Intermittent dosing regimens of azenosertib in the treatment of cancer

Abstract

Provided herein are methods of treating cancer using an improved intermittent dosing regimen for azenosertib or a pharmaceutically acceptable salt thereof to achieve a highly effective, safe, and well-tolerated dosing regimen for treating, among other things, 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 azenosertib or a pharmaceutically acceptable salt thereof according to an improved intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, each dosing week comprising about 2 to 7 consecutive dosing days and about 1 to 7 dosing-free days. In some embodiments, the intermittent dosing cycle is repeated, and the dosing weeks are separated by one, two, or more weeks of rest. In some aspects, azenosertib or a pharmaceutically acceptable salt thereof is administered as a combination therapy.

Description

[Technical Field]

[0001] Cross-reference to related art All applications for which a foreign or domestic priority claim is identified in the Application Data Sheet filed with this application are expressly incorporated herein by reference pursuant to 37 CFR § 1.57 and Rules §§ 4.18 and 20.6, including U.S. Provisional Patent Application Nos. 63 / 382,830, filed November 8, 2022, 63 / 459,543, filed April 14, 2023, and 63 / 506,025, filed June 2, 2023, each of which is incorporated by reference in its entirety, including any drawings. [Background technology]

[0002] Cell cycle checkpoints are important for DNA repair and ensure that cells restore genomic integrity 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 regulating the S, G2-M, and M cell cycle checkpoints. Wee1 inhibition causes cancer cells to progress into mitosis without repairing DNA damage, leading to premature mitotic entry and apoptosis. Wee1 inhibition increases replication stress by inducing abnormal firing of replication origins and depletion of nucleotide pools. Wee1 is overexpressed in various cancer types, and many Wee1 inhibitors and / or degraders are known to those skilled in the art. See, for example, WO2019 / 173082 and WO2020 / 069105.

[0003] Azenosertib is a small molecule Wee1 inhibitor that is highly potent and selective and has robust antitumor activity. Summary of the Invention

[0004] Provided herein, among other things, are methods of treating cancer using improved intermittent dosing regimens for azenosertib or a pharmaceutically acceptable salt thereof, administered to achieve a highly effective, safe, and well-tolerated 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 azenosertib therapy while minimizing toxicity. High-dose administration increases drug exposure, thereby increasing efficacy. As described throughout this application and in more detail in the Examples below, intermittent dosing regimens characterized by consecutive days of administration of azenosertib or a pharmaceutically acceptable salt thereof followed by days without administration (i.e., no drug treatment) can have greater efficacy than continuous dosing regimens. The improved intermittent dosing regimens for azenosertib provided herein increase the therapeutic index of azenosertib, reduce toxicity, and increase tolerability and safety.

[0005] Thus, provided herein are methods for treating tumors that initially appear to respond well to other anti-cancer drugs, but then the response stops and the tumor recurs in a drug-resistant form, such that continued administration provides little or no additional benefit.

[0006] In addition to reducing the toxicity of high doses in monotherapy, intermittent administration also has advantages in combination therapy. Many conventional anti-tumor agents are toxic, and continuous administration can lead to cumulative toxicity. Intermittent administration regimens can be used to administer one or more second therapeutic agents or Administering azenosertib or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable salt (e.g., an antitumor agent) reduces toxicity issues and increases efficacy. Subject adherence is also improved when azenosertib does not need to be administered continuously to achieve the same or better efficacy.

[0007] In some aspects, provided herein are methods of treating cancer, comprising administering to a subject in need thereof a daily dose of 350 mg, or its equivalent, or more of azenosertib or a pharmaceutically acceptable salt thereof, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, each dosing week comprising at least three consecutive dosing days and at least one day without dosing.

[0008] In some embodiments, provided herein are high doses of azenosertib or a pharmaceutically acceptable salt thereof, e.g., about 350 mg to about 800 mg once daily, or about 175 mg to about 400 mg twice daily in an intermittent dosing regimen, e.g., 5 days on ("on" days) followed by 2 days off ("off" days) (i.e., 5 / 2), 4 days on followed by 3 days off (i.e., 4 / 3), or 3 days on followed by 4 days off (i.e., 3 / 4), or 6 days on followed by 1 day off (i.e., 6 / 1). Alternatively, an intermittent dosing regimen of azenosertib or a pharmaceutically acceptable salt thereof may also be expressed as about 350 mg to about 800 mg once daily, or about 175 mg to about 400 mg twice daily, with an intermittent frequency, e.g., 5 on / 2 off, 4 on / 2 off, or 3 on / 4 off, among others.

[0009] In some embodiments, one or more weeks of administration are separated by at least one week of rest. In some embodiments, the intermittent administration regimen described herein (e.g., 7 / 0, 6 / 1, 5 / 2, 4 / 3, or 3 / 4) is implemented for 2 weeks followed by a one-week rest, or for 1 week followed by a one-week rest, thereby achieving high efficacy while increasing safety and tolerability in the treatment of cancer. In some embodiments, the intermittent administration regimen described herein (e.g., 7 / 0, 6 / 1, 5 / 2, 4 / 3, or 3 / 4) is implemented for 3 weeks followed by a one-week rest, or for 1 week followed by a one-week rest, thereby achieving high efficacy while increasing safety and tolerability in the treatment of cancer. In some embodiments, the intermittent dosing regimens described herein (e.g., 7 / 0, 6 / 1, 5 / 2, 4 / 3, or 3 / 4) are implemented for periods of more than 3 weeks followed by a week of rest, or a week followed by a week of rest, thereby achieving high efficacy while increasing safety and tolerability in the treatment of cancer.

[0010] In some aspects, provided herein is a method for treating cancer comprising administering to a subject in need thereof a daily dose of 100 mg or more of azenosertib or a pharmaceutically acceptable salt thereof according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, each dosing week comprising at least three consecutive dosing days and at least one dosing-free day, followed by at least one week of rest. In some embodiments, the daily dose of azenosertib is 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, or equivalents thereof or more. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered once daily in an intermittent dosing regimen at a dose of about 200 mg. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 225 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 250 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 275 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 250 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of greater than about 300 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 300 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 350 mg once daily.

[0011] In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 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 equivalents thereof or more. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 375 mg or more. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 400 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 425 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 450 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 475 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 500 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 525 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 550 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 575 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 600 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 625 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 650 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 675 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 700 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 725 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 750 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 775 mg.In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is about 800 mg or its equivalent.

[0012] In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is administered once a day.

[0013] In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is divided into two doses per day.

[0014] In some embodiments, each dosing week includes at least 4, 5, or 6 consecutive dosing days.

[0015] In some embodiments, each dosing week includes 5 consecutive dosing days and 2 days without dosing.

[0016] In some embodiments, each dosing week includes 4 consecutive dosing days and 3 dosing-free days.

[0017] In some embodiments, each dosing week includes 3 consecutive dosing days and 4 dosing-free days.

[0018] In some embodiments, each dosing week includes 7 consecutive dosing days and 7 dosing-free days.

[0019] In some embodiments, each intermittent administration cycle comprises about 7 to about 10 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 8 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 9 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 10 consecutive administration days.

[0020] In some embodiments, the intermittent dosing cycle comprises 21 consecutive dosing days and 7 dosing-free days.

[0021] In some embodiments, the intermittent dosing cycle comprises two consecutive dosing weeks.

[0022] In some aspects, provided herein are methods of treating cancer, comprising administering to a subject in need thereof a daily dose of 350 mg, or its equivalent, or more of azenosertib or a pharmaceutically acceptable salt thereof, according to an intermittent dosing cycle, wherein the intermittent dosing cycle includes at least two consecutive days of dosing and at least one day of no dosing.

[0023] In some embodiments, the intermittent administration cycle comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive administration days. In some embodiments, the intermittent administration cycle comprises more than 14 consecutive administration days. In some embodiments, the intermittent administration cycle comprises 21 consecutive administration days. In some embodiments, the intermittent administration cycle comprises 28 consecutive administration days. In some embodiments, the intermittent administration cycle comprises 32 consecutive administration days. In some embodiments, the intermittent administration cycle comprises 42 consecutive administration days.

[0024] In some embodiments, an intermittent administration cycle includes at least 1, 2, 3, 4, 5, 6, or 7 days without administration. In some embodiments, an intermittent administration cycle includes 1 day without administration. In some embodiments, an intermittent administration cycle includes about 2-7 days without administration. In some embodiments, an intermittent administration cycle includes 2 days without administration. In some embodiments, an intermittent administration cycle includes 3 days without administration. In some embodiments, an intermittent administration cycle includes 4 days without administration. In some embodiments, an intermittent administration cycle includes 5 days without administration. In some embodiments, an intermittent administration cycle includes 6 days without administration. In some embodiments, an intermittent administration cycle includes 7 days of administration.

[0025] In some embodiments, an intermittent administration cycle comprises about 2-7 consecutive administration days ("on" days) followed by about 1-7 rest periods ("off" days).

[0026] In some embodiments, the intermittent dosing cycle includes 5 consecutive dosing days and 2 dosing-free days.

[0027] In some embodiments, the intermittent dosing cycle includes 4 consecutive dosing days and 3 dosing-free days.

[0028] In some embodiments, the intermittent dosing cycle includes 3 consecutive days of dosing and 4 days without dosing.

[0029] In some embodiments, the intermittent dosing cycle includes six consecutive dosing days and one dosing-free day.

[0030] In some embodiments, the intermittent dosing cycle comprises 7 consecutive days of dosing and 7 days without dosing.

[0031] In some embodiments, the intermittent dosing cycle comprises 14 consecutive dosing days and 7 dosing-free days.

[0032] In some embodiments, the intermittent dosing cycle comprises 21 consecutive dosing days and 7 dosing-free days.

[0033] In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 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 equivalents thereof or more. In some embodiments, high-dose azenosertib or a pharmaceutically acceptable salt thereof is provided herein, for example, the dose is 375 mg or more. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 400 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 450 mg once daily. In some embodiments, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 550 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 575 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 600 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of greater than about 600 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 625 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 650 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 675 mg once daily.In some embodiments, azenosertib 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, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 mg once daily in an intermittent dosing regimen.

[0034] In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is administered once a day.

[0035] In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is divided equally into two doses per day.

[0036] In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is divided equally into three doses per day. In some embodiments, the daily dose of azenosertib is divided equally into four doses per day.

[0037] In some embodiments, the twice-daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg g, 350 mg, 375 mg, 400 mg, or their equivalents or more.

[0038] In some embodiments, the intermittent administration cycle is repeated.

[0039] In some embodiments, the method further comprises administering a second therapeutic agent or a pharmaceutically acceptable salt thereof during the intermittent administration cycle. Without wishing to be bound by any particular theory, administering azenosertib or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof may render a subject resistant to treatment with the second therapeutic agent or a pharmaceutically acceptable salt thereof alone responsive, prevent or reduce drug-related toxicity, and / or improve the efficacy of treatment compared to monotherapy. Combination therapy using intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof provides additional benefits to administration, for example, by requiring a lower effective dose of the second therapeutic agent, or a pharmaceutically acceptable salt thereof, and / or azenosertib or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is also administered using intermittent administration cycles. In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered using continuous administration cycles. In some embodiments, the second therapeutic agent, or a pharmaceutically acceptable salt thereof, is an anti-tumor agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent, or a pharmaceutically acceptable salt thereof, is an anti-cancer 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.

[0040] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in intermittent administration cycles in combination with one or more second therapeutic agents or pharmaceutically acceptable salts thereof. 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 therapeutic agent or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the second therapeutic agent is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent may be 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, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, cyclophosphamide, capecitabine, dexamethasone, etoposide, daunorubicin, ifosfamide, methotrexate, and vincristine or a pharmaceutically acceptable salt of any of the foregoing.

[0042] In some embodiments, the second therapeutic agent is selected from a PARP inhibitor, including 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) and a selective ER degrader (SERD), an ATR inhibitor, an ATM inhibitor, a CHK1 inhibitor, a DDR inhibitor, a targeted therapeutic agent, or a pharmaceutically acceptable salt of any of the foregoing.

[0043] In some embodiments, the second therapeutic agent administered in the intermittent dosing cycles is a PARP inhibitor, or a pharmaceutically acceptable salt thereof, and 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 any of the aforementioned. and a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the second therapeutic agent administered in the 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, zimverelimab, 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 of the foregoing.

[0045] In some embodiments, the second therapeutic agent administered in the 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 of the foregoing.

[0046] In some embodiments, the second therapeutic agent administered in the 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 of the foregoing.

[0047] In some embodiments, the second therapeutic agent administered in intermittent dosing cycles is a KRAS inhibitor or a pharmaceutically acceptable salt thereof, and 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, CAS 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 of the foregoing.

[0048] 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), relociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, vilociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or any pharmaceutically acceptable salt thereof.

[0049] 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 of the foregoing.

[0050] In some embodiments, the second therapeutic agent is a HER-2 antibody-drug conjugate or a pharmaceutically acceptable salt thereof, and the HER-2 antibody-drug conjugate is selected from the group consisting of fam-trastuzumab deruxtecan-nxki, Ado-trastuzumab emtansine (T-DM1), and acetaminophen (E2). 1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985, and XMT-1522, or a pharmaceutically acceptable salt of any of the foregoing.

[0051] 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 of the foregoing.

[0052] 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.

[0053] In some embodiments, the second therapeutic agent is a selective ER degrader (SERD), or a pharmaceutically acceptable salt thereof, and examples of the selective ER degrader include 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)benzylamino)-4-hydroxybenzoate (AZD9496), benzodiazepine ... (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brillanestran, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid 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 (Lintodestrant, G1T48), D- 0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (diledestrant, GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,The compound is selected from the group consisting of 7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidin-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 of the foregoing.

[0054] In some embodiments, the second therapeutic agent is an ATR inhibitor, or a pharmaceutically acceptable salt thereof, and examples of the ATR inhibitor include galtisertib, berzosertib, M4344, BAY1895344, selalasertib, schisandrin B, elimsertib, 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 of the foregoing.

[0055] 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 of the foregoing.

[0056] 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, ravusertib, SCH90076MK-8776, CCT245737, CCT244747, CHIR-124, PD 407824, PD-321852, PF-00477736, GDC-0425, GDC-0575, SB-218078, V158411, LY2606368, LY2603618, SAR-0206, XL-844, UCN-01, SOL-578, IMP 10, and CBP501, or a pharmaceutically acceptable salt of any of the foregoing.

[0057] In some embodiments, the second therapeutic agent is a targeted therapeutic agent or a pharmaceutically acceptable salt thereof, and the targeted therapeutic agent is bevacizumab, lenvatinib, encorafenib, and cetuximab, or a pharmaceutically acceptable salt of any of the foregoing.

[0058] In some embodiments, the cancer is glioblastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancer, head and neck cancer, leukemia, AML (acute myeloid leukemia), CLL (chronic lymphocytic leukemia), ALL (acute lymphocytic leukemia), myelodysplastic syndrome (MDS), skin cancer, adrenal gland cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, uterine cancer, esophageal cancer, eye cancer, gallbladder cancer, stomach cancer, gastrointestinal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hematological malignancies. , Kaposi's sarcoma, kidney cancer, pharyngeal and hypopharyngeal cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell, lung cancer, lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal carcinoma, ovarian cancer, osteosarcoma, sarcoma, gastrointestinal stromal tumor (GIST), pancreatic cancer, pituitary cancer, retinoblastoma, salivary gland cancer, gastric cancer, small intestine cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous adenocarcinoma, vaginal cancer, vulvar cancer, Wilms' tumor, solid tumors, liquid tumors.

[0059] In some embodiments, the cancer is a solid tumor or a hematological malignancy.

[0060] In some embodiments, the solid tumor is associated with the adrenal gland, ampulla of Vater, biliary tract, bladder / urinary tract, bone, intestine, breast, cervix, CNS / brain, esophagus / stomach, eye, head and neck, kidney, liver, lung, lymphatic system, bone marrow, ovary / fallopian tube, pancreas, penis, peripheral nervous system, peritoneum, pleura, prostate, skin, soft tissue, testicle, thymus, thyroid, uterus, vulva / vagina, or other (e.g., adenocarcinoma in situ, extragonadal germ cell tumor (EGCT), mixed cancer types).

[0061] In some embodiments, the solid tumor is uterine serous adenocarcinoma, ovarian cancer, peritoneal cancer, fallopian tube cancer, osteosarcoma, pancreatic cancer, or BRAF-mutated metastatic colorectal cancer. In some embodiments, the solid tumor is uterine serous adenocarcinoma. 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-mutated metastatic colorectal cancer.

[0062] In some embodiments, the cancer is a hematological malignancy.

[0063] In some embodiments, the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous 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). 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's macroglobulinemia. In some embodiments, the cancer is multiple myeloma (MM).

[0064] In some embodiments, the subject is administered azenosertib or a pharmaceutically acceptable salt thereof with food and / or an antiemetic agent.

[0065] In some embodiments, the subject is administered azenosertib or a pharmaceutically acceptable salt thereof on an empty stomach. In some embodiments, the subject is administered azenosertib or a pharmaceutically acceptable salt thereof at least 1 hour or 2 hours before a meal.

[0066] In some embodiments, the subject is administered an antiemetic agent for at least one administration cycle with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for at least two administration cycles with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for at least three administration cycles with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for at least four administration cycles with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for more than four administration cycles with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for all administration cycles of azenosertib administration.

[0067] In some embodiments, the antiemetic agent 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.

[0068] In some embodiments, the antiemetic agent is aprepitant, rolapitant, ondansetron, granisterone, dexamethasone, olanzapine, netupitant, palonosetron, and combinations thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the antiemetic agent is a combination of netupitant and palonosetron, or a pharmaceutically acceptable salt of any of the foregoing.

[0069] In some embodiments, the cancer is a platinum-refractory cancer.

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

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

[0072] In some embodiments, the cancer is a PARP inhibitor-resistant cancer.

[0073] In some embodiments, the cancer is an HRRm or HRD positive cancer.

[0074] In some embodiments, the cancer is advanced or metastatic cancer.

[0075] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of azenosertib, or a pharmaceutically acceptable salt thereof, of 250 mg, or its equivalent, or more, in an intermittent dosing cycle comprising 5 consecutive days of dosing and 2 days without dosing, and administering to a subject a daily dose of a PARP inhibitor (PARPi), or a pharmaceutically acceptable salt thereof, in an intermittent dosing cycle comprising 5 consecutive days of dosing and 2 days without dosing.

[0076] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of 300 mg or equivalent or more of azenosertib, or a pharmaceutically acceptable salt thereof, in an intermittent dosing cycle comprising 5 consecutive days of administration and 2 days without administration, and administering to a subject a daily dose of a PARP inhibitor (PARPi), or a pharmaceutically acceptable salt thereof, in an intermittent dosing cycle comprising 5 consecutive days of administration and 2 days without administration.

[0077] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of azenosertib, or a pharmaceutically acceptable salt thereof, of 350 mg, or its equivalent, or more, in an intermittent dosing cycle comprising 5 consecutive days of dosing and 2 days without dosing, and administering to a subject a daily dose of a PARP inhibitor (PARPi), or a pharmaceutically acceptable salt thereof, in an intermittent dosing cycle comprising 5 consecutive days of dosing and 2 days without dosing.

[0078] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of azenosertib, or a pharmaceutically acceptable salt thereof, of 400 mg, or its equivalent, or more, in an intermittent dosing cycle comprising 5 consecutive days of dosing and 2 days without dosing, and administering to said subject a daily dose of a PARP inhibitor (PARPi), or a pharmaceutically acceptable salt thereof, in an intermittent dosing cycle comprising 5 consecutive days of dosing and 2 days without dosing.

[0079] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of azenosertib, or a pharmaceutically acceptable salt thereof, of 450 mg, or its equivalent, or more, in an intermittent dosing cycle comprising 5 consecutive days of dosing and 2 days without dosing, and administering to said subject a daily dose of a PARP inhibitor (PARPi), or a pharmaceutically acceptable salt thereof, in an intermittent dosing cycle comprising 5 consecutive days of dosing and 2 days without dosing.

[0080] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in a daily dose of 450 mg or more of azenosertib or a pharmaceutically acceptable salt thereof.

[0081] 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), iniparib (BSI 201), E7016 (Esai), and CEP-9722, or a pharmaceutically acceptable salt of any of the foregoing.

[0082] In some embodiments, the PARPi is olaparib or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, olaparib is administered at a daily dose of 250 mg or more of azenosertib or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, olaparib is administered at a daily dose of 300 mg or more of azenosertib or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of the PARPi occur during the same week.

[0086] In some embodiments, the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of the PARPi occur consecutively (eg, every other week).

[0087] In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

[0088] In some embodiments, the cancer is metastatic or unresectable.

[0089] In one aspect, provided herein is a method for treating cancer, comprising administering to a subject a daily dose of 250 mg or its equivalent or greater of azenosertib or a pharmaceutically acceptable salt thereof in an intermittent administration cycle comprising five consecutive days of administration and two days without administration, and administering to a subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent administration cycle comprising four consecutive days of administration and three days without administration. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 300 mg, 350 mg, 400 mg, or 450 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 400 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 450 mg.

[0090] In one aspect, provided herein is a method for treating cancer, comprising administering to a subject a daily dose of 250 mg or its equivalent or greater of azenosertib or a pharmaceutically acceptable salt thereof in an intermittent administration cycle comprising three consecutive days of administration and four days without administration, and administering to a subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in an intermittent administration cycle comprising five consecutive days of administration and two days without administration. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 300 mg, 350 mg, 400 mg, or 450 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 400 mg. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 450 mg.

[0091] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of azenosertib or a pharmaceutically acceptable salt thereof of 200 mg, or its equivalent, or more, in an intermittent dosing cycle comprising 5 consecutive days of administration and 2 days without administration, and administering to a subject a daily dose of a chemotherapeutic agent, in an intermittent dosing cycle comprising 5 consecutive days of administration and 2 days without administration.

[0092] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg once daily in an intermittent dosing cycle of 5 consecutive days of administration and 2 days without administration, and paclitaxel 、 80 mg / m on days D1, D8, and D15 in a 28-day cycle 2 is administered at a dose of

[0093] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg once daily in an intermittent dosing cycle of 5 consecutive days of dosing and 2 days without dosing, and carboplatin AUC 5 mg / mL* min is administered on D1 of a 21-day cycle.

[0094] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in 5 consecutive doses. It is administered at a dose of 400 mg once daily in an intermittent dosing cycle of 2 days on and off, and 40 mg / m on D1 in a 28-day cycle. 2 PLD is administered at a dose of

[0095] As used in this application, the terms "about" and "approximately" are used as equivalents. Any numbers used in this application, whether about / approximately or not, are meant to cover any normal variations understood by one of ordinary skill in the relevant art.

[0096] Other features, objects, and advantages will become apparent in the following detailed description. It should be understood, however, that the detailed description, while indicating embodiments, is given by way of example only and not of limitation. Various changes and modifications within the scope of the present disclosure will become apparent to those skilled in the art from the detailed description.

[0097] The figures described below that make up the drawings are for purposes of illustration only and not limitation. [Brief explanation of the drawings]

[0098] [Figure 1A] Figure 1A is a graph showing the change in tumor volume in a human ovarian cancer cell line SKOV3 model treated with azenosertib at 60 mg / kg (continuously) at intervals, measured up to approximately 21 days after the start of treatment. Intermittent administration of azenosertib at 80 mg / mL for three cycles, 5 days on / 2 days off, was found to be more effective. [Figure 1B] Figure 1B is a graph showing the percent change in body weight of subjects treated with either a continuous dose (60 mg / kg) or an intermittent dose (80 mg / kg, 5 days on / 2 days off for 3 cycles) of azenosertib in an ovarian cancer model (SKOV3), measured up to approximately 21 days after initiation of treatment. [Figure 1C]Figure 1C is a graph showing the change in tumor volume in a non-small cell lung cancer (NSCLC) A427 model. At comparable cumulative doses, higher intermittent doses of azenosertib (e.g., 56 mg / kg or 112 mg / kg) administered for 4 cycles of 5 days on / 2 days off were found to be more effective than lower continuous doses (e.g., 40 mg / kg or 80 mg / kg, respectively). [Figure 1D] FIG. 1D is a graph showing the percent change in body weight corresponding to the treatment regimens in FIG. 1C, measured up to about 28 days after initiation of treatment. [Figure 1E] Figure 1E is a graph showing the change in tumor volume in a non-small cell lung cancer (NSCLC) A427 model. At comparable cumulative doses, a higher intermittent dose of azenosertib (e.g., 100 mg / kg) given for 4 cycles of 4 days on / 3 days off was found to be more effective than a lower continuous dose (e.g., 60 mg / kg) when measured up to about 25 days after the start of treatment. [Figure 1F] FIG. 1F is a graph showing the percent change in body weight corresponding to the treatment regimen in FIG. 1E, measured up to about 25 days after initiation of treatment. [Figure 1G] Figure 1G is a graph showing the change in tumor volume in the breast ductal carcinoma HCC1569 model. At comparable cumulative doses, higher intermittent doses of azenosertib (e.g., 100 mg / kg) in intermittent dosing regimens of 4 days on / 3 days off and 3 days on / 4 days off for three cycles were found to be more effective when measured up to about 24 days after the start of treatment compared with lower continuous doses (e.g., 60 mg / kg). Both intermittent dosing frequencies of 4 days on / 3 days off and 3 days on / 4 days off were found to be equally effective. [Figure 1H] FIG. 1H is a graph showing the percent change in body weight corresponding to the treatment regimen in FIG. 1G, measured up to about 24 days after initiation of treatment. [Figure 1I] FIG. 1I is a graph showing the change in tumor volume in the ovarian cancer OVCAR3 model following intermittent azenosertib treatment at a dose of 80 mg / kg in a 7 days on / 7 days off regimen for 3 cycles. [Figure 1J] FIG. 1J is a graph showing the percent change in body weight corresponding to the treatment regimen in FIG. 1I, measured up to about 32 days after initiation of treatment. [Figure 2A] Figure 2A is a graph showing the change in tumor volume in the ovarian cancer OVCAR3 model after intermittent treatment based on the same 5-day on / 2-day regimen for once-daily doses compared with twice-daily doses (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). For the same cumulative dose, once-daily doses were more effective than twice-daily doses. [Figure 2B] FIG. 2B is a graph showing the percent change in body weight corresponding to the treatment regimen in FIG. 2A, measured up to about 22 days after initiation of treatment. [Figure 2C] Figure 2C is a graph showing the change in tumor volume in the ovarian cancer OVCAR3 model. 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 once-daily continuous dose of 60 mg / kg. Both the higher intermittent doses of 5 days on / 2 days off and 4 days on / 3 days off were more effective than the lower continuous doses. [Figure 2D] FIG. 2D is a graph showing the percent change in body weight corresponding to the treatment regimen in FIG. 2C, measured up to about 24 days after initiation of treatment. [Figure 2E] Figure 2E is a graph showing tumor volume changes in the OVCAR3 ovarian cancer model. Azenosertib was administered at 100 mg / kg in two intermittent dosing regimens: 4 days on / 3 days off, or 3 days on / 4 days off for three cycles. Additionally, a continuous dose of 60 mg / kg was administered for 24 days, for a cumulative dose of 1440 mg. Three cycles of approximately 100 mg / kg for 4 days on / 3 days off were administered for a cumulative dose of 1200 mg, and three cycles of approximately 100 mg / kg for 3 days on / 4 days off were administered for a cumulative dose of 900 mg. Both intermittent doses demonstrated greater efficacy than continuous administration. [Figure 2F]FIG. 2F is a graph showing the percent change in body weight corresponding to the treatment regimen in FIG. 2E, measured up to about 24 days after initiation of treatment. [Figure 3] Figure 3 is a graph showing the PK / PD correlation between azenosertib and Wee1 target engagement. The graph shows that inhibition of pCDK1 increases Wee1 target engagement. Increasing drug dose or exposure also resulted in increased Wee1 target engagement. Doses above approximately 300 mg once daily demonstrated excellent target engagement and the highest AUC with at least a 50% reduction in p-CDK1 levels. [Figure 4] Figure 4 provides a model and skin biopsy staining showing that the reduction in p-CDK1 levels correlates with Wee1 inhibition. CDK1 phosphorylation (pCDK-1) is mediated by Wee1. It is contemplated that Wee1 inhibition with azenosertib results in pCDK1 inhibition. For example, the Y15 residue is not phosphorylated, and CDK1 levels in skin biopsies confirmed the reduction in p-CDK1 levels after treatment compared to baseline. [Figure 5A] FIG. 5A is a graph of azenosertib plasma concentrations from subjects receiving 350 mg once daily or 175 mg twice daily, 5 days on / 2 days off, on day 1 of cycle 1. [Figure 5B] FIG. 5B is a graph of azenosertib plasma concentrations from subjects receiving 350 mg once daily or 175 mg twice daily, 5 days on / 2 days off, on days 11 / 12 of cycle 1. [Figure 5C] Figure 5C is a graph of azenosertib plasma concentrations from subjects receiving a continuous dosing regimen compared to subjects receiving an intermittent 350 mg once daily dosing regimen 5 days on / 2 days off on Day 1 of Cycle 1. [Figure 5D] Figure 5D is a graph of azenosertib plasma concentrations from subjects receiving a continuous dosing regimen compared to subjects receiving an intermittent 350 mg once daily dosing regimen 5 days on / 2 days off on days 11 / 12 or 15 of cycle 1. [Figure 5E]Figure 5E is a graph of azenosertib plasma concentrations from subjects receiving a continuous dosing regimen compared to subjects receiving an intermittent 175 mg twice daily dosing regimen 5 days on / 2 days off on Day 1 of Cycle 1. [Figure 5F] Figure 5F is a graph of azenosertib plasma concentrations from subjects receiving a continuous dosing regimen compared to subjects receiving an intermittent 175 mg dosing regimen 5 days on / 2 days off on days 11 / 12 or 15 of cycle 1. [Figure 6A] Figures 6A-6G are exemplary graphs showing tumor growth inhibition or tumor volume reduction when treated with a WEE1 inhibitor alone or in combination with a PARPi in MDA-MB-436 triple-negative breast cancer tumor models: parental MDA-MB-436 (TP53, BRCA1 mutant) (Figures 6A and 6D), MDA-MB-436 NirR (TP53, BRCA1m reversion) (Figures 6B and 6E), and MDA-MB-436 OlaR (TP53, BRCA1m inversion) (Figures 6C, 6F, and 6G). [Figure 6B] Figures 6A-6G are exemplary graphs showing tumor growth inhibition or tumor volume reduction when treated with a WEE1 inhibitor alone or in combination with a PARPi in MDA-MB-436 triple-negative breast cancer tumor models: parental MDA-MB-436 (TP53, BRCA1 mutant) (Figures 6A and 6D), MDA-MB-436 NirR (TP53, BRCA1m reversion) (Figures 6B and 6E), and MDA-MB-436 OlaR (TP53, BRCA1m inversion) (Figures 6C, 6F, and 6G). [Figure 6C] Figures 6A-6G are exemplary graphs showing tumor growth inhibition or tumor volume reduction when treated with a WEE1 inhibitor alone or in combination with a PARPi in MDA-MB-436 triple-negative breast cancer tumor models: parental MDA-MB-436 (TP53, BRCA1 mutant) (Figures 6A and 6D), MDA-MB-436 NirR (TP53, BRCA1m reversion) (Figures 6B and 6E), and MDA-MB-436 OlaR (TP53, BRCA1m inversion) (Figures 6C, 6F, and 6G). [Figure 6D] Figures 6A-6G are exemplary graphs showing tumor growth inhibition or tumor volume reduction when treated with a WEE1 inhibitor alone or in combination with a PARPi in MDA-MB-436 triple-negative breast cancer tumor models: parental MDA-MB-436 (TP53, BRCA1 mutant) (Figures 6A and 6D), MDA-MB-436 NirR (TP53, BRCA1m reversion) (Figures 6B and 6E), and MDA-MB-436 OlaR (TP53, BRCA1m inversion) (Figures 6C, 6F, and 6G). [Figure 6E] Figures 6A-6G are exemplary graphs showing tumor growth inhibition or tumor volume reduction when treated with a WEE1 inhibitor alone or in combination with a PARPi in MDA-MB-436 triple-negative breast cancer tumor models: parental MDA-MB-436 (TP53, BRCA1 mutant) (Figures 6A and 6D), MDA-MB-436 NirR (TP53, BRCA1m reversion) (Figures 6B and 6E), and MDA-MB-436 OlaR (TP53, BRCA1m inversion) (Figures 6C, 6F, and 6G). [Figure 6F] Figures 6A-6G are exemplary graphs showing tumor growth inhibition or tumor volume reduction when treated with a WEE1 inhibitor alone or in combination with a PARPi in MDA-MB-436 triple-negative breast cancer tumor models: parental MDA-MB-436 (TP53, BRCA1 mutant) (Figures 6A and 6D), MDA-MB-436 NirR (TP53, BRCA1m reversion) (Figures 6B and 6E), and MDA-MB-436 OlaR (TP53, BRCA1m inversion) (Figures 6C, 6F, and 6G). [Figure 6G]Figures 6A-6G are exemplary graphs showing tumor growth inhibition or tumor volume reduction when treated with a WEE1 inhibitor alone or in combination with a PARPi in MDA-MB-436 triple-negative breast cancer tumor models: parental MDA-MB-436 (TP53, BRCA1 mutant) (Figures 6A and 6D), MDA-MB-436 NirR (TP53, BRCA1m reversion) (Figures 6B and 6E), and MDA-MB-436 OlaR (TP53, BRCA1m inversion) (Figures 6C, 6F, and 6G). [Figure 7A] Figures 7A-7D are exemplary graphs showing tumor volume reduction following treatment with azenosertib and / or niraparib in the HBCx-10 subject-derived xenograft (PDX) model (Figure 7A), the HBCx-17 PDX model (Figure 7B), the BRCA1 mutated CTG-0703 PDX model (Figure 7C), and the BRCA1 / 2 WT CTG-2213 PDX model (Figure 7D). [Figure 7B] Figures 7A-7D are exemplary graphs showing tumor volume reduction following treatment with azenosertib and / or niraparib in the HBCx-10 subject-derived xenograft (PDX) model (Figure 7A), the HBCx-17 PDX model (Figure 7B), the BRCA1 mutated CTG-0703 PDX model (Figure 7C), and the BRCA1 / 2 WT CTG-2213 PDX model (Figure 7D). [Figure 7C] Figures 7A-7D are exemplary graphs showing tumor volume reduction following treatment with azenosertib and / or niraparib in the HBCx-10 subject-derived xenograft (PDX) model (Figure 7A), the HBCx-17 PDX model (Figure 7B), the BRCA1 mutated CTG-0703 PDX model (Figure 7C), and the BRCA1 / 2 WT CTG-2213 PDX model (Figure 7D). [Figure 7D]Figures 7A-7D are exemplary graphs showing tumor volume reduction following treatment with azenosertib and / or niraparib in the HBCx-10 subject-derived xenograft (PDX) model (Figure 7A), the HBCx-17 PDX model (Figure 7B), the BRCA1 mutated CTG-0703 PDX model (Figure 7C), and the BRCA1 / 2 WT CTG-2213 PDX model (Figure 7D). [Figure 8] FIG. 8 shows an exemplary reduction in tumor volume following treatment with azenosertib and / or talazoparib in an OVCAR3 xenograft model. [Figure 9A] FIG. 9A is a pie chart showing the proportion of the subject population suffering from different types of cancer enrolled in azenosertib monotherapy trials. [Figure 9B] FIG. 9B is a graph of steady-state exposure (AUC0-24) versus dose of azenosertib comparing continuous and intermittent dosing regimens. [Figure 9C] FIG. 9C is a graph comparing maximum concentration (Cmax) levels in continuous and intermittent dosing. [Figure 9D] Figure 9D is a graph of steady-state exposure (AUC0-24) versus maximum concentration (Cmax) levels comparing continuous and intermittent dosing regimens for azenosertib monotherapy. [Figure 9E] FIG. 9E is a graph of the % change from baseline showing confirmed response rate after azenosertib monotherapy. [Figure 9F] FIG. 9F is a graph of the % change from baseline showing objective response rate in the ovarian and uterine serous carcinoma population following azenosertib monotherapy with continuous and intermittent dosing regimens. [Figure 9G] FIG. 9G is a graph of the percent change from baseline showing the best overall response for azenosertib monotherapy from baseline to week 30 of treatment. [Figure 9H] FIG. 9H is a graph showing overall response rate (ORR%) and median progression-free survival (MPFS%) in ovarian cancer. [Figure 9I] FIG. 9I is a graph showing overall response rate (ORR%) and median progression-free survival (MPFS%) in uterine serous adenocarcinoma. [Figure 10A] FIG. 10A is a graph showing the change in tumor volume in an animal model of the human ovarian cancer cell line OVCAR3 with azenosertib monotherapy at 60 mg / kg or 80 mg / kg qd (intermittent dosing 5 days on / 2 days off), paclitaxel monotherapy at 20 mg / kg qw, carboplatin monotherapy at 25 mg / kg qw, or azenosertib plus paclitaxel or azenosertib plus carboplatin combination therapy (same doses, same dosing regimens as monotherapy), at intervals measured up to about 24 days after initiation of treatment. [Figure 10B] FIG. 10B is a graph showing the change in body weight for subjects treated with monotherapy and combination therapy as described for FIG. 10A. [Figure 11A] FIG. 11A is a waterfall plot showing the maximum percent change in the sum of diameters of target lesions in subjects receiving the combination of azenosertib in combination with paclitaxel. [Figure 11B] FIG. 11B is a waterfall plot showing the maximum percent change in the sum of diameters of target lesions in subjects receiving the combination of azenosertib in combination with carboplatin. [Figure 11C] FIG. 11C is a waterfall plot showing the maximum percent change in the sum of diameters of target lesions in subjects receiving the combination of azenosertib in combination with gemcitabine. [Figure 12] Figure 12 shows Kaplan-Meier curves for progression-free survival in subjects receiving azenosertib combination therapy with paclitaxel, carboplatin, gemcitabine, or pegylated liposomal doxorubicin (PLD). DETAILED DESCRIPTION OF THE INVENTION

[0099] definition In order that this disclosure may be more readily understood, certain terms are first defined below. Additional definitions for these terms, as well as other terms, are set forth throughout the specification.

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are multiple definitions for terms herein, the terms in this section shall prevail unless otherwise stated.

[0101] As used herein, the term "about" has its ordinary meaning as understood by one of ordinary skill in the art, and thus indicates that a value includes the inherent variation of error for the method being used to determine the value or the variation that exists among multiple determinations.

[0102] As used herein, the term "modify" or "alter" or any form thereof means to modify, change, replace, delete, substitute, remove, alter, or convert.

[0103] As used herein, the terms "function" and "functional" have their ordinary meaning as understood by those of skill in the art and thus refer to biological, enzymatic, or therapeutic function.

[0104] As used herein, the term "endogenous" has its ordinary meaning as understood by those of skill in the art, and thus refers to the native or wild-type characteristics of a gene, protein, or cell. In some embodiments, an endogenous gene is the wild-type sequence of said gene. In some embodiments, an endogenous protein is the wild-type sequence of said protein. In some embodiments, an endogenous protein function is the wild-type function and activity level of said protein. In some embodiments, an endogenous cell is a wild-type cell.

[0105] The term "mutation" has its ordinary meaning as understood by those of skill in the art and refers to a change in a gene sequence. In some embodiments, the cell has multiple mutations. In some embodiments, the mutations are in coding regions of the genome. Mutations can range in size from a single nucleotide to large segments of a chromosome containing multiple genes. In some embodiments, at least one mutation is silent and does not significantly affect gene expression or function. In some embodiments, at least one mutation affects gene expression or function, such as gene amplification, overexpression, or increased copy number. In some embodiments, at least one mutation is silent and does not significantly affect 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 increases protein expression or function. In some embodiments, the mutations have a moderate effect on protein expression or function. In some embodiments, the at least one mutation has a large effect on protein expression or function. In some embodiments, the at least one mutation disrupts protein expression or function. Non-limiting examples of mutations include insertions, deletions, truncations, substitutions, duplications, translocations, and inversions. In some embodiments, the mutations are "somatic," i.e., occur in somatic cells, and are not heritable. In some embodiments, a subset of somatic cells in an organism have at least one mutation that other somatic cells do not have. In some embodiments, the mutations are "germline," i.e., occur in germ cells, and are heritable.

[0106] As disclosed herein, mutations can be monitored through various 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 test, DNA microarray, heteroduplex analysis, denaturing gradient gel electrophoresis, nucleotide sequencing, single-strand conformation polymorphism, restriction enzyme digestion assay, fluorescence in situ hybridization (FISH), comparative genomic hybridization, restriction fragment length polymorphism, amplification-refractory mutation PCR, nested PCR, multiplex ligation-dependent probe amplification, single-strand conformation polymorphism, and oligonucleotide ligation assay. Mutations can also be monitored via various antibody-based methods using biological samples, including, but not limited to, Western blotting, fluorescence-activated cell sorting, immunofluorescence, immunohistochemistry, immunocytochemistry, immunoprecipitation, enzyme-linked immunosorbent assay, radioimmunoassay, and electrochemiluminescence assay.

[0107] The term "cancer" is used herein in its normal biological sense and is understood by those skilled in the art. It can therefore include cancer of any cell type, for example, but not limited to, glioblastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, leukemia, skin cancer, adrenal gland cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, uterine cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, Hodgkin's lymphoma, blood tumors, hematological malignancies, Kaposi's sarcoma, kidney cancer, and pharyngeal cancer. 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, gastric cancer, small intestine cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous adenocarcinoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, solid tumors, or liquid tumors.

[0108] As used herein, the term "tumor" has its ordinary meaning as understood by those skilled in the art and refers to an abnormal growth of cells or tissue. In some embodiments, tumors are benign. In some embodiments, tumors are malignant. A tumor becomes cancerous when it metastasizes or spreads to other areas of the body. As used herein, the term "solid tumor" has its ordinary meaning as understood by those skilled in the art and refers to an abnormal mass of tissue that does not contain liquid areas or cysts. Non-limiting examples of solid tumors include sarcomas, carcinomas, or lymphomas. Many cancerous 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, sarcoma, neuroblastoma, or ovarian cancer. The terms "cancer" and "tumor" may generally be used interchangeably unless the context clearly indicates that a more specific meaning is intended.

[0109] As used herein, the term cell has its ordinary meaning as understood by those of skill in the art and can refer to any cell type. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0110] As used herein, the terms "individual," "subject," or "patient" have their ordinary meanings as understood by those skilled in the art, and thus include a human or non-human mammal. The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes, but is not limited to, monkeys (chimpanzees, apes, monkeys) and primates, including humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, or pigs. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant. In other embodiments, the subject may be an adult.

[0111] As used herein, the term "cancer therapy" has its ordinary meaning as understood by one of ordinary skill in the art and refers to therapeutic modalities (such as surgery and / or radiation) or anti-cancer agents such as small molecules, compounds, proteins, or other drugs used to treat, inhibit, or prevent cancer. Non-limiting examples of common classes of anti-cancer agents that can be used in 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, calcineurin inhibitors, CaM kinase II inhibitors, CD45 tyrosine phosphatase inhibitors, CDC25 phosphatase inhibitors, CHK kinase inhibitors, cyclooxygenase inhibitors, bRAF kinase inhibitors, and the like. enzyme inhibitors, cRAF kinase inhibitors, Ras inhibitors, cyclin-dependent kinase inhibitors, cysteine ​​protease inhibitors, DNA intercalators, DNA strand breakers, E3 ligase inhibitors, EGF pathway inhibitors, farnesyltransferase inhibitors, Flk-1 kinase inhibitors, glycogen synthase kinase-3 (GSK3) inhibitors, histone deacetylase (HDAC) inhibitors, I-kappa B-alpha kinase inhibitors, imidazotetrazinone, insulin tyrosine kinase inhibitors, c-Jun N-terminal kinase (JNK) inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, MDM2 inhibitors, MEK inhibitors, ERK inhibitors, MMP inhibitors, mTor inhibitors, NGFR tyrosine kinase inhibitors, p38MAP 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 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, aryletinone, altretamine, aminopterin, aminolevulinic acid, amsacrine asparaginase, atrasentan, bexarotene, carboquone, demecolcine, efaproxiral, elsamitrucin, etoglucide, hydroxycarbamide, leucovorin, lonidamine, lucantone, masoprocol, methyl aminolevulinate, mitoguazone, mitotane, oblimersen, omacetaxine, pegaspargase, porfimer sodium, prednimustine, citimagine seradenovec, talaporfin, temoporfin, trabectedin, or verteporfin. Examples of chemotherapeutic agents useful in treating cancer include carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin, doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapine, 5-azacytidine, capecitabine, AraC-FdUMP

[10] (CF-10), cladribine, decitabine, hydroxyurea, and oxaliplatin, or a pharmaceutically acceptable salt of any of the foregoing. Other examples of chemotherapeutic agents useful in treating cancer include azacitidine, bendamustine, and cyclosporine. and vincristine, or a pharmaceutically acceptable salt of any of the foregoing.

[0112] 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 interfere with 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 a compound with an inorganic acid such as hydrochloric 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 a compound with an organic 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-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form salts such as ammonium salts, alkali metal salts (such as sodium, potassium, or lithium salts), alkaline earth metal salts (such as calcium or magnesium salts), carbonate salts, bicarbonate salts, salts of organic bases (such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and the like), and salts with amino acids (such as arginine and lysine).

[0113] Where the compounds disclosed herein have unfilled valences, it is to be understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0114] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure can include any isotope of said 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 in the 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 possible isotopic forms, unless the context clearly indicates otherwise.

[0115] It is understood that the compounds described herein include crystalline forms (also known as polymorphs, which include different crystalline packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and can be formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0116] The term "rest" or "rest day" refers to a period of time or a day without administration, a day off treatment, or a rest day when azenosertib or a pharmaceutically acceptable salt thereof is not administered. For example, a break refers to the period following a dosing cycle or an intervening period between dosing weeks during which azenosertib administration is suspended.

[0117] The term "platinum-resistant cancer" refers to cancer that initially responds to treatment with a drug containing the metal platinum, but then relapses within a certain period of time. For example, ovarian cancer that relapses within six months of treatment is considered platinum-resistant.

[0118] The term "platinum-refractory cancer" refers to cancer that progresses during platinum-based therapy, including progression within 90 days of the last dose of any line of platinum-based regimen.

[0119] As used herein, "therapeutically effective amount" or "effective amount" refers to the amount of an active compound (e.g., azenosertib or a pharmaceutically acceptable salt thereof) that elicits the indicated biological or therapeutic response (i.e., symptomatic relief). For example, a therapeutically effective amount of such an azenosertib compound, salt, or composition is the amount necessary to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or to prolong the survival or slow the progression of the disease in the treated subject. This response may occur in a tissue, system, animal, or human and includes the alleviation of signs or symptoms of the disease or condition being treated. The therapeutically effective dose may be further adjusted depending on the type of subject, including, but not limited to, factors such as route of administration, age, weight, diet, and concomitant medications. For example, a therapeutic amount of an azenosertib compound, salt, or composition may be an amount or dose that results in the reduction, alleviation, or elimination of one or more symptoms caused by cancer, reduction in tumor size or volume, tumor elimination, and / or long-term disease stabilization (proliferation arrest) of the tumor. Furthermore, an effective amount of an azenosertib compound, salt, or composition can be an amount that results in a reduction in Wee1 activity and / or phosphorylation (such as phosphorylation of CDK1). Reductions in Wee1 activity are known to those skilled in the art and can be determined by assays of WEE1 intrinsic kinase activity and downstream substrate phosphorylation.

[0120] As used herein, the term "equivalent" of azenosertib or a pharmaceutically acceptable salt thereof refers to a compound having substantially the same strength or concentration of the same active ingredient, e.g., a salt or ester of the therapeutic moiety, optionally in substantially the same dosage form and route of administration. As used herein, the term "equivalent" includes "substitute pharmaceuticals" that contain the same therapeutic moiety, or precursor thereof, but not necessarily in the same amount or dosage form, or as a salt or ester, and "therapeutic equivalents" that are bioequivalent and have similar clinical efficacy and safety profiles. Equivalents do not necessarily contain the same inactive ingredients and may differ in characteristics such as shape, release mechanism, labeling, flavoring, or preservatives, or excipients. As used herein, the term "equivalent dose" refers to the above-mentioned effective amount of a compound, e.g., azenosertib in another salt or ester form.

[0121] As used herein, "cumulative dose" refers to the total dose resulting from repeated exposure from one or more dosing cycles over the treatment period.

[0122] As used herein, "exposure" refers to the drug level achieved in the body, for example, in plasma. Response can be evaluated in terms of either efficacy or safety. Exposure and response are parameters in determining a dose that balances drug efficacy and adverse events.

[0123] As used herein, "AUC" or "area under the curve" refers to the area under a plot of the plasma concentration of a drug versus time after administration, and provides insight into the extent of exposure to the drug and its rate of clearance from the body.

[0124] As used herein, "Cmax" refers to the peak concentration of a drug in the blood or target organ after a dose is administered.

[0125] As used herein, "dosing regimen" refers to a method by which an azenosertib compound is administered to a subject, including the route of administration, the amount of the dose, and the administration interval. A dosing regimen may include "regular" administration, in which a specific dose (e.g., 300 mg) is administered at regular intervals (e.g., once a day) for a specific period (e.g., 3 days). A dosing regimen may also include "intermittent" administration, during which one or more administration parameters, such as the dose and / or the administration interval, are varied or changed. For example, an intermittent administration phase may include a period of continuous administration followed by a "rest" phase, during which the azenosertib compound is not administered or is administered at a reduced dose and / or less frequently. A dosing regimen may further include one or more repeated cycles of the intermittent administration regimen.

[0126] As used herein, a "dosing cycle or intermittent dosing cycle" refers to a week of intermittent dosing, where each dosing week includes consecutive dosing days (e.g., 2-7 days) followed by a dosing-free day (e.g., 1-7 days). In some embodiments, an intermittent dosing cycle includes one or more dosing weeks, where each dosing week includes at least two consecutive dosing days and at least one rest day. In some embodiments, an intermittent dosing cycle includes one or more dosing weeks, where each dosing week includes at least three consecutive dosing days and at least one rest day.

[0127] As used herein, "administration week" refers to a week of intermittent administration regimen, including administration days and non-administration days.For example, an administration week is 2 days on / 5 days off, 3 days on / 4 days off, 4 days on / 3 days off, 5 days on / 2 days off, 6 days on / 1 day off, or 7 days on / 7 days off.As described herein, "on day" refers to the day on which azenosertib (alone or in combination) is administered to a patient, and "off day" refers to the day on which azenosertib (alone or in combination) is not administered.

[0128] When a range of values ​​is provided, it is understood that the upper and lower limits, and each intervening value between the upper and lower limits of the range, are encompassed within an embodiment.

[0129] Terms and phrases used in this application, and variations thereof, should be construed as open-ended rather than limiting, unless expressly stated otherwise, particularly in the appended claims. As an example of the foregoing, the term "including" should be read to mean "including, without limitation," "including but not limited to," or similar expressions. As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," is open-ended, and does not exclude additional, unrecited elements or method steps. The term "having" should be interpreted as "having at least." The term "including" should be interpreted as "including but not limited to." The term "example" is used to provide illustrative examples of the items under discussion, not an exhaustive or limiting list thereof. Additionally, terms such as "preferably," "preferred," "desired," "desirable," or words of similar import should not be understood to imply that a particular feature is critical, essential, or even essential to structure or function, but rather that it may or may not be utilized in a particular embodiment. It is merely intended to highlight alternative or additional features that may not be present. Additionally, the term "comprising" should be interpreted synonymously with the phrase "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.

[0130] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art can translate from plural to singular and / or from singular to plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity. The indefinite articles "a" or "an" do not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be advantageously used. Any reference signs in the claims should not be construed as limiting the scope.

[0131] Detailed Description Provided herein are methods for treating cancer using improved intermittent dosing regimens for azenosertib administration, particularly to achieve highly effective, safe, and well-tolerated dosing regimens for treating many different types of cancer. Provided herein are methods for treating cancers that are resistant to conventional therapy and recur. Provided herein are high-dose intermittent dosing regimens that unexpectedly increase efficacy over continuous administration. An advantage of the present disclosure is that it can improve tolerability by reducing toxicity.

[0132] In some aspects, provided herein are methods of treating cancer comprising administering to a subject in need thereof a daily dose of 350 mg, or its equivalent, or more of azenosertib or a pharmaceutically acceptable salt thereof according to an intermittent dosing cycle, wherein the intermittent dosing cycle includes one or more dosing weeks, each dosing week including at least three consecutive dosing days and at least one day without dosing.

[0133] In some aspects, provided herein is a method of administering to a subject in need thereof a daily dose of 100 mg or its equivalent or more of azenosertib or a pharmaceutically acceptable salt thereof according to an intermittent dosing cycle, wherein the intermittent dosing cycle includes one or more dosing weeks, each dosing week including at least three consecutive dosing days and at least one rest day followed by at least one week of rest.

[0134] In some aspects, provided herein are methods of treating cancer, comprising administering to a subject in need thereof a daily dose of 350 mg, or its equivalent, or more of azenosertib or a pharmaceutically acceptable salt thereof, according to an intermittent dosing cycle, wherein the intermittent dosing cycle includes at least two consecutive days of dosing and at least one day of no dosing.

[0135] Azenosertib is a Wee1 inhibitor and antitumor agent Azenosertib (also known 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 repair. Inhibiting Wee1 using azenosertib reduces tumors in multiple tumor cell lines and xenograft models. WO2019 / 173082, which describes methods for making azenosertib and its salts and compositions, and WO2019 / 173082 and WO2021 / 231653, which describe the compound azenosertib and methods for using it to treat cancer, are incorporated herein by reference.

[0136] [Table 1]

[0137] Wee1 functions to prevent replication of cells with modified DNA. The primary downstream target of Wee1 family kinases is the CDK1-cyclin B1 complex, also known as mitogen-promoting factor (MPF). Wee1 phosphorylates CDK1 on Tyr15, which keeps the MPF complex inhibited until mitosis.

[0138] Cancer treatment methods Administration route In some embodiments, an effective dose of azenosertib or a pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously. In some embodiments, an effective dose of azenosertib or a pharmaceutically acceptable salt thereof is administered orally. Alternative suitable techniques for administering an effective dose of azenosertib or a pharmaceutically acceptable salt thereof known to those skilled in the art may also be used, including, but not limited to, oral, rectal, topical pulmonary, aerosol, injection, infusion, and parenteral delivery, including, but not limited to, intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In other embodiments, azenosertib or a pharmaceutically acceptable salt thereof and / or a chemotherapeutic agent or a pharmaceutically acceptable salt thereof may be administered orally.

[0139] In some embodiments, an effective dose of azenosertib or a pharmaceutically acceptable salt thereof is administered orally, intravenously, subcutaneously, intrathecally, intramuscularly, intracavitary, intrapleurally, intralesionally, or intraarterially. In some embodiments, an effective dose of azenosertib or a pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously. In some embodiments, an effective dose of azenosertib or a pharmaceutically acceptable salt thereof is administered intrathecally, intramuscularly, intracavitary, intrapleurally, intralesionally, or intraarterially.

[0140] In some embodiments, an effective dose of azenosertib or a pharmaceutically acceptable salt thereof is administered orally.

[0141] Dosage cycle The treatment methods provided herein include administering azenosertib or a pharmaceutically acceptable salt thereof, and / or a second therapeutic agent (e.g., an antitumor or anticancer agent, a chemotherapeutic agent, etc.) (including a pharmaceutically acceptable salt) according to a suitable dosing schedule. For example, azenosertib or a pharmaceutically acceptable salt thereof, and / or a second therapeutic agent or a pharmaceutically acceptable salt thereof described herein may be administered once or multiple times daily (e.g., once, twice, three times, or four times daily) for a specified number of days, followed by a period during which no dose is given. This dosing cycle (consisting of administration days and non-administration days) may then be repeated.

[0142] The administration cycle is included within 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 1 year, 2 years, or longer. In some embodiments, the administration cycle is 3 days, 5 days, 7 days, 10 days, or 14 days. In some embodiments, the administration cycle is 7 days, 14 days, 21 days, 28 days, 36 days, 42 days, or longer.

[0143] Continuous administration In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in a continuous dosing regimen, for example, once a day or twice a day. For example, in some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 300 mg or more 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 equivalents thereof or more. In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, or equivalents thereof or more. A suitable dose of azenosertib or a pharmaceutically acceptable salt thereof may also be in the form of an equivalent dose (e.g., another salt form of the compound).

[0144] In some embodiments, the daily dose is divided equally into two doses per day. In some embodiments, the twice-daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, or equivalents thereof or more. In some embodiments, the daily dose is divided equally into three or four doses per day.

[0145] Intermittent administration An alternative administration approach is intermittent dosing regimen.Intermittent dosing regimen takes into account important determinants of response to treatment, including pharmacokinetic variability, the variability of various tissue types to azenosertib or its pharmaceutically acceptable salt, and quantitative exposure-response relationship (e.g., AUC or Cmax), thus overcoming some of the limitations of continuous fixed dose approach.Other factors include the occurrence of drug resistance.

[0146] Furthermore, pharmacokinetic (PK) variability impacts the outcome of combination therapies that are widely used to target many different types of cancer.

[0147] In an intermittent dosing regimen, exposure levels can rise and fall between drug doses. If the dosing interval is shorter than necessary for the drug to be completely eliminated, plasma drug levels will accumulate. Steady-state plasma drug is dose and clearance dependent. For intermittent dosing, the average plasma concentration resulting from the rise and fall of the drug is dependent on the dose and dosing interval.

[0148] Low doses given at frequent intervals result in smaller fluctuations in plasma levels than higher doses given at longer intervals. For example, for azenosertib, which has a mean half-life of 8 hours, it may take 3-5 half-lives to reach steady state during intermittent dosing, i.e., 1-2 days.

[0149] In some aspects, provided herein are methods of treating cancer, comprising administering to a subject in need thereof a daily dose of azenosertib or a pharmaceutically acceptable salt thereof at or above 350 mg, or its equivalent, according to an intermittent dosing cycle, wherein the intermittent dosing cycle comprises one or more dosing weeks, with each dosing week comprising at least three consecutive dosing days and at least one rest day.

[0150] Provided herein is administration of azenosertib or a pharmaceutically acceptable salt thereof at high doses, e.g., about 350 mg to about 800 mg once daily, or about 175 mg to about 400 mg twice daily in an intermittent dosing regimen, e.g., 5 days of dosing ("on" days) followed by 2 days without dosing ("off" days) (i.e., 5 / 2), 4 days of dosing followed by 3 days without dosing (i.e., 4 / 3), 3 days of dosing followed by 4 days without dosing (i.e., 3 / 4), 6 days of dosing followed by 1 day without dosing (i.e., 6 / 1), 7 days of dosing followed by 7 days without dosing. Alternatively, an intermittent dosing regimen of azenosertib or a pharmaceutically acceptable salt thereof may also be expressed as about 350 mg to about 800 mg once daily, or about 175 mg to about 400 mg twice daily, administered at an intermittent frequency, e.g., 5 on / 2 off, 4 on / 3 off, 3 on / 4 off, 6 on / 1 off, 7 on / 7 off, among others.

[0151] In some embodiments, one or more weeks of administration are separated by at least one week of rest. In some embodiments, the intermittent administration regimen described herein (e.g., 7 / 0, 6 / 1, 5 / 2, 4 / 3, or 3 / 4) is carried out with 2 weeks followed by a week of rest, or 1 week followed by a week of rest, thereby achieving high efficacy while increasing safety and tolerability in the treatment of cancer.

[0152] Further provided herein is a method of treating cancer, comprising administering to a subject in need thereof a daily dose of 100 mg, or its equivalent, or more of azenosertib or a pharmaceutically acceptable salt thereof according to an intermittent dosing cycle, wherein the intermittent dosing cycle includes one or more dosing weeks, each dosing week including at least three consecutive dosing days and at least one day without dosing, followed by at least one week of rest.

[0153] For example, in some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 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 equivalents thereof or more. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 350 mg or more once daily in an intermittent dosing regimen. In some embodiments, azenosertib 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, azenosertib 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, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 475 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 550 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 575 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 600 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 600 mg once daily. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 625 mg once daily in a continuous dosing regimen. In some embodiments, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 700 mg once daily in an intermittent dosing regimen.

[0154] In some embodiments, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, or equivalents thereof or more. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered once daily in an intermittent dosing regimen at a dose of about 200 mg. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered once daily in an intermittent dosing regimen at a dose of about 225 mg. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered once daily in an intermittent dosing regimen at a dose of about 250 mg. In some embodiments, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of more than about 300 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 350 mg once daily in an intermittent dosing regimen.

[0155] The daily dose of azenosertib or a pharmaceutically acceptable salt thereof is administered once a day or equally divided twice a day. For example, in some embodiments, the twice-daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, or equivalents thereof or more. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 175 mg twice a day in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg twice a day in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 225 mg twice a day in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 mg twice daily in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 275 mg twice daily in an intermittent dosing regimen. In some embodiments, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 350 mg twice daily in an intermittent dosing regimen.

[0156] In some embodiments, the daily dose is divided evenly into three or four doses per day. In some embodiments, the daily dose is divided evenly into three doses per day. In some embodiments, the daily dose is divided evenly into four doses per day.

[0157] Each dosing week includes at least 1 to 7 dosing days. Each dosing week includes at least 1 to 7 days without dosing. In some embodiments, each dosing week includes at least 2, 3, 4, 5, or 6 In some embodiments, each dosing week includes 5 consecutive dosing days and 2 days without dosing. In some embodiments, each dosing week includes 4 consecutive dosing days and 3 days without dosing. In some embodiments, each dosing week includes 3 consecutive dosing days and 4 days without dosing. In some embodiments, each dosing week includes 6 consecutive dosing days and 1 day without dosing. In some embodiments, each dosing week includes 7 consecutive dosing days and 7 days without dosing.

[0158] Each intermittent administration cycle comprises about 7 to about 10 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 8 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 9 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 10 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 14 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 21 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 28 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 32 consecutive administration days. In some embodiments, each intermittent administration cycle comprises about 42 consecutive administration days.

[0159] Further, an intermittent administration cycle comprises two or more consecutive administration weeks. In some embodiments, an intermittent administration cycle comprises two consecutive administration weeks. In some embodiments, an intermittent administration cycle comprises three consecutive administration weeks. In some embodiments, an intermittent administration cycle comprises four consecutive administration weeks. In some embodiments, an intermittent administration cycle comprises five consecutive administration weeks. In some embodiments, an intermittent administration cycle comprises six consecutive administration weeks. In some embodiments, an intermittent administration cycle comprises 6 to 12 weeks, 12 to 24 weeks, 24 to 48 weeks, or more consecutive administration weeks.

[0160] In some aspects, provided herein are methods of treating cancer, comprising administering to a subject in need thereof a daily dose of 350 mg or its equivalent or greater of azenosertib or a pharmaceutically acceptable salt thereof according to an intermittent dosing cycle, wherein the intermittent dosing cycle includes at least two consecutive dosing days and at least one dosing-free day. In some embodiments, the intermittent dosing cycle includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive dosing days. The dosing-free days are provided in intermittent dosing cycles including at least 2, 3, 4, 5, 6, or 7 dosing-free days. In some embodiments, the intermittent dosing cycle includes about 1 to 7 dosing-free days. In some embodiments, the intermittent dosing cycle includes one dosing-free day. In some embodiments, the intermittent dosing cycle includes two dosing-free days. In some embodiments, the intermittent dosing cycle includes three dosing-free days. In some embodiments, the intermittent dosing cycle includes four dosing-free days. In some embodiments, the intermittent administration cycle includes 5 days without administration. In some embodiments, the intermittent administration cycle includes 6 days without administration. In some embodiments, the intermittent administration cycle includes 7 days without administration.

[0161] In some embodiments, an intermittent administration cycle comprises about 2-7 consecutive administration days ("on" days) followed by a rest period of about 1-7 days ("off" days). In some embodiments, an intermittent administration cycle comprises 5 consecutive administration days and 2 days without administration. In some embodiments, an intermittent administration cycle comprises 4 consecutive administration days and 3 days without administration. In some embodiments, an intermittent administration cycle comprises 3 consecutive administration days and 4 days without administration. In some embodiments, an intermittent administration cycle comprises 6 consecutive administration days and 1 rest day. In some embodiments, an intermittent administration cycle comprises 7 consecutive administration days and 7 days without administration.

[0162] Further, in some embodiments, the intermittent dosing cycle comprises 14 consecutive dosing days and 7 dosing-free days.

[0163] As used herein, the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 375 mg / kg or more.In some embodiments, azenosertib 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, azenosertib 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, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 550 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 575 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 600 mg once daily in an intermittent dosing regimen. In some embodiments, azenosertib 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, azenosertib 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, azenosertib 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, azenosertib 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, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 mg once daily in an intermittent dosing regimen.In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of greater than about 800 mg once daily in an intermittent dosing regimen.

[0164] In some embodiments, the daily dose of azenosertib or its pharmaceutically acceptable salt is administered once a day.In some embodiments, the daily dose of azenosertib or its pharmaceutically acceptable salt is divided equally into two doses a day.In some embodiments, the daily dose of azenosertib or its pharmaceutically acceptable salt is divided equally into three or four doses a day.

[0165] In some embodiments, the intermittent administration cycle is repeated throughout the entire treatment period. In some embodiments, the dose and duration are varied. In some embodiments, the treatment is initiated at a high dose and reduced after one or more intermittent cycles. In some embodiments, the treatment is maintained at the same dose during the intermittent cycles.

[0166] Administration of food and / or antiemetic medication In some embodiments, the subject is administered azenosertib or a pharmaceutically acceptable salt thereof with food and / or an antiemetic agent (e.g., to minimize nausea and improve gastrointestinal tolerance). In some embodiments, the subject is administered azenosertib or a pharmaceutically acceptable salt thereof on an empty stomach. In some embodiments, the subject is administered an antiemetic agent with the administration of azenosertib or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the subject is administered azenosertib or a pharmaceutically acceptable salt thereof on an empty stomach. In some embodiments, the subject is administered azenosertib or a pharmaceutically acceptable salt thereof at least 1 hour or 2 hours before a meal.

[0168] In some embodiments, the subject is administered an antiemetic agent for at least one administration cycle with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for at least two administration cycles with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for at least three administration cycles with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for at least four administration cycles with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for more than four administration cycles with azenosertib administration. In some embodiments, the subject is administered an antiemetic agent for all administration cycles of azenosertib administration.

[0169] In some embodiments, the antiemetic agent 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.

[0170] In some embodiments, the antiemetic agent is aprepitant, rolapitant, ondansetron, granisterone, dexamethasone, olanzapine, netupitant, palonosetron, and combinations thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0171] In some embodiments, the antiemetic agent is aprepitant or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic agent is rolapitant or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic agent is ondansetron or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic agent is granisterone or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic agent is dexamethasone or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic agent is olanzapine or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic agent is netupitant or a pharmaceutically acceptable salt thereof. In some embodiments, the antiemetic agent is palonosetron. In some embodiments, the antiemetic agent is a combination of netupitant and palonosetron, or a pharmaceutically acceptable salt of any of the foregoing.

[0172] Type of cancer In some embodiments, the subject in need of treatment has cancer.

[0173] 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, other brain cancer, leukemia, skin cancer, adrenal gland cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, uterine cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, Hodgkin's lymphoma, blood tumors, hematological malignancies, Kaposi's sarcoma, kidney cancer, pharyngeal 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, thymus cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous adenocarcinoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, a solid tumor, or a liquid tumor.

[0174] In some embodiments, the cancer is a solid tumor or a hematological malignancy.

[0175] In some embodiments, the cancer is a solid tumor. In some embodiments, 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 triple-negative breast cancer (TNBC)), lung cancer (e.g., NSCLC), esophagogastric cancer, gastric cancer, esophageal cancer, renal cancer (e.g., pRCC, ccRCC, chromophobe RCC), head and neck cancer, osteosarcoma cancer, pancreatic cancer, brain cancer, adenoid cystic carcinoma (ACC), mesothelioma, liver cancer, glioblastoma (GBM), low-grade glioma (LGG), and / or gliomas with ... ), pheochromocytoma and paraganglioma (PCPG), cholangiocarcinoma, thyroid cancer, thymoma, uveal melanoma, and BRAF-mutated metastatic colorectal cancer.

[0176] 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 adenocarcinoma. 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 RCC). In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is osteosarcoma cancer. 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 cholangiocarcinoma. 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-mutated metastatic colorectal cancer.

[0177] In some embodiments, the solid tumor is associated with the adrenal gland, ampulla of Vater, biliary tract, bladder / urinary tract, bone, intestine, breast, cervix, CNS / brain, esophagus / stomach, eye, head and neck, kidney, liver, lung, lymphatic system, bone marrow, ovary / fallopian tube, pancreas, penis, peripheral nervous system, peritoneum, pleura, prostate, skin, soft tissue, testicle, thymus, thyroid, uterus, vulva / vagina, or other (e.g., adenocarcinoma in situ, extragonadal germ cell tumor (EGCT), mixed cancer types).

[0178] In some embodiments, the cancer is a hematological malignancy.

[0179] In some embodiments, the cancer is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous 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).

[0180] In some embodiments, the cancer is a platinum-refractory or platinum-resistant cancer.

[0181] In some embodiments, the cancer is a platinum-resistant cancer.

[0182] Combination therapy Provided herein are methods of using azenosertib, or a pharmaceutically acceptable salt thereof, in combination with one or more second therapeutic agents (e.g., combination therapy) or pharmaceutically acceptable salts thereof in an intermittent dosing regimen. Combination therapy refers to a regimen in which a subject is receiving two or more therapeutic agents (e.g., azenosertib, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent), or refers to a clinical intervention treated with a pharmaceutically acceptable salt thereof. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof are administered simultaneously. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof are administered sequentially. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered before the second therapeutic agent or a pharmaceutically acceptable salt thereof. In other embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered after the second therapeutic agent or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof are administered simultaneously. In some embodiments, azenosertib 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 in an alternating manner (e.g., azenosertib is administered before a dose of a second therapeutic agent or a pharmaceutically acceptable salt thereof, followed by azenosertib or a pharmaceutically acceptable salt thereof again, etc. In some embodiments, a second therapeutic agent or a pharmaceutically acceptable salt thereof is administered before a dose of azenosertib or a pharmaceutically acceptable salt thereof, followed by the second therapeutic agent or a pharmaceutically acceptable salt thereof again, etc.). In some embodiments, azenosertib, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent, or a pharmaceutically acceptable salt thereof, are administered in overlapping administration cycles.

[0184] In some embodiments, combination therapy in an intermittent administration cycle does not necessarily require that the individual agents be administered together (or necessarily simultaneously) in a single composition. In some embodiments, two or more therapeutic agents of the combination therapy (e.g., azenosertib or a pharmaceutically acceptable salt thereof, and a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof) are administered to a subject separately, e.g., in separate compositions, via separate routes of administration (e.g., oral administration of one agent and intravenous administration of another agent), and / or at different times. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents or pharmaceutically acceptable salts thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity), via the same route of administration, and / or simultaneously.

[0185] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered in intermittent administration cycles in combination with one or more second therapeutic agents or pharmaceutically acceptable salts thereof. 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 therapeutic agent or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the second therapeutic agent is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent may be 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, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, cyclophosphamide, capecitabine, dexamethasone, etoposide, daunorubicin, ifosfamide, methotrexate, and vincristine or a pharmaceutically acceptable salt of any of the foregoing.

[0187] In some embodiments, the second therapeutic agent is selected from a PARP inhibitor, including 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, a targeted therapeutic agent, or a pharmaceutically acceptable salt of any of the foregoing.

[0188] In some embodiments, the second therapeutic agent administered in the 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 of the foregoing.

[0189] In some embodiments, the second therapeutic agent administered in the 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, zimverelimab, toripalimab (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 of the foregoing.

[0190] In some embodiments, the second therapeutic agent administered in the intermittent dosing cycle is a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and 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 of the foregoing.

[0191] In some embodiments, the second therapeutic agent administered in the 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 of the foregoing.

[0192] In some embodiments, the second therapeutic agent administered in intermittent dosing cycles is a KRAS inhibitor or a pharmaceutically acceptable salt thereof, and 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, CAS 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 of the foregoing.

[0193] In some embodiments, the second therapeutic agent is a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof, and the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), relociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, and bilociclib. BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or any pharmaceutically acceptable salt thereof.

[0194] 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 of the foregoing.

[0195] 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-trastuzumab emtansine (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985, and XMT-1522, or a pharmaceutically acceptable salt of any of the foregoing.

[0196] 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 of the foregoing.

[0197] 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.

[0198] In some embodiments, the second therapeutic agent is a selective ER degrader (SERD), or a pharmaceutically acceptable salt thereof, and examples of the selective ER degrader include 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-methyl- (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brillanestran, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrant, RAD1901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brillanestran, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy) ... (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 (lintodestrant) , G1T48), D-0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (diledestrant, GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol N-[1-(3-fluoropropyl)azetidin-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 of the foregoing.

[0199] In some embodiments, the second therapeutic agent is an ATR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is selected from galtisertib, berzosertib, M4344, BAY1895344, selalasertib, schisandrin B, elimsertib, 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 of the foregoing.

[0200] 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 of the foregoing.

[0201] 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, ravusertib, 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, and UCN-01, SOL-578, IMP 10, and CBP501, or a pharmaceutically acceptable salt of any of the foregoing.

[0202] In some embodiments, the second therapeutic agent is a targeted therapeutic agent, or a pharmaceutically acceptable salt thereof, and the targeted therapeutic agent is bevacizumab, lenvatinib, encorafenib, and cetuximab, or a pharmaceutically acceptable salt of any of the foregoing.

[0203] In some embodiments, the second therapeutic agent for treating cancer in the intermittent dosing cycles 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 immunomodulatory agent, an immune cell antibody, an interferon, an interleukin, an HSP90 inhibitor, an antiandrogen, an antiestrogen, an antihypercalcemic 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, a cyclooxygenase ... Toxins, cRAF kinase inhibitors, Ras inhibitors, cyclin-dependent kinase inhibitors, cysteine ​​protease inhibitors, DNA intercalators, DNA strand breakers, E3 ligase inhibitors, EGF pathway inhibitors, farnesyltransferase inhibitors, Flk-1 kinase inhibitors, glycogen synthase kinase-3 (GSK3) inhibitors, histone deacetylase (HDAC) inhibitors, I-kappa B-alpha kinase inhibitors, imidazotetrazinone, insulin tyrosine kinase inhibitors, c-Jun N-terminal kinase (JNK) inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, MDM2 inhibitors, MEK inhibitors, ERK inhibitors, MMP inhibitors, mTor inhibitors, NGFR tyrosine kinase enzyme 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 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, arylsulfate administration of thionone, altretamine, aminopterin, aminolevulinic acid, amsacrine, asparaginase, atrasentan, bexarotene, carboquone, demecolcine, efaproxiral, elsamitrucin, etoglucide, hydroxycarbamide, leucovorin, lonidamine, lucantone, masoprocol, methyl aminolevulinate, mitoguazone, mitotane, oblimersen, omacetaxine, pegaspargase, porfimer sodium, prednimustine, citimagine seradenovec, talaporfin, temoporfin, trabectedin, or verteporfin, or a pharmaceutically acceptable salt of any of the foregoing.

[0204] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered with a second therapeutic agent, where the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof, on a 7-day-on / 7-day-off schedule to treat cancer. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered with a second therapeutic agent, where the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof, on a 7-day-on / 7-day-off schedule to treat ovarian cancer. In some embodiments, the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof, on a 7-day-on / 7-day-off schedule to treat advanced ovarian cancer. In some embodiments, the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof, on a 7-day-on / 7-day-off schedule to treat advanced platinum-resistant ovarian cancer. In some embodiments, the second therapeutic agent is niraparib or a pharmaceutically acceptable salt thereof, on a 7-day-on / 7-day-off schedule to treat advanced platinum-resistant ovarian cancer that has failed PARP inhibitor (PARPi) maintenance therapy. In other words, the cancer is PARP inhibitor resistant. In some embodiments, the second therapeutic agent is niraparib administered 7 days on / 7 days off to treat fallopian tube cancer. In some embodiments, the second therapeutic agent is niraparib or its pharmaceutically acceptable salt administered 7 days on / 7 days off to treat primary peritoneal cancer.

[0205] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered with a second therapeutic agent, where the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, administered 5 days on / 2 days off to treat cancer. In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered with a second therapeutic agent, where the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, administered 5 days on / 2 days off to treat ovarian cancer. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, administered 5 days on / 2 days off to treat advanced ovarian cancer. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, administered 5 days on / 2 days off to treat advanced platinum-resistant ovarian cancer. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof, administered 5 days on / 2 days off to treat advanced platinum-resistant ovarian cancer that has failed PARP inhibitor (PARPi) maintenance therapy. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof administered 5 days on / 2 days off to treat fallopian tube cancer. In some embodiments, the second therapeutic agent is olaparib or a pharmaceutically acceptable salt thereof administered 5 days on / 2 days off to treat primary peritoneal cancer.

[0206] In one aspect, intermittent dosing is described herein, including 5 consecutive days of dosing and 2 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 administration cycle comprising five consecutive days of administration and two days without administration. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of the PARPi occur during the same week. In some embodiments, the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of PARPi occur consecutively (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.

[0207] 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 azenosertib or a pharmaceutically acceptable salt thereof, in an intermittent administration cycle comprising five consecutive days of administration and two days without administration, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof, in an intermittent administration cycle comprising five consecutive days of administration and two days without administration. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent administration cycle of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycle of the PARPi occur during the same week. In some embodiments, the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of PARPi occur consecutively (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.

[0208] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of 350 mg or more, or a pharmaceutically acceptable salt thereof, in an intermittent administration cycle comprising five consecutive days of administration and two days without administration, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof, in an intermittent administration cycle comprising five consecutive days of administration and two days without administration. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent administration cycle of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycle of the PARPi occur during the same week. In some embodiments, the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of PARPi occur consecutively (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.

[0209] In one aspect, provided herein is a method of administering to a subject a daily dose of 400 mg or more, or an equivalent thereof, of azenosertib or a pharmaceutically acceptable salt thereof, in an intermittent dosing cycle comprising 5 consecutive days of administration and 2 days without administration, and 5 consecutive days of administration and 2 days without administration. and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in intermittent administration cycles comprising: (a) administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof; and (b) administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in intermittent administration cycles comprising: (a) administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof; and (c) administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof in intermittent administration cycles comprising: (a) administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof; and (b) administering to the subject a daily dose of a PARPi or a pharmaceutically acceptable salt thereof in intermittent administration cycles comprising: (i) administering to the subject a daily dose of a PARPi or a pharmaceutically acceptable salt thereof; and (ii .... In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of a PARPi occur during the same week. In some embodiments, the intermittent administration cycles of azenosert

[0210] In one aspect, provided herein is a method of treating cancer, comprising administering to a subject a daily dose of 450 mg or more, or a pharmaceutically acceptable salt thereof, in an intermittent administration cycle comprising five consecutive days of administration and two days without administration, and administering to the subject a daily dose of a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof, in an intermittent administration cycle comprising five consecutive days of administration and two days without administration. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 250 mg. In some embodiments, the olaparib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg. In some embodiments, the intermittent administration cycle of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycle of the PARPi occur during the same week. In some embodiments, the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of PARPi occur consecutively (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.

[0211] In one aspect, provided herein is a method of treating cancer, the method comprising administering to a subject a daily dose of 200 mg, or its equivalent, of azenosertib or a pharmaceutically acceptable salt thereof, in an intermittent dosing cycle comprising five consecutive days of dosing 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 days of dosing and two days without dosing.

[0212] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg once daily in an intermittent dosing cycle of 5 consecutive dosing days and 2 days without dosing, and paclitaxel is administered at 80 mg / m on D1, D8, D15 in a 28-day cycle. 2 is administered at a dose of

[0213] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg once daily in an intermittent dosing cycle of 5 consecutive days of dosing and 2 days without dosing, and carboplatin AUC 5 mg / mL* min is administered on D1 of a 21-day cycle.

[0214] In some embodiments, azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of 400 mg once daily in an intermittent dosing cycle of 5 consecutive dosing days and 2 days without dosing, and 40 mg / m on D1 in a 28-day cycle. 2 Pegylated liposomal doxorubicin (PLD) is administered at a dose of

[0215] In some embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof can be administered orally, intravenously, or intravenously. 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, topical pulmonary, aerosol, injection, infusion, and parenteral delivery, including, but not limited to, intramuscular, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection.

[0216] In some embodiments, the combination therapy comprises intermittent administration, i.e., comprises consecutive days of administration followed by days of rest in one or more administration cycles with intervening rest weeks. In some embodiments, the combination therapy comprises consecutive administration. In some embodiments, the combination therapy comprises consecutive administration of one of the agents.

[0217] Selecting a target 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.

[0218] In other embodiments, the subject is selected by determining the level of a cancer biomarker. In some embodiments, the subject is selected to have a predetermined level of a cancer biomarker, either below or above a predetermined threshold. In some embodiments, the subject is selected to have a BCRA1 and / or BRCA2 biomarker level below a predetermined threshold. In some embodiments, the subject is selected to have a TP53 biomarker level below a predetermined threshold. In some embodiments, the subject is selected to have a CA125 biomarker level below a predetermined threshold. In some embodiments, the subject is selected to have a CCNE1 biomarker level below a predetermined threshold.

[0219] In some embodiments, the subject is selected to have a BCRA1 and / or BRCA2 biomarker level above a predetermined threshold. In some embodiments, the subject is selected to have a TP53 biomarker level above a predetermined threshold. In some embodiments, the subject is selected to have a CA125 biomarker level above a predetermined threshold. In some embodiments, the subject is selected to have a CCNE1 biomarker level above a predetermined threshold.

[0220] In some embodiments, the subject has received one or more previous lines of cancer therapy, in some embodiments, the subject has received two or more previous lines of cancer therapy, in some embodiments, the subject has received three or more previous lines of cancer therapy, in some embodiments, the subject has received four or more previous lines of cancer therapy.

[0221] In some embodiments, the subject has received 1 to 5 prior lines of cancer therapy, hi 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.

[0222] In some embodiments, the previous line of anti-cancer treatment is a systemic cancer therapy. In some embodiments, the previous line of cancer treatment is in an advanced or metastatic setting. In some embodiments, the advanced or metastatic disease is stage III-IV.

[0223] In some embodiments, the previous line of treatment was a PARP inhibitor (PARPi) or In some embodiments, the previous line of treatment comprises a PARP inhibitor (PARPi) or a pharmaceutically acceptable salt thereof. In some embodiments, the previous line of treatment was treatment with a PARPi, either alone or in combination with other agents. In some embodiments, the previous line of treatment, the PARPi, was not discontinued due to toxicity.

[0224] In some embodiments, the subject has a disease with no known effective options or has refused standard or care therapy prior to treatment.

[0225] In some embodiments, the subject is platinum-resistant. In some embodiments, the subject is resistant to treatment with a therapeutic agent (e.g., an anti-cancer or anti-tumor agent). In some embodiments, combination therapy with azenosertib or a pharmaceutically acceptable salt thereof overcomes resistance to the second therapeutic agent or a pharmaceutically acceptable salt thereof and causes the subject to respond.

[0226] In some embodiments, the subject is 18 years of age or older.

[0227] 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 histologically confirmed cancer.

[0228] In some embodiments, the HRRm status of the subject is determined before treatment.In some embodiments, the HRRm status is determined by the assay known in the art for detecting HRRm status.In some embodiments, the subject sample is evaluated using formalin-fixed paraffin-embedded (IAM) tumor sample collected within 3 years after treatment.

[0229] In some embodiments, the HRRm status is determined based on mutations in a gene selected from BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

[0230] In some embodiments, the deleterious mutation in at least one of the genes involved in HRR is determined from prior CLIA-approved (or country-specific equivalent) genomic profiling.

[0231] In some embodiments, the subject has a homologous recombination repair deficiency (HRD) positive state. In some embodiments, the subject has been diagnosed with an HRD positive cancer selected from ovarian cancer (including recurrent ovarian cancer), breast cancer (such as 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 female. In some embodiments, the subject is a human.

[0232] Responsiveness In some embodiments, the treatment methods described herein result in a response rate of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or greater. In some embodiments, the response rate is measured by complete response (CR), partial response (PR), CA-125 50% response, or a combination thereof.

[0233] Progression-free survival (PFS) refers to the period during which a subject with a disease (e.g., cancer) survives without significant deterioration of the condition.Progression-free survival can be evaluated as the period during which there is no progression of tumor growth and / or the period during which the subject's disease state is not determined to be progressive disease. In certain embodiments, progression-free survival of a subject with cancer is assessed by assessing tumor size, tumor number, and / or metastasis.

[0234] In some embodiments, the treatment results in a progression-free survival (PFS) of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. In some embodiments, the treatment results in a progression-free survival (PFS) of 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or more. In some embodiments, the treatment results in a progression-free survival (PFS) of 1 year, 1.5 years, 2 years, 2.5 years or more.

[0235] As used herein, the term "progression" of tumor growth or "progressive disease" (PD), as used herein in reference to a cancerous condition, refers to an increase in the sum of the diameters of the target tumor. Progression for the purposes of determining progression-free survival is defined as 1) tumor assessment by CT / MRI clearly demonstrates progressive disease according to RECIST 1.1 criteria, or 2) additional diagnostic testing (e.g., histology / cytology, ultrasound techniques, endoscopy, positron emission tomography) identifies a new tumor or an existing tumor progresses beyond the threshold of the Gynecologic Cancer PD may also be determined when at least one of the following criteria is met: definite disease progression and / or CA-125 eligibility by the Global Cancer Institute Intergroup (GCIG) criteria (see Rustin et al., Int J Gynecol Cancer 2011;21:419-423, incorporated herein in its entirety); or 3) definite clinical signs and symptoms of PD unrelated to non-malignant or iatrogenic causes ([i] refractory cancer-related pain, [ii] worsening malignant bowel obstruction / functional disability, or [iii] definite symptomatic worsening of ascites or pleural effusion) and / or CA-125 progression by GCIG criteria.

[0236] As used herein, the term "partial response" or "PR" refers to a reduction in tumor progression in a subject, as indicated by a decrease in the sum of diameters of the target tumor relative to the baseline sum of diameters. In several embodiments, PR refers to a reduction of at least 30% in the sum of diameters relative to the baseline sum of diameters. Exemplary methods for evaluating partial response are specified by the 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).

[0237] As used herein, "stable" or "stable disease" (SD) tumor growth refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. In embodiments, stable 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 tumor relative to the baseline sum of the diameters. Exemplary methods for evaluating stable tumor growth or stable disease are specified by the 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).

[0238] As used herein, the term "complete response" or "CR" refers to the disappearance of all or substantially all target lesions. In some embodiments, a CR is defined as a reduction of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the sum of the diameters of the target tumor relative to the baseline sum of the diameters. CR refers to a percent reduction (i.e., tumor loss) of the total lesion diameter. In embodiments, CR indicates that less than 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the total lesion diameter remains after treatment. Exemplary methods for assessing complete response are specified by the 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). [Example]

[0239] Additional embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0240] Example 1. Comparison of continuous and intermittent dosing regimens of azenosertib at similar cumulative doses in various animal models of human cancer This example demonstrates a comparison of continuous and intermittent dosing regimens of azenosertib.

[0241] Human ovarian cancer SKOV3 model – sequential regimen vs. 5 / 2 regimen In an exemplary human ovarian cancer SKOV3 animal model, azenosertib was administered at a continuous dose of 60 mg / kg or intermittently at 80 mg / kg for three cycles of 5 days on / 2 days off (5 / 2).

[0242] The measured changes in tumor volume over 21 days indicated that intermittent administration of 80 mg / kg in three cycles of 5 days on / 2 days off was more effective than continuous administration in reducing tumor volume (Figure 1A). Figure 1B shows the corresponding changes in body weight during treatment.

[0243] Non-small cell lung cancer (NSCLC) A427 model - sequential versus 5 / 2 regimen In exemplary non-small cell lung cancer (NSCLC) A427 model, azenosertib is administered at a higher intermittent dose than the corresponding lower continuous dose.For example, azenosertib is administered at 56mg / kg in 4 administration cycles of 5 days on / 2 days off (5 / 2), and is compared with a lower continuous dose of 40mg / kg.Similarly, azenosertib is administered at 112mg / kg in 4 administration cycles of 5 days on / 2 days off, and is compared with a lower continuous dose of 80mg / kg.

[0244] Tumor volume (FIG. 1C) and body weight (FIG. 1D) were measured over 28 days after the start of treatment.

[0245] Results showed that all doses were well tolerated. Furthermore, at the same total cumulative dose, the higher intermittent dose (5 days on / 2 days off) achieved greater efficacy in reducing tumor volume than the lower continuous dose.

[0246] Non-small cell lung cancer (NSCLC) A427 model - sequential versus 4 / 3 regimen In an exemplary non-small cell lung cancer (NSCLC) A427 model, azenosertib was administered at a higher intermittent dose than the corresponding lower continuous dose. For example, azenosertib was administered at 100 mg / kg for 4 dosing cycles of 4 days on / 3 days off (4 / 3), compared to a lower continuous dose of 60 mg / kg.

[0247] The change in tumor volume over 25 days after tumor initiation is shown in Figure 1E, and the corresponding change in body weight during treatment is shown in Figure 1F.

[0248] The results showed that at similar total cumulative doses, a higher intermittent dose (4 days on / 3 days off) was more effective. demonstrated that it achieved slightly higher efficacy than the lower continuous dose.

[0249] Breast ductal carcinoma HCC1569 model - continuous regimens versus various intermittent (4 / 3, 3 / 4) regimens In an exemplary breast ductal carcinoma HCC1569 model, azenosertib was administered at a dose of approximately 100 mg / kg in three cycles of intermittent dosing regimens of 4 days on / 3 days off (4 / 3) and 3 days on / 4 days off (3 / 4) compared to lower continuous doses (e.g., 60 mg / kg). The change in tumor volume and the corresponding change in body weight up to approximately 24 days after initiation of treatment are plotted in Figure 1G and Figure 1H, respectively.

[0250] At comparable cumulative doses, the higher intermittent dose was found to be more effective when measured up to approximately 24 days after treatment initiation. Two intermittent dosing frequencies, 4 days on / 3 days off and 3 days on / 4 days off, were both found to be equally effective.

[0251] 7 / 7 regimen is effective in the OVCAR3 human ovarian cancer model In an exemplary human ovarian cancer OVCAR3 model, azenosertib was administered at a dose of approximately 100 mg / kg in a 7-day on / 7-day off (7 / 7) intermittent dosing regimen for three cycles. The changes in tumor volume and corresponding changes in body weight up to approximately 32 days after the start of treatment are plotted in Figure 1I and Figure 1J, respectively.

[0252] The results showed that the 7 / 7 intermittent dosing regimen was effective in reducing tumor volume.

[0253] Overall, the results showed that at similar total cumulative doses, the higher intermittent dosing regimen achieved more efficacy than the lower continuous dosing in a variety of tumor cell types.

[0254] Example 2. Comparison of continuous and intermittent dosing regimens of azenosertib at different doses and once-daily versus twice-daily regimens in various animal models of human cancer Human ovarian cancer OVCAR3 model - continuous vs. intermittent (5 / 2) regimen, once-daily vs. twice-daily regimen

[0255] In an exemplary human ovarian cancer OVCAR3 model, azenosertib was administered on a 5-day-on / 2-day-off (5 / 2) intermittent dosing regimen for once-daily doses (e.g., 80 mg / kg twice daily vs. 40 mg / kg twice daily and 100 mg / kg once daily vs. 50 mg / kg twice daily).

[0256] The changes in tumor volume were measured up to about 22 days after the start of treatment, as shown in Figure 2A, and the corresponding changes in body weight were measured as shown in Figure 2B.

[0257] For the same cumulative dose, the once-daily dose was more effective compared with the twice-daily dose.

[0258] Human ovarian cancer OVCAR3 model - continuous vs. intermittent (5 / 2, 4 / 3 at various doses) In exemplary human ovarian cancer OVCAR3 model, azenosertib was administered at two different doses in each of two intermittent administration regimens.Briefly, azenosertib was administered at about 80mg / kg (400mg cumulative dose) and 90mg / kg (450mg cumulative dose) for 5 cycles, with a 5-day on / 2-day off (5 / 2) intermittent regimen, and at 90mg / kg (450mg cumulative dose) and 100mg / kg (500mg cumulative dose) for 4 cycles, with a 4-day on / 3-day off (4 / 3) intermittent regimen.Results were compared with a continuous dose of 60mg / kg (300mg cumulative dose) for 22 days.

[0259] The changes in tumor volume and the corresponding changes in body weight up to about 24 days after the start of treatment are shown in FIG. 2C and FIG. 2D, respectively.

[0260] Overall, the results showed that both the higher intermittent doses at 5 / 2 and 4 / 3 were more effective than the lower continuous doses when the total cumulative dose was low.

[0261] Human ovarian cancer OVCAR3 model - continuous vs. intermittent (4 / 3, 3 / 4) In an exemplary human ovarian cancer OVCAR3 model, azenosertib was administered at 100 mg / kg in two intermittent dosing regimens, 4 days on / 3 days off (4 / 3) or 3 days on / 4 days off (3 / 4), for three cycles each, and continuously at 60 mg / kg for 24 days.

[0262] At a dose of approximately 100 mg / kg in 4 / 3 of the 3 cycles, the cumulative dose was 1200 mg, and at a dose of approximately 100 mg / kg in 3 / 4 of the 3 cycles, the cumulative dose was 900 mg. The results showing the change in tumor volume are shown in Figure 2E, and the corresponding change in body weight is shown in Figure 2F.

[0263] Overall, the results showed that both intermittent doses demonstrated greater efficacy than continuous dosing. Slightly greater efficacy was observed with the higher cumulative dose, i.e., the 4 / 3 regimen.

[0264] Example 3. PK / PD correlation of azenosertib and Wee1 target engagement Figure 3 is a graph showing the PK / PD correlation between azenosertib and Wee1 target engagement. The graph shows that inhibition of pCDK1 increases Wee1 target engagement. Increasing drug dose or exposure also resulted in increased Wee1 target engagement. Doses above approximately 300 mg once daily demonstrated excellent target engagement and the highest AUC with at least a 50% reduction in p-CDK1 levels.

[0265] Figure 4 provides a model and skin biopsy staining showing that the reduction in p-CDK1 levels correlates with Wee1 inhibition. CDK1 phosphorylation (pCDK-1) is mediated by Wee1. It is contemplated that Wee1 inhibition with azenosertib results in pCDK1 inhibition. For example, the Y15 residue is not phosphorylated, and CDK1 levels in skin biopsies confirmed the reduction in p-CDK1 levels after treatment compared to baseline.

[0266] Example 4. Pharmacokinetic data demonstrating clinical exposure achieved with intermittent dosing of azenosertib This example demonstrates the clinical exposure achieved with continuous and intermittent 5-day-on / 2-day-off (5 / 2) dosing regimens. A comparison is also made between once-daily and twice-daily dosing regimens. In some embodiments, azenosertib was administered with food and / or an antiemetic.

[0267] The results are shown as follows: Figure 5A is a graph of azenosertib plasma concentrations from subjects receiving 350 mg once daily on 5 / 2 or 175 mg twice daily on Day 1 of Cycle 1. Figure 5B is a graph of azenosertib plasma concentrations from subjects receiving 350 mg once daily on 5 / 2 or 175 mg twice daily on Day 11 / 12 of Cycle 1. Figure 5C is a graph of azenosertib plasma concentrations from subjects receiving a continuous dosing regimen compared to subjects receiving an intermittent dosing regimen of 350 mg once daily on 5 / 2 on Day 1 of Cycle 1. Figure 5D is a graph of azenosertib plasma concentrations from subjects receiving a continuous dosing regimen compared to subjects receiving an intermittent dosing regimen of 350 mg once daily on 5 / 2 on Day 11 / 12 or 15 of Cycle 1. Figure 5E shows the results for subjects receiving the 5 / 2 175 mg twice daily intermittent dosing regimen on Day 1 of Cycle 1 compared with subjects receiving the 5 / 2 175 mg twice daily intermittent dosing regimen. Figure 5F is a graph of azenosertib plasma concentrations from subjects receiving a continuous dosing regimen compared to subjects receiving an intermittent dosing regimen of 175 mg twice daily on 5 / 2 on days 11 / 12 or 15 of cycle 1. The results showed that the mean exposure of azenosertib was higher with intermittent dosing compared to continuous dosing of 350 mg once daily (or 175 mg twice daily).

[0268] Similar exposures from 350 mg once daily at steady state (10,300-15,800 h*ng / mL, n=3) were observed with 175 mg twice daily (AUC 13,300 h*ng / mL, n=1), and similar observations were made in the continuous dosing setting (Table 2 below).

[0269] [Table 2]

[0270] PK modeling predicted lower exposure at 5 / 2 on Day 12 (steady state) compared to continuous dosing, but surprisingly, no reduction in 5 / 2 exposure was observed.

[0271] Overall, the results of this study surprisingly and unexpectedly showed that equivalent or better exposure was achieved with intermittent dosing than with continuous dosing.

[0272] Example 5. Methods for establishing an intermittent dosing regimen for azenosertib in human subjects This example demonstrates a dose-escalation protocol for an intermittent once-daily dosing regimen based on an evaluation of dose-limiting toxicities of the azenosertib dosing regimen or a combination regimen with a second therapeutic agent (e.g., an antitumor or anticancer agent).

[0273] As shown in the preceding examples, briefly, intermittent dosing of azenosertib was initiated at approximately 200 mg once daily, 5 days on, 2 days off (5 / 2), and implemented 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 results indicated that the 5 / 2 dose level was not tolerated, a 4 / 3 regimen was initiated at that dose or a lower dose. Similarly, dosing on 4 / 3 was implemented in 50 mg increments. If a dose level on the once-daily 4 / 3 schedule was not tolerated, the dose level was reduced to once-daily 3 / 4 based on the occurrence of dose-limiting toxicities (DLTs) and / or other toxicities or adverse events. DLT was any adverse event (AE) occurring during cycle 1 that met at least one of the following criteria listed in Table 3: (Except when clearly attributable to external causes such as underlying disease).

[0274] [Table 3]

[0275] Intermittent dosing with longer breaks may be performed with additional days or weeks without dosing between.

[0276] Similarly, dosing starting at 175 mg twice daily was given 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) twice daily, adjusted based on dose-limiting toxicities as described above.

[0277] Overall, this example demonstrates that intermittent dosing schedules for azenosertib monotherapy or combination therapy can be identified as described herein.

[0278] Example 6. Treatment of cancer in a subject using an intermittent dosing regimen of azenosertib This example demonstrates the treatment of subjects selected for having a predetermined threshold cancer biomarker level by administering an effective dose of azenosertib (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, 800 mg once daily, or, e.g., 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 400 mg twice daily divided equally twice daily) as a single agent or in combination with a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0279] Additional inclusion criteria may include subjects with specific cancer types (e.g., high-grade serous ovarian cancer (HGSOC)), platinum resistance or refractory, or 1 to 3 prior lines of therapy (e.g., bevacizumab).

[0280] The selected subject is administered azenosertib according to the intermittent administration cycle provided herein.For example, the intermittent administration cycle comprises one or more administration weeks, and each administration week comprises at least 3 consecutive administration days and at least 1 day without administration, for example, 5 days of administration ("on" day) followed by 2 days without administration ("off" day) (i.e., 5 / 2), 4 days of administration followed by 3 days without administration (i.e., 4 / 3), or 3 days of administration followed by 4 days without administration (i.e., 3 / 4), 6 days of administration followed by 1 day without administration (i.e., 6 / 1), or 7 days of administration followed by 7 days without administration (i.e., 7 / 7).

[0281] Further, in some embodiments, one or more weeks of administration are separated by at least one week of rest. In some embodiments, the intermittent administration regimens described herein (e.g., 7 / 0, 5 / 2, 4 / 3, or 3 / 4) are carried out for two weeks followed by a one-week rest period, or one week of continuous administration days followed by a one-week rest period.

[0282] In some embodiments, the therapy is azenosertib monotherapy. In some embodiments, the therapy is combined with a second therapeutic agent or a pharmaceutically acceptable salt thereof (e.g., an anti-tumor agent).

[0283] In some embodiments, food and / or an antiemetic agent are also administered with azenosertib.

[0284] Treatment outcome is measured by tumor remission, reduction in tumor volume, and / or alleviation of symptoms associated with cancer or other cancer treatments.

[0285] Example 7. Intermittent dosing regimen of azenosertib and PARPi combination therapy This example demonstrates the treatment of subjects with homology-directed repair-mutated (HRRm) or homology-directed repair-deficient (HRD)-positive cancer using a combination therapy of azenosertib and intermittent administration of PARPi. As described in more detail below, WEE1 inhibition (e.g., using azenosertib) synergizes with PARPi, resulting in the resensitization of tumor cells to PARP inhibitors.

[0286] In vivo dose and schedule exploration of azenosertib and PARPi (niraparib, talazoparib), including investigation of alternating dosing, was evaluated. The antitumor activity of azenosertib in combination with niraparib, a PARPi, was evaluated in the MDA-MB-468 triple-negative breast cancer tumor model using an alternating weekly dosing schedule (Figures 6A-6C). Azenosertib alone achieved 52.6% tumor growth inhibition (TGI) at a dose of 60 mg / kg, while niraparib produced 47.7% TGI at 50 mg / kg as a single agent in this model. An alternating weekly dosing schedule of the combination of 60 mg / kg azenosertib and 50 mg / kg niraparib further enhanced antitumor activity, resulting in a 70.7% TGI (Figures 6D-6G).

[0287] Azenosertib and a PARPi (niraparib) were evaluated using an HRD+ TNBC PDX model with the model profile and HRD+ BRCA mutant ovarian tumor model shown in Table 4. Animals were treated with azenosertib at 60 mg / kg or niraparib at 35 mg / kg monotherapy or in combination with an intermittent dosing regimen of 5 days once daily followed by 2 days off (qd × 5 days on, 2 days off) for 4 cycles (28 days). As shown in Figures 7A-7D, the combination of azenosertib and niraparib results in increased tumor growth inhibition in the BRCA mutant model compared to monotherapy.

[0288] [Table 4]

[0289] Azenosertib and the PARPi (talazoparib) were evaluated using an intermittent dosing schedule in the OVCAR-3 model. In the OVCAR-3 ovarian cancer tumor model, the combination of azenosertib and the PARPi talazoparib showed promising activity when administered in an alternating dosing regimen (talazoparib 0.23 mg / kg 7 days on, 7 days off; azenosertib 60 mg / kg 7 days off, 7 days on) compared with either agent administered alone. As shown in Figure 8, alternating dosing regimens of the PARPi and WEE1 inhibitor (PARPi for 1 week, followed by WEE1 inhibitor for 1 week) demonstrated improved efficacy. Furthermore, the alternating dosing schedule may potentially reduce the overlapping toxicity of coadministration of the WEE1 inhibitor and PARPi.

[0290] clinical design Azenosertib in combination with the PARPi olaparib was evaluated in a phase I / Ib, open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of azenosertib as 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 either azenosertib monotherapy or the combination therapy, stratified based on tumor type.

[0291] Subjects will undergo a screening period of up to 28 days, after which they will receive treatment with azenosertib alone or in combination with olaparib in repeating 28-day cycles until they experience disease progression or meet any other protocol-defined withdrawal criteria. Monotherapy subjects will receive azenosertib (5 / 2) in 28-day cycles until disease progression or termination. Combination therapy subjects will receive alternating doses of olaparib and azenosertib in 28-day cycles until disease progression or termination. Olaparib and azenosertib will be administered at the doses shown in Table 5A below on an alternating 5 / 2 schedule with olaparib on Days 1 (C1D1) through 5 (C1D5) and C1D15-19 of Cycle 1, followed by azenosertib 5 / 2 on Days 8-12 and C1D22-26.

[0292] [Table 5A]

[0293] The dose and schedule of the combination therapy may be adjusted as shown in Table 5B. For example, "DL1a" indicates 350 mg on a 5:2 schedule. "X days on" indicates QD administration therebetween. DL1a can combine olaparib doses of 250 mg or 300 mg on a 5:2 schedule.

[0294] [Table 5B]

[0295] Subjects aged 18 years and older will be selected for combination therapy treatment based on: Histologically confirmed metastatic or unresectable breast, ovarian, pancreatic, or prostate cancer Mutations in any of the following genes determine HRRm status: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L

[0296] Subjects are also selected based on cancer type. Subjects with ovarian, breast, pancreatic, or prostate cancer are required to have RECIST v1.1 measurable and / or evaluable disease. Subjects with ovarian or pancreatic cancer must have RECIST v1.1 measurable disease, and subjects with prostate or breast cancer must have measurable and / or evaluable disease.

[0297] HRRm status can be determined by assays such as FoundationOne® CDx, Myriad (MyChoice® CDx), Tempus xT HRD, Caris Molecular, etc. Intel Comprehensive Tumor Profiling, or any other CLIA-certified (or local equivalent) laboratory, can also be used. Confirmed deleterious mutation in at least one gene involved in HRR, as determined from a previous CLIA-approved (or country-specific equivalent) genomic profiling.

[0298] Subjects are also selected based on their prior treatment history. Specifically, subjects must have received at least one, but not more than five, prior lines of systemic anti-cancer therapy in the advanced or metastatic setting. Previous therapy must include a PARPi, either alone or in combination with other agents. The PARPi must be the most recent treatment received prior to azenosertib combination therapy. If a PARPi treatment line is discontinued due to PARPi toxicity, the subject will be excluded from combination therapy with azenosertib and a PARPi (e.g., the olaparib regimen described above).

[0299] Tumor assessments will occur every 8 weeks ± 4 days from C1D1 until investigator-assessed documented progression, loss to follow-up, initiation of new anticancer therapy, withdrawal of consent, or study end. After treatment discontinuation, safety will be assessed 30 days after the last dose, and subjects will be followed for survival every 12 weeks until death, loss to follow-up, withdrawal of consent, or study end.

[0300] Dose escalation or modification with the alternative dosing options described above is based on an estimate of ORR for subjects treated at the maximum tolerated dose (MTD). The primary endpoint is ORR as assessed by the investigator using PCWG3-modified RECIST v1.1 criteria for prostate cancer and RECIST v1.1 criteria for all other indications. Secondary endpoints include ORR as assessed by the ICR, duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS) as assessed by the investigator and ICR, overall survival (OS), frequency and severity of TEAEs and plasma PK parameters for azenosertib and olaparib.

[0301] Example 8. Comparison of the safety and pharmacokinetic profiles of intermittent and continuous dosing regimens of azenosertib monotherapy in human cancer subjects In this example, a Phase Ia dose-escalation and a Phase Ib dose-expansion clinical trial was conducted to evaluate the safety and pharmacokinetics (PK), i.e., steady-state exposure (AUC 0-24 ) and concentration maximum (C max ) was evaluated.

[0302] In some cohorts, Phase 1a dose escalation was performed starting at doses below 200 mg and escalating to total daily doses of 200 mg, 300 mg, 350 mg, 400 mg, and 450 mg in a continuous dosing regimen. The dose used in Phase 1b was 300 mg QD.

[0303] In some cohorts, Phase Ia dose escalation was performed, starting with doses of 350 mg, 400 mg, 450 mg, and 500 mg total daily doses in a 5:2 or 4:3 dosing regimen. Doses used in Phase Ib were 350 mg and 400 mg in a 5:2 dosing regimen.

[0304] Tumor assessments (per RECIST 1.1) were performed every two cycles (6 weeks) in subjects recruited to the study. There were no biomarker requirements for enrollment in the study, nor were there any prior therapy requirements. Individuals within the cohort represented multiple tumor types (Figure 9A). Heavily pretreated subjects with advanced solid tumors were included in the continuous and intermittent dosing cohorts (Table 6).

[0305] [Table 6]

[0306] Fifty-one subjects were enrolled with uterine serous adenocarcinoma (USC) or high-grade serous ovarian cancer (HGSOC) after multiple prior therapies in cohorts treated with continuous or intermittent dosing schedules (Table 7A) and intermittent dosing schedule only (Table 7B).

[0307] [Table 7A]

[0308] [Table 7B]

[0309] The results of the study are shown in Figures 9B, 9C, 9D and Table 8.

[0310] The results showed that intermittent dosing significantly increased steady-state exposure (AUC 0-24 ), indicating that more subjects reached the predicted target effective steady-state exposure (Figure 9B).

[0311] As shown in Figures 9C and 9D, subjects receiving the intermittent dosing regimen achieved higher maximum concentration (Cmax) levels than subjects receiving the continuous dosing regimen.

[0312] A high response rate was observed in subjects treated with azenosertib monotherapy (Figure 9E). Of N=51 with at least one scan=40, the overall objective response rate (ORR%) with 95% CI was 27.5% (9.1%, 35.6%).

[0313] Furthermore, the intermittent dosing schedule doubled the objective response rate in the population with ovarian or uterine serous adenocarcinoma (USC), as shown in Figure 9F and Table 8. The ORR% was much higher in subjects on the intermittent dosing schedule. Complete response (CR), partial response (PR), and CR were also observed. The objective response rates (PR), stable disease (SD), and progressive disease (PD) are shown in Figures 9E-9G. Table 8 and Figure 9F show the objective response rates.

[0314] [Table 8]

[0315] Eighty-nine percent of USC and HGSOC subjects had a reduction in target lesions from the baseline scan. 95% of USC and HGSOC subjects had stable disease (SD) or partial response (PR) as their best overall response, with a median PFS of approximately 5.1 months for ovarian cancer and NR (i.e., not reached) for USC (Figure 9G). Early follow-up was performed with a median of 4.4 months, and 12 of 19 patients continued therapy. 10 of 13 patients in this study had previously received a PARP inhibitor. Preliminary clinical data indicate that azenosertib is active in ovarian cancer (Figure 9H) and that azenosertib also has activity in uterine serous adenocarcinoma (Figure 9I).

[0316] As the intermittent-dose cohort continued to be treated and monitored for response to treatment, meaningful and sustained clinical benefits were observed. Notably, median follow-up for both platinum-resistant ovarian cancer and uterine serous adenocarcinoma (USC) patients was extended to 9.2 months (vs. 4.4 months as previously described), median PFS was extended to 6.5 months (vs. 5.1 months for platinum-resistant ovarian cancer and NR for USC as previously described), and the overall response rate (ORR) was 36.8% (Table 9). Furthermore, azenosertib monotherapy, including intermittent administration, continues to demonstrate an excellent safety profile, with no observed cases of febrile neutropenia or sepsis and no reported discontinuations, which indicates better tolerability than other approved anti-cancer monotherapies, such as olaparib and mirvetuximab, as well as adavosertib (another WEE1 inhibitor) monotherapy.

[0317] [Table 9]

[0318] Overall, the results showed that azenosertib was active in multiple tumor types, including ovarian cancer and uterine serous adenocarcinoma, and that the intermittent dosing regimen was preferable in that more subjects achieved effective steady-state exposure and higher maximum concentration (Cmax) levels than the continuous dosing regimen.

[0319] Example 9. Determining the RP2D of azenosertib from a Phase I azenosertib dose optimization study in H subjects with ovarian cancer and uterine serous adenocarcinoma

[0320] In this example, a Phase I azenosertib dose optimization study was conducted to evaluate the recommended Phase II dose (RP2D) for azenosertib monotherapy.

[0321] In some cohorts, Phase 1a dose escalation was performed starting at doses below 200 mg and escalating to total daily doses of 200 mg, 300 mg, 350 mg, 400 mg, and 450 mg in a continuous dosing regimen. The dose used in Phase 1b was 300 mg QD. A total of 127 heavily pretreated subjects with advanced solid tumors were treated with azenosertib monotherapy at escalating dose levels on either a continuous once-daily or intermittent weekly dosing schedule. Across all tumor types, 74 subjects were treated on a continuous dosing schedule and 53 subjects on an intermittent dosing schedule.

[0322] Among response-evaluable subjects with combined ovarian and uterine serous adenocarcinoma (USC) (n=45), subjects receiving the intermittent dosing schedule (n=19) had a confirmed objective response rate (ORR, 95% CI) of 42.1% (8.4 / 58.1), and subjects receiving the continuous dosing schedule (n=26) had a confirmed ORR of 15.4% (4.4, 34.9). The overall response rate was 26.7% (9.1, 35.6) (Figure 9F and Table 8).

[0323] Steady-state exposure, as measured by AUC(0-24), more than doubled with the new intermittent RP2D compared with the AUC observed at 300 mg QD with continuous dosing. Intermittent dosing maintained the improved safety and tolerability of azenosertib compared with continuous dosing. Gastrointestinal, fatigue, and hematologic grade 3 and 4 treatment-related adverse events (TRAEs) were comparable or favorable with continuous dosing. No discontinuations due to TRAEs were observed in the intermittent cohort.

[0324] Based on Phase 1 dose-optimization data, the RP2D for azenosertib as monotherapy is 400 mg once daily (QD) on a 5-day-on, 2-day-off (5 / 2) weekly dosing schedule. This intermittent dosing schedule more than doubled steady-state drug exposure compared with continuous dosing, achieving promising efficacy signals while maintaining safety and improving tolerability. The RP2D also applies to cyclin E1+ (cyclin E1-positive), platinum-resistant high-grade serous ovarian cancer, uterine serous adenocarcinoma, and PARP inhibitor-resistant and platinum-resistant ovarian cancer in the current study.

[0325] Example 10. Intermittent dosing regimens for azenosertib in combination with chemotherapeutic agents such as paclitaxel, carboplatin, gemcitabine, or pegylated liposomal doxorubicin (PLD) Human ovarian cancer OVCAR3 model - Paclitaxel or carboplatin monotherapy versus azenosertib combination therapy

[0326] In an exemplary human ovarian cancer OVCAR3 animal model, azenosertib was administered intermittently at 60 mg / kg or 80 mg / kg for three cycles of 5 days on / 2 days off, while paclitaxel and carboplatin were also administered at 20 mg / kg and 25 mg / kg, respectively, once weekly for three weeks. Additionally, the combinations of azenosertib and paclitaxel, and azenosertib and carboplatin were administered according to the same dosing regimens and doses as the respective monotherapies.

[0327] The measured changes in tumor volume over 24 days showed that all combination treatments tested were more effective than the monotherapies in reducing tumor volume (Figure 10A). Figure 10B shows the corresponding changes in body weight during treatment.

[0328] Clinical Trial A phase Ib open-label multicenter clinical trial was conducted to evaluate the safety, tolerability, preliminary clinical activity, pharmacokinetics (PK), and pharmacodynamics of azenosertib in combination with chemotherapeutic agents, such as paclitaxel, carboplatin, gemcitabine, or pegylated liposomal doxorubicin (PLD).

[0329] The clinical trial consisted of four cohorts of participants with platinum-resistant or refractory epithelial ovarian, peritoneal, or fallopian tube cancer. Key eligibility criteria for inclusion were: high-grade serous ovarian cancer; electrocorticography (ECOG) performance status 0-2; platinum resistance / refractory status; up to three prior lines of chemotherapy; and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.

[0330] [Table 10]

[0331] Based on Table 10, baseline characteristics were well balanced between treatment groups. Approximately 20% of subjects had platinum-refractory disease, one-quarter had received a prior PARP inhibitor, 10% had enrolled in the study as a third or fourth line of treatment, and the majority had received one to two prior lines of treatment.

[0332] Each cohort was tested in combination with azenosertib and either paclitaxel, carboplatin, gemcitabine, or pegylated liposomal doxorubicin (PLD) in continuous and / or intermittent dosing regimens.

[0333] In one embodiment, azenosertib was tested in combination with paclitaxel. Azenosertib was administered starting at 200 mg QD 5 / 2 followed by intermittent doses of 300 mg QD 5 / 2. Patients were administered orally once daily for 28-day treatment cycles at two doses in a controlled dosing regimen. Paclitaxel was administered at 80 mg / m on days 1, 8, and 15 of each 28-day cycle. 2was administered intravenously over 60 minutes (±10 minutes).

[0334] In one embodiment, azenosertib was tested in combination with carboplatin. Azenosertib was orally administered once daily for a 28-day treatment cycle, starting with two doses of 300 mg QD 5 / 2 followed by two doses of 200 mg QD 5 / 2 in an intermittent dosing regimen for four doses. Carboplatin was administered intravenously at 5 mg / mL*min over 15 minutes on day 1 of each 21-day cycle (± 3 days).

[0335] In one embodiment, azenosertib was tested in combination with gemcitabine. Azenosertib was administered orally once daily for a 28-day treatment cycle, starting with three doses of 200 mg QD 5 / 2, followed by four doses of 200 mg QD 5 / 2 in an intermittent dosing regimen. Gemcitabine was administered at 1000 mg / m over 30 minutes on days 1 and 8 of each 21-day cycle. 2 and 600 mg / m 2 It was administered intravenously in two doses.

[0336] In one embodiment, azenosertib was tested in combination with pegylated liposomal doxorubicin (PLD). Azenosertib was administered starting at 200 mg QD followed by 400 mg PLD was administered orally once daily for 28-day treatment cycles at three doses in a QD 5 / 2 intermittent dosing regimen. PLD was administered as a single dose of 40 mg / m over 60 minutes on day 1 of each 28-day cycle every 4 weeks. 2 was administered intravenously.

[0337] The endpoints were to determine the phase II recommended dose (RP2D), safety, and preliminary clinical activity. From these clinical trials, the RP2D was determined to be (a) azenosertib 300 mg QD 5:2 in combination with paclitaxel 80 mg / m2 on D1, D8, and D15 (28-day cycle), (b) azenosertib 200 mg QD 5:2 in combination with carboplatin AUC 5 mg / mL*min on D1 (21-day cycle), (c) PLD 40 mg / m 2 The most effective treatment regimen was determined to be azenosertib 400 mg QD 5:2 (28-day cycle) in combination with gemcitabine. Azenosertib in combination with gemcitabine has sustained activity, and dose cohorts are ongoing to determine the maximum tolerated dose (MTD).

[0338] Treatment-related adverse events were assessed and were primarily hematologic (neutropenia, thrombocytopenia, anemia), gastrointestinal (nausea, vomiting, diarrhea), and fatigue, as well as toxicities from either chemotherapy or azenosertib. As with many combination therapy trials, assessing the contribution of individual agents to each adverse event is difficult. No new safety signals were observed in either group. Across treatment groups, intermittent azenosertib administration was associated with improved safety and tolerability. Severe adverse events were primarily hematologic and occurred at frequencies similar to those reported for combination chemotherapy regimens in this study population.

[0339] Clinical activity was assessed for each treatment as shown in Table 11, assessing DOR, duration of response, ORR, objective response rate, PFS, progression-free survival, and PLD, pegylated liposomal doxorubicin. Response-evaluable subjects were treated subjects with baseline measurable disease per RECIST version 1.1 and at least one post-baseline assessment. All objective responses were confirmed according to RECIST v 1.1.

[0340] [Table 11]

[0341] The results in Table 11 show that compared with historical control data of single-agent chemotherapy, azenosertib combination therapy with chemotherapy agents had a longer objective response rate (ORR), duration of response (mDOR), and median progression-free survival (mPFS).

[0342] The results of the clinical trial were plotted as a waterfall plot, which is an ordinal histogram showing the best percentage change in tumor size, with positive values ​​representing tumor size increases and negative values ​​representing tumor shrinkage. Each vertical column represents a single subject. Waterfall plots from this study evaluated the greatest percent change in the sum of target lesion diameters in subjects receiving azenosertib and paclitaxel combinations (Figure 11A), azenosertib and carboplatin (Figure 11B), and azenosertib and gemcitabine (Figure 11C). Abbreviations: CR: complete response, NE: not evaluable, PD: progressive disease, PR: partial response, SD: stable disease, uCR: unconfirmed complete response, uPR: unconfirmed partial response.

[0343] The progression-free survival observed with each treatment is shown in a Kaplan-Meier plot of the probability of progression-free treatment on the y-axis against time in months on the x-axis (Figure 12) and below in Table 12. The number of subjects at risk over the treatment period is shown in Table 13.

[0344] [Table 12]

[0345] [Table 13]

[0346] Overall, the results of clinical trials demonstrated that azenosertib was active in combination with chemotherapy and was safe, tolerable, and effective in combination with the tested chemotherapy agents, namely paclitaxel, carboplatin, gemcitabine, and pegylated liposomal doxorubicin (PLD), in the treatment of platinum-resistant or refractory (R / R) epithelial ovarian, peritoneal, or fallopian tube cancer. Furthermore, intermittent administration of azenosertib was associated with improved safety and tolerability.

[0347] Moreover, while the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. It should therefore 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 to cover all modifications and alternatives which come within the true scope and spirit of the present disclosure.

Claims

1. 1. A method of treating cancer, comprising: Administering to a subject in need thereof a daily dose of 350 mg or more, or the equivalent thereof, of azenosertib or a pharmaceutically acceptable salt thereof, according to an intermittent dosing cycle, The method, wherein the intermittent dosing cycle comprises one or more dosing weeks, each dosing week comprising at least three consecutive dosing days and at least one day without dosing.

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

3. 1. A method of treating cancer, comprising: Administering to a subject in need thereof a daily dose of 100 mg or more, or the equivalent thereof, of azenosertib or a pharmaceutically acceptable salt thereof, according to an intermittent dosing cycle, The method, wherein the intermittent dosing cycle comprises one or more dosing weeks, each dosing week comprising at least three consecutive dosing days and at least one day without dosing followed by at least one week of rest.

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

5. 5. The method of any one of claims 1 to 4, wherein the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 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 equivalents thereof or more.

6. 6. The method of any one of claims 1 to 5, wherein the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is administered once a day.

7. 6. The method of any one of claims 1 to 5, wherein the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is divided equally into two doses per day.

8. 8. The method of any one of claims 1 to 7, wherein each dosing week comprises at least 4, 5, or 6 consecutive dosing days.

9. 9. The method of any one of claims 1 to 8, wherein each dosing week comprises 5 consecutive dosing days and 2 dosing-free days.

10. 9. The method of any one of claims 1 to 8, wherein each dosing week comprises 4 consecutive dosing days and 3 days without dosing.

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

12. 9. Any one of claims 1 to 8, wherein each dosing week comprises 6 consecutive dosing days and 1 day without dosing. The method described below.

13. 9. The method of any one of claims 3 to 8, wherein each administration week comprises 7 consecutive administration days.

14. 14. The method of any one of claims 1 to 13, wherein the intermittent administration cycle comprises two consecutive administration weeks.

15. 1. A method of treating cancer, comprising: Administering to a subject in need thereof a daily dose of 350 mg or more, or the equivalent thereof, of azenosertib or a pharmaceutically acceptable salt thereof, according to an intermittent dosing cycle, The method, wherein said intermittent administration cycle comprises at least two consecutive days of administration and at least one day of no administration.

16. 16. The method of claim 15, wherein the intermittent administration cycle comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive administration days.

17. 17. The method of claim 15 or 16, wherein the intermittent administration cycle comprises at least 2, 3, 4, 5, 6, or 7 days without administration.

18. 18. The method of any one of claims 15 to 17, wherein the intermittent administration cycle comprises 5 consecutive days of administration and 2 days without administration.

19. 18. The method of any one of claims 15 to 17, wherein the intermittent administration cycle comprises 4 consecutive days of administration and 3 days without administration.

20. 18. The method of any one of claims 15 to 17, wherein the intermittent administration cycle comprises 3 consecutive days of administration and 4 days without administration.

21. 18. The method of any one of claims 15 to 17, wherein the intermittent administration cycle comprises 7 consecutive days of administration and 7 days without administration.

22. 18. The method of any one of claims 15 to 17, wherein the intermittent administration cycle comprises 14 consecutive days of administration and 7 days without administration.

23. 18. The method of any one of claims 15 to 17, wherein the intermittent administration cycle comprises 21 consecutive days of administration and 7 days without administration.

24. 24. The method of any one of claims 15-23, wherein the daily dose of azenosertib or a pharmaceutically acceptable salt thereof is 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 equivalents thereof or more.

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

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

27. 27. The method of claim 26, wherein the twice-daily azenosertib or a pharmaceutically acceptable salt thereof is 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, or equivalents thereof or more.

28. 28. The method of any one of claims 15 to 27, wherein the intermittent administration cycle is repeated.

29. 29. The method of any one of claims 1-28, wherein the method further comprises administering a second therapeutic agent, or a pharmaceutically acceptable salt thereof, during the intermittent administration cycle.

30. 30. The method of claim 29, (A) The second therapeutic agent or a pharmaceutically acceptable salt thereof is a chemotherapeutic agent or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent is selected from the group consisting of carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin (PLD), doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapine, 5-azacytidine, capecitabine, and AraC-FdUMP. [10] (CF-10), cladribine, decitabine, hydroxyurea, oxaliplatin, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, cyclophosphamide, capecitabine, dexamethasone, etoposide, daunorubicin, ifosfamide, methotrexate, and vincristine, or a pharmaceutically acceptable salt of any of the foregoing; (B) the second therapeutic agent is (a) a PARP inhibitor or a pharmaceutically acceptable salt thereof, wherein said 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 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, dimverelimab, 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 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 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 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, CAS No. 2378258-52-5), lonafarnib (SCH66336), RMC a KRAS inhibitor selected from the group consisting of CYP2000-0331, GDC-6036, LY3537982, D-1553, ARS-3248 (JNJ74699157), BI-1701963, and AU-8653 (AU-BEI-8653), or a pharmaceutically acceptable salt of any 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), relociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, vilociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or a pharmaceutically acceptable salt of any 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 of any of the foregoing; (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 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, eltamasoumab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343, or a pharmaceutically acceptable salt of any 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 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)benzoic acid (AZD9496), and benzophenone-1-yl. (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brillanestranestrant, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-methyl-2-methyl-4-phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (Elacestrant, RAD1901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brillanestranestrant, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-methyl-2-methyl-4-phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol) -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 (lindestrant, G1T48), D-0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (di a selective ER degrader selected from the group consisting of redestrant, 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)azetidin-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 of the foregoing; (l) An ATR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the ATR inhibitor is selected from galtisertib, berzosertib, M4344, BAY1895344, selalasertib, schisandrin B, elimsertib, 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 of the foregoing; (m) an ATM inhibitor or a pharmaceutically acceptable salt thereof, and selected from AZD7648, AZD0156, AZ31, AZ32, AZD1390, KU55933, KU59403, KU60019, CP-466722, CGK733, NVP-BEZ235, SJ573017, AZ31, AZ32, AZD1390, M4076SKLB-197, CGK733, M4076, M3541M4076, or a pharmaceutically acceptable salt thereof of any 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 the group consisting of prexasertib, AZD7762, ravusertib, 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, CN-01, SOL-578, IMP 10, and CBP501, or a pharmaceutically acceptable salt of any of the foregoing; (o) A method comprising administering a targeted therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the targeted therapeutic agent or a pharmaceutically acceptable salt thereof is selected from the group consisting of bevacizumab, lenvatinib, encorafenib, and cetuximab, or a pharmaceutically acceptable salt of any of the foregoing.

31. The cancer is glioblastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancer, head and neck cancer, leukemia, AML (acute myeloid leukemia), CLL (chronic lymphocytic leukemia), ALL (acute lymphocytic leukemia), myelodysplastic syndrome (MDS), skin cancer, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, uterine cancer, esophageal cancer, eye cancer, gallbladder cancer, stomach cancer, gastrointestinal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, blood tumors, Kaposi's sarcoma, kidney cancer, pharyngeal cancer. and the cancer is selected from the group consisting of 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, gastric cancer, small intestine cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer, uterine sarcoma, uterine serous adenocarcinoma, vaginal cancer, vulvar cancer, Wilms' tumor, solid tumor, liquid tumor.

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

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

34. 34. The method of claim 33, wherein 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 triple-negative breast cancer (TNBC)), lung cancer (e.g., NSCLC), esophagogastric cancer, gastric cancer, esophageal cancer, renal cancer (e.g., pRCC, ccRCC, chromophobe 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), cholangiocarcinoma, thyroid cancer, thymoma, uveal melanoma, and BRAF-mutated metastatic colorectal cancer.

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

36. 36. The method of claim 35, wherein the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous 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).

37. 37. The method of any one of claims 1 to 36, wherein the subject is administered azenosertib with food and / or an antiemetic agent.

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

39. 39. The method of any one of claims 1 to 38, wherein the subject is administered an antiemetic agent in conjunction with administration of azenosertib or a pharmaceutically acceptable salt thereof for at least two administration cycles.

40. 40. The method of claim 39, wherein the antiemetic agent 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. 41. The method of claim 40, wherein the antiemetic agent is aprepitant, rolapitant, ondansetron, granisterone, dexamethasone, olanzapine, netupitant, palonosetron, and combinations thereof, or a pharmaceutically acceptable salt of any of the foregoing.

42. 42. The method of any one of claims 1 to 41, wherein the cancer is a platinum-refractory cancer, a platinum-resistant cancer, or a platinum-sensitive cancer.

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

44. The method of any one of claims 1 to 43, wherein the cancer is a PARP inhibitor-resistant cancer.

45. The method of any one of claims 1 to 44, wherein the cancer is an HRRm or HRD positive cancer.

46. The method of any one of claims 1 to 45, wherein the cancer is an advanced or metastatic cancer.

47. 1. A method of treating cancer, comprising: administering to the subject a daily dose of 400 mg or more, or its equivalent, of azenosertib or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising 5 consecutive dosing days and 2 dosing-free days; 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 days of dosing and two days of no dosing.

48. 48. The method of claim 47, wherein the azenosertib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 450 mg or more of azenosertib or a pharmaceutically acceptable salt thereof.

49. 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 of the foregoing.

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

51. 51. The method of claim 50, wherein olaparib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 250 mg or more of azenosertib or a pharmaceutically acceptable salt thereof.

52. 51. The method of claim 50, wherein olaparib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 300 mg or more of azenosertib or a pharmaceutically acceptable salt thereof.

53. 53. The method of any one of claims 47-52, wherein the intermittent administration cycle of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycle of the PARPi or a pharmaceutically acceptable salt thereof occur during the same week.

54. 53. The method of any one of claims 47-52, wherein the intermittent administration cycles of azenosertib or a pharmaceutically acceptable salt thereof and the intermittent administration cycles of the PARPi or a pharmaceutically acceptable salt thereof occur on alternating weeks.

55. 53. 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. 56. The method of claim 55, wherein the cancer is metastatic or unresectable.

57. 1. A method of treating cancer, said method comprising: administering to the subject a daily dose of 200 mg or more, or its equivalent, of azenosertib or a pharmaceutically acceptable salt thereof in an intermittent dosing cycle comprising 5 consecutive dosing days and 2 dosing-free days; administering to the subject a daily dose of a chemotherapy agent in an intermittent dosing cycle comprising five consecutive days of administration and two days without administration.

58. Azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of 300 mg once daily in an intermittent dosing cycle of 5 consecutive days of administration and 2 days without administration, and paclitaxel is administered at 80 mg / m on days D1, D8, and D15 of a 28-day cycle. ２ 58. The method of claim 57, wherein the dose is

59. 58. The method of claim 57, wherein azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg once daily on D1 of a 21-day cycle in an intermittent dosing cycle of 5 consecutive dosing days and 2 days without dosing, and carboplatin AUC 5 mg / mL*min is administered.

60. Azenosertib or a pharmaceutically acceptable salt thereof is administered at a dose of 400 mg once daily in an intermittent dosing cycle of 5 consecutive dosing days and 2 days without dosing, and 40 mg / m on D1 of a 28-day cycle. ２ 59. The method of claim 58, wherein the dose is PLD.

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