, metabolism, and excretion; the drug's mechanism of action; disease etiology; and / or the molecular subtype of the disease being treated. Tissue samples are collected to understand mutational status. Genetic studies may include analysis of one or more candidate genes or analysis of genetic markers across the entire genome (where applicable). Mutational status in tumor tissue is analyzed. Additional analyses may be performed if this is anticipated to contribute to a further understanding of clinical data. Samples may be analyzed as part of a multi-study evaluation of genetic factors involved in the response to compound A or this class of investigational drugs to understand the investigational disease or related conditions.

[0580] Benefit-Risk Assessment

[0581] Off-target screening assays showed that compound A had no cross-reactivity to >125 molecular targets; therefore, treatment-related adverse events (TRAEs) were expected to be due to mechanism-based target effects. Potential major target organs for toxicity identified in 28-day rat and canine toxicology studies conducted in accordance with critical good laboratory practices were the heart (ECG changes in dogs), eyes (cataracts occurred only in rats), liver, bone marrow, lymphoid tissue, male reproductive system, and female reproductive system. Safety measures were implemented to monitor and protect patients from these effects. Patients underwent regular ECG assessments throughout the study. Liver and endocrine function were routinely and frequently assessed. Conservative drug discontinuation and parameter adjustments for QT prolongation or elevated liver enzyme events were clearly outlined.

[0582] Research evaluation and procedures

[0583] Efficacy evaluation

[0584] For tumor measurements, all disease sites, target lesions, and non-target lesions were assessed at baseline. Objective disease status was recorded at each evaluation. The same assessment methods and techniques (CT scans or MRI) used to characterize each lesion were employed at each subsequent screening evaluation. Table 7 shows the disease response criteria for target lesions and non-target lesions.

[0585] All patients in the study had a measurable lesion recorded by radiology within 28 days prior to the start of the study drug treatment, defined as at least one measurable lesion with the following characteristics: 1) a longest diameter ≥10 mm on axial images of a CT scan or MRI with a reconstructed interval ≤5 mm. If the slice thickness is no more than 5 mm, the longest diameter must be at least twice the thickness; 2) a longest diameter ≤20 mm on a chest X-ray (if well-defined and surrounded by an inflatable lung); CT is preferred, even without contrast agent; or 3) a short axis of lymph nodes ≥15 mm on a CT scan (CT slice thickness ≤5 mm). If there is only one measurable lesion and it is located within a previously radiated field of view, it must have shown progression according to RECIST v1.1.

[0586] The following conditions are considered unmeasurable lesions and should not be recorded: 1) mass <10 mm, 2) lymph node short axis 10-14 mm, 3) leptomeningeal disease, 4) ascites, pleural effusion or pericardial effusion, 5) skin or pulmonary lymphatic vessels involved, 6) abdominal mass or organ enlargement found on physical examination that cannot be measured by reproducible imaging techniques, 7) osteoblastic bone disease, and 8) benign and ambiguous (“cannot be ruled out”) findings should not be included.

[0587] Target lesions and non-target lesions

[0588] Lesions were described as "target" or "non-target." All measurable lesions (up to two lesions per organ, for a total of five lesions representing all affected organs) were identified as "target lesions" and measured and recorded at screening. Target lesions were selected based on their size (i.e., those with the longest diameter) and suitability for accurate repeatable measurements. The sum of the diameters of all target lesions was calculated and recorded as the baseline sum diameter. All other lesions not classified as target lesions (or disease sites) were identified as "non-target" lesions.

[0589] Scanning program

[0590] Contrast-enhanced CT scans of the chest, abdomen, and (as clinically indicated) pelvis are the preferred method for evaluating disease status; however, contrast-enhanced MRI may be performed if the patient has a hypersensitivity reaction to iodinated contrast agents or is likely to have one. As part of the imaging conducted in this study, positron emission tomography (PET) alone is unacceptable. If PET is performed, PET alone should not be used as grounds for patient withdrawal from the study due to the potential for false positives. PET progression must be confirmed by CT / MRI. If a combined 18F-deoxyglucose (FDG) PET-CT scan is performed, the CT portion of this examination should not be replaced by a dedicated CT scan for tumor measurement unless the CT performed as part of an FDG PET-CT is documented to have the same diagnostic quality as diagnostic CT using intravenous (IV) and oral contrast agents.

[0591] CT scan procedure

[0592] For all assessments, acquire and submit CT scans using consistent scanning parameters (spacing, thickness, field of view, etc.), noting any alternative imaging or parameter variations. If a patient develops a hypersensitivity reaction to iodinated contrast agents during the study, a contrast-free chest CT scan may be performed, and contrast-enhanced MRI scans of the remaining anatomical structures must be performed as described herein. Patients should be given an oral contrast agent (positive [e.g., barium or meglumine diatrizoate] or negative [e.g., water or saline] contrast agent, according to standard field care, to ensure adequate turbidity of the intestines prior to the examination. A minimum of 320 mg iodine / mL of non-ionic IV iodide contrast agent should be used, and the contrast agent volume should conform to the product label. Use the same contrast agent at the same concentration.

[0593] MRI scan procedure

[0594] If IV contrast agents are medically contraindicated during the study, dynamic contrast-enhanced MRI is an acceptable alternative to abdominal and pelvic CT scans. MRI must be performed using a 1.5T or 3.0T scanner. Changing the scanner field strength for individual patients is not permitted during the study (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 use optimized parameters to reduce motion artifacts and maximize signal-to-noise ratio and resolution. Breath-hold imaging, fast scanning techniques, and gadolinium should be used to maximize lesion identification. In addition to abdominal and (if applicable) pelvic MRI, contrast-free CT scans or digital chest X-rays of the chest must be acquired. Patients must be scanned only with approved extracellular contrast agents (e.g., Magnevist, Dataram, Omniscan). During the study, for a given patient, all examinations acquired before and after contrast administration should use the same equipment, field strength, sequence, scan parameters, localization, angle, timing, field of view, and slice thickness.

[0595] Disease remission assessment

[0596] Disease assessment and disease response assessment are performed every 8 weeks. Response is assessed in phases 1 and 2; in phase 2, the assessment is confirmed by blinded radiographic review. Partial or complete response is confirmed by repeated tumor imaging assessment at least 4 weeks from the date of first recorded response. Tumor imaging for confirming response may be performed as early as 4 weeks after the first indication of response, or at the next scheduled scan (i.e., 8 weeks later), as clinically indicated. Participants should not discontinue treatment once clinically stable until progression is confirmed.

[0597] Table 7. Disease remission criteria for target lesions and non-target lesions

[0598]

[0599] Abbreviation: LD = Longest Diameter.

[0600] tumor tissue

[0601] If the only biopsyable lesion in a patient is an isolated target lesion, it must be suitable for core biopsy, which will not impair the assessment of tumor measurement. If the patient has only one measurable lesion, a biopsy specimen should be obtained from a non-target lesion, and the lesion should not be located in a previously irradiated field of view unless progression is confirmed.

[0602] ctDNA

[0603] Mutation landscape analysis was performed on samples collected during screening and treatment, and the correlation between changes in circulating tumor DNA (ctDNA) levels and antitumor efficacy was evaluated.

[0604] Medical history, including cancer history and genotyping

[0605] A complete medical history should be recorded during screening and updated at baseline before administering the first dose of compound A. The medical history includes CRC history, including the patient's initial diagnosis, date of diagnosis, method of diagnosis, and all prior treatments, including radiation therapy and response to such treatments. As part of the patient's cancer history, the research center should submit any local histological or cytological reports obtained prior to enrollment. HIV history should be recorded. Mutation status from archived tests should be recorded. If possible, archived flow cytometry reports should be obtained from the patient's local facility and collected.

[0606] physical examination

[0607] During screening and safety follow-up visits, all patients underwent a comprehensive physical examination. The comprehensive physical examination included general appearance, head / ears / eyes / nose / throat, lungs / chest, heart, abdomen, lymph nodes, musculoskeletal system, extremities, and neurological examination.

[0608] electrocardiogram

[0609] All ECGs were repeated three times, with each ECG taken 2 minutes apart. If necessary, the QTc was calculated using Fridricia correction (QTcF). The QTcF was calculated using the average of the three ECGs. If the patient exhibited a QTcF prolongation ≥ grade 2, clinical chemistry samples were obtained (for measuring magnesium, potassium, and calcium). For a QTcF prolongation ≥ grade 3 (based on the average of three ECGs), a single concurrent PK sample was obtained as soon as possible, and the time of the last dose of the study drug was recorded.

[0610] Patients experiencing vomiting or diarrhea are advised to have their electrolytes checked and to undergo ECG more frequently. ECGs should be taken before and after starting any new medication, and after increasing the dose of any concomitant medication known to prolong the QTc.

[0611] All collected ECGs should be read locally first to enable real-time treatment decisions.

[0612] Time period and frequency for collecting AE and SAE information

[0613] All adverse events (AEs), including study-associated injuries (SAEs), are collected from the date of informed consent until the safety follow-up visit 30 days after the last dose of Compound A. Medical events that occurred before the start of Compound A but after informed consent was obtained are recorded. All SAEs are recorded and reported. Any SAE related to the investigational drug or study participation, including death, is reported at any time after the participant has withdrawn from the study.

[0614] Pharmacokinetics of Compound A

[0615] Blood samples were collected to measure the plasma concentration (PK) of compound A. The blood samples were centrifuged to prepare plasma. The samples collected for analyzing the concentration of compound A can also be used to evaluate safety or efficacy aspects related to problems that arise during or after the study.

[0616] Survival follow-up

[0617] All patients will receive survival follow-up calls: these calls will be made monthly for 11 months following the safety follow-up visit, then the frequency will change to once every 3 months. Follow-up dates will be recorded. Patient status will be collected until the patient misses follow-up, withdraws consent, or dies. The date of death will be recorded. Additionally, any new cancer therapies started by the patient after the termination of investigational treatment will be recorded.

[0618] Research terminated

[0619] After a patient terminates their participation in the study, record the date and reason for the termination.

[0620] equivalent

[0621] Details of one or more embodiments of this disclosure are set forth in the accompanying description. Preferred methods and materials will now be described, but any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure. Other features, objects, and advantages of this disclosure will be apparent from this description and from the claims. In the specification and the appended claims, the singular form includes the plural reference unless the context expressly provides otherwise. Unless otherwise defined, all technical and scientific terms used herein will have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications referenced in this specification are incorporated herein by reference.

[0622] The foregoing description is presented for illustrative purposes only and is not intended to limit this disclosure to its precise form, which is defined by the appended claims.

Claims

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.

2. 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.

3. A method of treating, preventing or reducing the severity of colorectal cancer in a subject in need thereof, said method consisting essentially of administering to said subject a pharmaceutical composition comprising a menin-MLL inhibitor.

4. 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 single anticancer agent, wherein the single anticancer agent is a menin-MLL inhibitor.

5. The method of 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.

6. The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is Compound A or Compound B.

7. The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is Compound A.

8. The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered at least once a day.

9. The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered twice daily.

10. The method according to any one of the preceding claims, wherein the menin-MLL inhibitor is administered three times daily.

11. The method according to any one of the preceding claims, wherein the method further comprises administering a CYP3A inhibitor.

12. The method according to any one of the preceding claims, wherein the method further comprises administering a CYP3A4 inhibitor.

13. The method of claim 12, wherein the CYP3A4 inhibitor is a strong CYP3A4 inhibitor.

14. The method of claim 13, wherein the strong 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 of any one of claims 1-10, wherein the method further comprises administering cobicistat.

16. The method of any one of claims 1-10, wherein the method further comprises administering cobicistat at least once daily.

17. The method of any one of claims 1-10, wherein the method further comprises administering cobicistat once daily.

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

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

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

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

22. The method of any one of claims 1-10, wherein the subject is not receiving a CYP3A inhibitor.

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

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

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

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

27. The method of claim 22 or 23, wherein the menin-MLL inhibitor is administered at a dose of about 276 mg, and wherein the menin-MLL inhibitor is administered three times daily.

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

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

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

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

32. The method of claim 30 or 31, wherein the at least one prior line of therapy is chemotherapy, radiation therapy, immunotherapy, targeted small molecule therapy, or biological therapy (eg, monoclonal antibody therapy).

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

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

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

36. The method of any of the preceding claims, wherein the subject has disease progression following at least one prior line of therapy for colorectal cancer.

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

38. The method of any of the preceding claims, wherein the subject is not receiving an EGFR inhibitor.

39. A method of treating, preventing, or reducing the severity of colorectal cancer in a subject in need thereof, the method comprising administering: A pharmaceutical composition comprising compound A, at least once a day, A pharmaceutical composition comprising cobicistat, at least once a day, and The subject was not receiving an EGFR inhibitor.

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

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

42. The method of any one of the preceding claims, wherein the subject has had disease progression following previous colorectal cancer therapy due to resistance to the previous colorectal cancer therapy.

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

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

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

46. ​​The method of claim 44, wherein the cancer is acute lymphoblastic leukemia.

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

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

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

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

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

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

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

54. A menin-MLL inhibitor for use in the preparation of a medicament for treating colorectal cancer according to a method as claimed in any one of the preceding claims, wherein the medicament does not comprise an EGFR inhibitor.

55. A kit comprising a menin-MLL inhibitor and printed instructions for using the menin-MLL inhibitor to treat colorectal cancer in a subject.

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

57. The method of claim 56, 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, wherein after administration, the area under the plasma concentration-time curve (AUC) of Compound A from time 0 to 24 hours is (0-24) ) is about 10,000 ng*h / mL to about 60,000 ng*h / mL.

58. The method of claim 56, 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, wherein after administration, the area under the plasma concentration-time curve (AUC 1000) of Compound A from time 0 to 24 hours is about 226 mg. (0-24) ) is about 14,000 ng*h / mL to about 65,000 ng*h / mL.

59. The method of claim 56, 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, wherein after administration, the area under the plasma concentration-time curve (AUC 1000) of Compound A from time 0 to 24 hours is about 276 mg. (0-24) ) is about 17,000 ng*h / mL to about 90,000 ng*h / mL.

60. The method of claim 56, 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, wherein after administration, the area under the plasma concentration-time curve (AUC 1000) of Compound A from time 0 to 24 hours is (0-24) ) is about 22,000ng*h / mL.

61. The method of claim 56, 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, wherein after administration, the area under the plasma concentration-time curve (AUC 1000) of Compound A from time 0 to 24 hours is about 226 mg. (0-24) ) is about 30,500ng*h / mL.

62. The method of claim 56, 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, wherein after administration, the area under the plasma concentration-time curve (AUC 1000) of Compound A from time 0 to 24 hours is about 276 mg. (0-24) ) is about 41,000ng*h / mL.

63. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, the method 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 every 8 hours at a dose of about 163 mg to about 276 mg, and wherein after administration, the minimum observed concentration (C min ) is about 100 ng / mL to about 2,400 ng / mL.

64. The method of claim 63, 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, wherein after administration, the minimum observed concentration (C min ) is about 100 ng / mL to about 1,400 ng / mL.

65. The method of claim 63, 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, wherein after administration, the minimum observed concentration (C min ) is about 100 ng / mL to about 1,600 ng / mL.

66. The method of claim 63, 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, wherein after administration, the minimum observed concentration (C min ) is about 100 ng / mL to about 2,400 ng / mL.

67. The method of claim 63, 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, wherein after administration, the minimum observed concentration (C min ) is about 400ng / mL.

68. The method of claim 63, 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, wherein after administration, the minimum observed concentration (C min ) is about 500ng / mL.

69. The method of claim 63, 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, wherein after administration, the minimum observed concentration (C min ) is about 800ng / mL.

70. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, the method 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 wherein after administration, the maximum observed concentration (C max ) is about 1,000 ng / mL to about 6,000 ng / mL.

71. The method of claim 70, 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, wherein after administration, the maximum observed concentration (C max ) is about 1,000 ng / mL to about 3,400 ng / mL.

72. The method of claim 70, 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, wherein after administration, the maximum observed concentration (C max ) is about 1,300 ng / mL to about 4,400 ng / mL.

73. The method of claim 70, 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, wherein after administration, the maximum observed concentration (C max ) is about 1,700 ng / mL to about 5,400 ng / mL.

74. The method of claim 70, 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, wherein after administration, the maximum observed concentration (C max ) is about 1700ng / mL.

75. The method of claim 70, 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, wherein after administration, the maximum observed concentration (C max ) is about 2400ng / mL.

76. The method of claim 70, 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, wherein after administration, the maximum observed concentration (C max ) is about 3,100 ng / mL.

77. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, the method 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 wherein after administration, the area under the plasma concentration-time curve (AUC) of Compound A from time 0 to 24 hours is (0-24) ) is about 19,000 ng*h / mL to about 110,000 ng*h / mL.

78. The method of claim 77, wherein Compound A is administered at a dose of about 163 mg every 12 hours, and wherein after administration, the area under the plasma concentration-time curve (AUC (0-24) ) is about 43,000ng*h / mL.

79. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, the method 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 wherein after administration, the minimum observed concentration (C min ) is about 200 ng / mL to about 2,800 ng / mL.

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

81. A method for treating, preventing, or reducing the severity of cancer in a subject in need thereof, the method 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 wherein after administration, the maximum observed concentration (C max ) is about 1,700 ng / mL to about 6,200 ng / mL.

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

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