Intermittent dosing regimen of AZENOSERTIB in treatment of cancer

Abstract

Provided herein, inter alia, is a method of treating cancer using an improved intermittent dosing regimen for the administration of Azenosertib, or a pharmaceutically acceptable salt thereof, to achieve a high efficacy, safe, and tolerable dosing regimen for the treatment of many different types of cancer. In one aspect, the method of treating cancer comprises administering a daily dose (e.g., greater than about 350 mg) of Asensertib, or a pharmaceutically acceptable salt thereof, according to an improved intermittent administration cycle, where the intermittent administration cycle comprises one or more weeks of administration, and each week of administration comprises between about 2 to 7 consecutive days of administration and between about 1 to 7 days of non-administration. In some embodiments, the intermittent administration cycle is repeated, where the weeks of administration are separated by a rest of one, two, or more weeks. In some aspects, Asensertib, or a pharmaceutically acceptable salt thereof, is administered as a combination therapy.

Description

[0001] Incorporation by reference into any priority application

[0002] Pursuant to 37 CFR 1.57 and sections 4.18 and 20.6, any and all applications that identify a foreign or domestic priority claim in the Application Data Sheet filed with this application are hereby expressly incorporated by reference, including U.S. Provisional Application No. 63 / 382,830 filed on November 8, 2022, U.S. Provisional Application No. 63 / 459,543 filed on April 14, 2023, and U.S. Provisional Application No. 63 / 506,025 filed on June 2, 2023, each of which is incorporated by reference in its entirety, including any drawings. Background Art

[0003] Cell cycle checkpoints are crucial for DNA repair, ensuring that cells restore the integrity of their genome before cell replication. Normal cells repair damaged DNA during G1 arrest. Cancer cells often have a defective G1-S checkpoint and rely on a functional G2-M checkpoint for DNA repair. Wee1 is a nuclear kinase that inhibits both CDK1 and CDK2 kinases and is involved in the regulation of cell cycle checkpoints in the S phase, G2-M phase, and M phase. Wee1 inhibition causes cancer cells to undergo mitosis without repairing DNA damage, leading to premature mitotic entry and apoptosis. Wee1 inhibition increases replication stress by inducing abnormal discharge of replication origins and depletion of nucleotide pools. Wee1 is overexpressed in various cancer types, and those skilled in the art are familiar with many Wee1 inhibitors and / or degraders. For example, see WO 2019 / 173082 and WO2020 / 069105.

[0004] Azenosertib is a highly potent and selective small molecule Wee1 inhibitor with proven anti-tumor activity. Summary of the Invention

[0005] In particular, a method for treating cancer is provided herein, which uses an improved intermittent dosing regimen for the administration of asenseti or a pharmaceutically acceptable salt thereof to achieve a highly effective, safe and tolerable treatment regimen for treating many different types of cancer. For example, the improved intermittent dosing provided herein has the benefit of increasing the efficacy of asenseti therapy while reducing toxicity. The administration of large doses increases drug exposure, thereby increasing efficacy. As described in more detail throughout the application, and in the examples below, the intermittent dosing regimen is characterized by the administration of continuous asenseti or a pharmaceutically acceptable salt thereof for several days, followed by no administration (i.e., no drug treatment) for several days, which may have a higher efficacy than a continuous dosing regimen. The improved intermittent dosing regimen of asenseti provided herein increases the therapeutic index of asenseti, reduces toxicity and increases tolerance and safety.

[0006] Thus, provided herein is a way to treat tumors that initially appear to respond well to other anticancer agents, but then the response ceases and the tumor recurs in a drug-resistant form such that continued dosing provides little or no additional benefit.

[0007] In addition to reducing the toxicity caused by high doses in monotherapy, intermittent dosing also has the advantages of combination therapy. Many conventional anti-tumor agents are toxic and continuous administration may lead to cumulative toxicity. Using an intermittent dosing regimen to administer a combination of asenseti or a pharmaceutically acceptable salt thereof and one or more second therapeutic agents or pharmaceutically acceptable salts thereof (e.g., anti-tumor agents) alleviates the problem of toxicity and increases efficacy. If the same or better efficacy can be achieved without the need for continuous administration of asenseti, the subject's compliance can also be improved.

[0008] In some aspects, provided herein is a method of treating cancer comprising administering to a subject in need thereof a daily dose of equal to or greater than 350 mg of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one day without dosing.

[0009] In some aspects, provided herein is an intermittent dosing regimen for administering a high dose of asenseti or a pharmaceutically acceptable salt thereof (e.g., between about 350 mg and about 800 mg once daily, or between about 175 mg and about 400 mg twice daily), such as 5 days of administration ("dosing" day) followed by 2 days of rest ("off" day) (i.e., 5 / 2), 4 days of administration followed by 3 days of rest (i.e., 4 / 3), or 3 days of administration followed by 4 days of rest (i.e., 3 / 4), or 6 days of administration followed by 1 day of rest (i.e., 6 / 1). Alternatively, the intermittent dosing regimen of asenseti or a pharmaceutically acceptable salt thereof is also represented by an intermittent frequency of, for example, 5 days of administration / 2 days of rest, 4 days of administration / 2 days of rest, 3 days of administration / 4 days of rest, etc., administered once daily at a dose of between about 350 mg and about 800 mg, or administered twice daily at a dose of between about 175 mg and about 400 mg.

[0010] In certain embodiments, one or more dosing weeks are separated by the rest of at least one week.In certain embodiments, intermittent dosing regimen as described herein (such as 7 / 0, 6 / 1, 5 / 2, 4 / 3 or 3 / 4) carries out 2 weeks of rest followed by a week, or carries out a week of rest followed by a week, so as to achieve high efficacy, while increasing the safety and tolerance for treating cancer.In certain embodiments, intermittent dosing regimen as described herein (such as 7 / 0, 6 / 1, 5 / 2, 4 / 3 or 3 / 4) carries out 3 weeks of rest followed by a week or carries out a week of rest followed by a week, so as to achieve high efficacy, while increasing the safety and tolerance for treating cancer.In certain embodiments, intermittent dosing regimen as described herein (such as 7 / 0, 6 / 1, 5 / 2, 4 / 3 or 3 / 4) carries out more than 3 weeks of rest followed by a week, or carries out a week of rest followed by a week, so as to achieve high efficacy, while increasing the safety and tolerance for treating cancer.

[0011] In some aspects, provided herein is a method for treating cancer, comprising administering to a subject in need thereof a daily dose of equal to or greater than 100 mg of asenseti or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one day without dosing, followed by at least one week of rest. In some embodiments, the daily dose of asenseti is equal to or greater than 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, or its equivalent. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 225 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 275 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of greater than about 300 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 350 mg once daily in an intermittent dosing regimen.

[0012] In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is equal to or greater than 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, or an equivalent thereof. In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is equal to or greater than 375 mg. In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is equal to about 400 mg. In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is equal to about 425 mg. In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is equal to about 450 mg. In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is equal to about 475 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 500 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 525 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 550 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 575 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 600 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 625 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 650 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 675 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 700 mg. In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to about 725 mg. In some embodiments, the daily dose of asensettin or a pharmaceutically acceptable salt thereof is equal to about 750 mg. In some embodiments, the daily dose of asensettin or a pharmaceutically acceptable salt thereof is equal to about 775 mg. In some embodiments, the daily dose of asensettin or a pharmaceutically acceptable salt thereof is equal to about 800 mg or its equivalent.

[0013] In some embodiments, the daily dose of asensertib or a pharmaceutically acceptable salt thereof is administered once daily.

[0014] In some embodiments, the daily dose of asensertib or a pharmaceutically acceptable salt thereof is divided into two doses per day.

[0015] In some embodiments, each dosing week comprises at least four, five, or six consecutive dosing days.

[0016] In some embodiments, each dosing week comprises five consecutive dosing days and two days without dosing.

[0017] In some embodiments, each dosing week comprises four consecutive dosing days and three days without dosing.

[0018] In some embodiments, each dosing week comprises three consecutive dosing days and four days without dosing.

[0019] In some embodiments, each dosing week comprises seven consecutive dosing days and seven days without dosing.

[0020] In some embodiments, each intermittent dosing cycle is comprised between about 7 to about 10 consecutive dosing days. In some embodiments, each intermittent dosing cycle is comprised between about 8 consecutive dosing days. In some embodiments, each intermittent dosing cycle is comprised between about 9 consecutive dosing days. In some embodiments, each intermittent dosing cycle is comprised between about 10 consecutive dosing days.

[0021] In some embodiments, an intermittent dosing cycle comprises twenty-one consecutive dosing days and seven days without dosing.

[0022] In some embodiments, the intermittent dosing cycle comprises two consecutive dosing weeks.

[0023] In some aspects, provided herein is a method of treating cancer comprising administering to a subject in need thereof a daily dose of equal to or greater than 350 mg of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises at least two consecutive dosing days and at least one day without dosing.

[0024] In some embodiments, the intermittent dosing cycle comprises at least three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen consecutive dosing days. In some embodiments, the intermittent dosing cycle comprises greater than fourteen consecutive dosing days. In some embodiments, the intermittent dosing cycle comprises twenty-one consecutive dosing days. In some embodiments, the intermittent dosing cycle comprises twenty-eight consecutive dosing days. In some embodiments, the intermittent dosing cycle comprises thirty-two consecutive dosing days. In some embodiments, the intermittent dosing cycle comprises forty-two consecutive dosing days.

[0025] In some embodiments, the intermittent dosing cycle comprises at least one, two, three, four, five, six, or seven days without dosing. In some embodiments, the intermittent dosing cycle comprises one day without dosing. In some embodiments, the intermittent dosing cycle comprises between about two and seven days without dosing. In some embodiments, the intermittent dosing cycle comprises two days without dosing. In some embodiments, the intermittent dosing cycle comprises three days without dosing. In some embodiments, the intermittent dosing cycle comprises four days without dosing. In some embodiments, the intermittent dosing cycle comprises five days without dosing. In some embodiments, the intermittent dosing cycle comprises six days without dosing. In some embodiments, the intermittent dosing cycle comprises seven days without dosing.

[0026] In some embodiments, an intermittent dosing cycle comprises between about two and seven consecutive dosing days ("dosing" days) followed by between about one and seven rest periods ("off" days).

[0027] In some embodiments, an intermittent dosing cycle comprises five consecutive dosing days and two days without dosing.

[0028] In some embodiments, an intermittent dosing cycle comprises four consecutive dosing days and three days without dosing.

[0029] In some embodiments, an intermittent dosing cycle comprises three consecutive dosing days and four days without dosing.

[0030] In some embodiments, an intermittent dosing cycle comprises six consecutive dosing days and one day without dosing.

[0031] In some embodiments, the intermittent dosing cycle comprises seven consecutive dosing days and seven days without dosing.

[0032] In some embodiments, the intermittent dosing cycle comprises fourteen consecutive dosing days and seven days without dosing.

[0033] In some embodiments, an intermittent dosing cycle comprises twenty-one consecutive dosing days and seven days without dosing.

[0034] In some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to or greater than 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, or its equivalent. In some embodiments, provided herein is a high dose of asenseti or a pharmaceutically acceptable salt thereof, for example, wherein the dose is or is greater than 375 mg. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 450 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 500 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 525 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 550 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 575 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 600 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose greater than about 600 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 625 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 650 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 675 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 700 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 750 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 775 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 mg once daily in an intermittent dosing regimen.

[0035] In some embodiments, the daily dose of asensertib or a pharmaceutically acceptable salt thereof is administered once daily.

[0036] In some embodiments, the daily dose of asensertib or a pharmaceutically acceptable salt thereof is divided equally into two doses daily.

[0037] In some embodiments, the daily dose of asensertib or a pharmaceutically acceptable salt thereof is divided into three doses per day. In some embodiments, the daily dose of asensertib is divided into four doses per day.

[0038] In some embodiments, the twice daily dosage of asensertib or a pharmaceutically acceptable salt thereof is equal to or greater than 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, or the equivalent thereof.

[0039] In some embodiments, the intermittent dosing cycles are repeated.

[0040] In some embodiments, the method further comprises administering a second therapeutic agent or a pharmaceutically acceptable salt thereof during an intermittent dosing cycle. Without wishing to be bound by any particular theory, asenseti or a pharmaceutically acceptable salt thereof is administered in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof, so that subjects resistant to treatment with a single second therapeutic agent or a pharmaceutically acceptable salt thereof respond, or prevent or reduce the toxicity of the agent and / or improve the efficacy of treatment compared to a monotherapy. Combination therapy using an intermittent dosing cycle of asenseti or a pharmaceutically acceptable salt thereof further benefits administration by requiring, for example, a lower effective dose of a second therapeutic agent or a pharmaceutically acceptable salt thereof, and / or asenseti or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is also administered using an intermittent dosing cycle. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered using a continuous dosing cycle. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is an antitumor agent or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is an anticancer agent or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, assensetib or a pharmaceutically acceptable salt thereof is administered in combination with one or more second therapeutic agents or pharmaceutically acceptable salts thereof in an intermittent dosing cycle. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is a targeted therapy or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the second therapeutic agent is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin (PLD), doxorubicin, gemcitabine, cytarabine, fludarabine, 5-fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapine, 5-azacytidine, capecitabine, AraC-FdUMP

[10] (CF-10), cladribine, decitabine, hydroxyurea, oxaliplatin, dapoxetine ... oxaliplatin, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, cyclophosphamide, capecitabine, dexamethasone, etoposide, daunorubicin, ifosfamide, methotrexate and vincristine, or a pharmaceutically acceptable salt of any one of the foregoing.

[0043] In some embodiments, the second therapeutic agent is selected from a PARP inhibitor, a PD1 inhibitor, a PD-L1 inhibitor, a Bcl-2 inhibitor, a KRAS inhibitor, a CDK4 / 6 inhibitor, a HER-2 inhibitor, a HER-2 antibody conjugate, a HER-2 bispecific antibody, a KRAS inhibitor, a CDK4 / 6 inhibitor, a selective ER modulator (SERM), a selective ER degrader (SERD), an ATR inhibitor, an ATM inhibitor, a CHK1 inhibitor, a DDR inhibitor and a targeted therapeutic agent, or a pharmaceutically acceptable salt of any one of the foregoing.

[0044] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a PARP inhibitor or a pharmaceutically acceptable salt thereof, wherein the PARP inhibitor is selected from the group consisting of olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), iniparib (BSI 201), E7016 (Esai) and CEP-9722, or a pharmaceutically acceptable salt of any one of the foregoing.

[0045] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a PD1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the PD1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, spartalizumab, ABBV-181, lodapolimab, zimberelimab, toripalimab (Tuoyi), tislelizumab, camrelizumab, sintilimab (Tyvyt), GB226, AK105, HLX-10, AK103, BAT-1306, GSL-010, CS1003, LZM009 and SCT-I10A, or a pharmaceutically acceptable salt of any one of the foregoing.

[0046] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CS1001, SHR-1316, TQB2450, BGB-A333, KL-A167, KN046, MSB2311 and HLX-20, or a pharmaceutically acceptable salt of any one of the foregoing.

[0047] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the Bcl-2 inhibitor is selected from the group consisting of ZN-d5, AGP-2575, AGP-1252, venetoclax (ABT-199), navitoclax (ABT-263), S55746 / BCL201, S65487, BGB-11417, FCN-338 and AZD0466, or a pharmaceutically acceptable salt of any one of the foregoing.

[0048] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a KRAS inhibitor or a pharmaceutically acceptable salt thereof, wherein the KRAS inhibitor is selected from the group consisting of sotorasib, adagrasib, JDQ443, MRTX-1257, MRTX1133, ARS-1620, ARS-853, ARS-107, BAY-293, BI-3406, BI-2852, BMS-214662, MRTX849, MRTX849-VHL (LC2), PROTAC K-Ras degrader-1 (Compound 518, Catalog No. 2378258-52-5), Lonafarnib (SCH66336), RMC-0331, GDC-6036, LY3537982, D-1553, ARS-3248 (JNJ74699157), BI-1701963 and AU-8653 (AU-BEI-8653), or a pharmaceutically acceptable salt of any one of the foregoing.

[0049] In some embodiments, the second therapeutic agent is a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, wherein the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), lerociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, birociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002 and MM-D37K, or a pharmaceutically acceptable salt of any one of the foregoing.

[0050] In some embodiments, the second therapeutic agent is a HER-2 antibody or a pharmaceutically acceptable salt thereof, wherein the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab and ZW25, or a pharmaceutically acceptable salt of any one of the foregoing.

[0051] In some embodiments, the second therapeutic agent is a HER-2 antibody-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the HER-2 antibody-drug conjugate is selected from the group consisting of fam-trastuzumab deruxtecan-nxki, Ado-trastuzumabemtansine (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985 and XMT-1522, or a pharmaceutically acceptable salt of any one of the foregoing.

[0052] In some embodiments, the second therapeutic agent is a HER2 bispecific antibody or a pharmaceutically acceptable salt thereof, wherein the HER2 bispecific antibody is selected from the group consisting of margetuximab, ertumaxomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302 and PRS-343, or a pharmaceutically acceptable salt of any one of the foregoing.

[0053] In some embodiments, the second therapeutic agent is a selective ER modulator (SERM) or a pharmaceutically acceptable salt thereof, wherein the selective ER modulator is selected from the group consisting of tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene and lasofoxifene, or a pharmaceutically acceptable salt of any one of the foregoing.

[0054] In some embodiments, the second therapeutic agent is a selective ER degrader (SERD) or a pharmaceutically acceptable salt thereof, wherein the selective ER degrader is selected from the group consisting of fulvestrant, (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrant), ant), RAD1901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (brilanestrant, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (LSZ102), (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1 (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (rintodestrant, G1T48), D-0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azac-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (Gilbertson, NY), Destran (giredestrant, GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidine-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), OP-1250 and LY3484356, or a pharmaceutically acceptable salt of any one of the foregoing.

[0055] In some embodiments, the second therapeutic agent is an ATR inhibitor or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is selected from Gartisertib, Berzosertib, M4344, BAY1895344, Ceralasertib, Schisandrin B, Elimusertib, NU6027, Dactolisib, ETPPT-46464, Torin 2, VE-821 and AZ20, Camonsertib, CGK733, ART-0380, ATRN-119 and ATRN-212, or a pharmaceutically acceptable salt of any one of the foregoing.

[0056] In some embodiments, the second therapeutic agent is an ATM inhibitor or a pharmaceutically acceptable salt thereof, wherein the ATM inhibitor is selected from AZD7648, AZD0156, AZ31, AZ32, AZD1390, KU55933, KU59403, KU60019, CP-466722, CGK733, NVP-BEZ235, SJ573017, AZ31, AZ32, AZD1390, M4076SKLB-197, CGK733, M4076, M3541 and M4076, or a pharmaceutically acceptable salt of any one of the foregoing.

[0057] In some embodiments, the second therapeutic agent is a CHK1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the CHK1 inhibitor is selected from Prexasertib, AZD7762, Rabusertib, SCH90076MK-8776, CCT245737, CCT244747, CHIR-124, PD 407824, PD-321852, PF-00477736, GDC-0425, GDC-0575, SB-218078, V158411, LY2606368, LY2603618, SAR-020106, XL-844, UCN-01, SOL-578, IMP 10 and CBP501, or a pharmaceutically acceptable salt of any one of the foregoing.

[0058] In some embodiments, the second therapeutic agent is a targeted therapeutic or a pharmaceutically acceptable salt thereof, wherein the targeted therapeutic is bevacizumab, lenvatinib, encorafenib, and cetuximab, or a pharmaceutically acceptable salt of any one of the foregoing.

[0059] In some embodiments, the cancer is selected from the group consisting of glioblastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, head and neck cancer, leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), skin cancer, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, stomach cancer, gastrointestinal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, blood cancer, Kaposi's sarcoma, sarcoma), renal cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal cancer, ovarian cancer, osteosarcoma, sarcoma, gastrointestinal stromal tumor (GIST), pancreatic cancer, pituitary cancer, retinoblastoma, salivary gland cancer, stomach cancer, small intestine cancer, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous carcinoma, vaginal cancer, vulvar cancer, Wilms tumor, solid tumors, and liquid tumors.

[0060] In some embodiments, the cancer is a solid tumor or a hematological malignancy.

[0061] In some embodiments, the solid tumor is associated with the adrenal gland, ampulla of Vater, bile duct, bladder / urinary tract, bone, intestine, breast, cervix, CNS / brain, esophagus / stomach, eye, head and neck, kidney, liver, lung, lymph, bone marrow, ovary / fallopian tube, pancreas, penis, peripheral nervous system, peritoneum, pleura, prostate, skin, soft tissue, testis, thymus, thyroid, uterus, vulva / vagina, or other (e.g., adenocarcinoma in situ, extragonadal germ cell tumor (EGCT), mixed cancer types).

[0062] In some embodiments, the solid tumor is uterine serous carcinoma, ovarian cancer, peritoneal cancer, fallopian tube cancer, osteosarcoma, pancreatic cancer, or BRAF mutant metastatic colorectal cancer. In some embodiments, the solid tumor is uterine serous carcinoma. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is peritoneal cancer. In some embodiments, the solid tumor is fallopian tube cancer. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is pancreatic cancer. In some embodiments, the solid tumor is BRAF mutant metastatic colorectal cancer.

[0063] In some embodiments, the cancer is a hematological malignancy.

[0064] In some embodiments, the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom macroglobulinemia, or multiple myeloma (MM). In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is chronic myelomonocytic leukemia (CMML). In some embodiments, the cancer is cutaneous B-cell lymphoma. In some embodiments, the cancer is cutaneous T-cell lymphoma. In some embodiments, the cancer is Hodgkin's lymphoma. In some embodiments, the cancer is non-Hodgkin's lymphoma. In some embodiments, the cancer is Waldenstrom macroglobulinemia. In some embodiments, the cancer is multiple myeloma (MM).

[0065] In some embodiments, the subject is administered asensertib, or a pharmaceutically acceptable salt thereof, with food and / or an antiemetic.

[0066] In some embodiments, the subject is administered asenzeltib or a pharmaceutically acceptable salt thereof on an empty stomach. In some embodiments, the subject is administered asenzeltib or a pharmaceutically acceptable salt thereof at least 1 hour or 2 hours before a meal.

[0067] In some embodiments, the subject is administered an antiemetic for at least one dosing cycle with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for at least two dosing cycles with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for at least three dosing cycles with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for at least four dosing cycles with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for more than four dosing cycles with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for all dosing cycles with the administration of asensettin.

[0068] In some embodiments, the antiemetic is selected from the group consisting of: an NK1 receptor antagonist, a 5-HT3 receptor antagonist, an oral steroid, a dopamine antagonist, and a serotonin antagonist.

[0069] In some embodiments, the antiemetic is aprepitant, rolapitant, ondansetron, granisteron, dexamethasone, olanzapine, netupitant, palonosetron, and combinations thereof, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the antiemetic is a combination of netupitant and palonosetron, or pharmaceutically acceptable salts of any of the foregoing.

[0070] In some embodiments, the cancer is a platinum-refractory cancer.

[0071] In some embodiments, the cancer is a platinum-resistant cancer.

[0072] In some embodiments, the cancer is a platinum-sensitive cancer.

[0073] In some embodiments, the cancer is a PARP inhibitor-resistant cancer.

[0074] In some embodiments, the cancer is an HRRm or HRD positive cancer.

[0075] In some embodiments, the cancer is advanced or metastatic cancer.

[0076] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of 250 mg or more of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

[0077] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of 300 mg or more of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

[0078] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of 350 mg or more of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

[0079] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of 400 mg or more of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

[0080] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of 450 mg or more of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

[0081] In some embodiments, assenserti or a pharmaceutically acceptable salt thereof is administered at a daily dose equal to or greater than 450 mg of assenserti or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the PARPi or a pharmaceutically acceptable salt thereof is selected from the group consisting of olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), ieniparib (BSI 201), E7016 (Esai) and CEP-9722, or a pharmaceutically acceptable salt of any one of the foregoing.

[0083] In some embodiments, the PARPi is olaparib or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, olaparib is administered at a daily dose equal to or greater than 250 mg of asensertib or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, olaparib is administered at a daily dose equal to or greater than 300 mg of asensertib or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the intermittent dosing period of asensertib or a pharmaceutically acceptable salt thereof and the intermittent dosing period of PARPi occur during the same week.

[0087] In some embodiments, the intermittent dosing cycles of asensertib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycles of PARPi occur sequentially (eg, every other week).

[0088] In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

[0089] In some embodiments, the cancer is metastatic or unresectable.

[0090] In one aspect, provided herein is a method for treating cancer comprising administering to a subject a daily dose of 250 mg or more of asensetin or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising four consecutive dosing days and three non-dosing days, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two non-dosing days. In some embodiments, the daily dose of asensetin or a pharmaceutically acceptable salt thereof is 300 mg, 350 mg, 400 mg, or 450 mg. In some embodiments, the daily dose of asensetin or a pharmaceutically acceptable salt thereof is 400 mg. In some embodiments, the daily dose of asensetin or a pharmaceutically acceptable salt thereof is 450 mg.

[0091] In one aspect, provided herein is a method for treating cancer comprising administering to a subject a daily dose of 250 mg or more of asensert or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising three consecutive dosing days and four non-dosing days, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two non-dosing days. In some embodiments, the daily dose of asensert or a pharmaceutically acceptable salt thereof is 300 mg, 350 mg, 400 mg, or 450 mg. In some embodiments, the daily dose of asensert or a pharmaceutically acceptable salt thereof is 400 mg. In some embodiments, the daily dose of asensert or a pharmaceutically acceptable salt thereof is 450 mg.

[0092] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, equal to or greater than 200 mg in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a chemotherapeutic agent in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

[0093] In some embodiments, assenserti or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, while paclitaxel is administered at a dose of 80 mg / m2 on D1, D8, and D15 of a 28-day cycle. 2 Dosage administration.

[0094] In some embodiments, assenserti or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, and carboplatin is administered at AUC5 mg / mL*min on D1 of a 21-day cycle.

[0095] In some embodiments, assenserti or a pharmaceutically acceptable salt thereof is administered at a dose of 400 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, and PLD is administered at a dose of 40 mg / m2 on D1 of a 28-day cycle. 2 Dosage administration.

[0096] As used in this application, the terms "about" and "approximately" are used as equivalents. Any number used in this application, whether or not there is "about", is intended to encompass any normal fluctuations understood by one of ordinary skill in the relevant art.

[0097] Other features, objects and advantages are apparent in the following detailed description. However, it should be understood that although embodiments are indicated, they are given in an illustrative and non-restrictive manner. According to the embodiments, various changes and modifications within the scope of this disclosure will become apparent to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] The figures described below, which together form the drawings, are for purposes of illustration only and are not limiting.

[0099] Figure 1A This graph shows changes in tumor volume in the human ovarian cancer cell line SKOV3 model, measured at intervals up to approximately 21 days after the start of treatment, at 60 mg / kg (continuous) of asenzel. Asenzel was found to be more effective when administered intermittently at 80 mg / mL for three cycles of 5 days on / 2 days off.

[0100] Figure 1B is a graph showing the percent change in body weight in subjects treated with continuous (60 mg / kg) or intermittent dosing (80 mg / kg, 5 days on / 2 days off for 3 cycles) of asensertib in an ovarian cancer model (SKOV3), as measured up to approximately 21 days after initiation of treatment.

[0101] Figure 1C Figure 2 is a graph showing changes in tumor volume in the A427 model of non-small cell lung cancer (NSCLC). At comparable cumulative doses, higher intermittent doses of assensertin (e.g., 56 mg / kg or 112 mg / kg) were compared with lower continuous doses (e.g., 40 mg / kg or 80 mg / kg, respectively) over four cycles of 5 days on / 2 days off, demonstrating greater efficacy.

[0102] Figure 1D Is displayed with Figure 1C A graph of the percent change in body weight corresponding to the treatment regimens in

[00155] , as measured up to approximately 28 days after initiation of treatment.

[0103] Figure 1E Figure 2 is a graph showing changes in tumor volume in the A427 model of non-small cell lung cancer (NSCLC). At comparable cumulative doses, a higher intermittent dose of assensertin (e.g., 100 mg / kg) was compared to a lower continuous dose (e.g., 60 mg / kg) over 4 cycles of 4 days on / 3 days off, and was found to be more effective, as measured until approximately 25 days after initiation of treatment.

[0104] Figure 1F Is displayed with Figure 1E A graph of the percent change in body weight corresponding to the treatment regimens in

[00155] , as measured up to approximately 25 days after initiation of treatment.

[0105] Figure 1G It is a graph showing changes in tumor volume in the breast ductal carcinoma HCC1569 model. At a comparable cumulative dose, a higher intermittent dose of Asensertib (e.g., 100 mg / kg) was compared with a lower continuous dose (e.g., 60 mg / kg) under an intermittent dosing regimen (3 cycles of 4-day dosing / 3-day rest and 3-day dosing / 4-day rest) and found to be more effective, as measured until about 24 days after initiation of treatment. It was found that the efficacy of the two intermittent dosing frequencies of 4-day dosing / 3-day rest and 3-day dosing / 4-day rest were comparable.

[0106] Figure 1H Is displayed with Figure 1G A graph of the percent change in body weight corresponding to the treatment regimens in

[00155] , as measured up to approximately 24 days after initiation of treatment.

[0107] Figure 1I It is a graph showing the changes in tumor volume according to intermittent asenosteril treatment (based on a dose of 80 mg / kg, 7-day on / 7-day off schedule, 3 cycles) in the ovarian cancer OVCAR3 model.

[0108] Figure 1J Is displayed with Figure 1I A graph of the percent change in body weight corresponding to the treatment regimens in

[00155] , as measured up to approximately 32 days after initiation of treatment.

[0109] Figure 2A It is a graph showing changes in tumor volume after intermittent treatment based on the same regimen of 5-day dosing / 2-day rest at a once-daily dose in the ovarian cancer OVCAR3 model compared to twice-daily doses (e.g., once daily 80 mg / kg vs. twice-daily 40 mg / kg and once daily 100 mg / kg vs. twice-daily 50 mg / kg). For the same cumulative dose, each once-daily dose is more effective than each twice-daily dose.

[0110] Figure 2B Is displayed with Figure 2A The percent change in body weight corresponding to the treatment regimen in [Diabetes+], as measured up to approximately 22 days after initiation of treatment.

[0111] Figure 2C This is a graph showing changes in tumor volume in the OVCAR3 model of ovarian cancer. Intermittent doses of 80 mg / kg (5 days on / 2 days off), 90 mg / kg (4 days on / 3 days off), or 100 mg / kg (4 days on / 3 days off) were compared with a continuous dose of 60 mg / kg once daily. The higher intermittent doses (5 days on / 2 days off and 4 days on / 3 days off) were more effective than the lower continuous dose.

[0112] Figure 2D Is displayed with Figure 2C A graph of the percent change in body weight corresponding to the treatment regimens in

[00155] , as measured up to approximately 24 days after initiation of treatment.

[0113] Figure 2EIt is a graph showing changes in tumor volume in the ovarian cancer OVCAR3 model. Assenseti was administered at about 100 mg / kg in two intermittent dosing regimens for three cycles each, the intermittent dosing regimen being 4 days of dosing / 3 days of stopping or 3 days of dosing / 4 days of stopping. In addition, 60 mg / kg was administered continuously for 24 days, with a cumulative dose of 1440 mg. At a dose of about 100 mg / kg for three cycles of 4 days of dosing / 3 days of stopping, the cumulative dose was 1200 mg, and at a dose of about 100 mg / kg for three cycles of 3 days of dosing / 4 days of stopping, the cumulative dose was 900 mg. The two intermittent doses showed higher efficacy than continuous administration.

[0114] Figure 2F Is displayed with Figure 2E A graph of the percent change in body weight corresponding to the treatment regimens in

[00155] , as measured up to approximately 24 days after initiation of treatment.

[0115] Figure 3 Figure 2 is a graph showing the PK / PD correlation of assensertin and Wee1 target engagement. The graph shows that inhibition of pCDK1 increases Wee1 target engagement. Increased drug dose or exposure also results in increased Wee1 target engagement. Doses greater than about 300 mg once daily exhibit the highest AUC, excellent target engagement, and at least a 50% reduction in p-CDK1 levels.

[0116] Figure 4 Provided are models and skin biopsy staining that demonstrate a decrease in p-CDK1 levels associated with Wee1 inhibition. CDK1 phosphorylation (pCDK-1) is mediated by Wee1. Wee1 inhibition by assensertib is expected to result in pCDK1 inhibition. For example, the Y15 residue is not phosphorylated, and CDK1 levels in skin biopsies were confirmed to be reduced relative to baseline in terms of p-CDK1 levels after treatment.

[0117] Figure 5A Figure 2 is a graph of assensertin plasma concentrations on Day 1 of Cycle 1 from subjects receiving 5-day dosing / 2-day rest at 350 mg once daily or 175 mg twice daily.

[0118] Figure 5B Figure 2 is a graph of assensertin plasma concentrations on Days 11 / 12 of Cycle 1 from subjects receiving 5-day on / 2-day off 350 mg once daily or 175 mg twice daily.

[0119] Figure 5C Figure 2 is a graph of assensertin plasma concentrations on Day 1 of Cycle 1 from subjects who received the continuous dosing regimen versus subjects who received the intermittent once daily 350 mg dosing regimen of 5 days on / 2 days off.

[0120] Figure 5D Figure 2 is a graph of assensertin plasma concentrations on Days 11 / 12 or 15 of Cycle 1 from subjects who received the continuous dosing regimen versus subjects who received the intermittent once daily 350 mg dosing regimen of 5 days on / 2 days off.

[0121] Figure 5E Figure 2 is a graph of assensertin plasma concentrations on Day 1 of Cycle 1 from subjects who received the continuous dosing regimen versus subjects who received the intermittent twice daily 175 mg dosing regimen of 5 days on / 2 days off.

[0122] Figure 5F Figure 2 is a graph of assensertin plasma concentrations on Days 11 / 12 or 15 of Cycle 1 from subjects who received the continuous dosing regimen versus subjects who received the intermittent 175 mg dosing regimen of 5 days on / 2 days off.

[0123] Figures 6A-6G is an exemplary graph showing tumor growth inhibition or tumor volume reduction in the following MDA-MB-436 triple negative breast cancer tumor model when treated with a WEE1 inhibitor alone or in combination with a PARPi: Parental MDA-MB-436 (TP53, BRCA1 mutant) ( Figure 6A and Figure 6D )、MDA-MB-436NirR(TP53, BRCA1m skipped generations)( Figure 6B and Figure 6E ), and MDA-MB-436OlaR (TP53, BRCA1m skipping inheritance) ( Figure 6C 、 Figure 6F and Figure 6G ).

[0124] Figures 7A-7D The results showed that after treatment with asenzel and / or niraparib, HBCx-10 patient-derived xenograft (PDX) models ( Figure 7A ), HBCx-17 PDX model ( Figure 7B ), BRCA1 mutation CTG-0703PDX model ( Figure 7C ) and BRCA1 / 2WT CTG-2213PDX models ( Figure 7D ) is an example of a reduction in tumor volume.

[0125] Figure 8 Demonstration of a reduction in tumor volume following treatment with asensertib and / or talazoparib in the OVCAR3 xenograft model.

[0126] Figure 9A is a pie chart showing the percentage of the population of subjects with different types of cancer who participated in the assensertin monotherapy trial.

[0127] Figure 9B is the steady-state exposure relative to the amount of asenzeltib (AUC 0-24 ) showing a comparison between continuous and intermittent dosing regimens.

[0128] Figure 9C is a graph comparing maximum concentration (Cmax) levels for continuous and intermittent dosing.

[0129] Figure 9D The maximum concentration (Cmax) levels of asenzeltiboosted monotherapy were compared with those of the intermittent dosing regimen relative to the steady-state exposure (AUC 0-24 ) picture.

[0130] Figure 9E is a graph showing the percent change (%) from baseline in confirmed response rate following asensertib monotherapy.

[0131] Figure 9F is a graph showing the percent change (%) from baseline in objective response rate in ovarian cancer and uterine serous carcinoma populations following continuous and intermittent dosing schedules of asensertib monotherapy.

[0132] Figure 9G is a graph showing the percent change (%) from baseline in best overall response to asensertib monotherapy through week 30 of treatment.

[0133] Figure 9H is a graph showing overall response rate (ORR%) and median progression-free survival (MPFS%) in ovarian cancer.

[0134] Figure 9I is a graph showing overall response rate (ORR%) and median progression-free survival (MPFS%) in uterine serous carcinoma.

[0135] Figure 10A This graph shows changes in tumor volume measured at intervals up to approximately 24 days after the start of treatment in the human ovarian cancer cell line OVCAR3 animal model, with monotherapy of asenzel 60 mg / kg or 80 mg / kg qd (intermittent dosing of 5 days on / 2 days off), monotherapy of paclitaxel 20 mg / kg qw, monotherapy of carboplatin 25 mg / kg qw, or combination therapy of asenzel + paclitaxel or asenzel + carboplatin (same dose, same dosing schedule as monotherapy).

[0136] Figure 10B Is displayed as Figure 10A Figure 2 shows the changes in body weight of subjects treated with the monotherapy and combination therapy.

[0137] Figure 11A is a waterfall plot showing the maximum change (%) in the sum of target lesion diameters in subjects administered a combination of asensenerg and paclitaxel.

[0138] Figure 11B is a waterfall plot showing the maximum change (%) in the sum of target lesion diameters in subjects administered a combination of asensertib and carboplatin.

[0139] Figure 11C is a waterfall plot showing the maximum change (%) in the sum of target lesion diameters in subjects administered a combination of asensertib and gemcitabine.

[0140] Figure 12 Depicted are Kaplan-Meier curves for progression-free survival in subjects administered combination therapy of asensertib with paclitaxel, carboplatin, gemcitabine, or pegylated liposomal doxorubicin (PLD). DETAILED DESCRIPTION

[0141] definition

[0142] To make the present disclosure more readily understood, certain terms are first defined as follows. Additional definitions of the following terms and other terms are set forth throughout the specification.

[0143] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. Unless otherwise indicated, all patents, applications, published applications and other publications cited herein are incorporated by reference in their entirety. Where multiple definitions exist for a term in this article, those in this section shall prevail unless otherwise stated.

[0144] As used herein, the term "about" has its ordinary meaning as understood by those skilled in the art, and thus indicates that a value includes the inherent variation of error for the method employed to determine the value or the variation that exists between multiple determinations.

[0145] As used herein, the term "modify" or "alter" or any form thereof means a modification, change, substitution, deletion, replacement, removal, variation, or conversion.

[0146] As used herein, the terms "function" and "functional" have their ordinary meaning as understood by those skilled in the art, and thus refer to a biological, enzymatic, or therapeutic function.

[0147] As used herein, the term "endogenous" has its ordinary meaning as understood by those skilled in the art, and therefore refers to the natural or wild-type nature of a gene, protein, or cell. In some embodiments, an endogenous gene is the wild-type sequence of the gene. In some embodiments, an endogenous protein is the wild-type sequence of the protein. In some embodiments, an endogenous protein function is the wild-type function and activity level of the protein. In some embodiments, an endogenous cell is a wild-type cell.

[0148] The term "mutation" has its ordinary meaning as understood by those skilled in the art and refers to an alteration in a gene sequence. In some embodiments, a cell has multiple mutations. In some embodiments, the mutation is located in a coding region of the genome. The size of the mutation can range from a single nucleotide to a large segment of a chromosome comprising multiple genes. In some embodiments, at least one mutation is silent and has no significant effect on gene expression or function. In some embodiments, at least one mutation has an effect on gene expression or function, such as gene amplification, overexpression, or increased copy number. In some embodiments, at least one mutation is silent and has no significant effect on protein expression or function. In some embodiments, at least one mutation has a small effect on protein expression or function. In some embodiments, at least one mutation has a moderate effect on protein expression or function. In some embodiments, at least one mutation has a large effect on protein expression or function. In some embodiments, at least one mutation prevents protein expression or function. Non-limiting examples of mutations include insertions, deletions, truncations, substitutions, duplications, transfers, and inversions. In some embodiments, the mutation is "somatic" or occurs in somatic cells and is not heritable. In some embodiments, a subset of somatic cells in an organism has at least one mutation that other somatic cells do not have. In some embodiments, the mutation is "germline" or occurs in germ cells and is heritable.

[0149] As disclosed herein, mutations can be monitored by a variety of sequencing, expression, or functional assays. Non-limiting examples include: DNA sequencing, RNA sequencing, DNA hybridization, protein sequencing, targeted genome sequencing, whole exome sequencing, whole genome sequencing, ATAC-sequencing, Sanger sequencing, PCR, qPCR, RT-PCR, RT-qPCR, next generation sequencing, protein truncation assay, DNA microarray, heterodimer analysis, denaturing gradient gel electrophoresis, nucleotide sequencing, single-stranded conformational polymorphism, restriction enzyme digestion assay, fluorescence in situ hybridization (FISH), comparative genomic hybridization, restriction fragment length polymorphism, amplification refractory mutation system PCR, nested PCR, multiplex ligation-dependent probe amplification, single-stranded conformational polymorphism, and oligonucleotide ligation assay. Mutations can also be monitored by a variety of antibody-based methods using biological samples, including but not limited to Western blotting, fluorescence-activated cell sorting, immunofluorescence, immunohistochemistry, immunocytochemistry, immunoprecipitation, enzyme-linked immunosorbent assays, radioimmunoassays, and electrochemiluminescence assays.

[0150] The term "cancer" is used herein in its normal biological sense and is understood by those skilled in the art. Thus, it can include cancer of any cell type, such as, but not limited to, glioblastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma and other brain cancers, leukemia, skin cancer, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, Hodgkin's lymphoma, hematological cancer, hematological malignancies, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung cancer, lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal cancer, ovarian cancer, osteosarcoma, pancreatic cancer, pituitary cancer, retinoblastoma, salivary gland cancer, stomach cancer, small intestine cancer, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous carcinoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, solid tumors, or liquid tumors.

[0151] As used herein, the term "tumor" has its usual meaning as understood by those skilled in the art, and refers to the abnormal growth of cells or tissues. In certain embodiments, the tumor is benign. In certain embodiments, the tumor is malignant. When the tumor metastasizes or spreads to other areas of the body, the tumor becomes cancer. As used herein, the term "solid tumor" has its usual meaning as understood by those skilled in the art, and refers to an abnormal tissue mass that does not contain a liquid area or cyst. Non-limiting examples of solid tumors include sarcomas, epithelial cell cancers (carcinomas), or lymphomas. Many cancer tissues can form solid tumors, such as but not limited to breast cancer, brain cancer, lung cancer, liver cancer, stomach cancer, spleen cancer, colon cancer, kidney cancer, pancreatic cancer, prostate cancer, uterine cancer, skin cancer, head cancer, neck cancer, sarcomas, neuroblastomas, or ovarian cancer. Unless the context clearly indicates that what is desired is a more specific meaning, the terms "cancer" and "tumor" can be used interchangeably.

[0152] As used herein, the term "cell" has its ordinary meaning as understood by those skilled in the art and may refer to any cell type. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0153] As used herein, the terms "individual," "subject," or "patient" have their ordinary meaning as understood by those skilled in the art, and thus include human and non-human mammals. The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes, but is not limited to, primates (including simians (chimpanzees, apes, monkeys) and humans), cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, or pigs. In some embodiments, the subject can be a human. In some embodiments, the subject can be a child and / or an infant. In other embodiments, the subject can be an adult.

[0154] As used herein, the term "cancer treatment" has its ordinary meaning as understood by those skilled in the art and refers to a therapeutic modality (e.g., surgery and / or radiation) or an anticancer agent, such as a small molecule, compound, protein, or other agent, used to treat, inhibit, or prevent cancer. Non-limiting examples of common classes of anticancer agents that can be used with any one or more of the alternatives described herein include alkylating agents, anti-EGFR antibodies, anti-Her-2 antibodies, antimetabolites, vinca alkaloids, platinum-based agents, anthracyclines, topoisomerase inhibitors, taxanes, antibiotics, immunomodulators, immune cell antibodies, interferons, interleukins, HSP90 inhibitors, antiandrogens, antiestrogens, antihypercalcemic agents, apoptosis inducers, Aurora kinase inhibitors, Bruton's tyrosine kinase inhibitors, kinase inhibitor), calcineurin inhibitor, CaM kinase II inhibitor, CD45 tyrosine phosphatase inhibitor, CDC25 phosphatase inhibitor, CHK kinase inhibitor, cyclooxygenase inhibitor, bRAF kinase inhibitor, cRAF kinase inhibitor, Ras inhibitor, cyclin-dependent kinase inhibitor, cysteine protease inhibitor, DNA intercalator, DNA strand break agent, E3 ligase inhibitor, EGF pathway inhibitor, farnesyltransferase inhibitor, Flk-1 kinase inhibitor, glycogen synthase kinase-3 (GSK3) inhibitor, histone deacetylase (HDAC) inhibitor, I-κB-α kinase inhibitor, imidazotetrazinone, insulin tyrosine kinase inhibitor, c-Jun-N-terminal kinase inhibitor kinase (JNK) inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, MDM2 inhibitors, MEK inhibitors, ERK inhibitors, MMP inhibitors, mTor inhibitors, NGFR tyrosine kinase inhibitors, p38 MAP kinase inhibitors, p56 tyrosine kinase inhibitors, PDGF pathway inhibitors, phosphatidylinositol 3-kinase inhibitors, phosphatase inhibitors, protein phosphatase inhibitors, PKC inhibitors, PKC delta kinase inhibitors, polyamine synthesis inhibitorsinhibitors), PTP1B inhibitors, protein tyrosine kinase inhibitors, SRC family tyrosine kinase inhibitors, Syk tyrosine kinase inhibitors, Janus (JAK-2 and / or JAK-3) tyrosine kinase inhibitors, retinoids, RNA polymerase II elongation inhibitors, serine / threonine kinase inhibitors, sterol biosynthesis inhibitors inhibitors), VEGF pathway inhibitors, chemotherapeutic agents, alitretinoin, hexamethylmelamine, aminopterin, aminolevulinic acid, amsacrine, asparaginase, atrasentan, bexarotene, carboquone, demecolcine, efaproxiral, elsamitrucin, etoglucid, hydroxycarbamide, leucovorin, lonidamine, lucanthone, masoprocol, methylaminolevulinate aminolevulinate), mitoguazone, mitotane, oblimersen, omacetaxine, pegaspargase, porfimer sodium, prednimustine, adenovirus vector site-coding gene (sitimageneExamples of chemotherapeutic agents that can be used for cancer treatment include carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin, doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triamcinolone, 5-azacitidine, capecitabine, AraC-FdUMP

[10] (CF-10), cladribine, decitabine, hydroxyurea and oxaliplatin, or a pharmaceutically acceptable salt of any one of the foregoing. Other examples of chemotherapeutic agents useful in cancer treatment include azacitidine, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, carboplatin, cytarabine, cyclophosphamide, cladribine, cisplatin, capecitabine, decitabine, dexamethasone, etoposide, fludarabine, gemcitabine, daunomycin, doxorubicin, ifosfamide, methotrexate, and vincristine, or a pharmaceutically acceptable salt of any of the foregoing.

[0155] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not invalidate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (e.g., 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting the compound with an organic acid, such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxoglutaric acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as an ammonium salt, an alkali metal salt (e.g., a sodium salt, a potassium salt, or a lithium salt), an alkaline earth metal salt (e.g., a calcium salt or a magnesium salt), a carbonate salt, a bicarbonate salt, a salt with an organic base (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine), and a salt with an amino acid (e.g., arginine and lysine).

[0156] It is understood that where compounds disclosed herein have unfilled valencies, the valencies are filled with hydrogen or an isotope thereof, for example, hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0157] It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages resulting from higher metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, reference to a compound herein encompasses all potential isotopic forms unless the context clearly indicates otherwise.

[0158] It should be understood that the compounds described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of the compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in a solvated form with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). In other embodiments, the compounds described herein exist in a non-solvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvents and can be formed with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.) during a crystallization procedure. When the solvent is water, a hydrate is formed, and when the solvent is alcohol, an alcoholate is formed. In addition, the compounds provided herein can exist in a non-solvated form as well as a solvated form. In general, for the purposes of the compounds and methods provided herein, the solvated form is considered to be equivalent to the non-solvated form.

[0159] The term "break" or "break day" refers to a period of time or a non-dosing day, a day of discontinuation of therapy, or a rest day when asenzelti or a pharmaceutically acceptable salt thereof is not administered. For example, a break refers to a period after a dosing cycle or a period of time between dosing weeks when asenzelti administration is suspended.

[0160] The term "platinum resistant cancer" refers to cancer that initially responds to treatment with drugs containing the metal platinum, but then recurs within a certain period of time. For example, ovarian cancer that recurs within 6 months of treatment is considered platinum resistant.

[0161] The term "platinum refractory cancer" refers to a cancer that progresses during platinum-based therapy (eg, progression within 90 days of the last administered dose of any line of platinum-based regimen).

[0162] As used herein, a "therapeutically effective amount" or "effective amount" refers to the amount of an active compound (e.g., ascension or a pharmaceutically acceptable salt thereof) that elicits an indicative biological or therapeutic response (i.e., alleviation of symptoms). For example, a therapeutically effective amount of this ascension compound, salt, or composition is the amount required to prevent, alleviate, or improve the symptoms of a disease or condition, or to prolong the survival of the treated subject or to slow the progression of the disease. This response can occur in a tissue, system, animal, or human, and includes alleviating the signs or symptoms of the disease or condition being treated. The therapeutically effective dose can be further adjusted depending on the route of administration, the type of subject (including but not limited to such factors as age, weight, diet, and concomitant medications). For example, a therapeutically effective amount of an ascension compound, salt, or composition can be an amount or dose that results in: a reduction, alleviation, or disappearance of one or more symptoms caused by cancer; a reduction in tumor size or volume; tumor elimination; and / or long-term disease stabilization (growth arrest) of a tumor. Furthermore, an effective amount of an assencil compound, salt, or composition can be an amount that results in a decrease in Wee1 activity and / or phosphorylation (e.g., phosphorylation of CDK1). Reduction in WEE1 activity is known to those skilled in the art and can be determined by analyzing WEE1 intrinsic kinase activity and downstream substrate phosphorylation.

[0163] As used herein, the term "equivalent" or "equivalents thereof" of assencillin or a pharmaceutically acceptable salt thereof refers to a compound containing the same active ingredient(s) (e.g., a salt or ester of a therapeutic moiety), optionally in substantially the same dosage form and route of administration, and at substantially the same strength or concentration. As used herein, the term "equivalent" includes "pharmaceutical alternatives" containing the same therapeutic moiety or its precursor (but not necessarily in the same amount or dosage form), or salt or ester, while "therapeutic equivalents" are bioequivalent and have similar clinical effects and safety profiles. Equivalents do not necessarily contain the same inactive ingredients; they may differ in properties such as shape, release mechanism, labeling, scoring, or excipients (including color, flavor, or preservatives). As used herein, the term "equivalent dose" refers to an effective amount of a compound, such as assencillin, in another salt or ester form, as described above.

[0164] As used herein, "cumulative dose" refers to the total dose resulting from repeated exposure over one or more dosing cycles during the treatment period.

[0165] As used herein, "exposure" refers to the level of drug achieved in the body (e.g., in plasma). Response can be assessed in terms of efficacy or safety. Exposure and response are parameters that determine the dose that strikes a balance between drug efficacy and adverse events.

[0166] As used herein, "AUC" or "area under the curve" refers to the area under the curve of plasma concentration of a drug versus time after dosing, and gives an understanding of the extent of exposure to the drug and its clearance from the body.

[0167] As used herein, "Cmax" refers to the maximum concentration of a drug in the blood, or in a target organ, after administration of a dose.

[0168] As used herein, the term "dosing regimen" refers to the manner in which the Asencil compound is administered to a subject, including the route of administration, dosage, and dosing interval. A dosing regimen may comprise "periodic" administration, during which a specific dose (e.g., 300 mg) is administered at regular intervals (e.g., once a day) for a specific period of time (e.g., three days). A dosing regimen may comprise "intermittent" administration, during which one or more dosing parameters (e.g., dosage and / or dosage interval) are changed or altered. For example, an intermittent dosing period may comprise a continuous administration period, followed by a "rest" period, during which the Asencil compound is not administered or is administered at a reduced dosage and / or at a lower frequency. A dosing regimen may further comprise one or more repeated cycles of an intermittent dosing regimen.

[0169] As used herein, "dosing cycle or intermittent dosing cycle" refers to an intermittent dosing week, wherein each dosing week includes consecutive dosing days (e.g., two to seven days) followed by no dosing days (e.g., one to seven days). In some embodiments, an intermittent dosing cycle includes one or more dosing weeks, and each dosing week includes at least two consecutive dosing days and at least one drug-free day. In some embodiments, an intermittent dosing cycle includes one or more dosing weeks, and each dosing week includes at least three consecutive dosing days and at least one drug-free day.

[0170] As used herein, a "dosing week" refers to a week of an intermittent dosing regimen that includes dosing days and non-dosing days. For example, a dosing week has 2 days of dosing and 5 days of rest; 3 days of dosing and 4 days of rest; 4 days of dosing and 3 days of rest; 5 days of dosing and 2 days of rest; 6 days of dosing and 1 day of rest; or 7 days of dosing and 7 days of rest. As used herein, a "dosing day" refers to a day on which a patient is administered asensettin (alone or in combination), and a "day off" refers to a day on which a patient is not administered asensettin (alone or in combination).

[0171] When a range of values is provided, it is understood that the upper and lower limits of the range and every intervening value between the upper and lower limits are encompassed within the embodiments.

[0172] Unless expressly stated otherwise, the terms and phrases used in this application and variations thereof (especially in the appended claims) should be understood as open-ended and not restrictive. As an example, the term "including" should be interpreted to mean "including, without limitation," "including but not limited to," etc.; as used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having" should be interpreted as "having at least"; the term "include" should be interpreted as "includes but is not limited to"; to); the term “example” is used to provide illustrative examples of the items being discussed rather than an exhaustive or limiting list thereof; and the use of terms such as “preferably,” “preferred,” or “desired,” or “desirable,” and words of similar import should not be construed to imply that certain features are critical, necessary, or even essential to structure or function, but are intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Furthermore, the term “comprising” should be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a compound, composition, or device, the term “comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0173] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art can translate from the plural to the singular and / or from the singular to the plural as appropriate to the context and / or application. Various singular / plural permutations and combinations may be explicitly set forth herein for the sake of clarity. The indefinite article "a" or "an" does not exclude plurality. The mere fact that certain measures are recited in mutually different clauses does not indicate that a combination of these measures cannot be used to advantage. Any reference to an element in the claims should not be construed as limiting the scope.

[0174] Detailed description

[0175] In particular, a method of treating cancer is provided herein using an improved intermittent dosing regimen for administering assensertin to achieve a highly effective, safe, and tolerable dosing regimen for treating many different types of cancer. A method of treating cancers that have become resistant to conventional therapies and have recurred is provided herein. A high-dose intermittent dosing regimen is provided herein that unexpectedly increases efficacy compared to continuous dosing. Advantages of the present disclosure may increase tolerability by reducing toxicity.

[0176] In some aspects, provided herein is a method of treating cancer comprising administering to a subject in need thereof a daily dose of equal to or greater than 350 mg of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one day without dosing.

[0177] In some aspects, provided herein is a method of treating cancer comprising

[0178] A daily dose of 100 mg or more of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, is administered to a subject in need thereof according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one rest day, followed by at least one week of rest.

[0179] In some aspects, provided herein is a method of treating cancer comprising administering to a subject in need thereof a daily dose of equal to or greater than 350 mg of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises at least two consecutive dosing days and at least one day without dosing.

[0180] Asenseti is a Wee1 inhibitor and antitumor agent

[0181] Asensettin (also identified as ZN-c3) (including pharmaceutically acceptable salts) is a potent small molecule inhibitor of Wee1 kinase, which plays a role in the G2 / M cell cycle checkpoint, preventing cells from entering mitosis before DNA damage is repaired. Inhibition of Wee1 using asensettin reduced tumors in a variety of tumor cell lines and xenograft models. Incorporated herein by reference are WO 2019 / 173082 for methods of making asensettin and its salts and compositions, WO 2019 / 173082 and WO 2021 / 231653 describing the compound asensettin and methods of using it to treat cancer.

[0182] Table 1. Structure and chemical name of Asenseti

[0183]

[0184] Wee1 acts to prevent cells with altered DNA from replicating. The primary downstream target of the Wee1 family of kinases is the CDK1-cyclin B1 complex, also known as mitotic promoting factor (MPF). Wee1 phosphorylates CDK1 at Tyr15, which inhibits the MPF complex until mitosis.

[0185] Methods for treating cancer

[0186] Route of administration

[0187] In some embodiments, the effective dose of Asenseti or its pharmaceutically acceptable salt is oral, intravenous, or subcutaneous administration. In some embodiments, the effective dose of Asenseti or its pharmaceutically acceptable salt is oral administration. Alternative suitable techniques for administering an effective dose of Asenseti or its pharmaceutically acceptable salt known to those skilled in the art can also be used, including but not limited to oral, rectal, pulmonary, external, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injection. In other embodiments, Asenseti or its pharmaceutically acceptable salt and / or chemotherapeutic agent or its pharmaceutically acceptable salt can be administered orally.

[0188] In some embodiments, the effective dose of asenseti or a pharmaceutically acceptable salt thereof is administered orally, intravenously, subcutaneously, intrathecally, intramuscularly, intracavitaryly, intrapleurally, intralesionally, or intraarterially. In some embodiments, the effective dose of asenseti or a pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously. In some embodiments, the effective dose of asenseti or a pharmaceutically acceptable salt thereof is administered intrathecally, intramuscularly, intracavitaryly, intrapleurally, intralesionally, or intraarterially.

[0189] In some embodiments, the effective dose of asensertib or a pharmaceutically acceptable salt thereof is administered orally.

[0190] Dosage cycle

[0191] The treatment methods provided herein include administering asenseti or a pharmaceutically acceptable salt thereof and / or a second therapeutic agent (e.g., an anti-tumor or anti-cancer agent, a chemotherapeutic agent, etc.) (including a pharmaceutically acceptable salt) in a suitable dosing schedule. For example, asenseti or a pharmaceutically acceptable salt thereof and / or a second therapeutic agent or a pharmaceutically acceptable salt thereof described herein can be administered once or more times daily (e.g., once, twice, three times, or four times a day) for a period of days, followed by no administration for a period of days. This dosing cycle (consisting of dosing days and no administration days) can then be repeated.

[0192] The dosing cycle is included in the treatment period. In some embodiments, the treatment period is 1 month, 2 months, 3 months, 4 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In some embodiments, the treatment period is one year, two years, or longer. In some embodiments, the dosing cycle is 3, 5, 7, 10, or 14 days. In some embodiments, the dosing cycle is 7 days, 14 days, 21 days, 28 days, 36 days, 42 days, or longer.

[0193] Continuous administration

[0194] In some embodiments, asenseti or its pharmaceutically acceptable salt is administered in a continuous dosing regimen, which includes, for example, once a day or twice a day administration. In some embodiments, the daily dose of asenseti or its pharmaceutically acceptable salt is 300 mg or greater than about 300 mg, for example, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, or its equivalent. In some embodiments, the daily dose of asenseti or its pharmaceutically acceptable salt is equal to or greater than 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, or its equivalent. Suitable dosages of asensertib or a pharmaceutically acceptable salt thereof may also be in the form of equivalent dosages (eg, the compound in the form of other salts).

[0195] In some embodiments, the daily dose is divided into two doses daily. In some embodiments, the twice-daily dose of asensetib or a pharmaceutically acceptable salt thereof is equal to or greater than 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, or their equivalents. In some embodiments, the daily dose is divided into three or four doses daily.

[0196] Intermittent dosing

[0197] An alternative dosing method is an intermittent dosing regimen. Intermittent dosing regimens overcome some of the limitations of continuous fixed-dose regimens by taking into account important determinants of therapeutic response, including pharmacokinetic variability, variability in the response of various tissue types to asensertin or its pharmaceutically acceptable salts, and quantitative exposure-response relationships (e.g., AUC or Cmax). Other factors include the development of drug resistance.

[0198] Furthermore, pharmacokinetic (PK) variability can impact the outcomes of combination therapies that are widely used to target many different types of cancer.

[0199] With intermittent dosing, drug exposure levels may rise and fall between doses. When the dosing interval is shorter than the time required for complete elimination of the drug, plasma drug levels accumulate. Steady-state plasma drug levels are dose- and clearance-dependent. With intermittent dosing, the average plasma concentration, as it rises or falls, depends on the dose and dosing interval.

[0200] Small doses at frequent intervals result in smaller fluctuations in plasma levels than larger doses administered at longer intervals. For example, for assensertin, which has a mean half-life of 8 hours, it may take three to five half-lives to reach steady state during intermittent dosing, i.e., 1 to 2 days.

[0201] In some aspects, provided herein is a method of treating cancer, comprising administering to a subject in need thereof a daily dose of equal to or greater than 350 mg of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one rest day.

[0202] Provided herein is an intermittent dosing regimen for administering a high dose of asenseti or a pharmaceutically acceptable salt thereof, for example, between about 350 mg and about 800 mg once daily, or between about 175 mg and about 400 mg twice daily, such as 5 days of administration ("dosing day") followed by 2 days of non-dosing ("off") days, i.e., 5 / 2; 4 days of administration followed by 3 days of non-dosing, i.e., 4 / 3; 3 days of administration followed by 4 days of non-dosing, i.e., 3 / 4; 6 days of administration followed by 1 day of non-dosing; 7 days of administration followed by 7 days of non-dosing. Alternatively, the intermittent dosing regimen of asenseti or a pharmaceutically acceptable salt thereof is also represented by an intermittent frequency of, for example, 5 days of administration / 2 days of non-dosing, 4 days of administration / 3 days of non-dosing, 3 days of administration / 4 days of non-dosing, 6 days of administration / 1 day of non-dosing, 7 days of administration / 7 days of non-dosing, etc., administered once daily at a dose of between about 350 mg and about 800 mg, or twice daily at a dose of between about 175 mg and about 400 mg.

[0203] In certain embodiments, one or more dosing weeks are separated by at least one week's rest. In certain embodiments, the intermittent dosing regimen described herein (e.g., 7 / 0, 6 / 1, 5 / 2, 4 / 3, or 3 / 4) is followed by a week's rest for 2 weeks, or a week's rest for one week, thereby achieving high efficacy while increasing the safety and tolerability of treating cancer.

[0204] Additionally, provided herein is a method for treating cancer comprising administering to a subject in need thereof a daily dose of equal to or greater than 100 mg of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one day without dosing, followed by at least one week of rest.

[0205] For example, in some embodiments, the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to or greater than 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, or its equivalent. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose equal to or greater than about 350 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 375 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 425 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 450 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 475 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 500 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 525 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 550 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 575 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 600 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 625 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 650 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 675 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 700 mg once daily in an intermittent dosing regimen.

[0206] In some embodiments, the daily dose of Asenseti or its pharmaceutically acceptable salt is equal to or greater than 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, or its equivalent. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 200 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 225 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 250 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 275 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose greater than about 300 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 325 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 350 mg once daily in an intermittent dosing regimen.

[0207] Asenseti or its pharmaceutically acceptable salt is administered once daily or divided equally into twice daily doses. For example, in some embodiments, Asenseti or its pharmaceutically acceptable salt twice daily is equal to or greater than 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, or its equivalent. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 175 mg twice daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 200 mg twice daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 225 mg twice daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 250 mg twice daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 275 mg twice daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 mg twice daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 325 mg twice daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 350 mg twice daily in an intermittent dosing regimen.

[0208] In some embodiments, the daily dose is divided into three or four doses per day. In some embodiments, the daily dose is divided into three doses per day. In some embodiments, the daily dose is divided into four doses per day.

[0209] Each dosing week comprises at least one to seven dosing days. Each dosing week comprises at least one to seven days without dosing. In some embodiments, each dosing week comprises at least two, three, four, five, or six consecutive dosing days. In some embodiments, each dosing week comprises five consecutive dosing days and two days without dosing. In some embodiments, each dosing week comprises four consecutive dosing days and three days without dosing. In some embodiments, each dosing week comprises three consecutive dosing days and four days without dosing. In some embodiments, each dosing week comprises six consecutive dosing days and one day without dosing. In some embodiments, each dosing week comprises seven consecutive dosing days and seven days without dosing.

[0210] Each intermittent dosing cycle contains between about 7 and about 10 consecutive dosing days. In some embodiments, each intermittent dosing cycle contains about 8 consecutive dosing days. In some embodiments, each intermittent dosing cycle contains about 9 consecutive dosing days. In some embodiments, each intermittent dosing cycle contains about 10 consecutive dosing days. In some embodiments, each intermittent dosing cycle contains about 14 consecutive dosing days. In some embodiments, each intermittent dosing cycle contains about 21 consecutive dosing days. In some embodiments, each intermittent dosing cycle contains about 28 consecutive dosing days. In some embodiments, each intermittent dosing cycle contains about 32 consecutive dosing days. In some embodiments, each intermittent dosing cycle contains about 42 consecutive dosing days.

[0211] In addition, the intermittent dosing cycle comprises more than one continuous dosing week. In some embodiments, the intermittent dosing cycle comprises two continuous dosing weeks. In some embodiments, the intermittent dosing cycle comprises three continuous dosing weeks. In some embodiments, the intermittent dosing cycle comprises four continuous dosing weeks. In some embodiments, the intermittent dosing cycle comprises five continuous dosing weeks. In some embodiments, the intermittent dosing cycle comprises six continuous dosing weeks. In some embodiments, the intermittent dosing cycle comprises between 6 and 12, 12 to 24, 24 to 48, or longer continuous dosing weeks.

[0212] In some aspects, provided herein is a method for treating cancer, comprising administering to a subject in need thereof a daily dose of equal to or greater than 350 mg of asensertib or a pharmaceutically acceptable salt thereof, or an equivalent thereof, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises at least two consecutive dosing days and at least one day without dosing. In some embodiments, the intermittent dosing cycle comprises at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen consecutive dosing days. The no-dosing days provided in the intermittent dosing cycle comprise at least two, three, four, five, six, or seven days without dosing. In some embodiments, the intermittent dosing cycle comprises no dosing between about one and seven days. In some embodiments, the intermittent dosing cycle comprises one day without dosing. In some embodiments, the intermittent dosing cycle comprises two days without dosing. In some embodiments, the intermittent dosing cycle comprises three days without dosing. In some embodiments, the intermittent dosing cycle comprises four days without dosing. In some embodiments, the intermittent dosing cycle comprises five days without dosing. In some embodiments, the intermittent dosing cycle comprises six days without dosing. In some embodiments, the intermittent dosing cycle comprises seven days without dosing.

[0213] In some embodiments, the intermittent dosing cycle includes continuous dosing days ("dosing" days) between about two and seven days, followed by a rest period ("drug withdrawal" days) between about one and seven days. In some embodiments, the intermittent dosing cycle includes five continuous dosing days and two days of no dosing. In some embodiments, the intermittent dosing cycle includes four continuous dosing days and three days of no dosing. In some embodiments, the intermittent dosing cycle includes three continuous dosing days and four days of no dosing. In some embodiments, the intermittent dosing cycle includes six continuous dosing days and one drug withdrawal day. In some embodiments, the intermittent dosing cycle includes seven continuous dosing days and seven days of no dosing.

[0214] Furthermore, in some embodiments, the intermittent dosing cycle comprises fourteen consecutive dosing days and seven days without dosing.

[0215] Provided herein is a method wherein the daily dose of asenseti or a pharmaceutically acceptable salt thereof is equal to or greater than 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, or its equivalent. In some embodiments, provided herein is a method for administering a high dose of asenseti or a pharmaceutically acceptable salt thereof, for example, wherein the dose is or is greater than 375 mg. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 450 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered at a dose of about 525 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 500 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 550 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 575 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 600 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 650 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 700 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 750 mg once daily in an intermittent dosing regimen. In some embodiments, Asenseti or its pharmaceutically acceptable salt is administered at a dose of about 775 mg once daily in an intermittent dosing regimen. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 800 mg once daily. In some embodiments, asenseti or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose greater than about 800 mg once daily.

[0216] In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is divided equally into twice daily doses. In some embodiments, the daily dose of asensetti or a pharmaceutically acceptable salt thereof is divided equally into three or four doses daily.

[0217] In certain embodiments, the intermittent dosing cycle is repeated throughout the treatment duration. In certain embodiments, the dosage and duration are variable. In certain embodiments, treatment begins with a high dose and is reduced after one or more intermittent cycles. In certain embodiments, treatment is maintained at the same dose during the intermittent cycles.

[0218] Administration of food and / or antiemetics

[0219] In some embodiments, the subject is administered asencil or a pharmaceutically acceptable salt thereof with food and / or an antiemetic (e.g., to minimize nausea and improve gastrointestinal tolerability). In some embodiments, the subject is administered asencil or a pharmaceutically acceptable salt thereof on an empty stomach. In some embodiments, the subject is administered an antiemetic in conjunction with the administration of asencil or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the subject is administered asenzeltib or a pharmaceutically acceptable salt thereof on an empty stomach. In some embodiments, the subject is administered asenzeltib or a pharmaceutically acceptable salt thereof at least 1 hour or 2 hours before a meal.

[0221] In some embodiments, the subject is administered an antiemetic for at least one dosing cycle with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for at least two dosing cycles with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for at least three dosing cycles with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for at least four dosing cycles with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for more than four dosing cycles with the administration of asensettin. In some embodiments, the subject is administered an antiemetic for all dosing cycles with the administration of asensettin.

[0222] In some embodiments, the antiemetic is selected from the group consisting of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, an oral steroid, a dopamine antagonist, and a serotonin antagonist, or a pharmaceutically acceptable salt of any of the foregoing.

[0223] In some embodiments, the antiemetic is aprepitant, rolapitant, ondansetron, ganisone, dexamethasone, olanzapine, netupitant, palonosetron, and combinations thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0224] In some embodiments, the antiemetic is aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic is rolapitant or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic is ondansetron or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic is ganisone or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic is dexamethasone or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic is olanzapine or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic is netupitant or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic is palonosetron. In some embodiments, the antiemetic is a combination of netupitant and palonosetron, or a pharmaceutically acceptable salt of either of the foregoing.

[0225] Cancer type

[0226] In some embodiments, the subject in need of treatment has cancer.

[0227] In some embodiments, the cancer is breast cancer, brain cancer, lung cancer, liver cancer, stomach cancer, spleen cancer, colon cancer, kidney cancer, pancreatic cancer, prostate cancer, uterine cancer, skin cancer, head cancer, neck cancer, sarcoma, neuroblastoma, or ovarian cancer. In some embodiments, the cancer is glioblastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma and other brain cancers, leukemia, skin cancer, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, Hodgkin's lymphoma, a blood cancer, a hematological malignancy, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung cancer, lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal cancer, ovarian cancer, osteosarcoma, pancreatic cancer, pituitary cancer, retinoblastoma, salivary gland cancer, stomach cancer, small intestine cancer, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous carcinoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, a solid tumor, or a liquid tumor.

[0228] In some embodiments, the cancer is a solid tumor or a hematological malignancy.

[0229] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is selected from endometrial cancer, ovarian cancer (e.g., HGSOC), uterine cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, melanoma, colorectal cancer, prostate cancer, testicular cancer, gallbladder cancer, bladder cancer, breast cancer (e.g., invasive breast cancer, triple-negative breast cancer (TNBC)), lung cancer (e.g., NSCLC), esophagogastric cancer, gastric cancer, esophageal cancer, renal cancer (e.g., pRCC, ccRCC, chromophobe cell carcinoma RCC), head and neck cancer, osteosarcoma cancer, pancreatic cancer, brain cancer, adenoid cystic carcinoma (ACC), mesothelioma, liver cancer, glioblastoma (GBM), low-grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), bile duct cancer, thyroid cancer, thymoma (thymona), uveal melanoma and BRAF mutant metastatic colorectal cancer.

[0230] In some embodiments, the solid tumor is endometrial cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer, germ cell cancer, or stromal cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the epithelial ovarian cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is uterine serous cancer. In some embodiments, the cancer is peritoneal cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is gallbladder cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is invasive breast cancer. In some embodiments, the cancer is triple-negative breast cancer (TNBC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is esophagogastric cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is renal cancer (e.g., pRCC, ccRCC, chromophobe cell carcinoma RCC). In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is glioblastoma (GBM). In some embodiments, the cancer is low-grade glioma (LGG). In some embodiments, the cancer is paraganglioma (PCPG). In some embodiments, the cancer is adenoid cystic carcinoma (ACC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is bile duct cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is thymoma. In some embodiments, the cancer is uveal melanoma. In some embodiments, the cancer is BRAF mutant metastatic colorectal cancer.

[0231] In some embodiments, the solid tumor is associated with the adrenal gland, ampulla of Vater, bile duct, bladder / urinary tract, bone, intestine, breast, cervix, CNS / brain, esophagus / stomach, eye, head and neck, kidney, liver, lung, lymph, bone marrow, ovary / fallopian tube, pancreas, penis, peripheral nervous system, peritoneum, pleura, prostate, skin, soft tissue, testis, thymus, thyroid, uterus, vulva / vagina, or other (e.g., adenocarcinoma in situ, extragonadal germ cell tumor (EGCT), mixed cancer types).

[0232] In some embodiments, the cancer is a hematological malignancy.

[0233] In some embodiments, the cancer is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, or multiple myeloma (MM).

[0234] In some embodiments, the cancer is a platinum-refractory cancer or a platinum-resistant cancer.

[0235] In some embodiments, the cancer is a platinum-resistant cancer.

[0236] Combination therapy

[0237] Provided herein is a method for using a combination of asencolor or a pharmaceutically acceptable salt thereof with one or more second therapeutic agents (e.g., combination therapy) or a pharmaceutically acceptable salt thereof in an intermittent dosing regimen. Combination therapy refers to a clinical intervention in which a subject is treated with two or more therapeutic agents (e.g., asencolor or a pharmaceutically acceptable salt thereof, and a second therapeutic agent) or a pharmaceutically acceptable salt thereof. In some embodiments, asencolor or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof are administered in parallel. In some embodiments, asencolor or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof are administered sequentially. In some embodiments, asencolor or a pharmaceutically acceptable salt thereof is administered before the second therapeutic agent or a pharmaceutically acceptable salt thereof. In other embodiments, asencolor or a pharmaceutically acceptable salt thereof is administered after the second therapeutic agent or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, assenseti or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof are administered simultaneously. In some embodiments, assenseti or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof are administered sequentially (e.g., the first regimen is administered before any dose of the second regimen). In some embodiments, two or more therapeutic agents or pharmaceutically acceptable salts thereof are administered alternately (e.g., assenseti is administered before administering a certain dose of a second therapeutic agent or a pharmaceutically acceptable salt thereof, followed by administering assenseti or a pharmaceutically acceptable salt thereof again, and so on). In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered before administering a certain dose of assenseti or a pharmaceutically acceptable salt thereof, followed by administering the second therapeutic agent or a pharmaceutically acceptable salt thereof again, and so on). In some embodiments, assenseti or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof are administered in overlapping dosing cycles.

[0239] In some embodiments, the combination therapy in the form of an intermittent dosing cycle does not necessarily require that the individual agents be administered together (or even simultaneously) in the form of a single composition. In some embodiments, the two or more therapeutic agents of the combination therapy (e.g., assensert or a pharmaceutically acceptable salt thereof and a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof) are administered to the subject via separate routes of administration (e.g., one agent orally and the other agent intravenously) and / or separately (e.g., in the form of separate compositions) at different time points. In some embodiments, assensert or a pharmaceutically acceptable salt thereof and one or more therapeutic agents or pharmaceutically acceptable salts thereof may be administered together via the same route of administration and / or simultaneously in the form of a combined composition, or even in the form of a combined compound (e.g., as part of a single chemical complex or covalent entity).

[0240] In some embodiments, assensetib or a pharmaceutically acceptable salt thereof is administered in combination with one or more second therapeutic agents or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent is a targeted therapy agent or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the second therapeutic agent is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin (PLD), doxorubicin, gemcitabine, cytarabine, fludarabine, 5-fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapine, 5-azacytidine, capecitabine, AraC-FdUMP

[10] (CF-10), cladribine (c

[00145] The present invention relates to a pharmaceutical composition comprising: a pharmaceutically acceptable salt of medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising: medicaments comprising:

[0242] In some embodiments, the second therapeutic agent is selected from a PARP inhibitor, a PD1 inhibitor, a PD-L1 inhibitor, a Bcl-2 inhibitor, a KRAS inhibitor, a CDK4 / 6 inhibitor, a HER-2 inhibitor, a HER-2 antibody conjugate, a HER-2 bispecific antibody, a KRAS inhibitor, a CDK4 / 6 inhibitor, a selective ER modulator (SERM), a selective ER degrader (SERD), an ATR inhibitor, an ATM inhibitor, a CHK1 inhibitor, a DDR inhibitor and a targeted therapeutic agent, or a pharmaceutically acceptable salt of any one of the foregoing.

[0243] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a PARP inhibitor or a pharmaceutically acceptable salt thereof, wherein the PARP inhibitor is selected from the group consisting of olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), ieniparib (BSI 201), E7016 (Esai) and CEP-9722, or a pharmaceutically acceptable salt of any one of the foregoing.

[0244] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a PD1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the PD1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiprilimab, spartalizumab, ABBV-181, lodalizumab, sepalizumab, toripalizumab (Tuoyi), tislelizumab, camrelizumab, sintilimab (Tyvyt), GB226, AK105, HLX-10, AK103, BAT-1306, GSL-010, CS1003, LZM009 and SCT-I10A, and a pharmaceutically acceptable salt of any one of the foregoing.

[0245] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CS1001, SHR-1316, TQB2450, BGB-A333, KL-A167, KN046, MSB2311 and HLX-20, or a pharmaceutically acceptable salt of any one of the foregoing.

[0246] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the Bcl-2 inhibitor is selected from the group consisting of: ZN-d5, AGP-2575, AGP-1252, Vitoras (ABT-199), Naviclas (ABT-263), S55746 / BCL201, S65487, BGB-11417, FCN-338 and AZD0466, or a pharmaceutically acceptable salt of any one of the foregoing.

[0247] In some embodiments, the second therapeutic agent administered in an intermittent dosing cycle is a KRAS inhibitor or a pharmaceutically acceptable salt thereof, wherein the KRAS inhibitor is selected from the group consisting of: sultoxib, dagrexib, JDQ443, MRTX-1257, MRTX1133, ARS-1620, ARS-853, ARS-107, BAY-293, BI-3406, BI-2852, BMS-214662, MRTX849, MRTX849-VHL (LC2), PROTAC K-Ras degrader-1 (compound 518, catalog number 2378258-52-5), lonafarnib (SCH66336), RMC-0331, GDC-6036, LY3537982, D-1553, ARS-3248 (JNJ74699157), BI-1701963 and AU-8653 (AU-BEI-8653), or a pharmaceutically acceptable salt of any one of the foregoing.

[0248] In some embodiments, the second therapeutic agent is a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, wherein the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, traceranib (G1T28), lerociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, bilociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002 and MM-D37K, or a pharmaceutically acceptable salt of any one of the foregoing.

[0249] In some embodiments, the second therapeutic agent is a HER-2 antibody or a pharmaceutically acceptable salt thereof, wherein the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab and ZW25, or a pharmaceutically acceptable salt of any one of the foregoing.

[0250] In some embodiments, the second therapeutic agent is a HER-2 antibody-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the HER-2 antibody-drug conjugate is selected from the group consisting of: fam-trastuzumab delutec-nxki, Ado-trastuzumab emtansine (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985 and XMT-1522, or a pharmaceutically acceptable salt of any one of the foregoing.

[0251] In some embodiments, the second therapeutic agent is a HER2 bispecific antibody or a pharmaceutically acceptable salt thereof, wherein the HER2 bispecific antibody is selected from the group consisting of magituximab, ertuinomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302 and PRS-343, or a pharmaceutically acceptable salt of any one of the foregoing.

[0252] In some embodiments, the second therapeutic agent is a selective ER modulator (SERM) or a pharmaceutically acceptable salt thereof, wherein the selective ER modulator is selected from the group consisting of tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene, and lasofoxifene, or a pharmaceutically acceptable salt of any of the foregoing.

[0253] In some embodiments, the second therapeutic agent is a selective ER degrader (SERD) or a pharmaceutically acceptable salt thereof, wherein the selective ER degrader is selected from the group consisting of fulvestrant, (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrol), rant), RAD1901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brindestran, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (LSZ102), (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1 -yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide (H3B-6545), (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (Lindodestran, G1T48), D-0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azac-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (Gilbert Destran, GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidine-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), OP-1250 and LY3484356, or a pharmaceutically acceptable salt of any one of the foregoing.

[0254] In some embodiments, the second therapeutic agent is an ATR inhibitor or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is selected from Gartisertib, Berzosertib, M4344, BAY1895344, Ceralasertib, Schisandrin B, Elimusertib, NU6027, Dactolisib, ETPPT-46464, Torin 2, VE-821 and AZ20, Camonsertib, CGK733, ART-0380, ATRN-119 and ATRN-212, or a pharmaceutically acceptable salt of any one of the foregoing.

[0255] In some embodiments, the second therapeutic agent is an ATM inhibitor or a pharmaceutically acceptable salt thereof, wherein the ATM inhibitor is selected from AZD7648, AZD0156, AZ31, AZ32, AZD1390, KU55933, KU59403, KU60019, CP-466722, CGK733, NVP-BEZ235, SJ573017, AZ31, AZ32, AZD1390, M4076SKLB-197, CGK733, M4076, M3541 and M4076, or a pharmaceutically acceptable salt of any one of the foregoing.

[0256] In some embodiments, the second therapeutic agent is a CHK1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the CHK1 inhibitor is selected from prelizumab, AZD7762, Rabusertib, SCH90076MK-8776, CCT245737, CCT244747, CHIR-124, PD 407824, PD-321852, PF-00477736, GDC-0425, GDC-0575, SB-218078, V158411, LY2606368, LY2603618, SAR-020106, XL-844, UCN-01, SOL-578, IMP 10 and CBP501, or a pharmaceutically acceptable salt of any one of the foregoing.

[0257] In some embodiments, the second therapeutic agent is a targeted therapeutic or a pharmaceutically acceptable salt thereof, wherein the targeted therapeutic is bevacizumab, lenvatinib, encorfenib, and cetuximab, or a pharmaceutically acceptable salt of any of the foregoing.

[0258] In some embodiments, the second therapeutic agent for cancer treatment in an intermittent dosing cycle is an alkylating agent, an anti-EGFR antibody, an anti-Her-2 antibody, an antimetabolite, a vinca alkaloid, a platinum-based agent, an anthracycline, a topoisomerase inhibitor, a taxane, an antibiotic, an immunomodulator, an immune cell antibody, an interferon, an interleukin, an HSP90 inhibitor, an anti-androgen, an anti-estrogen, an anti-hypercalcemic agent, an apoptosis inducer, an Aurora kinase inhibitor, a Bruton's tyrosine kinase inhibitor, a calcineurin inhibitor, a CaM kinase II inhibitor, a CD45 tyrosine phosphatase inhibitor, a CDC25 phosphatase inhibitor, a CHK kinase inhibitor, a cyclooxygenase inhibitor, a bRAF kinase inhibitor , cRAF kinase inhibitors, Ras inhibitors, cyclin-dependent kinase inhibitors, cysteine protease inhibitors, DNA intercalators, DNA strand breakers, E3 ligase inhibitors, EGF pathway inhibitors, farnesyl transferase inhibitors, Flk-1 kinase inhibitors, glycogen synthase kinase-3 (GSK3) inhibitors, histone deacetylase (HDAC) inhibitors, I-κB-α kinase inhibitors, tetrazabenzimidazoles, insulin tyrosine kinase inhibitors, c-Jun-N-terminal kinase inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, MDM2 inhibitors, MEK inhibitors, ERK inhibitors, MMP inhibitors, mTor inhibitors, NGFR tyrosine kinase inhibitors, p38 MAP kinase inhibitors, p56 tyrosine kinase inhibitors, PDGF pathway inhibitors, phosphatidylinositol 3-kinase inhibitors, phosphatase inhibitors, protein phosphatase inhibitors, PKC inhibitors, PKCδ kinase inhibitors, polyamine synthesis inhibitors, PTP1B inhibitors, protein tyrosine kinase inhibitors, SRC family tyrosine kinase inhibitors, Syk tyrosine kinase inhibitors, Janus (JAK-2 and / or JAK-3) tyrosine kinase inhibitors, retinoids, RNA polymerase II elongation inhibitors, serine / threonine kinase inhibitors, sterol biosynthesis inhibitors, VEGF pathway inhibitors, chemotherapeutic agents, alitretinoin, altretinoin, aminopterin, aminolevulinic acid, amsacrine, asparaginase, atrasentan, bexarotene, carboquinone, colcemid, ethoxycycline, elsamitrucin, ethoxydimidine, hydroxyurea, folinic acid, lonidamine, lucanthone, masopropol, methylaminolevulinate, mitoguanidine, mitotane, oblimersen, omacitaxin, pegaspargase, porfimer sodium, prednimustine, adenovirus vector targeting gene, talaporfin, temoporfin, trabectedin, or verteporfin, or a pharmaceutically acceptable salt of any one of the foregoing.

[0259] In some embodiments, assenseti or a pharmaceutically acceptable salt thereof is administered together with a second therapeutic agent for 7 days of dosing and 7 days of discontinuation to treat cancer, wherein the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, assenseti or a pharmaceutically acceptable salt thereof is administered together with a second therapeutic agent for 7 days of dosing and 7 days of discontinuation to treat ovarian cancer, wherein the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof, which is administered for 7 days and 7 days of discontinuation to treat advanced ovarian cancer. In some embodiments, the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof, which is administered for 7 days and 7 days of discontinuation to treat advanced platinum-resistant ovarian cancer. In some embodiments, the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof, which is administered for 7 days and 7 days of discontinuation to treat advanced platinum-resistant ovarian cancer that has failed to maintain PARP inhibitor (PARP inhibitor, PARPi) therapy. In other words, the cancer is PARP inhibitor-resistant. In some embodiments, the second therapeutic agent is niraparib, administered with 7 days on and 7 days off, to treat fallopian tube cancer. In some embodiments, the second therapeutic agent is niraparib, or a pharmaceutically acceptable salt thereof, administered with 7 days on and 7 days off, to treat primary peritoneal cancer.

[0260] In some embodiments, assenseti or a pharmaceutically acceptable salt thereof is administered together with a second therapeutic agent with 5 days of dosing and 2 days of drug withdrawal to treat cancer, wherein the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, assenseti or a pharmaceutically acceptable salt thereof is administered together with a second therapeutic agent with 5 days of dosing and 2 days of drug withdrawal to treat ovarian cancer, wherein the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, which is administered for 5 days and 2 days of drug withdrawal to treat advanced ovarian cancer. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, which is administered for 5 days and 2 days of drug withdrawal to treat advanced platinum-resistant ovarian cancer. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, which is administered for 5 days and 2 days of drug withdrawal to treat advanced platinum-resistant ovarian cancer that has failed to respond to PARP inhibitor (PARPi) maintenance therapy. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, administered with 5 days of dosing and 2 days of rest to treat fallopian tube cancer. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, administered with 5 days of dosing and 2 days of rest to treat primary peritoneal cancer.

[0261] In one aspect, provided herein is a method for treating cancer comprising administering to a subject a daily dose of 250 mg or more of asensetib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur during the same week. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur sequentially (e.g., every other week). In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. In some embodiments, the cancer is metastatic or unresectable.

[0262] In one aspect, provided herein is a method for treating cancer comprising administering to a subject a daily dose of 300 mg or more of asensetib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur during the same week. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur sequentially (e.g., every other week). In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. In some embodiments, the cancer is metastatic or unresectable.

[0263] In one aspect, provided herein is a method for treating cancer comprising administering to a subject a daily dose of 350 mg or more of asensetib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur during the same week. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur sequentially (e.g., every other week). In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. In some embodiments, the cancer is metastatic or unresectable.

[0264] In one aspect, provided herein is a method for treating cancer comprising administering to a subject a daily dose of 400 mg or more of asensetib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur during the same week. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur sequentially (e.g., every other week). In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. In some embodiments, the cancer is metastatic or unresectable.

[0265] In one aspect, provided herein is a method for treating cancer, comprising administering to a subject a daily dose of 450 mg or more of asensetib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur during the same week. In some embodiments, the intermittent dosing cycle of olaparib or a pharmaceutically acceptable salt thereof and the intermittent dosing cycle of PARPi occur sequentially (e.g., every other week). In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. In some embodiments, the cancer is metastatic or unresectable.

[0266] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, equal to or greater than 200 mg in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and administering to the subject a daily dose of a chemotherapeutic agent in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

[0267] In some embodiments, assenserti or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, while paclitaxel is administered at a dose of 80 mg / m2 on D1, D8, and D15 of a 28-day cycle. 2 Dosage administration.

[0268] In some embodiments, assenserti or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, and carboplatin is administered at AUC5 mg / mL*min on D1 of a 21-day cycle.

[0269] In some embodiments, assenserti or a pharmaceutically acceptable salt thereof is administered at a dose of 400 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, while pegylated liposomal doxorubicin (PLD) is administered at a dose of 40 mg / m2 on D1 of a 28-day cycle. 2 Dosage administration.

[0270] In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered by another mode of administration known to those skilled in the art, including but not limited to rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection.

[0271] In some embodiments, the combination therapy comprises intermittent administration of one or more dosing cycles separated by a rest week, i.e., comprising consecutive dosing days followed by a rest day. In some embodiments, the combination therapy comprises continuous administration. In some embodiments, the combination therapy comprises continuous administration of one of the agents.

[0272] Subject selection

[0273] In some embodiments, the subject is selected without determining the level of a cancer biomarker. In some embodiments, the subject is selected without determining the level of BRCA1 and / or BRCA2. In some embodiments, the subject is selected without determining the level of TP53. In some embodiments, the subject is selected without determining the level of CA125. In some embodiments, the subject is selected without determining the level of CCNE1.

[0274] In other embodiments, subjects are selected by determining the levels of cancer biomarkers. In some embodiments, subjects are selected who have a predetermined cancer biomarker level (below or above a predetermined threshold). In some embodiments, subjects are selected who have a BCRA1 and / or BRCA2 biomarker level below a predetermined threshold. In some embodiments, subjects are selected who have a TP53 biomarker level below a predetermined threshold. In some embodiments, subjects are selected who have a CA125 biomarker level below a predetermined threshold. In some embodiments, subjects are selected who have a CCNE1 biomarker level below a predetermined threshold.

[0275] In some embodiments, subjects are selected whose BCRA1 and / or BRCA2 biomarker levels are above a predetermined threshold. In some embodiments, subjects are selected whose TP53 biomarker levels are above a predetermined threshold. In some embodiments, subjects are selected whose CA125 biomarker levels are above a predetermined threshold. In some embodiments, subjects are selected whose CCNE1 biomarker levels are above a predetermined threshold.

[0276] In some embodiments, the subject has received one or more prior lines of cancer therapy. In some embodiments, the subject has received two or more prior lines of cancer therapy. In some embodiments, the subject has received three or more prior lines of cancer therapy. In some embodiments, the subject has received four or more prior lines of cancer therapy.

[0277] In some embodiments, the subject has received 1 to 5 prior lines of cancer therapy. In some embodiments, the subject has received 1 to 5 prior lines of cancer therapy, 2 to 5 prior lines of cancer therapy, 3 to 5 prior lines of cancer therapy, or 4 to 5 prior lines of cancer therapy.

[0278] In some embodiments, the prior line of anticancer therapy is systemic cancer therapy. In some embodiments, the prior line of cancer therapy is in an advanced or metastatic setting. In some embodiments, the advanced or metastatic disease is stage III to stage IV.

[0279] In some embodiments, the prior line therapy comprises a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof. In some embodiments, the immediately prior line therapy comprises a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof. In some embodiments, the prior line therapy is treatment with a PARPi alone or in combination with other drug(s). In some embodiments, the PARPi as the prior line therapy was not discontinued due to toxicity.

[0280] In some embodiments, the subject has a disease for which there are no known effective treatment options, or has refused standard or conventional therapy prior to treatment.

[0281] In some embodiments, the subject is platinum-resistant. In some embodiments, the subject is resistant to treatment with a therapeutic (e.g., anticancer or antitumor) agent. In some embodiments, combination therapy with asenzeltiel or a pharmaceutically acceptable salt thereof overcomes resistance to the second therapeutic agent or a pharmaceutically acceptable salt thereof and allows the subject to respond.

[0282] In some embodiments, the subject is 18 years of age or older.

[0283] In some embodiments, the subject has breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the subject has metastatic or unresectable breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the subject is selected based on the cancer confirmed histologically.

[0284] In some embodiments, the subject's HRRm status is determined prior to treatment. In some embodiments, HRRm status is determined using an assay known in the art for detecting HRRm status. In some embodiments, a formalin-fixed, paraffin-embedded (FFPE) tumor sample collected within 3 years of treatment is used to assess the subject's sample.

[0285] In some embodiments, HRRm status is determined based on a mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

[0286] In some embodiments, a deleterious mutation in at least one of the genes involved in HRR is determined by CLIA-approved (or nationally designated equivalent) prior genomic profiling.

[0287] In some embodiments, the subject has a homologous recombination deficiency (HRD) positive status. In some embodiments, the subject has been diagnosed with an HRD-positive cancer selected from the group consisting of ovarian cancer (including recurrent ovarian cancer), breast cancer (e.g., triple-negative breast cancer and / or metastatic breast cancer), prostate cancer (e.g., metastatic castration-resistant prostate cancer), fallopian tube cancer, and primary peritoneal cancer. In some embodiments, the subject is a woman. In some embodiments, the subject is a man.

[0288] Reactivity

[0289] In some embodiments, the treatment methods described herein result in a response rate equal to or greater than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, the response rate is measured by a complete response (CR), a partial response (PR), a CA-125 50% response, or a combination thereof.

[0290] Progression-free survival (PFS) refers to the period of time during which a subject with a disease (e.g., cancer) survives and the disease state does not significantly worsen. Progression-free survival can be assessed as the period of time during which there is no progression of tumor growth and / or during which the subject's disease state is not determined to be a progressive disease. In an embodiment, progression-free survival of a subject with cancer is assessed by assessing tumor size, number of tumors, and / or metastasis.

[0291] In some embodiments, treatment results in a progression-free survival (PFS) of 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, treatment results in a progression-free survival (PFS) of 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or longer. In some embodiments, treatment results in a progression-free survival (PFS) of 1 year, 1.5 years, 2 years, 2.5 years, or longer.

[0292] As used herein, the term "progression" of tumor growth, or the term "progressive disease" (PD) as used herein with reference to a cancer state, refers to an increase in the sum of the diameters of the tumors of interest. For the purpose of determining progression-free survival, progression may also be determined if at least one of the following criteria is met: 1) unequivocal demonstration of progressive disease by CT / MRI tumor assessment according to RECIST 1.1 criteria; or 2) identification of a new tumor or confirmation of an existing tumor by additional diagnostic testing (e.g., histology / cytology, ultrasound, endoscopy, positron emission tomography) according to the Gynecologic Cancer Intergroup (GCIG) criteria (see Rustin et al., Int J Gynecol Cancer 2011;21:419-423, which is incorporated herein in its entirety); or 3) definitive clinical signs and symptoms of PD unrelated to non-malignant or iatrogenic causes according to the GCIG criteria ([i] refractory cancer-related pain; [ii] worsening malignant bowel obstruction / dysfunction; or [iii] unequivocal symptomatic worsening of ascites or pleural effusion) and / or CA-125-progression.

[0293] As used herein, the term "partial response" or "PR" refers to a decrease in tumor progression in a subject, as indicated by a decrease in the sum of the diameters of the target tumor, taking the baseline total diameter as a reference. In an embodiment, PR refers to a decrease in the sum of the diameters by at least 30%, taking the baseline total diameter as a reference. Exemplary methods for assessing partial responses are identified by RECIST guidelines. See EA Eisenhauer et al., "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.)," Eur. J. of Cancer, 45: 228-247 (2009).

[0294] As used herein, tumor growth "stabilization" or "stable disease" (SD) refers to neither shrinking enough to meet PR nor increasing enough to meet PD. In an embodiment, stability refers to a change (increase or decrease) of less than 30%, 25%, 20%, 15%, 10%, or 5% in the sum of the diameters of the target tumors, taking the baseline total diameter as a reference. Exemplary methods for assessing tumor growth stabilization or stable disease are identified by RECIST guidelines. See EA Eisenhauer et al., "New response evaluation criteria insolid tumors: Revised RECIST guideline (version 1.1.)," Eur. J. of Cancer, 45: 228-247 (2009).

[0295] As used herein, the term "complete response" or "CR" is used to refer to the disappearance of all or substantially all target lesions. In an embodiment, CR refers to a reduction in the sum of the diameters of the target tumors (i.e., tumor disappearance) of about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, with the baseline total diameter being considered as a reference. In an embodiment, CR indicates that after treatment, there is less than about 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less total lesion diameter remaining. Exemplary methods for assessing complete response are identified by RECIST guidelines. See EA Eisenhauer et al., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45:228-247 (2009).

[0296] Examples

[0297] Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0298] Example 1. Comparison between continuous and intermittent dosing schedules at similar cumulative doses of asensertib in various human cancer animal models

[0299] This example illustrates a comparison between a continuous and intermittent dosing regimen of asensertib.

[0300] Human Ovarian Cancer SKOV3 Model - Continuous Versus 5 / 2 Regimen

[0301] In the exemplary human ovarian cancer SKOV3 animal model, assenserti was administered at a continuous dose of 60 mg / kg or an intermittent dose of 80 mg / kg for 3 cycles of 5 days on / 2 days off (5 / 2).

[0302] Tumor volume changes measured over 21 days showed that intermittent administration of 80 mg / kg for 3 cycles of 5 days on and 2 days off had a higher efficacy in reducing tumor volume than continuous administration ( Figure 1A ). Figure 1B Shows the corresponding weight changes during treatment.

[0303] Non-small cell lung cancer (NSCLC) A427 model - continuous versus 5 / 2 regimen

[0304] In the exemplary non-small cell lung cancer (NSCLC) A427 model, assenserti was administered at higher intermittent doses than the corresponding lower continuous dose. For example, assenserti was administered at 56 mg / kg for four cycles of 5 days on / 2 days off (5 / 2) and compared to a lower continuous dose of 40 mg / kg. Similarly, assenserti was compared to a lower continuous dose of 80 mg / kg at 112 mg / kg for four cycles of 5 days on / 2 days off.

[0305] After the initiation of treatment, tumor volume was measured for 28 days ( Figure 1C ) and weight ( Figure 1D ).

[0306] The results showed that all doses were well tolerated. In addition, at the same total cumulative dose, higher intermittent dosing (5 days on, 2 days off) achieved greater efficacy in reducing tumor volume than lower continuous dosing.

[0307] Non-small cell lung cancer (NSCLC) A427 model - continuous versus 4 / 3 regimen

[0308] In the exemplary non-small cell lung cancer (NSCLC) A427 model, assenserti was administered at higher intermittent doses than the corresponding lower continuous doses. For example, assenserti was administered at 100 mg / kg for four cycles of 4 days on / 3 days off (4 / 3) and compared to a lower continuous dose of 60 mg / kg.

[0309] The changes in tumor volume within 25 days after tumor initiation are shown in Figure 1E , and the corresponding weight changes during treatment are shown in Figure 1F middle.

[0310] The results showed that at similar total cumulative doses, higher intermittent dosing (4 days on, 3 days off) achieved slightly greater efficacy than lower continuous dosing.

[0311] Breast Ductal Carcinoma HCC1569 Model - Continuous Versus Various Intermittent (4 / 3, 3 / 4) Regimens

[0312] In an exemplary breast ductal carcinoma HCC1569 model, assensertin was administered at a dose of approximately 100 mg / kg on an intermittent dosing schedule of 3 cycles of 4 days on / 3 days off (4 / 3) and 3 days on / 4 days off (3 / 4) and compared to a lower continuous dose (e.g., 60 mg / kg). Figure 1G Tumor volume changes were plotted until approximately 24 days after the start of treatment in Figure 1H The corresponding weight changes are plotted in .

[0313] At comparable cumulative doses, the higher intermittent dose was found to be more effective, as measured until approximately 24 days after initiation of treatment. Both intermittent dosing frequencies of 4 days on / 3 days off and 3 days on / 4 days off were found to be equally effective.

[0314] Human Ovarian Cancer OVCAR3 Model - 7 / 7 Protocol

[0315] In the exemplary human ovarian cancer OVCAR3 model, assenserti was administered at a dose of approximately 100 mg / kg in an intermittent dosing schedule of 3 cycles of 7 days on / 7 days off (7 / 7). Figure 1I The changes in tumor volume were plotted until approximately 32 days after the start of treatment. Figure 1J The corresponding weight changes are plotted in .

[0316] The results showed that the 7 / 7 intermittent dosing regimen effectively reduced tumor volume.

[0317] Overall, the results showed that at similar total cumulative doses, higher intermittent dosing schedules achieved greater efficacy than lower continuous dosing across multiple tumor cell types.

[0318] Example 2. Comparison of different doses of asensertib and continuous and intermittent dosing schedules of once-daily versus twice-daily regimens in various human cancer animal models

[0319] Human Ovarian Cancer OVCAR3 Model - Continuous vs. Intermittent (5 / 2); Once-Daily vs. Twice-Daily Regimens

[0320] In the exemplary human ovarian cancer OVCAR3 model, assensertin was administered once daily based on an intermittent dosing schedule of 5 days on / 2 days off (5 / 2) compared to twice daily dosing (e.g., 80 mg / kg once daily vs. 40 mg / kg twice daily and 100 mg / kg once daily vs. 50 mg / kg twice daily).

[0321] Tumor volumes were measured up to approximately 22 days after the start of treatment. Figure 2A and the corresponding weight changes are shown in Figure 2B middle.

[0322] For the same cumulative dose, once-daily dosing was more effective than twice-daily dosing.

[0323] Human ovarian cancer OVCAR3 model - continuous vs. intermittent (5 / 2, 4 / 3, different doses)

[0324] In the exemplary human ovarian cancer OVCAR3 model, assensertib was administered at two different doses in each of two intermittent dosing schedules. Briefly, assensertib was administered at doses of approximately 80 mg / kg (cumulative dose of 400 mg) and 90 mg / kg (cumulative dose of 450 mg) for five cycles of a 5-day on / 2-day off (5 / 2) intermittent schedule, and also at 90 mg / kg (cumulative dose of 450 mg) and 100 mg / kg (cumulative dose of 500 mg) for four cycles of a 4-day on / 3-day off (4 / 3) intermittent schedule. The results were compared with a continuous dose of 60 mg / kg for 22 days (cumulative dose of 300 mg).

[0325] exist Figure 2C The changes in tumor volume until approximately 24 days after the start of treatment are shown in Figure 2D The corresponding weight changes are shown in .

[0326] Overall, the results showed that higher intermittent doses at both 5 / 2 and 4 / 3 were more effective than lower continuous doses at lower total cumulative doses.

[0327] Human Ovarian Cancer OVCAR3 Model - Continuous vs. Intermittent (4 / 3, 3 / 4)

[0328] In the exemplary human ovarian cancer OVCAR3 model, Asensertib was administered at approximately 100 mg / kg in two intermittent dosing regimens for three cycles: 4 days on / 3 days off (4 / 3) or 3 days on / 4 days off (3 / 4). In addition, continuous dosing of 60 mg / kg was continued for 24 days.

[0329] At a dose of about 100 mg / kg for 3 cycles of 4 / 3, the cumulative dose was 1200 mg, and at a dose of about 100 mg / kg for 3 cycles of 3 / 4, the cumulative dose was 900 mg. The results showing the change in tumor volume are shown in Figure 2E The corresponding weight changes are shown in Figure 2F middle.

[0330] Overall, the results showed that both intermittent dosing regimens showed greater efficacy than continuous dosing. A slightly greater efficacy was observed at the higher cumulative dose (i.e., the 4 / 3 regimen).

[0331] Example 3. PK / PD Correlation of Targeted Engagement of Asenseti and Wee1

[0332] Figure 3Figure 2 is a graph showing the PK / PD correlation of assensertin and Wee1 target engagement. The graph shows that inhibition of pCDK1 increases Wee1 target engagement. Increased drug dose or exposure also results in increased Wee1 target engagement. Doses greater than about 300 mg once daily exhibit the highest AUC, excellent target engagement, and at least a 50% reduction in p-CDK1 levels.

[0333] Figure 4 Provided are models and skin biopsy staining that demonstrate a decrease in p-CDK1 levels associated with Wee1 inhibition. CDK1 phosphorylation (pCDK-1) is mediated by Wee1. Wee1 inhibition by assensertib is expected to result in pCDK1 inhibition. For example, the Y15 residue is not phosphorylated, and CDK1 levels in skin biopsies were confirmed to be reduced relative to baseline in terms of p-CDK1 levels after treatment.

[0334] Example 4. Pharmacokinetic Data Showing Clinical Exposure Achieved with Intermittent Dosing of Asensertib

[0335] This example illustrates the clinical exposure achieved with a continuous dosing regimen and an intermittent 5-day on / 2-day off (5 / 2) dosing regimen. A comparison was also made between a once-daily dosing regimen and a twice-daily dosing regimen. In some embodiments, assensertib is administered with food and / or an antiemetic.

[0336] The result is as follows: Figure 5A Figure 2 is a graph of asenzeltiel plasma concentrations on Day 1 of Cycle 1 from subjects receiving 5 / 2 350 mg once daily or 175 mg twice daily. Figure 5B Figure 2 is a graph of asenzeltiel plasma concentrations on Days 11 / 12 of Cycle 1 from subjects receiving 5 / 2 350 mg once daily or 175 mg twice daily. Figure 5C is a graph of assensertin plasma concentrations on Day 1 of Cycle 1 from subjects receiving the once daily continuous dosing regimen versus subjects receiving the once daily 5 / 2 intermittent 350 mg dosing regimen. Figure 5D Figure 2 is a graph of assensertin plasma concentrations on Days 11 / 12 or 15 of Cycle 1 from subjects receiving the once daily continuous dosing regimen versus subjects receiving the once daily 5 / 2 intermittent 350 mg dosing regimen. Figure 5E is a graph of assensertin plasma concentrations on Day 1 of Cycle 1 from subjects receiving a twice daily continuous dosing regimen versus subjects receiving a twice daily 5 / 2 intermittent 175 mg dosing regimen. Figure 5FFigure 2 is a graph of asenzeltib plasma concentrations from subjects receiving a continuous twice daily dosing regimen versus subjects receiving a 5 / 2 intermittent 175 mg twice daily dosing regimen on Days 11 / 12 or 15 of Cycle 1. Results show that mean asenzeltib exposure was higher with intermittent dosing compared to continuous 350 mg once daily (or 175 mg twice daily).

[0337] Similar steady-state exposures were observed with 350 mg once daily (10,300 to 15,800 hr*ng / mL, n=3) as with 175 mg twice daily (AUC 13,300 hr*ng / mL, n=1), and similar observations were also made on the continuous background (Table 2 below).

[0338] Table 2. Pharmacokinetic data of continuous and intermittent dosing (5 / 2)

[0339]

[0340] Although PK simulations predicted lower exposure of 5 / 2 on day 12 (steady state) compared to continuous dosing, surprisingly, no reduction in exposure of 5 / 2 was observed.

[0341] Overall, the results of this study surprisingly and unexpectedly showed that intermittent dosing achieved comparable or better exposure compared to continuous dosing.

[0342] Example 5. Methods for Establishing an Intermittent Dosing Regimen for Asensertib in Human Subjects

[0343] This example demonstrates a dose escalation protocol for an intermittent once-daily dosing regimen based on the evaluation of dose-limiting toxicities of an asensertib dosing regimen or a combination regimen with a second therapeutic agent (eg, an anti-tumor or anti-cancer agent).

[0344] As shown in the aforementioned examples, in simple terms, intermittent administration of Asenseti begins with approximately 200 mg once daily for 5 days of administration and 2 days of drug withdrawal (5 / 2), and is run in 50 mg increments (e.g., 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg once daily). If the results show that the dose level is intolerable at 5 / 2, then the 4 / 3 regimen is started at the dose or at a lower dose. Similarly, the administration at 4 / 3 is run in 50 mg increments. If the dose level is intolerable under the 4 / 3 daily schedule, then the dose level is reduced to 3 / 4 daily based on dose-limiting toxicity (DLT) and / or other toxicities or adverse events. A DLT was defined as any AE occurring in Cycle 1 that met at least one of the following criteria described in Table 3 (other than those clearly attributable to an exogenous cause, such as an underlying disease).

[0345] Table 3. Dose-limiting toxicities

[0346]

[0347] Intermittent dosing with longer breaks can be implemented with additional no-dose days, or with rest weeks in between.

[0348] Similarly, twice daily dosing starting at 175 mg twice daily is run in 50 mg increments (e.g., 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, or their equivalents) and adjusted based on dose-limiting toxicities as above.

[0349] Overall, this example demonstrates determining an intermittent dosing schedule for asensertib monotherapy or combination therapy as described herein.

[0350] Example 6. Treatment of Cancer in a Subject Using an Intermittent Dosing Regimen of Asensertib

[0351] This example demonstrates treating a subject selected for a predetermined threshold level of a cancer biomarker by administering an effective dose of assensertin (e.g., 100 mg, 150 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg once daily, or, for example, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 400 mg twice daily divided equally into twice daily doses) alone or in combination with a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0352] Additional selection criteria may include subjects having a particular cancer type (eg, high-grade serous ovarian cancer (HGSOC), platinum-resistant or platinum-refractory), or receiving 1 to 3 prior lines of therapy (eg, bevacizumab).

[0353] Asensertib is administered to selected subjects according to the intermittent dosing cycle provided herein. For example, the intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one day of non-dosing, such as five days of dosing ("dosing" day), followed by two days of non-dosing ("rest" day), i.e. 5 / 2; four days of dosing, followed by three days of non-dosing, i.e. 4 / 3; or three days of dosing, followed by four days of non-dosing, i.e. 3 / 4; six days of dosing, followed by one day of non-dosing, i.e. 6 / 1; or seven days of dosing, followed by seven days of non-dosing, i.e. 7 / 7.

[0354] In addition, in some embodiments, one or more administration weeks are separated by a rest of at least one week.In certain embodiments, intermittent dosing regimen described herein (such as 7 / 0, 5 / 2, 4 / 3 or 3 / 4) carries out 2 weeks and then a rest of a week, or carries out a continuous administration day of one week and then a rest of one week.

[0355] In some embodiments, the therapy is assensertin monotherapy. In some embodiments, the therapy is combined with a second therapeutic agent or a pharmaceutically acceptable salt thereof (eg, an anti-tumor agent).

[0356] In some embodiments, food and / or an antiemetic are also administered with asensertib.

[0357] Treatment outcome is measured by tumor response, reduction in tumor size, and / or alleviation of symptoms associated with the cancer or other cancer treatment.

[0358] Example 7. Intermittent dosing regimen of asenseti and PARPi combination therapy

[0359] This example demonstrates the use of intermittent dosing combination therapy with asenzel and PARPi to treat subjects with homologous recombination repair mutation (HRRm) or homologous recombination deficiency (HRD)-positive cancers. As described in more detail below, WEE1 inhibition (e.g., using asenzel) and PARPi exert synergistic effects, leading to resensitization of tumor cells to PARP inhibitors.

[0360] The antitumor activity of the combination of asensertib and niraparib (PARPi) was evaluated in the MDA-MB-468 triple-negative breast cancer tumor model using a weekly alternating dosing schedule. Figures 6A-6C ), in this model, asenzel alone achieved 52.6% tumor growth inhibition (TGI) at a dose of 60 mg / kg; niraparib as a single agent resulted in a 47.7% TGI at 50 mg / kg. In the case of a weekly alternating dosing schedule, the combination of 60 mg / kg asenzel and 50 mg / kg niraparib further enhanced the anti-tumor activity, resulting in a 70.7% TGI ( Figures 6D-6G ).

[0361] Asenzel and PARPi (niraparib) were evaluated using the HRD+TNBC PDX model (the model profile of which is shown in Table 4) and the HRD+BRCA mutant ovarian tumor model. Animals were treated with 60 mg / kg of asenzel or 35 mg / kg of niraparib (alone or in combination) once daily for 5 days, followed by 2 days of rest (qd x 5 days of dosing, 2 days of rest) for 4 cycles (28 days). Figures 7A-7D As shown in , the combination of asensertib and niraparib provided increased tumor growth inhibition compared with monotherapy in a BRCA mutant model.

[0362] Table 4. Efficacy of Asensertin + PARPi in HRD + TNBC PDX Model

[0363] TNBC model Ki67 Her2 HRD Key mutations HBCx-10 94％ 1+ + TP53, BRCA2, PTEN loss, RB1 loss HBCx-17 94％ 0 + TP53, AKT1, BRCA2, CDKN2A, and KDM6A deficiency

[0364] The OVCAR-3 model was used to evaluate assensertib and PARPi (talazopanib) according to an intermittent dosing schedule. In the OVCAR3 ovarian cancer tumor model, the combination of assensertib and the PARPi talazopanib showed promising activity when administered in alternating dosing (talazopanib 0.23 mg / kg, 7 days on, 7 days off; assensertib 60 mg / kg, 7 days on, 7 days off) compared to either agent alone. Figure 8 As shown in , alternating dosing regimens with PARPi and WEE1 inhibitors (1 week of PARPi followed by 1 week of WEE1 inhibitor) showed improved efficacy. In addition, alternating dosing schedules can potentially eliminate overlapping toxicities of co-administration of WEE1 inhibitors and PARPi.

[0365] Clinical design

[0366] The combination of asensertib and PARPi (olaparib) was evaluated in a Phase 1 / 1b, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of asensertib as a monotherapy and when administered in combination with olaparib in adults with advanced ovarian, breast, prostate, or pancreatic cancer who had progressed on PARPi therapy. Subjects were randomized 1:1 to asensertib monotherapy or to combination therapy and stratified based on tumor type.

[0367] Subjects undergo a screening period of up to 28 days, followed by treatment with a single asenseti or in combination with olaparib, repeated for 28 days, until the subject experiences disease progression or meets the exit criteria specified by any other protocol. Monotherapy subjects receive asenseti (5 / 2) in a 28-day cycle until disease progression or termination. Combination therapy subjects receive alternating administration of olaparib and asenseti in a 28-day cycle until disease progression or termination. Olaparib and asenseti are administered at the doses shown in Table 5A below, according to the following alternating schedule: olaparib 5 / 2, on Cycle 1 Day 1 (C1D1) to Day 5 (D5) and C1D15 to 19, followed by asenseti 5 / 2, on C1D8 to 12 and C1D22 to 26.

[0368] Table 5A. Dosages of Asensertib and Olaparib

[0369] Asensetti Olaparib 450mg QD (5:2) 300 mg BID (5:2) 450mg QD (5:2) 250 mg twice daily (5:2) 400mg QD (5:2) 300 mg twice daily (5:2) 400mg QD (5:2) 250 mg twice daily (5:2) 350mg QD (5:2) 300 mg twice daily (5:2) 350mg QD (5:2) 250 mg twice daily (5:2) 300mg QD (5:2) 300 mg BID (5:2) 300mg QD (5:2) 250 mg twice daily (5:2) 250mg QD (5:2) 300 mg twice daily (5:2) 250mg QD (5:2) 250 mg twice daily (5:2)

[0370] Combination therapy doses and schedules can be adjusted as shown in Table 5B. For example, "DL1a" would indicate 350 mg taken according to a 5:2 schedule. "X Day Dosing" indicates QD dosing during the indicated time period. DL1a can also be combined with 250 mg or 300 mg of olaparib according to a 5:2 schedule.

[0371] Table 5B. Experimental doses of asensertib and olaparib

[0372]

[0373] Subjects 18 years of age or older were selected for combination therapy based on the following:

[0374] Histologically confirmed metastatic or unresectable breast, ovarian, pancreatic, or prostate cancer

[0375] A mutation in any of the following genes that would be considered HRRm status: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L

[0376] Subjects were also selected based on their cancer type. Subjects with ovarian cancer, breast cancer, pancreatic cancer, or prostate cancer must have a measurable and / or evaluable disease as measured by RECIST v1.1. Subjects with ovarian cancer or pancreatic cancer must have a measurable and / or evaluable disease as measured by RECIST v1.1; Subjects with prostate cancer or breast cancer must have a measurable and / or evaluable disease as measured by RECIST v1.1.

[0377] The HRRm status can be determined by e.g. CDx、Myriad( Determination can be made by using the following assays: CDx, TempusxT HRD, or Caris Molecular. Intelligence Comprehensive Tumor Profiling or any other CLIA-certified (or local equivalent) laboratory can also be used. At least one confirmed deleterious mutation in a gene involved in HRR, as determined by a previous CLIA-approved (or nationally designated equivalent) genomic profiling assay.

[0378] Subjects were also selected based on their prior treatment history. Specifically, subjects must have received at least 1 but no more than 5 prior lines of systemic anticancer therapy in the advanced or metastatic setting. The prior therapy must have included a PARPi alone or in combination with other (multiple) drugs. The PARPi must have been the most recent treatment received prior to combination therapy with asenzeltib. If PARPi line therapy was discontinued due to PARPi toxicity, the subject would be excluded from combination therapy with asenzeltib and a PARPi (e.g., the olaparib regimen described above).

[0379] Tumor assessments were performed every 8 weeks ± 4 days starting on C1D1 until investigator-assessed progression, loss to follow-up, initiation of new anticancer therapy, withdrawal of consent, or study termination. After treatment discontinuation, safety was assessed 30 days after the last dose, and survival was followed every 12 weeks until death, loss to follow-up, withdrawal of consent, or study termination.

[0380] Dose expansion or modification according to the above-mentioned alternating dosing options is based on the ORR estimate for treated subjects at the maximum tolerated dose (MTD). The primary endpoint is ORR, which is assessed by the investigator using the PCWG3-modified RECIST v1.1 criteria for prostate cancer and RECIST v1.1 criteria for all other indications. Secondary endpoints include ORR assessed by ICR; duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS) assessed by the investigator and ICR; overall survival (OS); the frequency and severity of TEAEs of assensertib and olaparib and plasma PK parameters.

[0381] Example 8. Comparison of the Safety and Pharmacokinetic Profiles of Intermittent and Continuous Dosing Regimens of Asensertib Monotherapy in Human Cancer Subjects

[0382] In this example, a Phase 1a dose escalation and Phase 1b dose expansion clinical study was conducted to evaluate the safety and pharmacokinetics (PK) of asensertib monotherapy, i.e., steady-state exposure (AUC 0-24 ) and the maximum concentration (C max ).

[0383] In some cohorts, the Phase 1a dose escalation started at a dose below 200 mg and increased to a total daily dose of 200 mg, 300 mg, 350 mg, 400 mg, and 450 mg in a continuous dosing schedule. The dose used in Phase 1b was 300 mg QD.

[0384] In some cohorts, phase 1a dose escalation was conducted starting with total daily doses of 350 mg, 400 mg, 450 mg, and 500 mg using a 5:2 or 4:3 dosing schedule. In phase 1b, doses of 350 mg and 400 mg were used using a 5:2 dosing schedule.

[0385] Subjects enrolled in the study underwent tumor assessment every 2 cycles (6 weeks) (according to RECIST 1.1). There were no biomarker requirements for participation in the study; nor were there any prior therapy requirements. The individuals in the cohort represented a variety of tumor types ( Figure 9AHeavily pre-treated subjects with advanced solid tumors were included in both the continuous and intermittent dosing cohorts (Table 6).

[0386] Table 6. Severely Pretreated Subjects with Advanced Solid Tumors in the Continuous and Intermittent Dosing Cohorts

[0387]

[0388] Fifty-one subjects with uterine serous carcinoma (USC) or high-grade serous ovarian cancer (HGSOC) following multiple prior therapies were enrolled in cohorts treated with continuous or intermittent dosing schedules (Table 7A) and with an intermittent dosing schedule only (Table 7B).

[0389] Table 7A. Heavily Pretreated Subjects with Uterine Serous Carcinoma (USC) and High-Grade Serous Ovarian Cancer (HGSOC) Following Multiple Prior Therapies (Combined Continuous and Intermittent Dosing Cohorts)

[0390] USC (N=26) HGSOC (N=25) Previous line of treatment Mean (range) 3.4(1-9) 5.3(1-18) Platinum resistance 27(100％) 25(100％) Previous treatments Previous PARPi 2(7.7) 17(68.0) Previous experimental agents 5(19.2) 7(28.0) Previous VEGF inhibitors 19(73.1) 21(84.0) Previous PD1 / PDL1 19(73.1) 5(20.0)

[0391] Table 7B. Heavily Pretreated Subjects with Uterine Serous Carcinoma (USC) and High-Grade Serous Ovarian Cancer (HGSOC) After Multiple Prior Therapies (Intermittent Dosing Cohort Only)

[0392] USC (N=6) HGSOC (N=13) Previous line of treatment Median (range) 3.5(1-6) 6(2-11) Platinum resistance 5(83.3％) 5(38.5％) Platinum-refractory NA 8(61.5％) Previous treatments Previous PARPi 1(16.7) 10(76.9) Previous experimental agents 0(0.0) 5(28.0) Previous VEGF inhibitors 5(83.3) 11(84.6) Previous PD1 / PDL1 6(100.0) 1(7.7)

[0393] The results of the study were shown in Figure 9B 、 Figure 9C 、 Figure 9D and Table 8.

[0394] The results showed that the steady-state exposure (AUC 0-24 ) steadily increased, and more subjects reached the projected target efficacious steady-state exposure ( Figure 9B ).

[0395] like Figure 9C and Figure 9D As shown in , subjects given the intermittent dosing regimen achieved higher maximum concentration (Cmax) levels than subjects given the continuous dosing regimen.

[0396] High confirmed response rates were seen in subjects treated with asenzeltib monotherapy ( Figure 9E Of n=51, with N=40 having at least 1 scan, the overall objective response rate (ORR%) with 95% CI was 27.5% (9.1%, 35.6%).

[0397] In addition, if Figure 9F As shown in Table 8, the intermittent dosing schedule doubled the objective response rate in the population with ovarian cancer or uterine serous carcinoma (USC). The ORR% was much higher in subjects who received the intermittent dosing schedule. Figures 9E-9G Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) are indicated in Table 8 and Figure 9F Objective response rate is shown.

[0398] Table 8. Objective response rates in the population with ovarian cancer or uterine serous carcinoma (USC).

[0399] Overall ORR % (95% CI) 26.7％(9.1％、35.6％) Continuous ORR% (95% CI) 15.4％(4.4％、34.9％) Intermittent ORR% (95% CI) 42.1％(8.4％、58.1％)

[0400] 89% of USC and HGSOC subjects had a reduction in target lesions from baseline scans. 95% of USC and HGSOC subjects had a best overall response of stable disease (SD) or partial response (PR); the median PFS for ovarian cancer was around 5.1 months, while for USC it was NR (not reached) ( Figure 9G At an interim 4.4-month early follow-up, 12 of the 19 participants remained on treatment. In this study, 10 of the 13 participants had received a previous PARP inhibitor.

[0401] Preliminary clinical data indicate that asensertib is active in ovarian cancer ( Figure 9H ) and asenseti is also active in uterine serous carcinoma ( Figure 9I ).

[0402] With the treatment of intermittent dosing cohort and monitoring the response to treatment, meaningful and lasting clinical benefits were observed. It should be noted that the mid-term follow-up (median follow-up-up) of two platinum-resistant ovarian cancer and uterine serous carcinoma (USC) patients was extended to 9.2 months (previously 4.4 months and as described above), and the median PFS was extended to 6.5 months (previously 5.1 months and USC were NR and as described above for platinum-resistant ovarian cancer), wherein the overall response rate (ORR) was 36.8% (Table 9). In addition, Asenseti monotherapy (including intermittent dosing of Asenseti monotherapy) continues to show excellent safety characteristics, and no cases of febrile neutropenia and sepsis were observed, and no suspension was reported, which indicates that it has better tolerance than other approved gynecological malignancy monotherapy (such as Olaparib and Mirvetuximab (Mirvetuximab) and Adavosertib (another WEE1 inhibitor) monotherapy).

[0403] Table 9. Objective response rates in the population with ovarian or uterine serous carcinoma (USC).

[0404]

[0405] Overall, the results showed that assensertin was active in multiple tumor types, including ovarian and uterine serous carcinoma, and that the intermittent dosing schedule was advantageous, as more subjects reached effective steady-state exposure and higher maximum concentration (Cmax) levels compared to the continuous dosing schedule.

[0406] Example 9. Determination of the RP2D for Asenzeltib from a Phase 1 Asenzeltib Dosing Optimization Study in Subjects with Ovarian and Uterine Serous Carcinoma

[0407] In this example, a phase 1 asenosteril dose optimization study was conducted to evaluate the recommended phase II dose (RP2D) of asenosteril monotherapy.

[0408] In some cohorts, the Phase 1a dose escalation started at a dose below 200 mg and increased to a total daily dose of 200 mg, 300 mg, 350 mg, 400 mg, and 450 mg in a continuous dosing schedule. The dose used in Phase 1b was 300 mg QD.

[0409] A total of 127 heavily pre-treated subjects with advanced solid tumors were treated with assensertin monotherapy at increasing dose levels, either continuously daily or intermittently weekly. Across all tumor types, 74 subjects were treated with a continuous dosing schedule, while 53 subjects were treated with an intermittent dosing schedule.

[0410] In the response-evaluable subjects in the combined ovarian and uterine serous carcinoma (USC) subgroup (n=45), the confirmed objective response rate (ORR%, 95% CI) was 42.1% (8.4 / 58.1) in subjects who received the intermittent dosing schedule (n=19) compared with 15.4% (4.4, 34.9) in subjects who received the continuous dosing schedule (n=26). The overall response rate was 26.7% (9.1, 35.6), Figure 9F and Table 8.

[0411] The steady-state exposure of the new intermittent RP2D (as measured by AUC(0 to 24)) was more than doubled compared to the AUC observed with continuous administration of 300 mg QD. Intermittent dosing maintained the safety profile of assensertin and improved tolerability compared to continuous dosing. Grade 3 and 4 treatment-related adverse events (TRAEs) for gastrointestinal, fatigue, and hematologic conditions were comparable or favorable compared to continuous dosing. No discontinuations due to TRAEs were observed in the intermittent cohort.

[0412] Based on the Phase 1 dose optimization data, the RP2D of assensertin as a monotherapy is 400 mg daily (QD) under a weekly administration schedule of 5 days of administration and 2 days of rest (5 / 2). Compared with continuous administration, this intermittent dosing schedule more than doubles the steady-state drug exposure and obtains promising efficacy signals while maintaining safety and improving tolerability. In the current study, the RP2D was also applied to cyclin E1+ (cyclin E1-positive status), platinum-resistant high-grade serous ovarian cancer, uterine serous carcinoma, and PARP inhibitor-resistant and platinum-resistant ovarian cancer.

[0413] Example 10. Intermittent dosing regimen for asenserti in combination with a chemotherapeutic agent such as paclitaxel, carboplatin, gemcitabine, or pegylated liposomal doxorubicin (PLD)

[0414] Human ovarian cancer OVCAR3 model - paclitaxel or carboplatin monotherapy versus combination therapy with asenseridine

[0415] In the exemplary human ovarian cancer OVCAR3 animal model, assenserti was administered at an intermittent dose of 60 mg / kg or 80 mg / kg for 3 cycles of 5 days on / 2 days off, while paclitaxel and carboplatin were also administered once a week at 20 mg / kg and 25 mg / kg, respectively, for 3 weeks. In addition, the combination of assenserti with paclitaxel and the combination of assenserti with carboplatin were administered according to the same dosing schedule and dose as their respective monotherapies.

[0416] Changes in tumor volume measurements over 24 days showed that all tested combination therapies had greater efficacy in reducing tumor volume than monotherapy ( Figure 10A ). Figure 10B Shows the corresponding weight changes during treatment.

[0417] Clinical Studies A Phase 1b open-label, multicenter clinical study was conducted to evaluate the safety, tolerability, preliminary clinical activity, pharmacokinetics (PK), and pharmacodynamics of asensertib in combination with chemotherapeutic agents, such as paclitaxel, carboplatin, gemcitabine, and pegylated liposomal doxorubicin (PLD).

[0418] The clinical study consisted of four cohorts of participants with platinum-resistant or refractory (R / R) epithelial ovarian, peritoneal, or fallopian tube cancer. Key eligibility criteria for inclusion were: high-grade serous ovarian cancer; Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; platinum-resistant / refractory; up to three prior lines of chemotherapy; and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

[0419] Table 10. Baseline Characteristics of Trial Participants

[0420]

[0421]

[0422] Baseline characteristics were well balanced across treatment arms based on Table 10. Approximately 20% of subjects had platinum-refractory disease, one-quarter had received a prior PARP inhibitor, 10% were enrolled in the trial as their third or fourth line of therapy, and the majority had received 1 to 2 prior lines of therapy.

[0423] Each cohort was tested with asenserti in combination with paclitaxel, carboplatin, gemcitabine, or pegylated liposomal doxorubicin (PLD) in continuous and / or intermittent dosing schedules.

[0424] In one embodiment, asensetib was tested in combination with paclitaxel. Asensetib was administered orally once daily in a 28-day treatment cycle in two doses with an intermittent dosing regimen (starting with 200 mg QD 5 / 2, followed by 300 mg QD 5 / 2). Paclitaxel was administered at 80 mg / m2 on D1, D8, and D15 of each 28-day cycle. 2 The dose was administered intravenously over 60 minutes (± 10 minutes).

[0425] In one embodiment, asenserti was tested in combination with carboplatin. Asenserti was administered orally once daily in four doses over a 28-day treatment cycle using an intermittent dosing regimen (starting with a second dose of 300 mg QD 5 / 2, followed by a second dose of 200 mg QD 5 / 2). Carboplatin was administered intravenously at 5 mg / mL*min on day 1 of each 21-day cycle (±3 days) for 15 minutes or longer.

[0426] In one embodiment, asensetib was tested in combination with gemcitabine. Asensetib was administered orally once daily in four doses in an intermittent dosing regimen (starting with three doses of 200 mg QD, followed by 200 mg QD 5 / 2) over a 28-day treatment cycle. Gemcitabine was administered intravenously in two doses of 1000 mg / m on Day 1 and Day 8 of each 21-day cycle. 2 and 600 mg / m 2 Administer intravenously over 30 minutes or more.

[0427] In one embodiment, asenseti was tested in combination with pegylated liposomal doxorubicin (PLD). Asenseti was orally administered once daily in a 28-day treatment cycle in three doses with an intermittent dosing regimen (starting with 200 mg QD, followed by 400 mg QD 5 / 2). PLD was administered every 4 weeks at 40 mg / m2 on day 1 of each 28-day cycle. 2 The dose was administered intravenously over 60 minutes.

[0428] The endpoints determined the recommended phase 2 dose (RP2D), safety, and preliminary clinical activity. Based on these clinical studies, the RP2D was determined to be: (a) asenzeltiel 300 mg QD 5:2 with paclitaxel 80 mg / m 2 (on D1, D8, and D15 of a 28-day cycle); (b) the combination of 200 mg QD 5:2 of asenzeltib and carboplatin AUC 5 mg / mL*min on D1 of a 21-day cycle; (c) the combination of 400 mg QD 5:2 of asenzeltib and PLD 40 mg / mL*min 2 The combination of asenzeltib and gemcitabine has durable activity and is undergoing dose cohorts to determine the maximum tolerated dose (MTD).

[0429] Treatment-related adverse effects were assessed and were primarily hematologic (neutropenia, thrombocytopenia, anemia), gastrointestinal (nausea, vomiting, diarrhea), and fatigue, similar to the toxicity of chemotherapy or asenzeltib. As with many combination therapy trials, it is difficult to assess the impact of individual drugs on each adverse event. No new safety signals were seen in any arm. In the treatment arm, intermittent dosing of asenzeltib was associated with improved safety and tolerability. Serious adverse events were primarily hematologic and were similar to the frequency reported for combination chemotherapy regimens in this subject population.

[0430] Clinical activity of each treatment was assessed as shown in Table 11, evaluating DOR, duration of response; ORR, objective response rate; PFS, progression-free survival; and PLD, pegylated liposomal doxorubicin. Response-evaluable subjects were those with measurable disease at baseline according to RECIST version 1.1 and at least one post-baseline assessment. All objective responses were confirmed according to RECIST v1.1.

[0431] Table 11. Clinical activity of asenseti combinations

[0432]

[0433] The results in Table 11 show that the combination therapy of asensertib and chemotherapeutic agents has a longer objective response rate (ORR), duration of response (mDOR), and median progression-free survival (mPFS) compared with historical control data of single-agent chemotherapy.

[0434] The results of the clinical study were plotted as a waterfall plot, which is an ordered histogram depicting the optimal percentage change in tumor size, where positive values represent an increase in tumor size and negative values represent a decrease in tumor size. Each vertical column represents a single subject. The waterfall plot for this study evaluated the maximum change (%) in the sum of target lesion diameters in subjects who were administered the following combination: assencillin and paclitaxel ( Figure 11A ); Asenzeltiel and carboplatin ( Figure 11B ), and asensetib and gemcitabine ( Figure 11C Abbreviations: CR, complete response; NE, non-evaluable; PD, progressive disease; PR, partial response; SD, stable disease; uCR, unconfirmed complete response; uPR, unconfirmed partial response.

[0435] The observed progression-free survival with each treatment is shown in Kaplan-Meier plots (probability of treatment-free progression on the y-axis versus time in months on the x-axis) ( Figure 12 ) and in Table 12 below. The number of subjects at risk during the treatment duration is shown in Table 13.

[0436] Table 12. Median progression-free survival (PFS), in months

[0437]

[0438] Table 13. Number of subjects at risk receiving various treatments over time.

[0439] 0 months 5 months 10 months 15 months 20 months Asenseti + Paclitaxel 26 11 1 0 Asenseti + Carboplatin 36 8 4 1 1 Asensetib + Gemcitabine 18 4 1 0 Asenset+PLD 35 18 7 4 0

[0440] Overall, clinical study results show that the combination of asensertib and chemotherapeutic agents is active and is safe, durable, and effective in treating platinum-resistant or refractory (R / R) epithelial ovarian, peritoneal, or fallopian tube cancer in combination with the tested chemotherapeutic agents (i.e., paclitaxel, carboplatin, gemcitabine, or pegylated liposomal doxorubicin (PLD)). In addition, intermittent dosing of asensertib is associated with improved safety and tolerability.

[0441] Furthermore, although the foregoing has been described in considerable detail by way of illustration and example for purposes of clarity and understanding, it will be appreciated by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather are intended to simultaneously cover all modifications and alternatives that come within the true scope and spirit of the present disclosure.

Claims

1. A method for treating cancer, comprising administering to a subject in need thereof a daily dose of Azenosertib or a pharmaceutically acceptable salt thereof, or its equivalent, equal to or greater than 350 mg according to an intermittent dosing cycle, The intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one day without dosing.

2. The method of claim 1, wherein the one or more dosing weeks are separated by at least one week of rest.

3. A method for treating cancer, comprising administering to a subject in need thereof a daily dose of equal to or greater than 100 mg of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, The intermittent dosing cycle comprises one or more dosing weeks, and each dosing week comprises at least three consecutive dosing days and at least one day of no dosing, followed by at least one week of rest.

4. The method of claim 3, wherein the daily dose of asensertib or a pharmaceutically acceptable salt thereof is equal to or greater than 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, or their equivalents.

5. The method of any one of the preceding claims, wherein the daily dose of asensertib or a pharmaceutically acceptable salt thereof is equal to or greater than 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, or the equivalent thereof.

6. The method according to any one of the preceding claims, wherein the daily dose of asensertib or a pharmaceutically acceptable salt thereof is administered once daily.

7. The method according to any one of claims 1 to 5, wherein the daily dose of asensertib or a pharmaceutically acceptable salt thereof is divided equally into twice daily doses.

8. The method of any one of the preceding claims, wherein each dosing week comprises at least four, five, or six consecutive dosing days.

9. The method according to any one of the preceding claims, wherein each dosing week comprises five consecutive dosing days and two days without dosing.

10. The method according to any one of claims 1 to 8, wherein each dosing week comprises four consecutive dosing days and three days without dosing.

11. The method according to any one of claims 1 to 8, wherein each dosing week comprises three consecutive dosing days and four days without dosing.

12. The method according to any one of claims 1 to 8, wherein each dosing week comprises six consecutive dosing days and one day without dosing.

13. The method according to any one of claims 3 to 8, wherein each dosing week comprises seven consecutive dosing days.

14. The method of any one of the preceding claims, wherein the intermittent dosing cycle comprises two consecutive dosing weeks.

15. A method for treating cancer, comprising administering to a subject in need thereof a daily dose of equal to or greater than 350 mg of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, according to an intermittent dosing cycle, The intermittent administration cycle comprises at least two consecutive administration days and at least one day without administration.

16. The method of claim 15, wherein the intermittent dosing cycle comprises at least three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen consecutive dosing days.

17. The method of claim 15 or 16, wherein the intermittent dosing cycle comprises at least two, three, four, five, six, or seven days without dosing.

18. The method of any one of claims 15 to 17, wherein the intermittent dosing cycle comprises five consecutive dosing days and two days without dosing.

19. The method of any one of claims 15 to 17, wherein the intermittent dosing cycle comprises four consecutive dosing days and three days without dosing.

20. The method of any one of claims 15 to 17, wherein the intermittent dosing cycle comprises three consecutive dosing days and four days without dosing.

21. The method of any one of claims 15 to 17, wherein the intermittent dosing cycle comprises seven consecutive dosing days and seven days without dosing.

22. The method of any one of claims 15 to 17, wherein the intermittent dosing cycle comprises fourteen consecutive dosing days and seven days without dosing.

23. The method of any one of claims 15 to 17, wherein the intermittent dosing cycle comprises twenty-one consecutive dosing days and seven days without dosing.

24. The method of any one of claims 15 to 23, wherein the daily dose of asensertib or a pharmaceutically acceptable salt thereof is equal to or greater than 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, or the equivalent thereof.

25. The method of any one of claims 15 to 24, wherein the daily dose of asensertib or a pharmaceutically acceptable salt thereof is administered once daily.

26. The method according to any one of claims 15 to 25, wherein the daily dose of asensertib or a pharmaceutically acceptable salt thereof is divided equally into two doses daily.

27. The method of claim 26, wherein the twice daily dose of asensertib or a pharmaceutically acceptable salt thereof is equal to or greater than 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, or the equivalent thereof.

28. The method of any one of claims 15 to 27, wherein the intermittent dosing cycles are repeated.

29. The method of any one of the preceding claims, wherein the method further comprises administering a second therapeutic agent, or a pharmaceutically acceptable salt thereof, during the intermittent dosing period.

30. The method of claim 29, wherein: (A) The second therapeutic agent or a pharmaceutically acceptable salt thereof is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin (PLD), doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapine, 5-azacytidine, capecitabine, AraC-FdUMP[10] (CF-10), cladribine, decitabine, hydroxyurea, oxaliplatin, dapoxetine ... oxaliplatin, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, cyclophosphamide, capecitabine, dexamethasone, etoposide, daunorubicin, ifosfamide, methotrexate and vincristine, or a pharmaceutically acceptable salt of any one of the foregoing; or (B) the second therapeutic agent is selected from: (a) a PARP inhibitor or a pharmaceutically acceptable salt thereof, wherein the PARP inhibitor is selected from the group consisting of olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), iniparib (BSI 201), E7016 (Esai) and CEP-9722, or a pharmaceutically acceptable salt of any one of the foregoing; (b) a PD1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the PD1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, spartalizumab, ABBV-181, lodapolimab, zimberelimab, toripalimab (Tuoyi), tislelizumab, camrelizumab, sintilimab (Tyvyt), GB226, AK105, HLX-10, AK103, BAT-1306, GSL-010, CS1003, LZM009, and SCT-I10A, or a pharmaceutically acceptable salt of any one of the foregoing; (c) a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CS1001, SHR-1316, TQB2450, BGB-A333, KL-A167, KN046, MSB2311 and HLX-20, or a pharmaceutically acceptable salt of any one of the foregoing; (d) a Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the Bcl-2 inhibitor is selected from the group consisting of ZN-d5, AGP-2575, AGP-1252, venetoclax (ABT-199), navitoclax (ABT-263), S55746 / BCL201, S65487, BGB-11417, FCN-338 and AZD0466, or a pharmaceutically acceptable salt of any one of the foregoing; (e) a KRAS inhibitor or a pharmaceutically acceptable salt thereof, wherein the KRAS inhibitor is selected from the group consisting of sotorasib, adagrasib, JDQ443, MRTX-1257, MRTX1133, ARS-1620, ARS-853, ARS-107, BAY-293, BI-3406, BI-2852, BMS-214662, MRTX849, MRTX849-VHL (LC2), PROTAC K-Ras degrader-1 (Compound 518, Catalog No. 2378258-52-5), Lonafarnib (SCH66336), RMC-0331, GDC-6036, LY3537982, D-1553, ARS-3248 (JNJ74699157), BI-1701963, and AU-8653 (AU-BEI-8653), or a pharmaceutically acceptable salt of any one of the foregoing; (f) a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, wherein the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), lerociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, birociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002 and MM-D37K, or a pharmaceutically acceptable salt of any one of the foregoing; (g) a HER-2 antibody, or a pharmaceutically acceptable salt thereof, wherein the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25, or a pharmaceutically acceptable salt thereof; (h) a HER-2 antibody-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the HER-2 antibody-drug conjugate is selected from the group consisting of fam-trastuzumab deruxtecan-nxki, Ado-trastuzumab emtansine (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985 and XMT-1522, or a pharmaceutically acceptable salt of any one of the foregoing; (i) a HER2 bispecific antibody or a pharmaceutically acceptable salt thereof, wherein the HER2 bispecific antibody is selected from the group consisting of margetuximab, ertumaxomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343, or a pharmaceutically acceptable salt of any one of the foregoing; (j) a selective ER modulator (SERM) or a pharmaceutically acceptable salt thereof, wherein the selective ER modulator is selected from the group consisting of tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene and lasofoxifene, or a pharmaceutically acceptable salt of any one of the foregoing; (k) a selective ER degrader (SERD) or a pharmaceutically acceptable salt thereof, wherein the selective ER degrader is selected from the group consisting of fulvestrant, (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrant, RAD1 901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (brilanestrant, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (LSZ102), (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridine- ((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azac-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (Gilidestrant, G1T48), D-0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azac-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (Gilidestrant, G1T48), (giredestrant), GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidine-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), OP-1250, and LY3484356, or a pharmaceutically acceptable salt of any one of the foregoing; (1) an ATR inhibitor or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is selected from Gartisertib, Berzosertib, M4344, BAY1895344, Ceralasertib, Schisandrin B, Elimusertib, NU6027, Dactolisib, ETPPT-46464, Torin 2, VE-821 and AZ20, Camonsertib, CGK733, ART-0380, ATRN-119 and ATRN-212, or a pharmaceutically acceptable salt of any one of the foregoing; (m) an ATM inhibitor or a pharmaceutically acceptable salt thereof, wherein the ATM inhibitor or a pharmaceutically acceptable salt thereof is selected from AZD7648, AZD0156, AZ31, AZ32, AZD1390, KU55933, KU59403, KU60019, CP-466722, CGK733, NVP-BEZ235, SJ573017, AZ31, AZ32, AZD1390, M4076SKLB-197, CGK733, M4076, M3541 and M4076, or a pharmaceutically acceptable salt of any one of the foregoing; (n) a CHK1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the CHK1 inhibitor or a pharmaceutically acceptable salt thereof is selected from Prexasertib, AZD7762, Rabusertib, SCH90076MK-8776, CCT245737, CCT244747, CHIR-124, PD 407824, PD-321852, PF-00477736, GDC-0425, GDC-0575, SB-218078, V158411, LY2606368, LY2603618, SAR-020106, XL-844, UCN-01, SOL-578, IMP 10 and CBP501, or a pharmaceutically acceptable salt of any one of the foregoing; and (o) a targeted therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the targeted therapeutic agent or a pharmaceutically acceptable salt thereof is bevacizumab, lenvatinib, encorafenib and cetuximab, or a pharmaceutically acceptable salt of any one of the foregoing.

31. The method of any one of the preceding claims, wherein the cancer is selected from the group consisting of glioblastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, head and neck cancer, leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), skin cancer, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, stomach cancer, gastrointestinal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, hematological cancer, Kaposi's sarcoma, sarcoma), renal cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal cancer, ovarian cancer, osteosarcoma, sarcoma, gastrointestinal stromal tumor (GIST), pancreatic cancer, pituitary cancer, retinoblastoma, salivary gland cancer, stomach cancer, small intestine cancer, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous carcinoma, vaginal cancer, vulvar cancer, Wilms tumor, solid tumors, and liquid tumors.

32. The method of claim 31 , wherein the cancer is a solid tumor or a hematological malignancy.

33. The method of claim 32, wherein the cancer is a solid tumor.

34. The method of claim 33, wherein the solid tumor is selected from the group consisting of endometrial cancer, ovarian cancer (e.g., HGSOC), uterine cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, melanoma, colorectal cancer, prostate cancer, testicular cancer, gallbladder cancer, bladder cancer, breast cancer (e.g., invasive breast cancer, triple-negative breast cancer (TNBC)), lung cancer (e.g., NSCLC), esophagogastric cancer, gastric cancer, esophageal cancer, renal cancer (e.g., pRCC, ccRCC, chromophobe cell carcinoma RCC), head and neck cancer, osteosarcoma cancer, pancreatic cancer, brain cancer, adenoid cystic carcinoma (ACC), mesothelioma, liver cancer, glioblastoma (GBM), low-grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), bile duct cancer, thyroid cancer, thymoma, uveal melanoma, and BRAF mutant metastatic colorectal cancer.

35. The method of claim 32, wherein the cancer is a hematological malignancy.

36. The method of claim 35, wherein the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom macroglobulinemia, or multiple myeloma (MM).

37. The method of any one of the preceding claims, wherein assensertin is administered to the subject with food and / or an antiemetic.

38. The method of claim 37, wherein asensertib or a pharmaceutically acceptable salt thereof is administered to the subject on an empty stomach.

39. The method of any one of the preceding claims, wherein the subject is administered an antiemetic for at least two dosing cycles concomitantly with the administration of asensertib or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the antiemetic is selected from the group consisting of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, an oral steroid, a dopamine antagonist, and a serotonin antagonist, or a pharmaceutically acceptable salt of any of the foregoing.

41. The method of claim 40, wherein the antiemetic is aprepitant, rolapitant, ondansetron, granisteron, dexamethasone, olanzapine, netupitant, palonosetron, and combinations thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

42. The method of any one of the preceding claims, wherein the cancer is a platinum-refractory cancer, a platinum-resistant cancer, or a platinum-sensitive cancer.

43. The method of claim 42, wherein the cancer is a platinum-resistant cancer.

44. The method of any one of the preceding claims, wherein the cancer is a PARP inhibitor-resistant cancer.

45. The method of any one of the preceding claims, wherein the cancer is a HRRm or HRD positive cancer.

46. The method of any one of the preceding claims, wherein the cancer is an advanced or metastatic cancer.

47. A method of treating cancer, comprising: administering to the subject a daily dose of 400 mg or more of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and The subject is administered a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

48. The method of claim 47, wherein the asenosteril or a pharmaceutically acceptable salt thereof is administered at a daily dose equal to or greater than 450 mg of asenosteril or a pharmaceutically acceptable salt thereof.

49. The method of claim 47 or 48, wherein the PARPi or a pharmaceutically acceptable salt thereof is selected from the group consisting of olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), iniparib (BSI 201), E7016 (Esai) and CEP-9722, or a pharmaceutically acceptable salt of any one of the foregoing.

50. The method of claim 49, wherein the PARPi is olaparib or a pharmaceutically acceptable salt thereof.

51. The method of claim 50, wherein olaparib or a pharmaceutically acceptable salt thereof is administered at a daily dose equal to or greater than 250 mg of asensertib or a pharmaceutically acceptable salt thereof.

52. The method of claim 50, wherein olaparib or a pharmaceutically acceptable salt thereof is administered at a daily dose equal to or greater than 300 mg of asensertib or a pharmaceutically acceptable salt thereof.

53. The method of any one of claims 47 to 52, wherein the intermittent dosing period of asensertib or a pharmaceutically acceptable salt thereof, and the intermittent dosing period of the PARPi or a pharmaceutically acceptable salt thereof occur during the same cycle.

54. The method of any one of claims 47 to 52, wherein the intermittent dosing cycles of asensertib or a pharmaceutically acceptable salt thereof, and the intermittent dosing cycles of the PARPi or a pharmaceutically acceptable salt thereof occur every other week.

55. The method of any one of claims 47 to 52, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

56. The method of claim 55, wherein the cancer is metastatic or unresectable.

57. A method for treating cancer, the method comprising administering to the subject a daily dose of asensertib or a pharmaceutically acceptable salt thereof, or its equivalent, equal to or greater than 200 mg in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing, and The subject is administered a daily dose of the chemotherapeutic agent in an intermittent dosing cycle comprising five consecutive dosing days and two days without dosing.

58. The method of claim 57, wherein asensertib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, and paclitaxel is administered at a dose of 80 mg / m2 on D1, D8, and D15 of a 28-day cycle. 2 Dosage administration.

59. The method of claim 57, wherein asensertib or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, and carboplatin is administered at an AUC of 5 mg / mL*min on D1 of a 21-day cycle.

60. The method of claim 58, wherein asensertib or a pharmaceutically acceptable salt thereof is administered at a dose of 400 mg once daily in an intermittent dosing cycle of five consecutive dosing days and two days without dosing, and PLD is administered at a dose of 40 mg / m2 on D1 of a 28-day cycle. 2 Dosage administration.

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