Homologous recombination repair deficiency (HRD) as a predictive biomarker for treating cancer with WEE1 inhibitors.

Abstract

This disclosure provides, in particular, a method for treating cancer, comprising administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to subjects selected to have homologous recombination repair deficiency (HRD).

Description

Technical Field

[0001] Cross - reference to Related Applications For example, in the application data sheets or requests filed in this application, all applications in which claims of foreign or domestic priority are identified are incorporated herein by reference under 37 CFR 1.57 of the United States Patent Law, and Rules 4.18 and 20.6, which include U.S. Provisional Patent Application No. 63 / 506,029 filed on June 2, 2023, U.S. Provisional Patent Application No. 63 / 599,420 filed on November 15, 2023, and U.S. Provisional Patent Application No. 63 / 635,159 filed on April 17, 2024, each of which is hereby expressly incorporated herein by reference in its entirety.

Background Art

[0002] DNA damage is typically resolved by various pathways and proteins that repair the damaged DNA. Among these pathways, prominent are the proteins involved in homologous recombination, which is a type of DNA repair where nucleotide sequences are exchanged between two similar or identical molecules of DNA, usually resulting in error - free repair of the damaged DNA. However, inaccurate substitution of nucleotides into DNA can cause mutations and other genetic alterations that can lead to the development and progression of cancer. Inappropriate DNA repair can lead to cell death, tumor progression, and cancer. Cell - cycle checkpoints are important for proper DNA repair, ensuring that cells do not proceed with cell replication until the integrity of the genome is restored. There remains a need for therapies that can effectively and reliably treat cancers with DNA repair deficiencies.

Summary of the Invention

[0003] This disclosure is partly based on the finding that homologous recombination deficiency or homologous repair deficiency (HRD) status may be used as a predictive biomarker for the effective treatment of cancer with WEE1 inhibitors (e.g., azenocertib, ZN-c3). In particular, HRD status may be used as a predictive biomarker for the effective treatment of cancer that is resistant to other therapy lines (e.g., chemotherapy, PARP inhibitor therapy).

[0004] This disclosure provides, in particular, a method for treating chemotherapy-resistant cancers (e.g., platinum-resistant cancers, PARP inhibitor-resistant cancers) by administering a WEE1 inhibitor to HRD-positive subjects. In some embodiments, the WEE1 inhibitor (e.g., azenocertib) is administered in combination with one or more PARP inhibitors (e.g., olaparib, niraparib, salparib).

[0005] For example, homologous recombination deficiency (HRD) is a biomarker present in the most advanced stages of cancer (e.g., ovarian cancer). This disclosure provides, among other things, a method for selecting subjects, or a method for selecting a stage or subtype of cancer (by determining or having determined an HRD status), and a method for treating cancer by administering a WEE1 inhibitor. This disclosure, among other things, shows that HRD-positive subjects are more responsive to azenocertib therapy, PARP inhibitor therapy, or a combination thereof. Furthermore, this disclosure shows that subjects who are HRD-positive but resistant to treatment with PARP inhibitors (e.g., olaparib, niraparib, salparib) are responsive to azenocertib therapy.

[0006] DNA damage and various gene mutations can lead to the development of cancer. Even small amounts of DNA damage can contribute to cancer. In some cases, the body can repair DNA to ensure cell survival, but if the DNA damage is too great, the cell will die. The body repairs damaged DNA by using tumor suppressor genes (e.g., BRCA genes in particular) and a protein called poly(ADP-ribose) polymerase (PARP). If the tumor suppressor gene is pathogenic (e.g., a pathogenic BRCA mutation), cancer cells are repaired by PARP. PARP inhibitors can prevent DNA repair by PARP, which can induce cell death and thereby inhibit tumor growth.

[0007] WEE1 is a tumor suppressor that induces G2 / M arrest via inhibitory phosphorylation of CDK1 (Cdc2) on Tyr15, preventing entry into mitosis and enabling DNA repair during DNA damage. WEE1 inhibitors (e.g., azenocertib) also prevent DNA repair and thereby inhibit tumor growth. In particular, this disclosure provides WEE1 inhibitors for the treatment of PARP-resistant cancers.

[0008] While we do not wish to be bound by any particular theory, the combined inhibition of PARP and WEE1 is intended to be synergistic in controlling tumor growth (e.g., ovarian cancer, triple-negative breast cancer, etc.) by increasing replication stress in cancer cells, for example.

[0009] In some embodiments, a method for treating cancer is provided herein, comprising determining, or having determined, whether a subject has homologous repair deficiency (HRD) or HRD-positive (HRD+) status, and, if the subject has HRD or HRD-positive (HRD+) status, administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof, wherein the administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of cancer in the subject.

[0010] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is about 200 to about 450 mg / day, or about 200 to about 400 mg / day, or about 200 to about 350 mg / day, or about 250 to about 400 mg / day, or about 250 to about 350 mg / day, or any of the aforementioned equivalents.

[0011] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 mg / day or an equivalent thereof.

[0012] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 to about 300 mg / day, or an equivalent thereof.

[0013] In some embodiments, the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 300 to about 350 mg / day, or an equivalent thereof.

[0014] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 350 to about 400 mg / day, or an equivalent thereof.

[0015] In some embodiments, the effective dose is administered once daily (QD).

[0016] In some embodiments, the effective dose is administered twice daily (BID).

[0017] In some embodiments, the effective dose is administered in a continuous dosing schedule.

[0018] In some embodiments, the effective dose is administered on an intermittent dosing schedule.

[0019] In some embodiments, the intermittent dosing schedule includes five dosing days and two dosing rest days in each of the dosing weeks of one week or more. In some embodiments, the intermittent dosing schedule includes five consecutive dosing days and two consecutive dosing rest days in each of the dosing weeks of one week or more.

[0020] In some embodiments, HRD or HRD-positive (HRD+ state) is caused by cancer having homologous recombination repair mutations (HRRm). In some embodiments, HRRm is a mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. In some embodiments, HRD or HRD-positive (HRD+ state) is caused by cancer having mutations in BRCA1 and / or BRCA2. In some embodiments, HRD or HRD-positive (HRD+ state) is caused by cancer having a BRCA1 pathogenic mutation. In some embodiments, the BRCA1 pathogenic mutation is BRCA1 Glu1607Ter That is the case.

[0021] In some embodiments, HRD or HRD-positive (HRD+ state) is caused by cancer having homologous recombination repair reverse mutations. In some embodiments, homologous recombination repair reverse mutations are mutations in genes selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. In some embodiments, HRD or HRD-positive (HRD+ state) is caused by cancer having homologous recombination repair reverse mutations in BRCA1 and / or BRCA2. In some embodiments, HRD or HRD-positive (HRD+ state) is caused by cancer having a BRCA1 splicing isoform. In some embodiments, the BRCA1 splicing isoform is the BRCA1-D11q splicing isoform.

[0022] In some embodiments, the cancer has additional mutations in genes selected from the group consisting of TP53, AKT1, BRCA2, CDKN2A, KDM6A, PTEN, RB1, and FAM35A.

[0023] In some embodiments, the method involves administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to subjects selected to have cancer with a BRCA1 / 2 variant or a BRCA1 / 2-positive condition.

[0024] In some embodiments, the method involves administering to a subject an effective dose of azenocertib or a pharmaceutically acceptable salt thereof in combination with an effective dose of a PARP inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the PARP inhibitor is niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the effective dose of niraparib or a pharmaceutically acceptable salt thereof is about 150 to about 350 mg / day, or about 150 to about 300 mg / day, or about 150 to about 250 mg / day, or about 200 to about 350 mg / day, or about 200 to about 300 mg / day, or about 200 mg / day, or about 300 mg / day, or about 250 mg / day. In one embodiment, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the effective dose of olaparib or a pharmaceutically acceptable salt thereof is about 300 to about 800 mg / day, or about 300 to about 400 mg / day, or about 600 to about 800 mg / day, or about 300 mg / day, or about 400 mg / day, or at least about 300 mg / day, or at least about 400 mg / day, or about 600 mg / day, or at least about 600 mg / day, or about 800 mg / day. In one embodiment, the effective dose of olaparib or a pharmaceutically acceptable salt thereof is administered twice daily (BID). In some embodiments, the PARP inhibitor is a PARP1 selective inhibitor. or a pharmaceutically acceptable salt thereof. In one embodiment, the PARP1 selective inhibitor is salparib or a pharmaceutically acceptable salt thereof. In some embodiments, an effective dose of salparib or a pharmaceutically acceptable salt thereof is about 5 to about 100 mg / day, or at least about 5 mg / day, or about 50 to about 100 mg / day, or about 50 to about 80 mg / day, or about 50 to about 70 mg / day, or about 50 to about 60 mg / day, or about 60 to about 70 mg / day, or about 60 mg / day.

[0025] In some embodiments, the subject has received one or more previous lines of treatment, e.g., one or more previous chemotherapy regimens (monotherapy or combination therapy), or at least one previous line of treatment including a PARP inhibitor (i.e., the subject has previously received a PARP inhibitor or a pharmaceutically acceptable salt thereof). In one embodiment, the cancer is chemotherapy-resistant. In one embodiment, the cancer is platinum-resistant. In one embodiment, the cancer is PARP inhibitor-resistant. In one embodiment, the cancer is both chemotherapy-resistant and PARP inhibitor-resistant. In one embodiment, the cancer is both platinum-resistant and PARP inhibitor-resistant.

[0026] In some embodiments, cancers include gliablastoma (GBM), astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, head and neck cancers, 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, colon cancer, colorectal cancer, uterine cancer, endometrial cancer, esophageal cancer, eye cancer, and gallbladder cancer. Stomach cancer, gastrointestinal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, hematological malignancies, head cancer, hematological malignancies, Kaposi's sarcoma, kidney cancer, pharyngeal / hypopharyngeal cancer, liver cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal cancer, cervical cancer, ovarian cancer, osteosarcoma, sarcoma, gastrointestinal stromal tumor (GIST), pancreatic cancer, pituitary cancer, prostate cancer, kidney cancer, retinoblastoma, salivary gland cancer, skin cancer, stomach Cancer, small intestine cancer, splenic cancer, sarcoma, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, serous adenocarcinoma of the uterus (USC), uterine CS, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, Wilms' tumor, solid tumors or liquid tumors, HGSOC, invasive breast cancer, triple-negative breast cancer (TNBC), esophageal and gastric cancer, gastric cancer, esophageal cancer, pRCC, ccRCC, chromophobic RCC, head and neck cancer, adenoid cystic carcinoma (ACC), The group is comprised of diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), low-grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), cholangiocarcinoma, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), thymoma, BRAF-mutated metastatic colorectal cancer, and uveal melanoma.

[0027] In some embodiments, the cancer is a solid tumor or a hematological malignancy.

[0028] In some embodiments, cancer is a solid tumor.

[0029] In some embodiments, the solid tumor is ovarian cancer.

[0030] In some embodiments, the ovarian cancer is epithelial ovarian cancer.

[0031] In some embodiments, epithelial ovarian cancer is high-grade serous ovarian cancer (HGSOC).

[0032] In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is endometrial carcinoma or endometrial cancer. In some embodiments, the cancer is serous adenocarcinoma (USC). In some embodiments, the cancer is peritoneal cancer (e.g., primary peritoneal cancer). In some embodiments, the cancer is fallopian tube cancer.

[0033] In some embodiments, the cancer is breast cancer. In one embodiment, the cancer is triple-negative. It is breast cancer. In one embodiment, the breast cancer is HER2-expressing or HER2-positive (HER2+) breast cancer.

[0034] In some embodiments, the cancer is prostate cancer.

[0035] In some embodiments, a method for treating PARP inhibitor-resistant breast cancer is provided herein, comprising determining, or having determined, whether a subject has homologous recombination repair deficiency (HRD) or HRD-positive (HRD+) status, and, if the subject has HRD or HRD-positive (HRD+) status, administering azenocertib or a pharmaceutically acceptable salt thereof in an effective dose, wherein the administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of cancer in the subject.

[0036] In some embodiments, HRD or HRD-positive (HRD+ state) is caused by PARP inhibitor-resistant breast cancer with a BRCA1 reverse mutation.

[0037] In some embodiments, HRD or HRD-positive (HRD+ state) is due to PARP inhibitor-resistant breast cancer having a BRCA1 mutation. In some embodiments, HRD or HRD-positive (HRD+ state) is due to PARP inhibitor-resistant breast cancer having a BRCA1 splicing isoform. In some embodiments, the BRCA1 splicing isoform is the BRCA1-Δ11q splicing isoform.

[0038] In some embodiments, the cancer has an additional mutation in the gene FAM35A. In some embodiments, the cancer has an additional mutation in the gene TP53.

[0039] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 mg / day or an equivalent thereof.

[0040] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 to about 300 mg / day, or an equivalent thereof.

[0041] In some embodiments, the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 300 to about 350 mg / day, or an equivalent thereof.

[0042] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 350 to about 400 mg / day, or an equivalent thereof.

[0043] In some embodiments, the method involves administering to a subject an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof in combination with an effective dose of a PARP inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is niraparib, olaparib, salparib, or any of the aforementioned pharmaceutically acceptable salts. In one embodiment, the PARP inhibitor is niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the effective dose of niraparib or a pharmaceutically acceptable salt thereof is about 150 to about 350 mg / day, or about 150 to about 300 mg / day, or about 150 to about 250 mg / day, or about 200 to about 350 mg / day, or about 200 to about 300 mg / day, or about 200 mg / day, or about 300 mg / day, or about 250 mg / day. In one embodiment, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, an effective dose of olaparib or a pharmaceutically acceptable salt thereof is approximately 300 to approximately 800 mg / day, or approximately 300 to approximately 400 mg / day, or approximately 600 to approximately 800 mg / day, or approximately 300 mg / day, or approximately 400 mg / day, or at least approximately 300 mg / day, or at least approximately 400 mg / day, or approximately 600 mg / day, or at least approximately 60 The dose is 0 mg / day or approximately 800 mg / day. In one embodiment, an effective dose of olaparib or a pharmaceutically acceptable salt thereof is administered twice daily (BID). In some embodiments, the PARP inhibitor is a PARP1 selective inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the PARP1 selective inhibitor is salparib or a pharmaceutically acceptable salt thereof. In some embodiments, an effective dose of salparib or a pharmaceutically acceptable salt thereof is approximately 5 to approximately 100 mg / day, or at least approximately 5 mg / day, or approximately 50 to approximately 100 mg / day, or approximately 50 to approximately 80 mg / day, or approximately 50 to approximately 70 mg / day, or approximately 50 to approximately 60 mg / day, or approximately 60 to approximately 70 mg / day, or approximately 60 mg / day.

[0044] In some embodiments, PARP inhibitor-resistant breast cancer is niraparib-resistant.

[0045] In some embodiments, PARP inhibitor-resistant breast cancer is olaparib-resistant.

[0046] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered on an intermittent dosing schedule.

[0047] In some embodiments, the intermittent dosing schedule includes five dosing days and two dosing rest days in each of the dosing weeks of one week or more. In some embodiments, the intermittent dosing schedule includes five consecutive dosing days and two consecutive dosing rest days in each of the dosing weeks of one week or more.

[0048] In some embodiments, a method for treating chemotherapy-resistant ovarian cancer is provided herein, comprising determining whether a subject has homologous recombination repair deficiency (HRD) or is HRD-positive (HRD+), and if the subject has HRD or is HRD-positive (HRD+), administering azenocertib or a pharmaceutically acceptable salt thereof in an effective dose, wherein the administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of cancer in the subject.

[0049] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 mg / day or an equivalent thereof.

[0050] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 to about 300 mg / day, or an equivalent thereof.

[0051] In some embodiments, the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 300 to about 350 mg / day, or an equivalent thereof.

[0052] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 350 to about 400 mg / day, or an equivalent thereof.

[0053] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered on an intermittent dosing schedule.

[0054] In some embodiments, the intermittent dosing schedule includes five dosing days and two dosing rest days in each of the dosing weeks of one week or more. In some embodiments, the intermittent dosing schedule includes five consecutive dosing days and two consecutive dosing rest days in each of the dosing weeks of one week or more.

[0055] In some embodiments, chemotherapy-resistant ovarian cancer is platinum-resistant.

[0056] In some embodiments, chemotherapy-resistant ovarian cancer is further resistant to PARP inhibitors or pharmaceutically acceptable salts thereof.

[0057] In some embodiments, HRD or HRD-positive (HRD+ state) is caused by cancer having mutations in BRCA1 and / or BRCA2.

[0058] In some embodiments, HRD includes copy number variation, somatic copy number change (SCNA), aneuploidy, loss of heterozygosity (LOH), large-scale state transition (LST), and / or telomere allele mismatch (TAI).

[0059] In some embodiments, the HRD status is determined using a functional assay or genome sequencing.

[0060] In some embodiments, the HRD status is determined using an HRD score.

[0061] In some embodiments, the method further includes determining, or having determined, the cyclin E expression level in a subject.

[0062] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered orally, intravenously, subcutaneously, intraarachnoidally, intramuscularly, intracavitarially, intrapleurally, intrafocally, or intraarterially.

[0063] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered orally.

[0064] In some embodiments, the treatment results in a response rate of 50% or more.

[0065] In some embodiments, the response rate is defined as complete response (CR), partial response (PR), CA-125 Measured by a 50% response rate, or a combination thereof.

[0066] In some embodiments, the treatment results in a progression-free survival (PFS) of 6 months or more.

[0067] In some embodiments, cancer inhibition is measured by inhibition of tumor growth.

[0068] In some embodiments, inhibition of tumor growth is measured by a reduction in tumor volume.

[0069] In one embodiment, the present invention provides a method for treating cancer, comprising administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to a subject selected to have cancer with homologous recombination repair deficiency (HRD).

[0070] In another embodiment, the Specified Accession of the Present Provision is a method for treating cancer, comprising administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to subjects selected to have cancer having a homologous recombination repair deficiency-positive (HRD-positive or HRD+) condition.

[0071] In some embodiments, cancer has homologous recombination repair mutations (HRRm). In some embodiments, cancer has homologous recombination repair reverse mutations.

[0072] In some embodiments, HRRm is a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. It is a mutation in the gene. In some embodiments, HRRm is a pathogenic mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. In some embodiments, HRRm is a mutation that is likely to be pathogenic in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. In some embodiments, HRRm is a homozygous deletion in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

[0073] In some embodiments, HRD or HRD-positive (HRD+) status is caused by a mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. In some embodiments, HRD or HRD-positive (HRD+) status is caused by a revert mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. In some embodiments, the mutation or modification includes any change in the gene or the expression of the gene. In some embodiments, the modification includes dysregulation of expression. In some embodiments, the dysregulation includes promoter methylation.

[0074] In some embodiments, the HRD or HRD-positive (HRD+) condition is caused by a cancer with mutations in BRCA1 and / or BRCA2. In some embodiments, the HRD or HRD-positive (HRD+) condition is caused by a revert mutation in BRCA1 and / or BRCA2.

[0075] In some embodiments, the cancer has additional mutations in genes selected from the group consisting of TP53, AKT1, BRCA2, CDKN2A, KDM6A, PTEN, RB1, and FAM35A.

[0076] In some embodiments, the HRD or HRD-positive (HRD+) condition is caused by cancer having a BRCA1 splicing isoform. In one embodiment, the HRD or HRD-positive (HRD+) condition is caused by cancer having a BRCA1-D11q splicing isoform.

[0077] In one embodiment, a method for treating cancer disclosed herein comprises administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to a subject selected to have cancer having a BRCA1 / 2 variant or a BRCA1 / 2BRCA1-positive condition.

[0078] In some embodiments, HRD includes copy number variation, somatic copy number change (SCNA), aneuploidy, loss of heterozygosity (LOH), large-scale state transition (LST), and / or telomere allele mismatch (TAI).

[0079] In some embodiments, the HRD-positive (HRD+) status is determined using a functional assay or genomic sequencing.

[0080] In some embodiments, the HRD-positive (HRD+) status is determined using an HRD score.

[0081] In some embodiments, the HRD-positive (HRD+) status is determined using a GIS score (Genome Instability Score).

[0082] In some embodiments, the method further includes selecting subjects based on cyclin E1 levels. In some embodiments, the method further includes selecting subjects based on cyclin E1 expression. In some embodiments, the method further includes selecting subjects based on CCNE1 gene amplification.

[0083] In some embodiments, the method further includes selecting subjects based on the level of replication stress. In some embodiments, CCNE1 amplification or high expression increases replication stress.

[0084] In some embodiments, the method further comprises administering to a subject an effective dose of a PARP inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the PARP inhibitor is niraparib or a pharmaceutically acceptable salt thereof. In one embodiment, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In one embodiment, the PARP inhibitor is a PARP1 selective inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the PARP1 selective inhibitor is salparib (AZD5305) or a pharmaceutically acceptable salt thereof. In one embodiment, azenocertiveb or a pharmaceutically acceptable salt thereof and the PARP inhibitor or a pharmaceutically acceptable salt thereof are administered to the subject concurrently or incidentally, and azenocertiveb or a pharmaceutically acceptable salt thereof is administered optionally on an intermittent dosing schedule. In one embodiment, azenocertiveb or a pharmaceutically acceptable salt thereof, and a PARP inhibitor or a pharmaceutically acceptable salt thereof, are administered sequentially to the subject, while azenocertiveb or a pharmaceutically acceptable salt thereof is administered selectively on an intermittent dosing schedule. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof, and a PARP inhibitor or a pharmaceutically acceptable salt thereof, are administered sequentially to the subject, while azenocertiveb or a pharmaceutically acceptable salt thereof is administered selectively on an intermittent dosing schedule. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof, and a PARP inhibitor or a pharmaceutically acceptable salt thereof, are administered sequentially to the subject, while azenocertiveb or a pharmaceutically acceptable salt thereof is administered before the PARP inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, azenocertib or a pharmaceutically acceptable salt thereof and a PARP inhibitor or a pharmaceutically acceptable salt thereof are administered to the subject sequentially, with the PARP inhibitor or a pharmaceutically acceptable salt thereof being administered before azenocertib or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the subject is receiving one or more prior treatment lines.

[0086] In some embodiments, the cancer is platinum-resistant.

[0087] In some embodiments, the cancer is resistant to PARP inhibitors.

[0088] In some embodiments, the subject has previously received a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is approximately 50–400 mg / day, approximately 100–400 mg / day, approximately 150–400 mg, approximately 200–400 mg / day, approximately 200–375 mg / day, or approximately 200–350 mg / day. The dosage is approximately 200-300 mg / day, 200-400 mg / day, 250-450 mg / day, 300-450 mg / day, or 400-600 mg / day, or equivalents thereof.

[0090] In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 550 mg / day, or about 600 mg / day, or equivalents thereof.

[0091] In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is at least about 300 mg / day of azenocertiveb or its equivalent. In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is at least about 350 mg / day of azenocertiveb or its equivalent.

[0092] In some embodiments, the effective dose is approximately 400 mg / day of azenocertive or its equivalent. In some embodiments, the effective dose is at least approximately 400 mg / day of azenocertive or its equivalent.

[0093] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, or three times daily.

[0094] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered once daily.

[0095] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered once daily in a continuous dosing regimen.

[0096] In some embodiments, azenocertib or a pharmaceutically acceptable salt thereof is administered in intermittent dosing cycles at an effective dose of approximately 400 mg / day or an equivalent thereof.

[0097] In some embodiments, the intermittent dosing cycle includes five consecutive dosing days and two dosing rest days. In some embodiments, the method includes administering azenocertiveb or a pharmaceutically acceptable salt thereof at a dose of approximately 400 mg / day, with a weekly dosing schedule of five on days and two off days (5:2). In some embodiments, the method includes administering azenocertiveb or a pharmaceutically acceptable salt thereof at a dose of approximately 400 mg / day, with five consecutive dosing days and two dosing rest days per week.

[0098] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered orally, intravenously, subcutaneously, intraarachnoidally, intramuscularly, intracavitarially, intrapleurally, intrafocally, or intraarterially.

[0099] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered orally.

[0100] In some embodiments, the treatment results in response rates of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or higher.

[0101] In some embodiments, the response rate is defined as complete response (CR), partial response (PR), CA-125 Measured by a 50% response rate, or a combination thereof.

[0102] In some embodiments, the treatment results in progression-free survival (PFS) of 5, 6, 7, 8, 9, 10, 11, or 12 months or longer.

[0103] In some embodiments, the method further includes first determining the HRD status before selecting a subject. In some embodiments, the method further includes first determining the HRD status before treating a subject with azenocertib or a pharmaceutically acceptable salt thereof. In some embodiments, the method further includes determining the HRD status during treatment with azenocertib or a pharmaceutically acceptable salt thereof.

[0104] Other features, purposes, and advantages are evident in the detailed description below. However, it should be understood that the detailed description illustrates embodiments but is provided for illustrative purposes only and is not limiting. Various changes and modifications within the scope of this disclosure will be evident to those skilled in the art from the detailed description. Brief explanation of the drawing

[0105] The drawings are for illustrative purposes only and are not limiting. [Brief explanation of the drawing]

[0106] [Figure 1A]Figure 1A is a chart showing the genotype and dosage of azenocertiveb in subjects with cancers (e.g., serous adenocarcinoma (USC) and ovarian cancer) selected for evaluation of HRRm association in subjects treated with azenocertiveb at doses of 300 mg or more. LT300 = azenocertiveb <300 mg, SD = stable disease, PR = partial response, cPR = confirmed partial response, CR = complete remission, PD = progressive disease, uPR = unconfirmed partial response (uPR), O = ovarian cancer, U = uterine cancer. Response criteria are based on the Response Evaluation Criteria for Solid Tumors (RECIST) guidelines. [Figure 1B] Figure 1B is a chart showing the changes in HRRm status and tumor size for each subject receiving more than 300 mg of azenocertib. [Figure 1C] Figure 1C is a chart showing the best overall tumor response (BOR) and tumor size changes for each subject in Figure 1B. [Figure 1D] Figure 1D shows the stratification of the target population and survival probability of HRRm in subjects receiving at least 300 mg (300 mg+) of azenocertiveb. [Figure 2A] Figures 2A to 2D are graphs showing tumor volume and tumor growth inhibition (TGI%) in mice inoculated with 22RV1 cells treated with azenocerutib alone or in combination with a PARP inhibitor. Figures 2A and 2B are graphs showing tumor volume of 22RV1 xenografts in mice treated with azenocerutib alone or in combination with niraparib. Figures 2C and 2D are graphs showing tumor volume of 22RV1 xenografts in mice treated with azenocerutib alone or in combination with olaparib. [Figure 2B]Figures 2A to 2D are graphs showing tumor volume and tumor growth inhibition (TGI%) in mice inoculated with 22RV1 cells treated with azenocerutib alone or in combination with a PARP inhibitor. Figures 2A and 2B are graphs showing tumor volume of 22RV1 xenografts in mice treated with azenocerutib alone or in combination with niraparib. Figures 2C and 2D are graphs showing tumor volume of 22RV1 xenografts in mice treated with azenocerutib alone or in combination with olaparib. [Figure 2C] Figures 2A to 2D are graphs showing tumor volume and tumor growth inhibition (TGI%) in mice inoculated with 22RV1 cells treated with azenocerutib alone or in combination with a PARP inhibitor. Figures 2A and 2B are graphs showing tumor volume of 22RV1 xenografts in mice treated with azenocerutib alone or in combination with niraparib. Figures 2C and 2D are graphs showing tumor volume of 22RV1 xenografts in mice treated with azenocerutib alone or in combination with olaparib. [Figure 2D] Figures 2A to 2D are graphs showing tumor volume and tumor growth inhibition (TGI%) in mice inoculated with 22RV1 cells treated with azenocerutib alone or in combination with a PARP inhibitor. Figures 2A and 2B are graphs showing tumor volume of 22RV1 xenografts in mice treated with azenocerutib alone or in combination with niraparib. Figures 2C and 2D are graphs showing tumor volume of 22RV1 xenografts in mice treated with azenocerutib alone or in combination with olaparib. [Figure 3A] Figure 3A is a graph showing the tumor volume of the HBCx-9 patient-derived xenograft (PDX) model described in Example 3. [Figure 3B] Figures 3B and 3C are exemplary graphs showing the reduction in tumor volume in the HBCx-10 PDX model (Figure 3B) and the HBCx-17 PDX model (Figure 3C) after treatment with azenocertib and / or niraparib. [Figure 3C]Figures 3B and 3C are exemplary graphs showing the reduction in tumor volume in the HBCx-10 PDX model (Figure 3B) and the HBCx-17 PDX model (Figure 3C) after treatment with azenocertib and / or niraparib. [Figure 4A] Figure 4A is an exemplary graph showing the tumor volume of the BRCA1 WT PDX model (OVA2-BUR) described in Example 4. [Figure 4B] Figure 4B is an exemplary graph showing the change in tumor volume in a BRCA1-mutated pathogenic CTG-0703 PDX model after treatment with azenocertib and / or niraparib. [Figure 4C] Figure 4C is an exemplary graph showing tumor volume in a BRCA1 benign variant (CTG-2213) PDX model after treatment with azenocertib and / or niraparib. [Figure 5A] Figures 5A to 5C are illustrative graphs showing the percentage inhibition of WEE1 inhibitors (azenocertib and AZD1775) or PARP inhibitors (niraparib and olaparib) in PARP inhibitor-sensitive and resistant triple-negative breast cancer cell lines in vitro. [Figure 5B] Figures 5A to 5C are illustrative graphs showing the percentage inhibition of WEE1 inhibitors (azenocertib and AZD1775) or PARP inhibitors (niraparib and olaparib) in PARP inhibitor-sensitive and resistant triple-negative breast cancer cell lines in vitro. [Figure 5C] Figures 5A to 5C are illustrative graphs showing the percentage inhibition of WEE1 inhibitors (azenocertib and AZD1775) or PARP inhibitors (niraparib and olaparib) in PARP inhibitor-sensitive and resistant triple-negative breast cancer cell lines in vitro. [Figure 5D]Figures 5D–5G are illustrative graphs showing tumor volume in animals after treatment with WEE1 inhibitor alone or in combination with a PARP inhibitor in a PARP inhibitor-sensitive model and two PARP inhibitor-resistant models. The parental MDA-MB-436 (TP53, BRCA1 mutant) remained sensitive to the PARP inhibitor (Figures 5A and 5D), while MDA-MB-436 NirR (TP53, BRCA1m inverse) (Figures 5B and 5E) and MDA-MB-436 OlaR (TP53, BRCA1m inverse) (Figures 5C, 5F, and 5G) were resistant to the PARP inhibitor. [Figure 5E] Figures 5D–5G are illustrative graphs showing tumor volume in animals after treatment with WEE1 inhibitor alone or in combination with a PARP inhibitor in a PARP inhibitor-sensitive model and two PARP inhibitor-resistant models. The parental MDA-MB-436 (TP53, BRCA1 mutant) remained sensitive to the PARP inhibitor (Figures 5A and 5D), while MDA-MB-436 NirR (TP53, BRCA1m inverse) (Figures 5B and 5E) and MDA-MB-436 OlaR (TP53, BRCA1m inverse) (Figures 5C, 5F, and 5G) were resistant to the PARP inhibitor. [Figure 5F] Figures 5D–5G are illustrative graphs showing tumor volume in animals after treatment with WEE1 inhibitor alone or in combination with a PARP inhibitor in a PARP inhibitor-sensitive model and two PARP inhibitor-resistant models. The parental MDA-MB-436 (TP53, BRCA1 mutant) remained sensitive to the PARP inhibitor (Figures 5A and 5D), while MDA-MB-436 NirR (TP53, BRCA1m inverse) (Figures 5B and 5E) and MDA-MB-436 OlaR (TP53, BRCA1m inverse) (Figures 5C, 5F, and 5G) were resistant to the PARP inhibitor. [Figure 5G]Figures 5D–5G are illustrative graphs showing tumor volume in animals after treatment with WEE1 inhibitor alone or in combination with a PARP inhibitor in a PARP inhibitor-sensitive model and two PARP inhibitor-resistant models. The parental MDA-MB-436 (TP53, BRCA1 mutant) remained sensitive to the PARP inhibitor (Figures 5A and 5D), while MDA-MB-436 NirR (TP53, BRCA1m inverse) (Figures 5B and 5E) and MDA-MB-436 OlaR (TP53, BRCA1m inverse) (Figures 5C, 5F, and 5G) were resistant to the PARP inhibitor. [Figure 6] Figure 6 shows exemplary pathological scans of subjects with HRD+PARP inhibitor-resistant platinum-resistant ovarian cancer at screening and after treatment with azenocertib. [Figure 7A] Figures 7A and 7B are graphs analyzing the overall survival of subjects with USCs selected to have HRRm or HRRwt and a TP53 mutation status, with overall survival measured after sample collection or initiation of carboplatin treatment. [Figure 7B] Figures 7A and 7B are graphs analyzing the overall survival of subjects with USCs selected to have HRRm or HRRwt and a TP53 mutation status, with overall survival measured after sample collection or initiation of carboplatin treatment. [Figure 8A] Figures 8A to 8E are graphs and tables showing IC50 values ​​for in vitro cell viability after treatment with azenocertib, olaparib, or AZD5305 in cell lines UWB1289, HCC1937, COV362, HCC1569, and HCC1395. [Figure 8B] Figures 8A to 8E are graphs and tables showing IC50 values ​​for in vitro cell viability after treatment with azenocertib, olaparib, or AZD5305 in cell lines UWB1289, HCC1937, COV362, HCC1569, and HCC1395. [Figure 8C]Figures 8A to 8E are graphs and tables showing IC50 values ​​for in vitro cell viability after treatment with azenocertib, olaparib, or AZD5305 in cell lines UWB1289, HCC1937, COV362, HCC1569, and HCC1395. [Figure 8D] Figures 8A to 8E are graphs and tables showing IC50 values ​​for in vitro cell viability after treatment with azenocertib, olaparib, or AZD5305 in cell lines UWB1289, HCC1937, COV362, HCC1569, and HCC1395. [Figure 8E] Figures 8A to 8E are graphs and tables showing IC50 values ​​for in vitro cell viability after treatment with azenocertib, olaparib, or AZD5305 in cell lines UWB1289, HCC1937, COV362, HCC1569, and HCC1395. [Figure 9] Figure 9 is a graph showing tumor volume and tumor growth inhibition (TGI%) in mice inoculated with PARP inhibitor-resistant HCC1937 triple-negative breast cancer (TNBC) cells after treatment with azenocertib monotherapy or in combination with olaparib administered either concurrently or in alternating weeks. [Figure 10A] Figures 10A and 10B are graphs showing tumor volume and tumor growth inhibition (TGI%) in mice inoculated with PARP inhibitor-resistant SUM149PT triple-negative breast cancer (TNBC) cells after azenocertib monotherapy or in combination with olaparib or AZD5305 administered concurrently. [Figure 10B] Figures 10A and 10B are graphs showing tumor volume and tumor growth inhibition (TGI%) in mice inoculated with PARP inhibitor-resistant SUM149PT triple-negative breast cancer (TNBC) cells after azenocertib monotherapy or in combination with olaparib or AZD5305 administered concurrently. Definition [Modes for carrying out the invention]

[0107] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those 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. If a term in this specification has multiple definitions, the term in this section shall prevail unless otherwise stated.

[0108] As used herein, the term “about” has its ordinary meaning as understood by those skilled in the art, and thus indicates that the value includes the inherent variation in the error of the method used to determine the value (e.g., ±10%), or the variation that exists between multiple determinations.

[0109] As used herein, the terms “modification” or “alteration,” or any form thereof, mean modification, alteration, replacement, deletion, substitution, removal, change, or transformation.

[0110] As used herein, the terms “function” and “functional” have their ordinary meanings as understood by those skilled in the art, and therefore refer to biological, enzymatic, or therapeutic functions.

[0111] As used herein, the term “endogenous” has its usual meaning as understood by those skilled in the art, and therefore 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, 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.

[0112] The term “mutation” has the usual meaning understood by those skilled in the art and refers to a change in the gene sequence. In some embodiments, cells have multiple mutations. In some embodiments, mutations are located in the coding region of the genome. Mutations can range in size from a single base pair to a large segment of a chromosome containing multiple genes. In some embodiments, at least one mutation is silent. In some embodiments, mutations may not have a significant effect on gene expression or function. In some embodiments, at least one mutation affects gene expression or function, such as gene amplification, overexpression, or copy number increase. In some embodiments, at least one mutation is silent (e.g., does not alter the coding sequence). In some embodiments, at least one mutation has a small effect on protein expression or function. In some embodiments, at least one mutation has a moderate effect on protein expression or function. In some embodiments, at least one mutation has a significant effect on protein expression or function. In some embodiments, at least one mutation interferes with protein expression or function. Non-limiting examples of mutations include insertions, deletions, shortenings, substitutions, duplications, translocations, and inversions. In some embodiments, the mutation is “somatic,” meaning it occurs within somatic cells and is not hereditary. In some embodiments, a subset of somatic cells in an organism has at least one mutation that other somatic cells do not have. In some embodiments, the mutation occurs in the "germ cell lineage," i.e., within germ cells, and is hereditary.

[0113] As disclosed herein, mutations can be monitored through a variety of sequencing, expression, or functional assays. Non-limiting examples include DNA sequencing, RNA sequencing, DNA hybridization, protein sequencing, targeted genome sequencing, whole exome sequencing, whole genome sequencing, ATAC sequencing, Sanger sequencing, PCR, qPCR, RT-PCR, RT-qPCR, next-generation sequencing, protein cleavage assays, DNA microarrays, heteroduplex analysis, denaturing gradient gel electrophoresis, nucleotide sequencing, single-stranded structural polymorphism, restriction enzyme digestion assays, fluorescence in situ hybridization (FISH), comparative genome hybridization, restriction fragment length polymorphism, amplification of refractory mutant systems PCR, nested PCR, multiplex ligation-dependent probe amplification, single-stranded structural polymorphism, and oligonucleotide ligation assays. Mutations can also be monitored through a variety of antibody-based methods using biological samples, including but not limited to Western blotting, fluorescence-activated cell sorting, immunofluorescence, immunohistochemistry, immunocytochemistry, immunoprecipitation, enzyme-linked immunoadsorption assays, radioimmunoassays, and electrochemiluminescence assays.

[0114] The term "cancer" is used herein in its ordinary biological sense and will be understood by those skilled in the art. Therefore, the term cancer includes cancer of any cell type, for example, but is not limited to, gliablastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, leukemia, 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, gastrointestinal cancer, Hodgkin lymphoma, hematological malignancies, hematological malignancies, Kaposi's sarcoma, kidney cancer, pharyngeal cancer. This may include 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, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, serous adenocarcinoma of the uterus, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, Wilms' tumor, solid tumor, or liquid tumor.

[0115] As used herein, the term “tumor” has its usual meaning as understood by those skilled in the art and refers to the abnormal growth of cells or 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 usual meaning as understood by those skilled in the art and refers to the abnormal mass of tissue that does not contain any fluid areas or cysts. Non-limiting examples of solid tumors include sarcomas, carcinomas, or lymphomas. Many cancerous tissues can form solid tumors, such as, but are 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, cervical cancer, sarcoma, neuroblastoma, or ovarian cancer. The terms “cancer” and “tumor” may generally be used interchangeably unless the context explicitly indicates that a more specific meaning is intended.

[0116] As used herein, the term “cell” has the ordinary meaning understood by those skilled 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.

[0117] Where used herein, the terms “individual,” “subject,” or “subject” have their ordinary meanings as understood by those skilled in the art, and therefore include humans and non-human mammals. The term “mammal” is used in its ordinary biological sense. Thus, this specifically includes monkeys (chimpanzees, apes, primates) and humans, cattle, and other animals. This includes, but is not limited to, primates, including sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, or swine. In some embodiments, the subject may be human. In some embodiments, the subject may be a child and / or infant. In other embodiments, the subject may be an adult.

[0118] As used herein, the term “cancer treatment” has the ordinary meaning understood by those skilled in the art and refers to a therapeutic modality (such as surgery and / or radiation) or an anticancer agent such as a small molecule, compound, protein, or other drug used to treat, inhibit, or prevent cancer. Non-limiting examples of a common class of anticancer agents available in one or more of the substitutes described herein include alkylating agents, anti-EGFR antibodies, anti-Her-2 antibodies, antimetabolites, vinca alkaloids, platinum-based drugs, anthracyclines, topoisomerase inhibitors, taxanes, antibiotics, immunomodulators, immune cell antibodies, interferons, interleukins, HSP90 inhibitors, antiandrogens, antiestrogens, antihypercalcemia 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. -ase 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, imidazotetradinone, 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 Examples include agents, chemotherapeutic agents, allerretinon, altretamine, aminopterin, aminolevulinic acid, amsacrin, asparaginase, atrasentan, bexarotene, carbocon, demecolsin, efapoxial, erusamitrusin, etogluside, hydroxycarbamide, leucovorin, ronidamine, rucanton, masopropyl, methyl aminolevulinate, mitogwazone, mitotane, oblimersen, omasetaxin, pegaspargase, porfimer sodium, prednimustine, citimazine seradenovec, talaporfin, temoporfin, trabectedin, or verteporfin. Examples of chemotherapy agents useful for cancer treatment include carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin, doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapines, 5-azacitidine, capecitabine, AraC-FdUMP

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

[0119] 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 a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (e.g., 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting compounds with bases 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), carbonates, bicarbonates, salts of organic bases (such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, etc.), and salts containing amino acids (such as arginine and lysine).

[0120] If the compounds disclosed herein have an unfilled valence, it should be understood that the valence is filled with hydrogen or its isotopes, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0121] It is understood that the compounds described herein may be isotope-labeled. Substitution with isotopes, such as deuterium, may result in certain therapeutic benefits arising from greater metabolic stability, such as increased in vivo half-life or reduced drug requirements. Each chemical element represented in a compound structure may contain any isotope of that element. For example, in a compound structure, the presence of a hydrogen atom in the compound may be explicitly disclosed or understood. At any position in a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references to compounds herein encompass all potential isotopic forms unless the context explicitly indicates otherwise.

[0122] The compounds described herein are understood to include crystalline forms (also known as polymorphs, which include different crystalline packing arrangements of the same elemental composition of the compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with a pharmaceutically acceptable solvent such as water or ethanol. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during a crystallization process using a pharmaceutically acceptable solvent such as water or ethanol. Hydrates are formed when the solvent is water, or alkoxides are formed when the solvent is alcohol. Furthermore, the compounds provided herein may exist in both unsolvated and solvated forms. Generally, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0123] If a range of values ​​is provided, it is understood that the upper and lower limits, as well as each intermediate value between the upper and lower limits of the range, are included within the embodiment.

[0124] The terms and phrases used in this application, and their variations thereof, should be interpreted as open-ended, not restrictive, unless otherwise expressly stated, particularly in the attached claims. As an example, the term “including” is not equivalent to “including, without limitation.” The terms "including but not limited to" or similar expressions should be read as meaning "including but not limited to." As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," and is comprehensive or open-ended and does not exclude additional undescribed elements or method steps. The term "having" should be interpreted as "having at least." The term "includes" should be interpreted as "includes but not limited to." The term "example" is used to provide illustrative examples of the items under consideration and is not an exhaustive or restrictive list thereof. Furthermore, the use of terms such as “preferably,” “preferred,” “desired,” or “desirable,” and similar words, should not be understood as implying that a particular feature is critically important, essential, or even important to the structure or function, but rather is simply intended to highlight alternative or additional features that may or may not be used in a particular embodiment. In addition, the term “includes” should be interpreted as synonymous with the phrases “have at least” or “include at least.” When used in the context of compounds, compositions, or devices, the term “includes” means that the compound, composition, or device includes at least the listed features or components, but may also include additional features or components.

[0125] With regard to the use of substantially any plural and / or singular terms herein, those skilled in the art can paraphrase from plural to singular and / or singular to plural as appropriate to the context and / or use. Various singular / plural substitutions may be explicitly stated herein for clarity. The indefinite articles “a” or “an” do not exclude the plural. The mere fact that certain measures are enumerated in mutually distinct dependent claims does not imply that combinations of these measures cannot be used advantageously. Any reference numerals in the claims should not be construed as limiting the scope.

[0126] As used herein, the terms “its equivalent” or “any of the aforementioned equivalents” refer to the above-mentioned effective doses of the compound, for example, azenocertib in other salt forms.

[0127] The terms “rest” or “rest day” refer to a period during which azenocertib or a pharmaceutically acceptable salt thereof is not administered, or a rest day, a day off from treatment, or a rest day. For example, rest refers to an intervening period during which azenocertib administration is temporarily suspended for a period following an administration cycle or during an administration week.

[0128] The term "platinum-resistant cancer" refers to cancer that initially responds to treatment with drugs containing metallic platinum (such as, but not limited to, carboplatin, cisplatin, and oxaliplatin), but then relapses within a certain period. For example, ovarian cancer that recurs within six months of treatment is considered platinum-resistant. The term "platinum-resistant cancer" also refers to cancer that is resistant at the start of treatment with platinum-containing drugs and does not respond to platinum-containing drugs during treatment with platinum-containing drugs.

[0129] The term "PARP inhibitor-resistant cancer" refers to cancer that initially responds to treatment with at least one PARP inhibitor (such as, but not limited to, olaparib, niraparib, and AZD5305) but then recurs within a certain period of time. For example, ovarian cancer and / or triple-negative breast cancer that recurs within six months of treatment is considered PARP inhibitor-resistant. It is considered resistant. The term "PARP inhibitor-resistant cancer" also refers to cancer that is resistant at the start of treatment with at least one PARP inhibitor and does not respond to PARP inhibitors during treatment with PARP inhibitors.

[0130] As used herein, “pathogenic variant” refers to a mutation that increases the risk of developing a particular type of cancer. For example, “BRCA pathogenic variant” refers to a BRCA1 or BRCA2 variant that increases the risk of developing cancer, for example, germline pathogenic variants in BRCA1 / BRCA2 are associated with ovarian cancer, fallopian tube cancer, primary peritoneal cancer, male breast cancer, prostate cancer, pancreatic cancer, and early-onset breast cancer. BRCA1 / 2 pathogenic variants are associated with a 45%–85% higher risk of developing breast cancer and / or a 10%–46% higher risk of developing ovarian cancer. Several BRCA1 / 2 pathogenic variants known in the art are disclosed in BRCA Exchange (https: / / www.brcaexchange.org / variants?search=pathogenic), which are incorporated herein by reference in their entirety.

[0131] Various aspects are described in detail in the following sections. The use of these sections is not intended to limit the disclosure. Each section may apply to any aspect of the disclosure. In this application, unless otherwise stated, the use of “or” means “and / or”. Detailed explanation

[0132] This disclosure provides, in particular, HRD or HRD status as a predictive biomarker for therapeutic methods of treating cancer by administering a WEE1 inhibitor or a pharmaceutically acceptable salt thereof (e.g., azenocertib, also known as ZN-c3, or a pharmaceutically acceptable salt thereof) to HRD-positive subjects, and the HRD-positive (HRD+) status can be used as a predictive biomarker for treating such cancer. This disclosure provides, in particular, a method of treating chemotherapy-resistant cancer (e.g., platinum-resistant cancer, PARP inhibitor-resistant cancer) by administering a WEE1 inhibitor or a pharmaceutically acceptable salt thereof to HRD-positive (HRD+) subjects. In some embodiments, the WEE1 inhibitor or a pharmaceutically acceptable salt thereof (e.g., azenocertib, or a pharmaceutically acceptable salt thereof) is administered in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof (e.g., olaparib, niraparib, salparib, or any of the aforementioned pharmaceutically acceptable salts).

[0133] In some embodiments, a method for treating cancer is provided herein, comprising determining, or having determined, whether a subject has homologous repair deficiency (HRD), and, if the subject is HRD+, administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof, wherein the administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of cancer in the subject.

[0134] In some embodiments, a method for treating PARP inhibitor-resistant breast cancer is provided herein, comprising determining, or having determined, whether a subject requiring treatment has homologous recombination repair deficiency (HRD), and, if the subject is HRD+, administering azenocertib or a pharmaceutically acceptable salt thereof in an effective dose, wherein the administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of the PARP inhibitor-resistant breast cancer in the subject. In some embodiments, the PARP inhibitor-resistant breast cancer is niraparib-resistant. In some embodiments, the PARP inhibitor-resistant breast cancer is olaparib-resistant.

[0135] In some embodiments, a method for treating chemotherapy-resistant ovarian cancer, wherein treatment is necessary for A method is provided herein that comprises determining whether an elephant has homologous recombination repair deficiency (HRD), and if the subject is HRD+, administering azenocertib or a pharmaceutically acceptable salt thereof in an effective dose, wherein the administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of chemotherapy-resistant ovarian cancer in the subject.

[0136] In some embodiments, chemotherapy-resistant ovarian cancer is platinum-resistant.

[0137] In some embodiments, chemotherapy-resistant ovarian cancer is further resistant to PARP inhibitors or pharmaceutically acceptable salts thereof.

[0138] This disclosure provides, in particular, a method for treating cancer in subjects selected to have homologous recombination repair deficiency (HRD).

[0139] This disclosure further provides a method for treating cancer, comprising administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to subjects selected to have homologous recombination repair deficiency (HRD). [ka]

[0140] The compound azenocertib and its pharmaceutically acceptable salts are WEE1 inhibitors. The chemical structure of compound azenocertib is shown above. Compound azenocertib and its pharmaceutically acceptable salts can be prepared in various ways. See, for example, WO2019 / 173082. WO2019 / 173082 and WO2021 / 231653 describe compound azenocertib and methods of using it to treat cancer. These terms may be used interchangeably herein.

[0141] WEE1 is a tyrosine kinase that is a key component of ATR-mediated G2 cell cycle checkpoint regulation, which prevents entry into mitosis in response to cellular DNA damage. WEE1 activation leads to selective phosphorylation of CDK2, thereby modulating the CDK2-cyclin A / E complex that controls G1 / S phase progression. Inhibition of WEE1 can lead to excessive replication activity, thereby potentially causing replication breakdown. WEE1 inhibition may sensitize tumors and induce tumor cell death.

[0142] In one embodiment, a method for treating cancer is provided herein, comprising administering an effective dose of a WEE1 inhibitor to subjects selected to have homologous recombination repair deficiency (HRD). Examples of additional WEE1 inhibitors for use in the method described herein include the following publications: WO 2019 / 074979, WO 2020 / 210383, WO 2020 / 210375, WO 2020 / 210377, WO 2020 / 210380, WO 2020 / 210381, WO 2022 / 082174, US 2022 / 0162229, US 2022 / 0168313, US 2022 / 0169646, US 2022 / 0220115, US 11,332,473, WO 2019 / 173082, WO 2019 / 011228, WO 2019 / 138227 , WO 2018 / 162932, WO 2018 / 011570, WO 2018 / 011569, US 2022 / 0194947, WO 2018 / 090939, WO 2019 / 011228, US 2019 / 0308984, US 2020 / 0131192, WO 2021 / 073491, WO 2022 / 188802, US 11,345,710, US 11,345,711, WO 2015 / 092431, WO 2015 / 019037, WO 2014 / 167347, WO 2007 / 126122, WO 2011 / 034743, US 2007 / 0254892, WO 2008 / 133866, US 2016 / 0060258, WO 2019 / 085933, WO 2020 / 221358, EP 3712150, WO 2018 / 133829, WO 2021 / 047627, US 2021 / 0403451, WO 2020 / 083404, US 2022 / 0324848, WO 2019 / 037678, WO 2018 / 171633, CN 113387962, WO 2019 / 165204, WO 2012 / 161812, WO 2013 / 012681, WO 2013 / 013031, WO 2013 / 059485, WO 2013 / 126656, US 2012 / 0220572, US 2013 / 0018045, KR 2016035878, KR 2020016567, WO 2018 / 056621, WO 2017 / 075629, WO 2019 / 169065, WO 2019 / 134539, WO 2020 / 028814, US 2021 / 0309630, WO 2020 / 069105, WO 2020 / 192581, US 2022 / 0194960, CN 114831993, CN 115073466, CN 111718348, WO 96 / 34867, WO 2008 / 153207, WO 2010 / 067888, WO 2009 / 054332, WO 2021 / 074251, CN 112142763, WO 2020 / 259724, US 2022 / 0259210, WO 2019 / 096322, CN 112142747, CN 112142748, US 2022 / 0324868, WO 2021 / 043152, WO2021 / 254389, WO 2022 / 171088, WO 2022 / 171126, WO 2022 / 171128, WO 2022 / 174765, WO 2022 / 174796, CN 112442049, CN 114072411, CN 113402520, CN113387962, KR 2022081171, WO 2022 / 124748, WO 2022 / 155202, CN 114591334, CN 113402250, WO Examples include those described in 2021 / 074251 and CN 115197221, each of which is incorporated herein by reference in its entirety.

[0143] In some embodiments, the WEE1 inhibitor is selected from AZD1775, SC0191, PD0166285, NUV-569, STC-8123, IMP7068, Debio 0123, SY-4835, SPH-6162, APR-1051 (formerly ATRN-W1051), SGR-3515, and ACR-2316, or any combination thereof (including any pharmaceutically acceptable salts mentioned above).

[0144] In other embodiments, the WEE1 inhibitor is the molecule shown below, or a pharmaceutically acceptable salt or N-oxide thereof. [ka]

[0145] In some embodiments, the WEE1 inhibitor is the following compound: [ka] Alternatively, one of the pharmaceutically acceptable salts mentioned above is selected.

[0146] In some embodiments, the WEE1 inhibitor is the following compound: [ka] Alternatively, one of the pharmaceutically acceptable salts mentioned above is selected.

[0147] In some embodiments, the WEE1 inhibitor is the following compound: [ka] or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the WEE1 inhibitor is the following compound: [ka] Alternatively, one of the pharmaceutically acceptable salts mentioned above is selected. Homologous recombination deficiency (HRD)

[0149] Homologous recombination (HR) is a conserved DNA repair process that enables the exchange of genetic information between identical or closely related DNA molecules. HR regulates high-fidelity repair of double-strand breaks (DSBs) and functions primarily during the late S and G2 phases of the cell cycle, utilizing intact sister chromatids as templates for error-free repair. It is most widely used by cells to accurately repair toxic breaks (i.e., DNA damage) that occur on both strands of DNA (e.g., double-strand breaks (DSBs)). DNA damage can originate from extrinsic (external) sources such as UV light, radiation, or chemical damage, or from endogenous (internal) sources such as errors in DNA replication or other cellular processes that produce DNA damage. The most common lesion of cellular DNA is single-strand breaks (SSBs), occurring at a rate of tens of thousands per cell per day. It occurs. DNA damage resulting in double-strand breaks (DSBs) is typically repaired by the HR process.

[0150] Deficiencies in homologous recombination can lead to the use of other DNA repair pathways, such as non-homologous end joining (NHEJ). However, NHEJ is more prone to errors compared to homologous recombination in DNA repair, resulting in a higher number of mutations and, consequently, an increased risk of chromosomal instability and tumor transformation.

[0151] Homologous recombination deficiency ("HR deficiency" or "HRD," or homologous recombination repair deficiency) is a condition that occurs in tumors through the loss of the homologous recombination DNA repair pathway. HRD is a phenotype characterized by the inability of cells to effectively repair DNA double-strand breaks using the HRR pathway. As will be explained in more detail below, the terms "HRD" and "HRP" refer to the presence or absence of the HRD phenotype. Cancer may be characterized as homologous recombination deficiency (also called homologous repair deficiency, HR deficiency, HRD, or HRD-positive (HRD+)). Alternatively, cancer may be characterized as homologous recombination proficient (also called homologous repair proficient, or HRP or HRD-negative (HRD-)).

[0152] HRD has various synonyms in the art, and such terms, in particular, include HRD-positive (HRD+) (meaning that the cancer is characterized as HRD), and are terms that may be used interchangeably herein. Similarly, terms such as non-HRD and HRP, in particular, include HRD-negative (HRD-) (meaning that the cancer is not characterized as HRD). The use of the terms HRD, non-HRD, and HRP herein should be interpreted accordingly.

[0153] If cancer cells have HRD (e.g., deficient HR), the likelihood of the cells recovering from DSB decreases, and instead of the cells continuing to proliferate, they are led to apoptosis (programmed cell death).

[0154] In some embodiments, HRD may arise through alterations in genes selected from BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. In some cases, HRD may arise through biallelic inactivation of BRCA1 and / or BRCA2. In some embodiments, HRD may arise through alterations in RAD51C. In some embodiments, HRD may arise through alterations in ATM. In some embodiments, HRD may arise through alterations in BARD1. In some embodiments, HRD may arise through alterations in BRIP1. In some embodiments, HRD may arise through alterations in CDK12. In some embodiments, HRD may arise through alterations in CHEK1. In some embodiments, HRD may arise through alterations in CHEK2. In some embodiments, HRD may arise through alterations in FANCL. In some embodiments, HRD may arise through alterations in PALB2. In some embodiments, HRD may occur via a change in RAD51B. In some embodiments, HRD may occur via a change in RAD51C. In some embodiments, HRD may occur via a change in RAD51D. In some embodiments, HRD may occur via a change in RAD54L.

[0155] In some embodiments, the gene change includes a change in gene expression. In some embodiments, the gene change includes a change in gene sequence.

[0156] HRD is a specific, characteristic megabase-scale accumulation that occurs over time in the absence of HR repair. HRD can be detected in DNA sequencing data by counting changes in copy number. HRD can also occur as a result of numerous genetic lesions. Medical history and selection of subjects

[0157] As described herein, subjects may be selected based on changes in genes selected from BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

[0158] In some embodiments, the gene is BRCA1. In some embodiments, the gene is BRCA2. In some embodiments, the BRCA1 mutation is a BRCA1 pathogenic mutation. In some embodiments, the BRCA1 pathogenic mutation is BRCA1 Glu1607Ter In some embodiments, HRD is a BRCA1 revertant mutation. In some embodiments, HRD is a BRCA1 splice variant. In some embodiments, the BRCA1 splice variant is a BRCA1-Δ11q mutant.

[0159] In some embodiments, the gene is RAD51C. In some embodiments, the gene is ATM. In some embodiments, the gene is BARD1. In some embodiments, the gene is BRIP1. In some embodiments, the gene is CDK12. In some embodiments, the gene is CHEK1. In some embodiments, the gene is CHEK2. In some embodiments, the gene is FANCL. In some embodiments, the gene is PALB2. In some embodiments, the gene is RAD51B. In some embodiments, the gene is RAD51C. In some embodiments, the gene is RAD51D. In some embodiments, the gene is RAD54L.

[0160] In some embodiments, the subjects have BRCA1 / 2 mutation (germline or somatic)-associated epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0161] HRD status can result from point mutations or other genetic changes such as copy number variations, somatic copy number changes (SCNA), aneuploidy, loss of heterozygosity (LOH), large-scale state transitions (LST), and / or telomere allele imbalance (TAI).

[0162] In some embodiments, the subject has HRD due to copy number variation, somatic copy number change (SCNA), aneuploidy, loss of heterozygosity (LOH), large-scale state transition (LST), and / or telomere allele imbalance (TAI).

[0163] In some embodiments, the subject has HRD due to copy number variation. In some embodiments, the subject has HRD due to somatic cell copy number change (SCNA). In some embodiments, the subject has HRD due to aneuploidy. In some embodiments, the subject has HRD due to loss of heterozygosity (LOH). In some embodiments, the subject has HRD due to large-scale state transition (LST). In some embodiments, the subject has HRD due to telomere allele imbalance (TAI).

[0164] In some embodiments, the method further includes first determining the HRD or HRRm biomarker status before the selection step.

[0165] In some embodiments, the subject is receiving one or more prior lines of treatment. In some embodiments, the subject is receiving two prior lines of treatment. In some embodiments, the subject is receiving three prior lines of treatment. In some embodiments, the subject is receiving three or more prior lines of treatment. In some embodiments, the subject is receiving treatment as monotherapy or W The patient has received one or more previous treatment lines, including at least one PARP inhibitor, whether as combination therapy with a chemotherapy agent other than an EE1 inhibitor (such as azenocertib).

[0166] In some embodiments, the subjects have recurrent or refractory cancer. In some embodiments, the subjects are platinum-resistant. In some embodiments, the subjects are platinum-refractory. How to determine HRD status

[0167] The selection of subjects or the characterization of cancer types may be based on HRD biomarker status using various methods known in the art. In some embodiments, HRD is characterized by harmful or suspected harmful BRCA mutations and / or genomic instability. In some embodiments, HRD is characterized by harmful or suspected harmful BRCA mutations. In some embodiments, HRD is characterized by genomic instability.

[0168] In some embodiments, HRD status is assessed by BRCA1 / 2 mutation status and / or specific patterns of genomic instability. These patterns are measured by evaluating a combination of one or more genome-wide measures, and an HRD-associated genomic instability score (e.g., gLOH+TAI+LST) is derived. In some embodiments, HRD status is defined by BRCA1 / 2 mutation status and / or genomic instability measured by gLOH.

[0169] In some embodiments, the HRD status is an absolute value or a standard. In some embodiments, the HRD status is determined based on whether the subject has a genetic alteration in one or more genes within the HR pathway.

[0170] In some embodiments, the HRD status is determined using information derived from RNA sequencing and DNA sequencing of cancer tissue. In some embodiments, DNA sequencing data from matched cancer tissue and germline tissue are used together to determine the HRD status. In some embodiments, the HRD status is determined based on predictions using RNA or DNA sequencing information.

[0171] In some embodiments, the HRD status is determined using mRNA transcription data generated from cancer tissue or a subject. In some embodiments, the HRD status is determined using genome-wide loss of heterozygosity (gLOH), which is determined from DNA sequencing data generated from cancer tissue. In some embodiments, the HRD status is determined using DNA sequencing from a matched non-cancerous tissue.

[0172] In some embodiments, the HRD state is determined using both RNA and DNA sequencing data.

[0173] In some embodiments, HRD-negative status is classified as a genetic profile that has no single nucleotide variants, no short insertions or deletions, and / or has a diploid copy number in the BRCA1 and BRCA2 genes.

[0174] In some embodiments, an HRD-positive state is classified as containing a nucleotide variant, insertion, or deletion in a gene selected from BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

[0175] In some embodiments, an HRD-positive state is classified as including one or more features of RNA and / or DNA sequencing data (e.g., mRNA expression levels for multiple genes, a measure of loss of genomic heterozygosity, a measure of genomic and / or transcriptome rearrangement (e.g., one or more of insertions, deletions, gene fusions, inversions, etc.), a measure of genomic methylation, etc.).

[0176] In some embodiments, HRD variant testing is based on known pathogenicity variants in the germline sequences of one or more HR-related genes (e.g., BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and / or RAD54L). H3m mutation

[0177] The methods provided herein include selecting subjects based on their HRRm status. In some embodiments, subjects are selected for treatment with a WEE1 inhibitor (e.g., azenocertib or a pharmaceutically acceptable salt thereof) based on mutations in one or more of the following genes used to determine the HRRm status: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and / or RAD54L.

[0178] In some embodiments, testing for HRRm status is based on the presence of known pathogenic variants in the germline sequences of one or more HR-related genes (e.g., BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and / or RAD54L).

[0179] In some embodiments, HRD is caused by a modification of a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. In some embodiments, the gene modification includes changes related to function, activity, or expression. In some embodiments, the gene modification includes pathogenic or harmful changes.

[0180] HRRm status can be determined by assays such as FoundationOne® CDx, Myriad (MyChoice® CDx), Tempus xT HRD, Caris Molecular, etc. Intelligent Comprehensive Tumor Profiling, or any other CLIA-accredited (or local equivalent) laboratory may also be used. Adverse mutations in at least one of the genes involved in HRR were identified from previous CLIA-accredited (or country-specific equivalent) genomic profiling. HRD diagnostic methods

[0181] In some embodiments, the HRD status is determined by a diagnostic assay. In some embodiments, the HRD status is determined using a genotyping assay. In some embodiments, the HRD status is determined using a phenotypic assay. The HRD status can be determined using any method known in the art. For example, an exemplary method is described in Stewart MD et al., Oncologist. 2022 Mar 11;27(3):167-174. (PMID:35274707, PMCID:PMC89144) This is described in 93), which is incorporated herein by reference in its entirety.

[0182] In some embodiments, the diagnostic test is a molecular (sequence)-based indicative of the HRD status of cancer. This is a vitro diagnostic test. In some embodiments, the clinical-grade HRD assay detects "genomic scarring," which can be used as a measure of HRD. The HRD genomic scarring assay assesses the proportion of genomic regions with LOH determined via tumor single nucleotide polymorphism (SNP) sequencing (FoundationOne CDx, Foundation Medicine) or via a genomic instability score (GIS) calculated by combining three factors obtained from allele-specific copy number profiles of SNP-LOH: telomere allele mismatch (TAI) and large-scale metastasis (LST) (myChoice CDx, Myriad Genetics, HRDsig, Foundation Medicine).

[0183] In some embodiments, the HRD diagnostic assay is a companion diagnostic used in treatment with PARP inhibitors. For example, in some embodiments, the diagnostic test is a molecular (sequence)-based in vitro diagnostic test for HRD status in cancer ("MyChoice"), available from Myriad Genetics, Inc. This test is approved by the FDA (U.S.) as a companion diagnostic for the use of the PARP inhibitor niraparib.

[0184] In some embodiments, HRD is defined by tumor BRCA mutations or a composite genomic instability score of 42 or higher (cancer is characterized as HRD if its test score (HRD score) is 42 or higher, otherwise as non-HRD (HRP)).

[0185] In some embodiments, the HRD score is determined by the BRCA1 / 2 mutation status. In some embodiments, the BRCA1 / 2 mutation is indicated as homologous recombination deficiency (HRD) positive. In some embodiments, the diagnostic method is the MyChoice diagnostic test from Myriad Genetics, Inc. In some embodiments, the HRD status is based on a predetermined threshold. In some embodiments, the threshold is a 42-test score (HRD score) for characterizing (or classifying) cancer as HRD or HRP (non-HRD).

[0186] In some embodiments, the diagnostic method includes an LOH% score that measures the percentage of genomic LOH as a marker of HRD positivity, where LOH ≥ 16% is indicated as high LOH%. In some embodiments, the diagnostic method is FoundationOne CDx (Foundation Medicine). In some embodiments, FoundationOne CDx (Foundation Medicine) includes an LOH% score that measures the percentage of genomic LOH as a marker of HRD positivity, where LOH ≥ 16% is indicated as high LOH%. HRD score

[0187] HRD positivity can be classified using an HRD score. The HRD score can be determined by considering one or more features of RNA and / or DNA sequencing data (e.g., mRNA expression levels for multiple genes, a measure of loss of genomic heterozygosity, a measure of genomic and / or transcriptome rearrangement (e.g., one or more of insertions, deletions, gene fusions, inversions, etc.), a measure of genomic methylation, etc.). An exemplary method for determining the HRD score is described, for example, in Lotan, TL, et.al. Mod Pathol 34, 1185-1193 (2021), which is incorporated herein by reference in its entirety.

[0188] In some embodiments, the HRD score may be determined using one or more features associated with homologous recombination deficiency. In some embodiments, such features include one or more of the following: cancer-associated mutation score, telomere allele mismatch score, cancer-associated large state transition (LST) score, loss of heterozygosity (LOH) score, proportion of heterozygous genome (fLOH), and homologous recombination deficiency score (the sum of one or more of the telomere allele mismatch (NtAI) score, large state transition (LST) score, proportion of heterozygous genome (fLOH), and / or loss of heterozygosity (LOH) score). In some embodiments, the homologous recombination deficiency (HRD) score is the sum of NtAI, LST, and LOH.

[0189] The telomere allele mismatch (NtAI) score relates to the number of subtelomeric regions with allele mismatches that begin beyond the centromere and extend to the telomere. The largest state transition (LST) score generally relates to the number of large chromosomal breaks between adjacent regions of at least about 10 megabases (Mb), although specific threshold sizes may increase or decrease. The loss of heterozygosity score (HRD-LOH) relates to the number of regions with loss of heterozygosity, generally greater than 15 Mb (specific threshold sizes may increase or decrease), but shorter than the entire chromosome. In some embodiments, features may include one or more of the NtAI, LST, LOH, or HRD scores (the sum of one or more of NtAI, LST, and LOH).

[0190] In some embodiments, one or more features include LST. In some embodiments, one or more features do not include NtAI. In some embodiments, one or more features do not include LOH. In some embodiments, one or more features do not include NtAI and LOH. In some embodiments, the HRD score, NtAI score, LST score, and / or LOH score are determined by microarray or by sequencing of cancer-derived nucleic acids (e.g., whole exome sequencing or whole genome sequencing). In some embodiments, the percentage of genome with loss of heterogeneity (fLOH) may be used as a feature. Additional biomarkers

[0191] In some embodiments, subjects have already been identified as having one or more additional biomarkers. In some embodiments, additional biomarkers are included in the selection criteria. In some embodiments, additional biomarkers are not included in the selection criteria. In other embodiments, subjects are selected by determining the levels of other cancer biomarkers.

[0192] In some embodiments, subjects are selected based on the CCNE1 gene amplification state, cyclin E1 overexpression level (or cyclin E1 state), and HRD state.

[0193] In some embodiments, subjects are selected based on cyclin E levels. In some embodiments, cyclin E is cyclin E1. In some embodiments, CCNE1 levels are measured by gene expression levels. In some embodiments, CCNE1 levels are compared to normal tissue to determine whether the expression level is an overexpression level. In some embodiments, CCNE1 levels are measured by gene overexpression levels.

[0194] In some embodiments, the gene biomarker overexpression level is determined by detecting the amount of gene mRNA or protein. In some embodiments, cyclin E1 overexpression is determined by mRNA levels. In some embodiments, cyclin E1 overexpression is determined by protein levels. In some embodiments, the cyclin E1 overexpression level is determined by the cyclin E1 H-score.

[0195] Cyclin E1 mRNA or protein can be measured by any method known in the art, including but not limited to immunohistochemistry (IHC) tests, reporter genes, Northern blotting, Western blotting, fluorescence in situ hybridization (FISH), reverse transcription PCR, or RNA-Seq-based assays.

[0196] In some embodiments, cyclin E1 overexpression is determined using RNA detection of cyclin E. In some embodiments, cyclin E1 overexpression is determined using RNA sequencing.

[0197] In some embodiments, cyclin E1 overexpression is measured by quantitative readout. In some embodiments, cyclin E1 overexpression is measured by qualitative readout.

[0198] In some embodiments, cyclin E1 overexpression is measured by signal intensity. In some embodiments, signal intensity is determined using Western blotting. In some embodiments, relative signal intensity is quantified.

[0199] In some embodiments, subjects are selected to have a TP53 biomarker level below a predetermined threshold. In some embodiments, subjects are selected to have a TP53 biomarker level above a predetermined threshold.

[0200] In some embodiments, subjects are selected to have CA125 biomarker levels below a predetermined threshold. In some embodiments, subjects are selected to have CA125 biomarker levels above a predetermined threshold. Treatment method

[0201] This disclosure provides a method for treating cancer using a compound known as azenocertib or a pharmaceutically acceptable salt thereof, wherein subjects are selected to have an HRD-positive condition (e.g., genetic modification in one or more HRRm genes), and azenocertib (and its pharmaceutically acceptable salt) is a WEE1 inhibitor of the following formula: [ka]

[0202] WO 2019 / 173082 and WO 2021 / 231653 describe the compound azenocertib, both of which are incorporated herein by reference in their entirety.

[0203] In several embodiments, the methods described herein produce a therapeutic effect (e.g., a desired pharmacological and / or physiological effect). The therapeutic effect may include partially or completely curing a disease, alleviating one or more adverse symptoms caused by the disease, and / or delaying the progression of the disease. For this purpose, the method involves administering an effective dose of a therapeutic agent (e.g., azenocertib or a pharmaceutically acceptable salt thereof, and / or a second chemotherapeutic agent (including any of the aforementioned pharmaceutically acceptable salts)). The effective dose may be the amount and duration of administration necessary to achieve the desired therapeutic outcome (e.g., tumor growth inhibition, progression-free survival, complete response, partial response, etc.). The effective dose may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the binder to induce the desired response in the individual.

[0204] In some embodiments, the therapeutic response may be determined according to the Response Evaluation Criteria for Solid Tumors (RECIST) criteria.

[0205] In some embodiments, the treatment results in a response rate of 50% or higher. In some embodiments, the response rate is measured by complete response (CR), partial response (PR), CA-125 50% response, or a combination thereof.

[0206] In some embodiments, the treatment results in a progression-free survival (PFS) of 6 months or more.

[0207] In some embodiments, cancer inhibition is measured by inhibition of tumor growth. In some embodiments, inhibition of tumor growth is measured by reduction of tumor volume. Route of administration

[0208] In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously. In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is administered orally. Alternatively, suitable techniques known to those skilled in the art for administering an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof may be used, including, but not limited to, oral, rectal, pulmonary topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intrathecal, intramedullary, subarachnoid, direct intraventricular, intraperitoneal, intranasal, and intraocular injections. In other embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof, and / or chemotherapeutic agents (including pharmaceutically acceptable salts thereof) may be administered orally.

[0209] In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is administered orally, intravenously, subcutaneously, intraarachnoidally, intramuscularly, intracavitally, intrapleurally, intrafocally, or intraarterially. In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously. In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is administered intraarachnoidally, intramuscularly, intracavitally, intrapleurally, intrafocally, or intraarterially.

[0210] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered orally. Azenocertib Dosage and Schedule

[0211] In some embodiments, the methods described herein include intermittent administration, i.e., one or more administration cycles including an intervening rest week, comprising consecutive administration days followed by rest days. In some embodiments, the methods described herein include continuous administration. In some embodiments, the methods described herein include combination therapy, comprising consecutive administration of one of the drugs. In some embodiments, the methods described herein include combination therapy comprising consecutive administration of one of the drugs and intermittent administration of azenocertib or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is administered based on the subject's body weight. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 2 mg / kg to about 20 mg / kg. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 2 to about 18 The concentrations are approximately mg / kg, 2-16 mg / kg, 2-14 mg / kg, 2-12 mg / kg, 2-10 mg / kg, 2-8 mg / kg, 2-6 mg / kg, 3-4 mg / kg, 3-5 mg / kg, or 4-6 mg / kg. In some applications, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is at least about 2 mg / kg, at least about 3 mg / kg, at least about 4 mg / kg, at least about 5 mg / kg, at least about 6 mg / kg, at least about 7 mg / kg, at least about 8 mg / kg, at least about 9 mg / kg, at least about 10 mg / kg, at least about 11 mg / kg, at least about 12 mg / kg, at least about 13 mg / kg, at least about 14 mg / kg, at least about 15 mg / kg, at least about 16 mg / kg, at least about 17 mg / kg, at least about 18 mg / kg, or at least about 19 mg / kg.

[0213] In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof may also be in the form of an equivalent dose (e.g., another salt form of the compound). In some embodiments, the effective dose is a fixed dose. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is in the range of about 200 to about 800 mg / day, or an equivalent, once daily. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is in the range of about 200 to about 600 mg / day, or an equivalent, once daily. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is in the range of about 300 to about 600 mg / day, or an equivalent, once daily. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is in the range of about 400 to about 600 mg / day, or an equivalent, once daily. In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is in the range of about 400 to about 800 mg / day once daily, or an equivalent thereof. In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is in the range of about 50 to about 350 mg / day, about 50 to about 290 mg / day, about 100 to about 290 mg / day, about 100 to about 250 mg / day, about 150 to about 250 mg / day, or about 180 to about 220 mg / day once daily, or an equivalent thereof. In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is in the range of about 50 to about 400 mg / day, about 100 to about 400 mg / day, about 150 to about 400 mg / day, about 200 to about 400 mg / day, about 200 to about 375 mg / day, about 200 to about 350 mg / day, about 200 to about 300 mg / day, about 200 to about 400 mg / day, or about 400 to about 600 mg / day, or equivalents thereof, once daily.

[0214] In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 50 mg / day, approximately 100 mg / day, approximately 150 mg / day, approximately 200 mg / day, approximately 250 mg / day, approximately 300 mg / day, approximately 325 mg / day, approximately 350 mg / day, approximately 375 mg / day, approximately 400 mg / day, approximately 450 mg / day, approximately 500 mg / day, approximately 550 mg / day, or approximately 600 mg / day, or equivalents thereof, once daily.

[0215] In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 200 mg / day or an equivalent once daily. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 300 mg / day or an equivalent once daily. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 400 mg / day or an equivalent once daily. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 500 mg / day or an equivalent once daily. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 600 mg / day or an equivalent once daily. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 700 mg / day or an equivalent once daily. In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered once daily, approximately 800 ml. g / day, or its equivalent.

[0216] In some embodiments, an effective amount of asenoceltib or a pharmaceutically acceptable salt thereof is about 375 mg / day, about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day, about 500 mg / day, about 550 mg / day, about 600 mg / day, about 625 mg / day, about 650 mg / day, about 675 mg / day, about 700 mg / day, about 725 mg / day, about 750 mg / day, about 775 mg / day, or about 800 mg / day or more, or equivalents thereof. In some embodiments, the present disclosure provides for the administration of a high dose of asenoceltib or a pharmaceutically acceptable salt thereof, for example, the dose is about 375 mg / day or more.

[0217] In some embodiments, an effective amount of asenoceltib or a pharmaceutically acceptable salt thereof is at least about 250 mg / day. In some embodiments, an effective amount of asenoceltib or a pharmaceutically acceptable salt thereof is about 300 mg / day. In some embodiments, the dose of asenoceltib or a pharmaceutically acceptable salt thereof is about 350 mg / day. In some embodiments, the dose of asenoceltib or a pharmaceutically acceptable salt thereof is about 400 mg / day.

[0218] In some embodiments, an effective amount of asenoceltib or a pharmaceutically acceptable salt thereof is about 250 to about 450 mg / day. In some embodiments, an effective amount of asenoceltib or a pharmaceutically acceptable salt thereof is at least about 300 mg / day. In some embodiments, an effective amount of asenoceltib or a pharmaceutically acceptable salt thereof is about 300 mg. In some embodiments, an effective amount of asenoceltib or a pharmaceutically acceptable salt thereof is about 400 mg / day.

[0219] In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 60 to about 120 mg / kg. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 60 mg / kg. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 80 mg / kg. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 100 mg / kg. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 120 mg / kg.

[0220] In some embodiments, the cancer is ovarian cancer, and the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 60 mg / kg in one or more cycles of 5:2 (5 days on: 2 days rest). In some embodiments, the cancer is ovarian cancer, and the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 80 mg / kg in one or more cycles of 5:2 (5 days on: 2 days rest). In some embodiments, the cancer is ovarian cancer, the HRD is a BRCA1 mutation, and the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is at least approximately 60 mg / kg. In some embodiments, the cancer is ovarian cancer, the HRD is a BRCA1 mutation, and the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is at least approximately 80 mg / kg.

[0221] In some embodiments, the cancer is prostate cancer, and the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 60 mg / kg in one or more cycles of 5:2 (5 days on: 2 days rest). In some embodiments, the cancer is prostate cancer, and the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 80 mg / kg in one or more cycles of 5:2 (5 days on: 2 days rest). In some embodiments, the cancer is prostate cancer, the HRD is a BRCA1 mutation, and the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is at least approximately 60 mg / kg. In some embodiments, the cancer is prostate cancer, the HRD is a BRCA1 mutation, and the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof The acceptable salt is at least about 80 mg / kg. Treatment cycle

[0222] The methods of the present disclosure include administering asenoceltib or a pharmaceutically acceptable salt thereof according to a suitable dosing schedule. In some embodiments, the effective dose is administered once daily. In some embodiments, the effective dose is administered twice daily. In some embodiments, the effective dose is administered three times daily. In some embodiments, the effective dose is administered on a continuous dosing schedule. In some embodiments, the effective dose is administered on an intermittent dosing schedule. In some embodiments, the intermittent dosing cycle includes 5 days of dosing days (e.g., 5 consecutive days of dosing days) and 2 days of dosing rest days.

[0223] In some embodiments, asenoceltib or a pharmaceutically acceptable salt thereof is administered in combination with a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof according to a suitable dosing schedule. For example, asenoceltib or a pharmaceutically acceptable salt thereof as described herein, and / or a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof, may be administered one or more times per day (e.g., once, twice, or three times per day) for a specific number of days, followed by a period of non-administration days. Then, this treatment cycle (including dosing days and not including dosing rest days) may be repeated.

[0224] In some embodiments, the treatment cycle is a period of 3 to 28 days. In some embodiments, the treatment cycle is 5, 7, 10, or 14 days. In some embodiments, the treatment cycle is 21 or 28 days. In some embodiments, the treatment cycle is repeated.

[0225] In some embodiments, the present invention provides a method for treating cancer, comprising administering to a subject in need of treatment an effective dose of approximately 350 mg or more of azenocertib or a pharmaceutically acceptable salt thereof or an equivalent thereof, in accordance with intermittent administration cycles, wherein the intermittent administration cycle comprises at least one administration week, and each administration week comprises at least three consecutive administration days and at least one administration rest day.

[0226] In some embodiments, the Disclosure provides administering high doses of azenocertive or a pharmaceutically acceptable salt thereof, for example, about 350 mg to about 800 mg once daily, or about 175 mg to about 400 mg twice daily in an intermittent dosing regimen, for example, 5 days of administration ("on" days) followed by 2 days of rest ("off" days) (i.e., 5 / 2), 4 days of administration followed by 3 days of rest (i.e., 4 / 3), or 3 days of administration followed by 4 days of rest (i.e., 3 / 4), or 6 days of administration followed by 1 day of rest (i.e., 6 / 1). Alternatively, intermittent dosing regimens of azenocertib or a pharmaceutically acceptable salt thereof are also expressed, among other things, as administering approximately 350 mg to approximately 800 mg once daily, or approximately 175 mg to approximately 400 mg twice daily, at intermittent frequencies, e.g., 5 on / 2 off, 4 on / 2 off, 3 on / 4 off. In some embodiments, the intermittent dosing cycle includes 5 consecutive dosing days and 2 dosing rest days.

[0227] In some embodiments, administration weeks of one week or more are separated by at least one week of rest. In some embodiments, the intermittent dosing regimens described herein (e.g., 7 / 0, 6 / 1, 5 / 2, 4 / 3, or 3 / 4) are implemented with two weeks followed by one week of rest, or one week followed by one week of 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, 5 / 2, 6 / 1, 4 / 3, or 3 / 4) are implemented with three weeks followed by one week of rest, or one week followed by one week of 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 administered for periods exceeding three weeks, followed by a one-week break, or one week followed by a one-week break, thereby achieving high efficacy while increasing safety and tolerability in the treatment of cancer.

[0228] In some embodiments, a method for treating cancer is provided herein, comprising administering to a subject in need of treatment an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof or equivalent thereof in an intermittent dosing cycle of about 100 mg or more, wherein the intermittent dosing cycle comprises at least one dosing week, and each dosing week comprises at least three consecutive dosing days and at least one dosing rest day, followed by at least one rest week. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 100 mg / day, about 125 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, about 275 mg / day, about 300 mg / day, about 325 mg / day, or about 350 mg / day or more, or equivalent thereof. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at an effective dose of approximately 200 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at an effective dose of approximately 225 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at an effective dose of approximately 250 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at an effective dose of approximately 275 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at an effective dose of more than approximately 300 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at an effective dose of approximately 300 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at an effective dose of approximately 350 mg once daily.

[0229] In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 250 mg / day, about 275 mg / day, about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day, about 500 mg / day, about 550 mg / day, about 600 mg / day, about 625 mg / day, about 650 mg / day, about 675 mg / day, about 700 mg / day, about 725 mg / day, about 750 mg / day, about 775 mg / day, or about 800 mg / day or more, or equivalents thereof. In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 250 mg / day or more. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 275 mg / day or more. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 300 mg / day or more. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 325 mg / day or more. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 350 mg / day or more. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 375 mg / day or more. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 400 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 425 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 450 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 475 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 500 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 550 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 600 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 625 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 650 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 675 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 700 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 725 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 750 mg / day. In some embodiments, the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 775 mg / day. In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is about 800 mg / day or an equivalent thereof.

[0230] In some embodiments, the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is approximately 250 to approximately 450 mg / day.

[0231] In some embodiments, the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is approximately 300 mg / day.

[0232] In some embodiments, the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is approximately 350 mg / day.

[0233] In some embodiments, the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is approximately 400 mg / day.

[0234] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered once daily.

[0235] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is divided into two doses per day.

[0236] In some embodiments, the effective dose of asenocarb or a pharmaceutically acceptable salt thereof is divided into three administrations per day.

[0237] In some embodiments, each dosing week includes at least 4, 5, or 6 consecutive dosing days.

[0238] In some embodiments, each dosing week includes 5 consecutive dosing days and 2 days of dosing rest.

[0239] In some embodiments, each dosing week includes 4 consecutive dosing days and 3 days of dosing rest.

[0240] In some embodiments, each dosing week includes 3 consecutive dosing days and 4 days of dosing rest.

[0241] In some embodiments, each dosing week includes 7 consecutive dosing days and 7 days of dosing rest.

[0242] In some embodiments, each intermittent dosing cycle includes from about 7 days to about 10 consecutive dosing days. In some embodiments, each intermittent dosing cycle includes about 8 consecutive dosing days. In some embodiments, each intermittent dosing cycle includes about 9 consecutive dosing days. In some embodiments, each intermittent dosing cycle includes about 10 consecutive dosing days.

[0243] In some embodiments, an intermittent dosing cycle includes 21 consecutive dosing days and 7 days of dosing rest days.

[0244] In some embodiments, an intermittent dosing cycle includes 2 consecutive dosing weeks.

[0245] In some aspects, a method of treating cancer, comprising administering to a subject in need of treatment an effective dose of asenocarb or a pharmaceutically acceptable salt thereof or an equivalent thereof of about 350 mg / day or more according to an intermittent dosing cycle, the intermittent dosing cycle including at least 2 consecutive dosing days and at least 1 day of dosing rest, is provided herein.

[0246] In some embodiments, an intermittent dosing cycle includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive dosing days. In some embodiments, an intermittent dosing cycle includes more than 14 consecutive dosing days. In some embodiments, an intermittent dosing cycle includes 21 consecutive dosing days. In some embodiments, an intermittent dosing cycle includes 28 consecutive dosing days. In some embodiments, an intermittent dosing cycle includes 32 consecutive dosing days. In some embodiments, an intermittent dosing cycle includes 42 consecutive dosing days.

[0247] In some embodiments, the intermittent dosing cycle includes at least 1, 2, 3, 4, 5, 6, or 7 days of rest days. In some embodiments, the intermittent dosing cycle includes 1 day of rest days. In some embodiments, the intermittent dosing cycle includes about 2 to about 7 days of rest days. In some embodiments, the intermittent dosing cycle includes 2 days of rest days. In some embodiments, the intermittent dosing cycle includes 3 days of rest days. In some embodiments, the intermittent dosing cycle includes 4 days of rest days. In some embodiments, the intermittent dosing cycle includes 5 days of rest days. In some embodiments, the intermittent dosing cycle includes 6 days of rest days. In some embodiments, the intermittent dosing cycle includes 7 days of dosing.

[0248] In some embodiments, an intermittent dosing cycle includes approximately 2 to 7 consecutive dosing days ("on" days) followed by approximately 1 to 7 resting days ("off" days).

[0249] In some embodiments, the intermittent dosing cycle includes five consecutive days of administration and two days of administration rest.

[0250] In some embodiments, the intermittent dosing cycle includes four consecutive days of administration and three days of administration rest.

[0251] In some embodiments, the intermittent dosing cycle includes three consecutive days of administration and four days of administration rest.

[0252] In some embodiments, the intermittent dosing cycle includes six consecutive days of administration and one day of administration rest.

[0253] In some embodiments, the intermittent dosing cycle includes seven consecutive days of administration and seven days of administration rest.

[0254] In some embodiments, the intermittent dosing cycle includes 14 consecutive days of administration and 7 days of administration rest.

[0255] In some embodiments, the intermittent dosing cycle includes 21 consecutive days of administration and 7 days of administration rest.

[0256] In some embodiments, an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is approximately 375 mg / day, approximately 400 mg / day, approximately 425 mg / day, approximately 450 mg / day, approximately 475 mg / day, approximately 500 mg / day, approximately 550 mg / day, approximately 600 mg / day, approximately 625 mg / day, approximately 650 mg / day, approximately 675 mg / day, approximately 700 mg / day, approximately 725 mg / day, approximately 750 mg / day, approximately 775 mg / day, or approximately 800 mg / day or more, or equivalents thereof.

[0257] In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 300 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 350 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 400 mg once daily.

[0258] In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of at least about 300 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of at least about 350 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of at least about 400 mg once daily.

[0259] In some embodiments, the disclosure provides administration of high doses of azenocertiveb or a pharmaceutically acceptable salt thereof, for example, doses of about 375 mg or more. In some embodiments, azenocertiveb 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, azenocertiveb 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, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 500 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of about 550 mg once daily. In some embodiments, azenocertiveb 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, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 625 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 650 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 700 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 750 mg once daily. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 775 mg once daily. In some embodiments, azenocertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing regimen at a dose of approximately 800 mg once daily.

[0260] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered once daily.

[0261] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is divided equally into two doses per day.

[0262] In some embodiments, an effective dose of azenocertib or a pharmaceutically acceptable salt thereof is divided equally into three daily doses. In some embodiments, an effective dose of azenocertib The pharmaceutically acceptable salt is divided equally into four daily doses.

[0263] In some embodiments, twice daily doses of azenocertiveb or a pharmaceutically acceptable salt thereof are approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, or more, or equivalents thereof.

[0264] In some embodiments, intermittent administration cycles are repeated. In some embodiments, a method for treating cancer is provided herein, comprising administering to a subject in need of treatment an effective dose of azenocertib or a pharmaceutically acceptable salt thereof or equivalent thereof, in an intermittent dosing cycle of about 400 mg / day or more, wherein the intermittent dosing cycle comprises five consecutive days of administration and two days of administration rest.

[0265] In some embodiments, the method further includes administering a second chemotherapeutic agent during intermittent dosing cycles. While we do not wish to be bound by any particular theory, administering azenocertiveb or a pharmaceutically acceptable salt thereof in combination with a second chemotherapeutic agent may induce a response in subjects resistant to treatment with the second chemotherapeutic agent or its pharmaceutically acceptable salt alone, or prevent or reduce drug toxicity and / or improve the efficacy of treatment compared to monotherapy. Combination therapy using intermittent dosing cycles may offer further benefits to administration, for example, by requiring lower effective doses of the second chemotherapeutic agent or its pharmaceutically acceptable salt, and / or azenocertiveb (including its pharmaceutically acceptable salt).

[0266] In some embodiments, azenocertib or a pharmaceutically acceptable salt thereof is administered in intermittent dosing cycles in combination with one or more second chemotherapeutic agents (including pharmaceutically acceptable salts thereof). Types of PHP

[0267] Cancer can be treated using the method described herein.

[0268] As described herein, cancer is associated with “homologous recombination deficiency,” “homologous recombination repair deficiency,” “homologous repair deficiency,” “HRD,” “HRD-positive,” or “HRD+,” which refer to a reduction or impairment of the homologous recombination process.

[0269] In some embodiments, cancer is also associated with CCNE1 gene amplification and / or increased cyclin E1 expression levels (e.g., cyclin E-amplified cancer, cyclin E-overexpressing cancer / non-amplified cancer, cyclin E-driven cancer).

[0270] In some embodiments, cancers include gliablastoma (GBM), astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, head and neck cancers, 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, colon cancer, colorectal cancer, uterine cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, stomach cancer, gastrointestinal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, hematological malignancies, head cancers, hematological malignancies, Kaposi's sarcoma, kidney cancer, pharyngeal and hypopharyngeal cancers, Liver cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal cancer, cervical cancer, ovarian cancer, osteosarcoma, sarcoma, gastrointestinal stromal tumor (GIST), pancreatic cancer, pituitary cancer, prostate cancer, kidney cancer, retinoblastoma, salivary gland cancer, skin cancer, gastric cancer, small intestine cancer, splenic cancer, sarcoma, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, serous adenocarcinoma (USC), uterine CS, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, Wilms' tumor, solid tumors or liquid tumors, HGSOC, invasive breast cancer, triple-negative breast cancer These include breast cancer (TNBC), gastric esophageal cancer, gastric cancer, esophageal cancer, pRCC, ccRCC, chromophobic RCC, head and neck cancer, adenoid cystic carcinoma (ACC), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), low-grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), cholangiocarcinoma, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), thymoma, BRAF-mutated metastatic colorectal cancer, or uveal melanoma.

[0271] In some embodiments, the subject has cancer. 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, cervical cancer, sarcoma, neuroblastoma, or ovarian cancer.

[0272] In some embodiments, cancers include gliablastoma, astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, leukemia, 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, gastrointestinal cancer, Hodgkin lymphoma, hematological malignancies, hematological malignancies, Kaposi's sarcoma, kidney cancer, pharyngeal and hypopharyngeal cancers, liver cancer, lung cancer, Lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal carcinoma, ovarian cancer, osteosarcoma, pancreatic cancer, pituitary cancer, retinoblastoma, salivary gland cancer, gastric cancer, small intestine cancer, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, serous adenocarcinoma (USC), vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, Wilms' tumor, solid tumor, or liquid tumor.

[0273] In some embodiments, cancer is a solid tumor or a hematological malignancy. In some embodiments, solid tumors are selected from endometrial cancer, gallbladder cancer, ovarian cancer, HGSOC, endometrial cancer, melanoma, colorectal cancer, bladder cancer, breast cancer, invasive breast cancer, triple-negative breast cancer (TNBC), prostate cancer, lung cancer, NSCLC, SCLC, esophageal and gastric cancer, gastric cancer, esophageal cancer, kidney cancer, pRCC, ccRCC, chromophobe RCC, head and neck cancer, osteosarcoma, pancreatic cancer, brain cancer, uterine cancer, uterine cancer, adenoid cystic carcinoma (ACC), mesothelioma, cervical cancer, diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), liver cancer, gliablastoma (GBM), testicular cancer, low-grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), cholangiocarcinoma, thyroid cancer, thymoma, and uveal melanoma.

[0274] In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer, germ cell carcinoma, or stromal carcinoma. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the epithelial ovarian cancer is high-grade serous ovarian cancer (HGSOC).

[0275] In some embodiments, the cancer is associated with organs selected from 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, adenocarcinoma in situ, extragonadal germ cell tumor (EGCT), mixed adenocarcinoma, high-grade ovarian neuroendocrine carcinoma, high-grade serous fallopian tube carcinoma (HGSFT), ovarian choriocarcinoma, and ovarian cancer NOS (OCNOS).

[0276] In some embodiments, the cancer is a primary cancer originating from an associated organ. In some embodiments, the cancer is a primary peritoneal cancer.

[0277] In some embodiments, the cancer has metastasized to related organs.

[0278] In some embodiments, the cancer is a solid tumor or a hematological malignancy.

[0279] In some embodiments, cancer is a solid tumor.

[0280] In some embodiments, solid tumors are selected from endometrial cancer, gallbladder cancer, ovarian cancer (e.g., HGSOC), endometrial cancer, melanoma, colorectal cancer, bladder cancer, breast cancer (e.g., invasive triple-negative breast cancer (TNBC)), prostate cancer, lung cancer (e.g., NSCLC, SCLC), esophageal and gastric cancer, gastric cancer, esophageal cancer, renal cancer (e.g., pRCC, ccRCC, chromophobe RCC), head and neck cancer, osteosarcoma, pancreatic cancer, brain cancer, uterine cancer, uterine cancer, adenoid cystic carcinoma (ACC), mesothelioma, cervical cancer, diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), liver cancer, gliablastoma (GBM), testicular cancer, low-grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), cholangiocarcinoma, thyroid cancer, thymoma, and uveal melanoma.

[0281] In some embodiments, the cancer is acute myeloid leukemia (AML).

[0282] In some embodiments, the tumor is a neuroendocrine tumor, a neuroendocrine prostate cancer, or a pancreatic neuroendocrine tumor.

[0283] In some embodiments, the solid tumor is ovarian cancer.

[0284] In some embodiments, ovarian cancer is epithelial ovarian cancer, germ cell carcinoma, or stromal carcinoma.

[0285] In some embodiments, the ovarian cancer is epithelial ovarian cancer.

[0286] In some embodiments, the ovarian cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments, the ovarian cancer is platinum-resistant ovarian cancer (PROC). In some embodiments, the ovarian cancer is CCNE1-amplified ovarian cancer. In some embodiments, the ovarian cancer is cyclin E1-overexpressing cancer. In some embodiments, the ovarian cancer is cyclin E1-overexpressing / non-CCNE1-amplified cancer. PARP inhibitor-resistant cancer

[0287] In some embodiments, cancer is PARP inhibitor resistant. PARP inhibitor resistance refers to the unresponsiveness of cancer to treatment with PARP inhibitors (including pharmaceutically acceptable salts thereof). In some embodiments, PARP inhibitor-resistant cancer is inherently resistant to treatment with PARP inhibitors (including pharmaceutically acceptable salts thereof). In some embodiments, PARP inhibitor-resistant cancer has acquired resistance to treatment with PARP inhibitors (including pharmaceutically acceptable salts thereof). For example, cancer cells with mutations in tumor suppressor genes cannot repair DNA through homologous recombination. PARP inhibitors cause DNA damage that can be repaired by normal cells but not by tumor cells, and therefore, PARP inhibitors selectively kill tumor cells rather than normal cells. In some embodiments, a reversion mutation occurs in a tumor suppressor gene (e.g., BRCA reversion) that allows tumor cells to survive after PARP inhibitor treatment. In some embodiments, PARP inhibitor resistance is due to changes in other genes, such as TP53BP1.

[0288] In some embodiments, the PARP inhibitor is selected from the group consisting of olaparib, niraparib, lucaparib, talazoparib, veliparib, pamiparib (BGB-290), iniparib (BSI 201), salparib (AZD-5305), E7016 (Esai), and CEP-9722, or any pharmaceutically acceptable salt of any of the above.

[0289] In some embodiments, the cancer is olaparib-resistant. In some embodiments, the cancer is niraparib-resistant. In some embodiments, the cancer is salparib-resistant. In some embodiments, the cancer is lucaparib-resistant. In some embodiments, the cancer is talazoparib-resistant. It is resistant. In some embodiments, the cancer is veliparib resistant. In some embodiments, the cancer is pamiparib resistant. In some embodiments, the cancer is iniparib resistant. In some embodiments, the cancer is E7016 resistant. In some embodiments, the cancer is CEP-9722 resistant. In some embodiments, a method for treating PARP inhibitor-resistant breast cancer is provided herein, comprising determining, or having determined, whether a subject requiring treatment has homologous recombination repair deficiency (HRD), and, if the subject is HRD+, administering azenocertiveb or a pharmaceutically acceptable salt thereof in an effective dose, wherein the administration of azenocertiveb or a pharmaceutically acceptable salt thereof results in inhibition of the PARP inhibitor-resistant breast cancer in the subject. In some embodiments, the PARP inhibitor-resistant breast cancer is niraparib resistant. In some embodiments, the PARP inhibitor-resistant breast cancer is olaparib resistant.

[0290] In some embodiments, the cancer is serous adenocarcinoma of the uterus (USC).

[0291] In some embodiments, the cancer is osteosarcoma.

[0292] In some embodiments, the solid tumor is serous adenocarcinoma of the uterus, ovarian cancer, peritoneal cancer, fallopian tube cancer, osteosarcoma, pancreatic cancer, or BRAF-mutated metastatic colorectal cancer.

[0293] In some embodiments, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Waldenström macroglobulinemia, or multiple myeloma (MM). chemotherapy resistant cancer

[0294] In some embodiments, the cancer is resistant to chemotherapy. In some embodiments, the cancer is resistant to one or more chemotherapy regimens. In some embodiments, the cancer is refractory to one or more chemotherapy regimens. In some embodiments, the chemotherapeutic agent is selected from bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, carboplatin, cisplatin, cyclophosphamide, cladribine, paclitaxel, docetaxel, pegylated liposomal doxorubicin (PLD), dexamethasone, doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapine, azacitidine, 5-azacitidine, capecitabine, AraC-FdUMP

[10] (CF-10), cladribine, etoposide, decitabine, daunorubicin, doxorubicin, ifosfamide, methotrexate, vincristine, hydroxyurea, oxaliplatin, or any pharmaceutically acceptable salt of any of the above. In some embodiments, the cancer is platinum-refractory or platinum-resistant cancer.

[0295] Platinum-resistant cancers are cancers that respond to treatment with drugs containing metallic platinum, such as cisplatin and carboplatin, but recur within a specific timeframe, for example, ovarian cancer that recurs six months after remission. Platinum resistance, defined as a lack of response or recurrence within six months of platinum-based chemotherapy, is a determinant of survival.

[0296] In some embodiments, the cancer is platinum-refractory cancer. Platinum-refractory cancer is cancer that does not respond to treatment with anticancer drugs containing metallic platinum, such as cisplatin and carboplatin.

[0297] In some embodiments, a method for treating chemotherapy-resistant ovarian cancer, wherein treatment is necessary for A method is provided herein that comprises determining whether an elephant has homologous recombination repair deficiency (HRD) or an HRD status, and, if the subject has HRD or is HRD-positive (HRD+), administering azenocertib or a pharmaceutically acceptable salt thereof in an effective dose, wherein the administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of chemotherapy-resistant ovarian cancer in the subject. In some embodiments, the chemotherapy-resistant ovarian cancer is platinum-resistant. In some embodiments, the chemotherapy-resistant ovarian cancer is further resistant to PARP inhibitors or pharmaceutically acceptable salts thereof. Combination therapy

[0298] This disclosure provides a method of using azenocertiveb or a pharmaceutically acceptable salt thereof in combination with one or more additional agents (e.g., combination therapy with a chemotherapeutic agent (including a pharmaceutically acceptable salt thereof)). In one embodiment, this disclosure provides a method of treating cancer, comprising administering an effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof and a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof to a subject selected to have a homologous recombination repair deficiency (HRD) biomarker.

[0299] Combination therapy refers to a clinical intervention in which a subject is simultaneously exposed to two or more treatment regimens (e.g., azenocertib or a pharmaceutically acceptable salt thereof, and a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof). In some embodiments, two or more chemotherapy regimens (containing their salts) may be administered concurrently. In some embodiments, two or more chemotherapy regimens (containing their salts) may be administered sequentially (e.g., the first regimen is administered before any dose of the second regimen). In some embodiments, two or more chemotherapy regimens (containing their salts) may be administered in overlapping dosing regimens.

[0300] In some embodiments, combination therapy does not necessarily require that individual agents (including pharmaceutically acceptable salts thereof) be administered together (or not necessarily simultaneously) in a single composition. In some embodiments, two or more treatment regimens of combination therapy (e.g., azenocertib or a pharmaceutically acceptable salt thereof, and a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof) are administered separately, for example, in separate compositions, via separate routes of administration (e.g., one agent orally and the other intravenously), and / or at different time points in time to the subject. In some embodiments, two or more chemotherapeutic agents (including pharmaceutically acceptable salts thereof) may be administered together in a combination composition or as a combination compound (e.g., as part of a single chemical complex or covalent entity), via the same route of administration, and / or simultaneously.

[0301] In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof and a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered simultaneously. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof and a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered sequentially. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered before the second chemotherapeutic agent or a pharmaceutically acceptable salt thereof. In other embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof is administered after the second chemotherapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, azenocertiveb or a pharmaceutically acceptable salt thereof and a second chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered intermittently.

[0302] In some embodiments, the second chemotherapeutic agent is bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, carboplatin, cisplatin, cyclophosphamide, cladribine, paclitaxel, docetaxel, pegylated liposomal doxorubicin (PLD), dexamethasone, doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, and tri Selected from apine, azacitidine, 5-azacitidine, capecitabine, AraC-FdUMP

[10] (CF-10), cladribine, etoposide, decitabine, daunorubicin, doxorubicin, ifosfamide, methotrexate, vincristine, hydroxyurea, oxaliplatin, or any pharmaceutically acceptable salt of any of the above.

[0303] In some embodiments, cancer treatment includes alkylating agents, anti-EGFR antibodies, anti-Her-2 antibodies, antimetabolites, vinca alkaloids, platinum-based drugs, anthracyclines, topoisomerase inhibitors, taxanes, antibiotics, immunomodulators, immune cell antibodies, interferons, interleukins, HSP90 inhibitors, antiandrogens, antiestrogens, antihypercalcemia 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, cRAF kinase inhibitors, R AS 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, imidazotetradinone, 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, allergens Non, Altretamine, Aminopterin, Aminolevulinic Acid, Amsacrin, Asparaginase, Atrasentan, Bexarotene, Carbocon, Demecolsin, Efaproxial, Elsamitrusin, Etoglucid, Hydroxycarbamide, Leucovorin, Ronidamine, Lucanton, Masopropyl, Methyl Aminolevulinate, Mitoguazone, Mitotan, Oblimersen, Omasetaxin, Pegaspargase, Porfimer Sodium, Prednimustine, Citimazine Seradenovec, Talaporfin, Temoporfin, Trabectedin, and / or Verteporfin, or any pharmaceutically acceptable salt of any of the above.

[0304] In some embodiments, the method includes administering a second therapeutic agent or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the second therapeutic agent is a PARP inhibitor or a pharmaceutically acceptable salt thereof, the PARP inhibitor being selected from the group consisting of olaparib, niraparib, lucaparib, talazoparib, veliparib, pamiparib (BGB-290), iniparib (BSI 201), salparib (AZD5305), E7016 (Esai), and CEP-9722, or any of the aforementioned pharmaceutically acceptable salts. In some embodiments, the second therapeutic agent is a PARP1 selective inhibitor, such as salparib (AZD5305).

[0306] In some embodiments, azenocertib or a pharmaceutically acceptable salt thereof is administered in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is niraparib, olaparib, or salparib (AZD5305), or any of the aforementioned pharmaceutically acceptable salts.

[0307] In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapeutic agent is a PD1 inhibitor or a pharmaceutically acceptable salt thereof, the PD1 inhibitor being selected from the group consisting of nivolumab, pembrolizumab, semiprimab, spartalizumab, ABBV-181, rhodapolimab, zimbererimab, tripalimab (Tuoyi), tisrelizumab, camrelizumab, cintilimab (Tyvyt), GB226, AK105, HLX-10, AK103, BAT-1306, GSL-010, CS1003, LZM009, and SCT-I10A, or any of the aforementioned pharmaceutically acceptable salts.

[0308] In some embodiments, the second therapeutic agent is a PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, the PD-L1 inhibitor being selected from the group consisting of atezolizumab, avelumab, durvalumab, KN035, CS1001, SHR-1316, TQB2450, BGB-A333, KL-A167, KN046, MSB2311, and HLX-20, or any of the aforementioned pharmaceutically acceptable salts.

[0309] In some embodiments, the second therapeutic agent is a Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, the Bcl-2 inhibitor being 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 any of the aforementioned pharmaceutically acceptable salts.

[0310] In some embodiments, the second therapeutic agent is a KRAS inhibitor or a pharmaceutically acceptable salt thereof, where the KRAS inhibitor is sotrasib, 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 The following are selected from the group consisting of Degrader-1 (compound 518, CAS number 2378258-52-5), ronafarnib (SCH66336), RMC-0331, GDC-6036, LY3537982, D-1553, ARS-3248 (JNJ74699157), BI-1701963, and AU-8653 (AU-BEI-8653), or any pharmaceutically acceptable salt of any of the above.

[0311] In some embodiments, the second therapeutic agent is a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, the CDK4 / 6 inhibitor being selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), rerocyclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, birocyclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or any of the aforementioned pharmaceutically acceptable salts.

[0312] In some embodiments, the second therapeutic agent is a HER-2 antibody or a pharmaceutically acceptable salt thereof, the HER-2 antibody being selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25, or any of the aforementioned pharmaceutically acceptable salts.

[0313] In some embodiments, the second therapeutic agent is a HER-2 antibody-drug conjugate or a pharmaceutically acceptable salt thereof, the HER-2 antibody-drug conjugate being fam-trastuzumab deruxtecan-nxki, Ado-trastuzumab emtansine (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, The group consists of PF-06804103, SYD985, and XMT-1522, or any of the aforementioned pharmaceutically acceptable salts.

[0314] In some embodiments, the second therapeutic agent is a HER2 bispecific antibody or a pharmaceutically acceptable salt thereof, the HER2 bispecific antibody being selected from the group consisting of margetuximab, erzmaxomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343, or any of the aforementioned pharmaceutically acceptable salts.

[0315] In some embodiments, the second therapeutic agent is a selective ER modulator (SERM) or a pharmaceutically acceptable salt thereof, the selective ER modulator being selected from the group consisting of tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene, and rasofoxifene, or any pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the second therapeutic agent is a selective ER degrading agent (SERD) or a pharmaceutically acceptable salt thereof, wherein the selective ER degrading agent is fulvestrant, (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl (E)-5,6,7,8-tetrahydronaphthalene-2-ol (Erasestrant, RAD1901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazole-5-yl)buta-1-en-1-yl)phenyl)acrylic acid (Brillanestrant, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic Acid (LSZ102), (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazole-5-yl)-2-phenylbuto-1-en-1-yl)pyridine-2-yl)oxy)ethyl)amino)buta-2-enamide (H3B-6545), (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (lint destrand, G1T48), D-0 502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2,2-difluoropropan-1-ol(diledestrant, GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidine-3-yl)oxy)phenyl)-6,Selected from the group consisting of 7-dihydro-5H-benzo[7]anulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidine-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinoline-6-yl]pyridine-3-amine (AZD9833), OP-1250, and LY3484356, or any pharmaceutically acceptable salt of any of the above.

[0317] In some embodiments, the second therapeutic agent is an ATR inhibitor or a pharmaceutically acceptable salt thereof, the ATR inhibitor being selected from gulticertive, bezocertib, M4344, BAY1895344, seracertib, cisandrin B, elimsertib, NU6027, dactricib, ETPPT-46464, trin 2, VE-821, AZ20, camoncertib, CGK733, ART-0380, ATRN-119, and ATRN-212, or any of the aforementioned pharmaceutically acceptable salts.

[0318] In some embodiments, the second therapeutic agent is an ATM inhibitor or a pharmaceutically acceptable salt thereof, the ATM inhibitor being 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 any of the aforementioned pharmaceutically acceptable salts.

[0319] In some embodiments, the second therapeutic agent is a CHK1 inhibitor or a pharmaceutically acceptable salt thereof, the CHK1 inhibitor being selected from prexacertib, AZD7762, ravacertib, SCH90076MK-8776, CCT245737, CCT244747, CHIR-124, PD 407824, PD-321852, PF-00477736, GDC-0425, GDC-0575, SB-218078, V158411, LY2606368, LY2603618, SAR-020106, XL-844, UCN-01, SOL-578, IMP 10, and CBP501, or any of the aforementioned pharmaceutically acceptable salts.

[0320] In some embodiments, the second therapeutic agent is a targeted therapeutic agent or a pharmaceutically acceptable salt thereof, the targeted therapeutic agent being selected from bevacizumab, lenvatinib, encorafenib, and cetuximab, or any of the aforementioned pharmaceutically acceptable salts.

[0321] In some embodiments, the chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docetaxel, pegylated liposomal doxorubicin, doxorubicin, gemcitabine, cytarabine, fludarabine, fluorouracil (5-FU), irinotecan, topotecan, temozolomide, triapines, 5-azacitidine, capecitabine, AraC-FdUMP

[10] (CF-10), cladribine, decitabine, hydroxyurea, and oxaliplatin, or any pharmaceutically acceptable salt of any of the above. In other embodiments, the chemotherapeutic agent is azacitidine, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, carboplatin, cytarabine, cyclophosphamide, cladribine, cisplatin, capecitabine, decitabine, dexamethasone, etoposide, fludarabine, gemcitabine, daunorubicin, doxorubicin, ifosfamide, methotrexate, and vincristine, or any pharmaceutically acceptable salt thereof.

[0322] In some embodiments, the second chemotherapeutic agent is carboplatin, paclitaxel, gemcitabine, or pegylated liposomal doxorubicin (PLD), or a pharmaceutically acceptable salt of any of the above.

[0323] In some embodiments, the second chemotherapeutic agent is encorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, the second chemotherapeutic agent is cetuximab or a pharmaceutically acceptable salt thereof. In some embodiments, the second chemotherapeutic agent consists of a combination of encorafenib and cetuximab, or any of the aforementioned pharmaceutically acceptable salts.

[0324] In one embodiment, a method for treating cancer is provided herein, comprising administering to a subject an effective dose of approximately 400 mg or more of azenocertib or a pharmaceutically acceptable salt thereof or an equivalent thereof in an intermittent administration cycle including five consecutive administration days and two administration rest days, and administering to a subject an effective dose of a PARP inhibitor (PARP inhibitor) or a pharmaceutically acceptable salt thereof in an intermittent administration cycle including five consecutive administration days and two administration rest days. Administration of the second chemotherapy agent

[0325] In some embodiments, the second chemotherapeutic agent is carboplatin, paclitaxel, gemcitabine, or pegylated liposomal doxorubicin (PLD), or a pharmaceutically acceptable salt of any of the above.

[0326] In some embodiments, the second chemotherapeutic agent is carboplatin or a pharmaceutically acceptable salt thereof, which is administered intravenously once during the treatment cycle for at least 15 minutes in a dose ranging from about 1 to about 10 mg / mL* minutes. In some embodiments, the second chemotherapeutic agent is carboplatin or a pharmaceutically acceptable salt thereof, which is administered intravenously once during the treatment cycle for at least 15 minutes in a dose ranging from about 3 to about 6 mg / mL* minutes. In some embodiments, the second chemotherapeutic agent is carboplatin or a pharmaceutically acceptable salt thereof, administered once during the treatment cycle for 15 minutes or more, at doses of approximately 1 to approximately 10 mg / mL* min, approximately 2 to approximately 10 mg / mL* min, approximately 3 to approximately 10 mg / mL* min, approximately 4 to approximately 10 mg / mL* min, approximately 5 to approximately 10 mg / mL* min, approximately 6 to approximately 10 mg / mL* min, and approximately It is administered intravenously in doses ranging from approximately 7 to 10 mg / mL* minutes, approximately 8 to 10 mg / mL* minutes, approximately 9 to 10 mg / mL* minutes, approximately 2 to 8 mg / mL* minutes, approximately 2 to 7 mg / mL* minutes, approximately 3 to 7 mg / mL* minutes, approximately 4 to 7 mg / mL* minutes, approximately 5 to 7 mg / mL* minutes, approximately 4 to 6 mg / mL* minutes, approximately 2 to 6 mg / mL* minutes, approximately 3 to 8 mg / mL* minutes, and approximately 9 to 10 mg / mL* minutes.

[0327] In some embodiments, the second chemotherapeutic agent is PLD or a pharmaceutically acceptable salt thereof, which is administered once during the treatment cycle over 60 minutes at a dose of approximately 10 to approximately 100 mg / m². 2 It is administered intravenously in doses within the range of [dose range]. In some embodiments, the second chemotherapeutic agent is PLD or a pharmaceutically acceptable salt thereof, which is administered once during the treatment cycle over 60 minutes at a dose of approximately 5 to approximately 50 mg / m². 2 It is administered intravenously in doses within the range of [dose range]. In some embodiments, the second chemotherapeutic agent is PLD or a pharmaceutically acceptable salt thereof, which is administered once during the treatment cycle over 60 minutes at a dose of approximately 10 to approximately 40 mg / m². 2 It is administered intravenously in doses within this range.

[0328] In some embodiments, the second chemotherapeutic agent is PLD or a pharmaceutically acceptable salt thereof, and PLD or a pharmaceutically acceptable salt thereof is administered intravenously once during a treatment cycle over 60 minutes at a dose in the range of about 10 to about 100 mg / m 2 2, about 10 to about 90 mg / m 2 2, about 10 to about 80 mg / m 2 2, about 10 to about 70 mg / m 2 2, about 10 to about 60 mg / m 2 2, about 10 to about 50 mg / m 2 2, about 10 to about 40 mg / m 2 2, about 10 to about 30 mg / m 2 2, about 10 to about 20 mg / m 2 2, about 20 to about 90 mg / m 2 2, about 30 to about 90 mg / m 2 2, about 40 to about 90 mg / m 2 2, about 50 to about 90 mg / m 2 2, about 60 to about 90 mg / m 2 2, about 70 to about 90 mg / m 2 2, about 20 to about 80 mg / m 2 2, about 20 to about 70 mg / m 2 2, about 20 to about 60 mg / m 2 2, about 20 to about 50 mg / m 2 2, about 20 to about 40 mg / m 2 or about 30 to about 40 mg / m 2 2 and is administered intravenously at a dose within this range.

[0329] In some embodiments, the second chemotherapeutic agent is paclitaxel or a pharmaceutically acceptable salt thereof, and paclitaxel or a pharmaceutically acceptable salt thereof is administered intravenously three times during a treatment cycle over 60 minutes (+10 minutes) at a dose in the range of about 10 to about 120 mg / m 2 2. In some embodiments, the second chemotherapeutic agent is paclitaxel or a pharmaceutically acceptable salt thereof, and paclitaxel or a pharmaceutically acceptable salt thereof is administered intravenously three times during a treatment cycle over a maximum of 3 hours at a dose in the range of about 10 to about 100 mg / m 2 2, about 20 to about 100 mg / m 2 2, about 30 to about 100 mg / m 2, about 40~100mg / m 2 , about 50~100mg / m 2 , about 60~100mg / m 2 , about 70~100mg / m 2 , about 80~100mg / m 2 , about 90~100mg / m 2 , about 10 to about 90mg / m 2 , about 10 to about 80mg / m 2 , about 10~70mg / m 2 , about 10 to about 60mg / m 2 , about 10~50mg / m 2 , about 10 to about 40mg / m 2 , about 10~30mg / m 2 , about 30~70mg / m 2 , about 40~70mg / m 2 , about 50~70mg / m 2 , about 60~70mg / m 2 , about 30 to about 90mg / m 2 , or approximately 30-80 mg / m² 2 It is administered intravenously in doses within this range.

[0330] In some embodiments, the second chemotherapeutic agent is paclitaxel or a pharmaceutically acceptable salt thereof, administered at a maximum dose of 3 hours, up to 3 times during the treatment cycle, at a dose of approximately 40 to approximately 100 mg / m². 2 It is administered intravenously in doses within this range.

[0331] In some embodiments, the second chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof, which is administered once during the treatment cycle for more than 15 minutes at a dose of approximately 500 to approximately 1500 mg / m². 2 It is administered intravenously in doses within this range.

[0332] In some embodiments, the second chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof, administered at a dose of approximately 100 to approximately 1000 mg / m² over 15 minutes or more, up to three times during the treatment cycle.2 , about 100~1000mg / m 2 , about 100~900mg / m 2 , about 100 to about 800mg / m 2 , about 100 to about 700mg / m 2 , about 100~about 600mg / m 2 , about 100 to about 500mg / m 2 , about 100 to about 400mg / m 2 , about 100~300mg / m 2 , about 100~200mg / m 2 , about 200~about 1000mg / m 2 , about 300~about 1000mg / m 2 , about 400 to about 1000mg / m 2 , about 500~1000mg / m 2 , about 600~about 1000mg / m 2 , about 700~1000mg / m 2 , about 800~1000mg / m 2 , about 200~800mg / m 2 , about 200~700mg / m 2 , about 200~about 600mg / m 2 , about 200~500mg / m 2 , about 300~900mg / m 2 , about 300 to about 800mg / m 2 , about 400~700mg / m 2 , about 500~700mg / m 2 , about 500~800mg / m 2 , or approximately 600-900 mg / m² 2 It is administered intravenously in doses within this range.

[0333] In some embodiments, the second chemotherapeutic agent is gemcitabine or a pharmaceutically acceptable salt thereof, administered at a dose of approximately 100 to approximately 1000 mg / m² over 15 minutes or more, up to three times during the treatment cycle. 2 It is administered intravenously in doses within this range. Responsiveness

[0334] In some embodiments, the treatment methods described herein result in response rates of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or higher. In some embodiments, the response rate is measured by complete response (CR), partial response (PR), CA-125 50% response, or a combination thereof. In some embodiments, the response is determined based on progression-free survival. In some embodiments, the response is determined based on tumor response. In some embodiments, the response is determined based on clinical benefit rate (CBR). In some embodiments, the response is determined based on disease control rate (DCR). In some embodiments, the response is determined based on overall survival (OS).

[0335] Progression-free survival (PFS) refers to the period during which a subject with a disease (e.g., cancer) survives without significant deterioration of their condition. Progression-free survival can be assessed as the period during which there is no progression of tumor growth and / or the period during which the subject's disease status is not determined to be progressive. In this context, progression-free survival for subjects with cancer is assessed by evaluating tumor size, tumor number, and / or metastasis.

[0336] In some embodiments, the treatment results in a progression-free survival (PFS) of 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or longer. In some embodiments, the treatment results in a progression-free survival (PFS) of 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or longer. In some embodiments, the treatment results in a progression-free survival (PFS) of 1 year, 1.5 years, 2 years, or 2.5 years or longer.

[0337] As used herein, and as used herein in relation to cancerous status, the terms “progression” or “progressive disease” (PD) of tumor growth refer to an increase in the total diameter of the target tumor. For the purpose of determining progression-free survival, progression is defined as 1) tumor evaluation by CT / MRI clearly showing progressive disease according to RECIST 1.1 criteria, or 2) additional diagnostic tests (e.g., histology / cytology, ultrasound techniques, endoscopy, positron emission tomography) identifying a new tumor or determining that an existing tumor is eligible for clear progressive disease and / or CA-125 progression according to Gynecologic Cancer Intergroup (GCIG) criteria (Rustin et al., Int J It may also be determined if at least one of the following criteria is met: 3) Definitive clinical signs and symptoms of PD unrelated to non-malignant or iatrogenic causes ([i] refractory cancer-related pain, [ii] worsening of malignant bowel obstruction / dysfunction, or [iii] clear symptomatic worsening of ascites or pleural effusion) and / or CA-125 progression according to GCIG criteria.

[0338] As used herein, the terms “partial response” or “PR” refer to a reduction in tumor progression in a subject, indicated by a decrease in the sum of diameters of the target tumors relative to the sum of diameters at baseline. In some embodiments, PR refers to a reduction of at least 30% of the total diameter relative to the total diameter at baseline. Exemplary methods for evaluating partial response are specified by the RECIST guidelines. EAEisenhauer, et See al., "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1)", Eur. J.of Cancer, 45: 228-247 (2009).

[0339] As used herein, “stable” or “stable disease” (SD) of tumor growth means that there is neither sufficient shrinkage to qualify for PR nor sufficient growth to qualify for PD. In embodiments, stability refers to a change (increase or decrease) of less than 30%, 25%, 20%, 15%, 10%, or 5% of the sum of diameters of the target tumor relative to the sum of diameters at baseline. Exemplary methods for assessing stable or stable disease of tumor growth are specified by the RECIST guidelines. EAEisenhauer, et al., “New See "Response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1)," Eur. J.of Cancer, 45: 228-247 (2009).

[0340] As used herein, the terms “complete response” or “CR” are used to mean the disappearance of all or substantially all target lesions. In several embodiments, CR is defined as 80%, 85%, 90%, and 9% of the sum of diameters of the target tumors relative to the sum of diameters of the baseline tumors. This refers to a reduction of 1%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (i.e., loss of tumor). In embodiments, CR indicates that less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the sum of lesion diameters remains after treatment. Exemplary methods for evaluating complete response are identified by the RECIST guidelines. See EAEisenhauer, et al., "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1)," Eur. J.of Cancer, 45: 228-247 (2009). Examples [Examples]

[0341] Additional embodiments are disclosed in further detail in the following embodiments, but this is not intended to limit the scope of the claims. Example 1 - HRD-positive status is associated with tumor response in cancer subjects treated with azenocertib.

[0342] This example demonstrates the efficacy of azenocertib in HRD+ cancers (e.g., cancers with one or more HRRm) in terms of tumor response and progression-free survival. Subjects with serous uterine carcinoma (USC) or high-grade serous ovarian cancer (HGSOC) were treated with azenocertib and grouped by azenocertib dose of less than 300 mg (LT300) or 300 mg or more (300 mg+). Table 1 shows the selection of subjects based on HRRm status. "All subjects" in parentheses includes all subjects in this study, including those receiving LT300. [Table 1]

[0343] The tumor response of the subjects selected in Table 1 was evaluated when treated with azenoceretib doses of 300 mg or more, or less than 300 mg. In the USC population treated with azenoceretib ≥300 mg (300+), HRRm positivity was associated with a better tumor response (p=0.01) (Figures 1B and 1C). The median HRRm was -33%, and the median HRR wt was -5%. Figure 1A shows the genotype and dose of individual subjects. In subjects treated with azenoceretib ≥300 mg, HRRm status as a biomarker was associated with a better progression-free survival. The HRRm-controlled population was associated with an 8.3 month progression-free survival compared to the HRR wt-controlled population, which had an average progression-free survival of 4.2 months (Figure 1D). HRRm status is associated with better progression-free survival in subjects treated with at least 300 mg of azenosertib, supporting an effective dose of 300 mg or more in subjects with HRD. did. Example 2 - In vivo efficacy of azenocertib in subcutaneous xenograft mice with prostate cancer 22RV1

[0344] This example demonstrates the in vivo therapeutic efficacy of azenocertib alone or in combination with a PARP inhibitor (olaparib or niraparib) in subcutaneous xenografts of 22RV1 (prostate cancer cell line) in CB17 SCID mice.

[0345] The prostate cancer cell line 22RV1 carries the BRCA2 pathogenic mutation (HRD+). Table 2 summarizes the groups and treatments. Briefly, 72 tumor-bearing mice were randomized and assigned to nine groups using a randomized block design based on tumor volume, with 8 mice per group. Each mouse was given 22RV1 tumor cells (5 × 10⁶) in 0.2 mL of Matrigel mixture. 6 Cells (mouse) were subcutaneously inoculated into the right flank. For tumor efficacy studies, the tumor size was 199.94 mm. 3 Treatment was initiated when the condition reached this stage (14 days after vaccination). [Table 2]

[0346] Tumor size was measured in two dimensions twice a week using calipers, and the formula was:

number

number

[0347] Two-way ANOVA, followed by the Bonferroni post-hoc test, was performed to compare tumor volume between the vehicle group and the other groups. Figures 2A-2D and Table 3 show tumor growth inhibition (TGI%) during the treatment period. [Table 3]

[0348] Overall, the results showed that azenocertib alone, and in combination with niraparib or olaparib, resulted in a reduction in tumor growth volume and tumor inhibition. Example 3 - In vivo antitumor efficacy of azenocertib in a patient-derived xenograft (PDX) breast cancer model

[0349] This example demonstrates the antitumor efficacy of azenocertib and niraparib, used alone or in combination, in HBCx-9, HBCx-10, and HBCx-17 triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) models using immunodeficient female mice.

[0350] The HRD+TNBC PDX models (HBCx-10 and HBCx-17) and the HRD-TNBC PDX model (HBCx-9) have their HRD status and profile... The animals were treated with azenocertiveb and / or niraparib, as shown in Table 4. The animals were treated with 60 mg / kg azenocertiveb or 35 mg / kg niraparib, either alone or in combination, for 4 cycles (28 days) using an intermittent dosing regimen of 5 days of administration followed by 2 days off (qd x 5 days on, 2 days off). [Table 4]

[0351] Table 5 summarizes the groups and administration schedule. Treatment was initiated 28 days after tumor cell transplantation. The study period ended 28 days after the start of treatment. [Table 5]

[0352] Relative weight (RBW) is calculated for each measurement by dividing body weight by body weight at the start of treatment. Individual weight loss percentages are calculated using the following formula:

number

[0353] The average weight loss rate is calculated using the formula:

number

[0354] The mean relative body weight (RBW) curve was obtained by plotting the mean RBW against time for each experimental group. Delta relative body weight (relative body weight of the treatment group compared to the relative body weight of the control group) was used for statistical analysis. The mean individual body weights are shown in Table 6. [Table 6]

[0355] Combination therapy resulted in a statistically significant reduction in tumor volume. Body weight data and clinical observations of 60 mg / kg azenocertib and 35 mg / kg niraparib, either as monotherapy or in combination, were well-tolerated and did not induce any associated weight loss or observable clinical signs. Azenocertib and azenocertib in combination with niraparib resulted in increased inhibition of tumor growth in the HRD+ model (Figures 3B and 3C) compared to the HRD- model (Figure 3A). Example 4 - In vivo efficacy of azenocertib in combination with a PARP inhibitor in a BRCA mutant ovarian PDX model.

[0356] This example demonstrates the antitumor efficacy of azenocertiveb and niraparib, used alone or in combination, in ovarian xenograft (PDX) models derived from patients carrying BRCA1 and / or BRCA2 mutations. The OVA2-BUR model has an HRD-negative / BRCA1 WT phenotype. Glu1607Ter (Pathogenic) variants and BRCA1 Pro1099Leu Tumor growth inhibition was also measured using a (benign) mutant PDX model. Table 7 shows the treatment groups, doses, and schedules. [Table 7]

[0357] Relative body weight (RBW), individual body weight, and average weight loss rate were calculated for each measurement by dividing body weight by body weight at the start of treatment, as described in Example 3. Average individual body weights are shown in Table 8. [Table 8]

[0358] Figure 4A shows tumor volume changes using azenocertiveb, niraparib alone, or in combination. Body weight data and clinical observations for 60 mg / kg azenocertiveb and 35 mg / kg niraparib indicate that these compounds were well-tolerated, either alone or in combination, and did not induce any associated weight loss or observable clinical signs. Combination therapy also resulted in a statistically significant reduction in tumor volume in the BRCA1 mutant (HRD+) model. Interestingly, azenocertiveb alone or in combination with niraparib resulted in increased suppression of tumor growth in the HRD+ (e.g., BRCA1 pathogenic mutant shown in Figure 4B) ovarian PDX model compared to the BRCA1 WT (Figure 4A) or benign BRCA1 mutant (Figure 4C) model. Example 5 - Efficacy of azenocertib in HRD+ breast cancer resistant to acquired PARP inhibitors

[0359] This example demonstrates the efficacy of azenasertib in an HRD+ xenograft cancer model with acquired resistance to PARP inhibitors. Azenasertib is active in a PARP inhibitor-resistant xenograft model with a BRCA reversion mutation. Cells with a BRCA reversion mutation can be considered HRD+ due to genomic instability (TAI, LST, LOH, etc.). BRCA reversion mutations are an established mechanism of resistance to both platinum-based chemotherapeutic agents and PARP inhibitors. In vivo exploration of WEE1 inhibitors (azenasertib, adavosertib) and PARP inhibitors (niraparib, olaparib) was evaluated. The antitumor activity of azenasertib or PARP inhibitors was evaluated in the parental MDA-MB-436 triple-negative breast cancer tumor cell line (Figure 5A), or two derived lines of MDA-MB-436 with in vitro acquired resistance to niraparib (Nir R , Figure 5B) or olaparib (Ola R , Figure 5C), as shown in Table 9.

Table 9

[0360] The MDA-MB-436 PARP inhibitor-resistant strain was generated by long-term in vitro treatment with PARP inhibitors that are olaparib (Ola R ) or niraparib (Nir R ). Resistant cells were confirmed by sequencing to have a BRCA1 reversion mutation. The parental MDA-MB-436 cell line remained sensitive to PARP inhibitors as expected (Figure 5A), while Nir R (Figure 5B) and Ola R(Figure 5C) The MDA-MB-436 cell line is no longer sensitive to PARP inhibitors but is sensitive to azenocertive. Azenocertive activity was further confirmed in vivo in PARP inhibitor-resistant MDA-MB-436 CDX models. In MDA-MB-436 niraparib-resistant models (Figure 5E) and MDA-MB-436 olaparib-resistant models (Figures 5F and 5G), azenocertive administered at 80 mg / kg achieved a significant reduction in tumor volume compared to PARP inhibitors. (Progenitor TNBC animal model) Figure 5D shows the treatment of WEE1 inhibitors or PARP inhibitors in patients without PARP inhibitor resistance. In summary, these data indicate that olaparib and niraparib-resistant models remain sensitive to WEE1 inhibition but not to PARP inhibitors.

[0361] Furthermore, these data suggest that azenocertib may overcome PARP inhibitor resistance in patients with BRCA reverse mutations. Example 6 - Efficacy of azenocertib in human subjects with HRD+ platinum-resistant ovarian cancer and PARP inhibitor resistance.

[0362] Subjects with HGSOC who were selected to have an HRD+ status (e.g., BRCA1m), as confirmed by a qualitative next-generation sequencing-based in vitro diagnostic test (FoundationOne® CDx), were administered azenocerutib at a dose of at least 400 mg once daily for 5 consecutive days, followed by a 2-day off schedule. Subjects received azenocerutib for 5 months. The subjects were 64-year-old women who had previously received the following seven treatment lines: (1) carboplatin / paclitaxel / bevacizumab / olaparib (PD), (2) pembrolizumab (PD), (3) NaPi2b-targeted ADC (XMT-1536) (PD), (4) carboplatin / gemcitabine / bevacizumab (PD), (5) pegylated doxorubicin (PD), (6) topotecan (PD), and (7) PABP-1 RNP (ATRC-101) (PD). After treatment with azenocerutib, the subjects showed a -48% cPR. As shown in Figure 6, the target lesions in the subjects were no longer visible.

[0363] These data demonstrate that azenocertib alone is effective against both HRD+ PARP inhibitor-sensitive and PARP inhibitor-resistant cancers. Furthermore, azenocertib combined with a PARP inhibitor can restore antitumor effects in PARP inhibitor-resistant HRD+ cancers. Example 7 - HRRm status associated with better overall survival in human subjects with serous adenocarcinoma of the uterus (USC)

[0364] Overall survival (OS) analysis was performed on HRRm and HRRwt or HRRm-negative subjects with USC (selected based on TP53 mutation status) from the Caris Life Science database (serum endometrial cancer) (Figures 7A and 7B). Figure 7A measures OS from the time of sample collection. Figure 7B measures OS from the time of initiation of carboplatin treatment. The OS analysis shows that HRRm subjects had a better overall survival. Example 8 - In vitro efficacy of azenocertib in additional PARP inhibitor-sensitive and PARP inhibitor-resistant cell line models

[0365] Azenocertib, olaparib, and AZD5305 (PARP1 selective inhibitor) were individually tested in vitro in a panel of HRD+ cells as shown in Table 10. Briefly, cells were seeded in the recommended medium at a density of 1,000 cells per well in 96-well plates. After 24 hours, drug treatment was performed, and cells were incubated at 37°C in 5-cell doubling increments. Cell viability was measured using CellTiter-Glo (CTG) (Promega) as recommended by the manufacturer. The viability percentage was calculated as the percentage of cell viability compared to a vehicle control with DMSO alone. Dose-response curves were fitted using Graphpad Prism 9 and IC50 was calculated. 50 The value was determined. [Table 10]

[0366] As shown in the dose-response curves in Figures 8A–8E, azenocertib reduces tumor cell proliferation in HRD+ cells that are both PARP inhibitor-sensitive and PARP inhibitor-resistant. Resistance to PARP inhibitors in cell lines HCC1937, COV362, and HCC1569 is shown in the curves and IC for olaparib and AZD5305. 50 This is confirmed by the values ​​(Figures 8B-8D). PARP inhibitor resistance in HCC1937 is conferred by the FAM35A inactivating mutation. Example 9 - In vivo antitumor efficacy of azenocertib monotherapy and azenocertib + PARP inhibitor combination therapy in a xenograft (CDX) model derived from a PARP inhibitor-resistant triple-negative breast cancer cell line.

[0367] The study in Example 9 demonstrates the antitumor activity of azenoceretib in a PARP inhibitor-resistant xenograft model of HRD+TNBC. The antitumor activity of azenoceretib monotherapy or in combination with olaparib was evaluated in an in vivo HCC1937 model in mice (Figure 9), and Table 11 summarizes the groups and treatments. This example demonstrates the efficacy of azenoceretib in a BRCA mutant TNBC model resistant to PARP inhibitors due to the aforementioned FAM35A mutation. Treatment with olaparib monotherapy at 100 mg / kg QD confirmed HCC1937 resistance to PARP inhibitors. Azenoceretib monotherapy at 60 or 80 mg / kg QD 5:2 achieved significant tumor growth inhibition of 80% and 89%, respectively. Concurrent combination therapy with olaparib at 100 mg / kg QD and azenocerutib at 60 or 80 mg / kg QD (5:2) also achieved significant tumor growth inhibition of 89% or 99%, respectively. Furthermore, combination therapy with alternating / consecutive weeks of olaparib at 100 mg / kg QD and azenocerutib at 80 mg / kg QD (5:2) was tested, but showed lower efficacy than both concurrent and consecutive monotherapy with azenocerutib. These data suggest that azenocerutib may overcome PARP inhibitor resistance in BRCA mutant TNBCs, including BRCA mutant TNBCs with FAM35A mutations. [Table 11]

[0368] SUM149PT is a TNBC xenograft model possessing a BRCA1 splice isoform (Δ11q) that produces a cleaved, partially functional protein, thereby promoting resistance to PARP inhibitors. Azenocertiveb monotherapy and its combination with olaparib or AZD5305 were evaluated in vivo in the SUM149PT model in mice (Figures 10A-10B), and Table 12 summarizes the groups and treatments. SUM149PT resistance to PARP inhibitors was confirmed by monotherapy with olaparib at 100 mg / kg QD (Figure 10A) or the PARP1 selective inhibitor AZD5305 at 0.1 or 1 mg / kg QD (Figure 10B). Azenocertiveb monotherapy at 60, 80, and 100 mg / kg QD 5:2 achieved TGI of 82%, 91%, and 101%, respectively. Concomitant use of olaparib at 100 mg / kg QD and azenocertib at 60 or 80 mg / kg QD (5:2) showed a 96% success rate for each drug. And achieved a TGI of 105% (Figure 10A), while concurrent use of AZD5305 at 0.1 or 1 mg / kg QD and azenocertiveb at 80 mg / kg QD (5:2) achieved TGI of 105% and 109%, respectively (Figure 10B). These data suggest that azenocertiveb can overcome PARP inhibitor resistance in BRCA mutant TNBCs, including BRCA mutant TNBCs with the BRCA1 splice isoform (Δ11q) and BRCA mutant TNBCs with mutations in FAM35A. [Table 12] Equivalents and range

[0369] Those skilled in the art will be able to recognize or confirm many equivalents to the specific embodiments of the invention described herein by means of ordinary experiments alone. The scope of this disclosure is not intended to be limited to the foregoing description, but rather to be as set forth in the following claims.

Claims

1. A method of treating cancer, A method comprising administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to subjects selected to have cancer with homologous recombination repair deficiency (HRD).

2. The method according to claim 1, wherein the HRD is caused by a mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

3. A method of treating cancer, A method comprising administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to subjects selected to have cancer with homologous recombination repair deficiency (HRD-positive or HRD+) status.

4. The method according to claim 3, wherein the HRD-positive (HRD+) state is caused by a mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

5. A method of treating cancer, To determine whether the subject has homologous repair deficiency (HRD) or HRD-positive (HRD+) status, or to have determined such status. If the subject has HRD or is HRD-positive (HRD+), the subject is administered an effective dose of azenocertib or a pharmaceutically acceptable salt thereof. A method wherein administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of the cancer in the subject.

6. The method according to claim 5, wherein the HRD or HRD-positive (HRD+) state is caused by a mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

7. The method according to any one of claims 1 to 6, wherein the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 200 to about 450 mg / day, or about 200 to about 400 mg / day, or about 200 to about 350 mg / day, or about 250 to about 400 mg / day, or about 250 to about 350 mg / day, or any equivalent thereof.

8. The method according to any one of claims 1 to 7, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 mg / day or an equivalent thereof.

9. The method according to any one of claims 1 to 8, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 to about 300 mg / day or an equivalent thereof.

10. The method according to any one of claims 1 to 8, wherein the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is at least about 300 to about 350 mg / day or an equivalent thereof.

11. The method according to any one of claims 1 to 8, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 350 to about 400 mg / day or an equivalent thereof.

12. The method according to any one of claims 1 to 11, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered once daily (QD).

13. The method according to any one of claims 1 to 12, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered on an intermittent dosing schedule.

14. The method according to claim 13, wherein the intermittent administration schedule includes five administration days and two administration rest days in each of the administration weeks of one week or more.

15. The method according to claim 13 or 14, wherein the intermittent administration schedule includes, in each of the administration weeks of one week or more, five consecutive administration days and two consecutive administration rest days.

16. The method according to any one of claims 1 to 15, wherein the HRD or HRD-positive (HRD+ state) is caused by the cancer having a homologous recombination repair mutation (HRRm).

17. The method according to claim 16, wherein the HRRm is a mutation in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

18. The method according to claim 17, wherein the HRD or HRD-positive (HRD+ state) is caused by the cancer having a mutation in BRCA1 and / or BRCA2.

19. The method according to claim 18, wherein the HRD or HRD-positive (HRD+ state) is caused by the cancer having a BRCA1 pathogenic mutation.

20. The aforementioned BRCA1 pathogenic mutation is BRCA1 Ｇｌｕ１６０７Ｔｅｒ The method according to claim 19.

21. The method according to any one of claims 1 to 20, wherein the HRD or HRD-positive (HRD+ state) is caused by the cancer having a homologous recombination repair reversion mutation.

22. The method according to claim 21, wherein the homologous recombination repair reversion mutation is located in a gene selected from the group consisting of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

23. The method according to any one of claims 1 to 22, wherein the cancer has additional mutations in genes selected from the group consisting of TP53, AKT1, BRCA2, CDKN2A, KDM6A, PTEN, RB1, and FAM35A.

24. The method according to any one of claims 1 to 23, wherein the HRD or HRD-positive (HRD+ state) is caused by the cancer having a BRCA1 splicing isoform.

25. The BRCA1 splicing isoform is BRCA1-Δ11q splicing The method according to claim 24, wherein the material is a guaisoform.

26. The method according to any one of claims 1 to 25, wherein the method comprises administering an effective dose of azenocertib or a pharmaceutically acceptable salt thereof to a subject selected to have cancer having a BRCA1 / 2 variant or a BRCA1 / 2-positive state.

27. The method according to any one of claims 1 to 26, wherein the method comprises administering to the subject an effective dose of azenocertib or a pharmaceutically acceptable salt thereof in combination with an effective dose of a PARP inhibitor or a pharmaceutically acceptable salt thereof.

28. The method according to claim 27, wherein the PARP inhibitor is niraparib or a pharmaceutically acceptable salt thereof.

29. The method according to claim 27, wherein the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof.

30. The method according to claim 27, wherein the PARP inhibitor is a PARP1-selective inhibitor or a pharmaceutically acceptable salt thereof.

31. The method according to claim 30, wherein the PARP1 selective inhibitor is salparib (AZD5305) or a pharmaceutically acceptable salt thereof.

32. The method according to any one of claims 1 to 31, wherein the subject is receiving one or more prior treatment lines.

33. The method according to any one of claims 1 to 32, wherein the cancer is platinum-resistant.

34. The method according to any one of claims 1 to 33, wherein the cancer is resistant to PARP inhibitors.

35. The method according to claim 33 or 34, wherein the subject has previously received a PARP inhibitor or a pharmaceutically acceptable salt thereof.

36. The aforementioned cancers include gliablastoma (GBM), astrocytoma, meningioma, craniopharyngioma, medulloblastoma, other brain cancers, head and neck cancers, 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, colon cancer, colorectal cancer, uterine cancer, endometrial cancer, esophageal cancer, eye cancer, and gallbladder cancer. Cancer, stomach cancer, gastrointestinal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, hematological malignancies, head cancer, hematological malignancies, Kaposi's sarcoma, kidney cancer, pharyngeal and hypopharyngeal cancer, liver cancer, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lymphoma, mesothelioma, melanoma, multiple myeloma, neuroblastoma, nasopharyngeal cancer, cervical cancer, ovarian cancer, osteosarcoma, sarcoma, gastrointestinal stromal tumor (GIST), pancreatic cancer, pituitary cancer, prostate cancer, kidney cancer Retinoblastoma, salivary gland cancer, skin cancer, gastric cancer, small intestine cancer, splenic cancer, sarcoma, testicular cancer, thymic cancer, thyroid cancer, uterine cancer, uterine sarcoma, serous adenocarcinoma of the uterus (USC), uterine CS, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, Wilms' tumor, solid tumors or liquid tumors, HGSOC, invasive breast cancer, triple-negative breast cancer (TNBC), esophageal and gastric cancer, gastric cancer, esophageal cancer, pRCC, ccRC C, chromophobic RCC, head and neck cancer, adenoid cystic carcinoma (ACC), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), low-grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), cholangiocarcinoma, acute myeloid leukemia (AML), CLL (chronic lymphocytic leukemia), ALL (acute lymphocytic leukemia), myelodysplastic syndrome (MDS), thymoma, BR The method according to any one of claims 1 to 35, selected from the group consisting of AF-mutated metastatic colorectal cancer and uveal melanoma.

37. The method according to claim 36, wherein the cancer is ovarian cancer.

38. The method according to claim 37, wherein the epithelial ovarian cancer is high-grade serous ovarian carcinoma (HGSOC).

39. The method according to claim 36, wherein the cancer is breast cancer.

40. The method according to claim 39, wherein the breast cancer is triple-negative breast cancer.

41. The method according to claim 39, wherein the breast cancer is HER2-expressing or HER2-positive (HER2+) breast cancer.

42. The method according to claim 36, wherein the cancer is endometrial cancer.

43. The method according to claim 36, wherein the cancer is serous adenocarcinoma of the uterus (USC).

44. The method according to any one of claims 1 to 35, wherein the cancer is peritoneal cancer (for example, primary peritoneal cancer).

45. The method according to any one of claims 1 to 35, wherein the cancer is fallopian tube cancer.

46. A method for treating PARP inhibitor-resistant breast cancer, To determine whether the subject has homologous repair deficiency (HRD) or HRD-positive (HRD+) status, or to have determined such status. If the subject has HRD or is HRD-positive (HRD+), the subject is administered an effective dose of azenocertib or a pharmaceutically acceptable salt thereof. A method wherein administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of the cancer in the subject.

47. The method according to claim 46, wherein the HRD or HRD-positive (HRD+ state) is caused by the PARP inhibitor-resistant breast cancer having a BRCA1 reverse mutation.

48. The method according to claim 46, wherein the HRD or HRD-positive (HRD+ state) is caused by the PARP inhibitor-resistant breast cancer having a BRCA1 mutation.

49. The method according to any one of claims 46 to 48, wherein the HRD or HRD-positive (HRD+ state) is caused by the cancer having a BRCA1 splicing isoform.

50. The method according to claim 49, wherein the BRCA1 splicing isoform is a BRCA1-Δ11q splicing isoform.

51. The method according to any one of claims 47 to 50, wherein the cancer has an additional mutation in the gene FAM35A.

52. The method according to any one of claims 47 to 51, wherein the cancer has an additional mutation in the gene TP53.

53. The method according to any one of claims 46 to 52, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 mg / day or an equivalent thereof.

54. The method according to any one of claims 46 to 53, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 to about 300 mg / day or an equivalent thereof.

55. The method according to any one of claims 46 to 53, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 300 to about 350 mg / day or an equivalent thereof.

56. The method according to any one of claims 46 to 55, wherein the method comprises administering to the subject an effective dose of azenocertib or a pharmaceutically acceptable salt thereof in combination with an effective dose of a PARP inhibitor or a pharmaceutically acceptable salt thereof.

57. The method according to claim 56, wherein the PARP inhibitor is niraparib, olaparib, or salparib, or a pharmaceutically acceptable salt of any of the foregoing.

58. The method according to any one of claims 46 to 57, wherein the PARP inhibitor-resistant breast cancer is niraparib-resistant.

59. The method according to any one of claims 46 to 57, wherein the PARP inhibitor-resistant breast cancer is olaparib-resistant.

60. The method according to any one of claims 46 to 59, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing schedule.

61. The method according to claim 60, wherein the intermittent administration schedule includes five administration days and two administration rest days in each of the administration weeks of one week or more.

62. A method for treating chemotherapy-resistant ovarian cancer, To determine whether the subject has homologous repair deficiency (HRD) or HRD-positive (HRD+) status, or to have determined such status. If the subject has HRD or is HRD-positive (HRD+), the subject is administered an effective dose of azenocertib or a pharmaceutically acceptable salt thereof. A method wherein administration of azenocertib or a pharmaceutically acceptable salt thereof results in inhibition of the cancer in the subject.

63. The method according to claim 62, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is at least about 250 mg / day or an equivalent thereof.

64. The method according to claim 62 or 63, wherein the effective dose of azenocertiveb or a pharmaceutically acceptable salt thereof is about 350 to about 400 mg / day or an equivalent thereof.

65. The method according to any one of claims 62 to 64, wherein the effective dose of azenocertib or a pharmaceutically acceptable salt thereof is administered in an intermittent dosing schedule.

66. The aforementioned intermittent administration schedule consists of 5 administration days in each of the administration weeks of one week or more. The method according to claim 65, including two days of administration suspension.

67. The method according to any one of claims 62 to 66, wherein the HRD or HRD-positive (HRD+ state) is caused by the cancer having a mutation in BRCA1 and / or BRCA2.

68. The method according to any one of claims 1 to 67, wherein the treatment results in a response rate of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more.

69. The method according to claim 68, wherein the response rate is measured by complete response (CR), partial response (PR), CA-125 50% response, or a combination thereof.

70. The method according to any one of claims 1 to 69, wherein the treatment results in a progression-free survival (PFS) of 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or longer.

71. The method according to any one of claims 1 to 70, further comprising first determining the HRD state before selecting the object.

72. The method according to claims 1 to 71, wherein the HRD includes copy number variation, somatic copy number change (SCNA), aneuploidy, loss of heterozygosity (LOH), large-scale state transition (LST), telomere allele imbalance (TAI), or a combination thereof.

73. The method according to any one of claims 1 to 72, wherein the HRD-positive (HRD+) status is determined using a functional assay or genome sequencing.

74. The method according to any one of claims 1 to 72, wherein the HRD-positive (HRD+) state is determined using an HRD score.

75. The method according to any one of claims 5 to 74, wherein the inhibition of the cancer is measured by the inhibition of tumor growth.

76. The method according to any one of claims 5 to 75, wherein the inhibition of the cancer is measured by a reduction in tumor volume.

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