Cdk2 inhibitor blu-222 for treating cancer

Abstract

The present disclosure provides an improved method of treating cancer using N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl) methyl)-1H-pyrazolo [3, 4-b] pyrazine-6-amine, or a pharmaceutically acceptable salt thereof.

Description

Cross-references to related applications

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 484,383, filed February 10, 2023, and U.S. Provisional Patent Application No. 63 / 505,507, filed June 1, 2023, the disclosure of each of which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0002] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that play a central role in the cell cycle process. CDK levels remain relatively constant throughout the cell cycle, and selective activation of specific CDKs ensures the correct sequence of steps in the cell cycle process. CDK activation requires heterodimerization with regulatory subunits called cyclins. Cell cycle dysregulation is a common feature of human cancers.

[0003] Cyclin-dependent kinase 2 (CdK2) participates in a range of biological activities. CDK2 is a key cell cycle regulator, active from late G1 phase through the entire S phase. CDK2 participates in the DNA damage response (DDR) via the homologous recombination (HR) pathway. CDK2 also regulates various aspects of the apoptosis pathway. Cyclin E1 (CCNE1), cyclin E2 (CCNE2), cyclin A1 (CCNA1), and cyclin A2 (CCNA2), along with p21Cip1 / Waf1, p27Kip1, and p57Kip2 (cyclin-dependent kinase inhibitors of the cyclin-CDK2 complex), are the main regulators of CDK2 activity. In cancer, dysregulation of CDK2 binding by cyclin E1, E2, A1, or A2, or dysregulation of the activity of cyclin-dependent kinase inhibitor proteins, may occur. (See S. Tadesse et al., Drug DiscoveryToday, Vol. 25, No. 2, February 2020) CDK2 dysregulation may occur through several mechanisms. CCNE1 amplification and / or overexpression have been confirmed in ovarian and breast cancer (see Scaltriti, M. et al., Proc. Natl Acad. Sci. USA 108, 3761–3766 (2011); and Etemadmoghadam, D. et al., Proc. Natl Acad. Sci. USA 110, 19489–19494 (2013). Poor outcomes in gastric, endometrial, and other cancers are associated with CCNE1 overexpression and / or amplification (see Ooi et al., Hum Pathol. (2017) 61:58–67; and Noske et al., Oncotarget (2017) 8:14794–14805).

[0004] While these findings suggest that CDK2 is a potential target for cancers with dysregulated CDK2 activity, no agents that selectively target CDK2 have been approved to date. Therefore, there is a need to develop new selective CDK2 inhibitors.

[0005] The structure of a CDK2 inhibitor referred to herein as "Compound (I)" or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine is shown below: Compound (I) There is a need to develop improved methods for treating cancer subjects with compound (I), including dosing regimens. Summary of the Invention

[0006] In one aspect, this disclosure provides a method of treating a subject suffering from cancer with compound (I) or a pharmaceutically acceptable salt thereof. This disclosure provides a dosage regimen for compound (I) or a pharmaceutically acceptable salt thereof for treating cancer. More specifically, this disclosure provides a method of treating cancer comprising orally administering, daily, an amount of compound (I) from 100 mg to 1600 mg to a subject in need. (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1600 mg of compound (I). The purpose of this disclosure is to provide a novel method for treating cancer subjects with a safe and effective daily dose. Compound (I) has oral bioavailability. Compound (I) is highly potent and has CDK family selectivity and overall kinase selectivity.

[0007] In some implementation schemes, the cancer is selected from breast cancer, endometrial cancer, esophageal cancer, stomach cancer, lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

[0008] This article also provides methods for treating patients with amplified CCNE1 expression levels who have or are at risk of developing solid tumors, including oral administration of compound (I) in amounts ranging from 100 mg to 1600 mg daily to subjects in need: (I), or a pharmaceutically acceptable salt of compound (I) in an amount equivalent to 100 mg to 1600 mg.

[0009] The solid tumor cancers under consideration can be at least one of the following: uterine cancer (including uterine carcinosarcoma, endometrial cancer of the uterine corpus (UCEC)), endometrial cancer, breast cancer (including invasive breast cancer, TNBC (triple-negative breast cancer), ER (estrogen receptor)+ / HER2 (human epidermal growth factor 2)- breast cancer, HR (hormone receptor)+ / HER2 (human epidermal growth factor 2)- breast cancer, HER2- breast cancer, HER2-low breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), gastric cancer (including gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer (CRC), and pancreatic cancer. Cancers including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myelodysplastic neoplasm (MPN), sarcoma (including osteosarcoma), esophageal cancer (including esophageal cancer and esophageal adenocarcinoma), bladder cancer (including bladder urothelial carcinoma (BLCA)), lung cancer (including squamous cell carcinoma and non-small cell lung cancer, such as EGFRm (epidermal growth factor receptor mutant) + non-small cell lung cancer), bile duct cancer, adrenocortical carcinoma, or mesothelioma.

[0010] On the other hand, this disclosure provides a method for determining changes in the levels of one or more biomarkers after administering 100 mg to 1600 mg of compound (I) or a pharmaceutically acceptable salt of an amount equivalent to 100 mg to 1600 mg of compound (I) to a subject who has cancer or is at risk of developing cancer, wherein treatment with compound (I) alters the levels of one or more biomarkers. Attached Figure Description

[0011] Figure 1 This shows the study design of an ongoing Phase 1 / 2 open-label first-in-human study (NCT05252416). BC, breast cancer; CCNE1Cyclin E1; CDK, cyclin-dependent kinase; CDK4 / 6i, CDK4 / 6 inhibitor; EC, endometrial cancer; GC, gastric cancer; HER2–, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; OC, ovarian cancer; SOC, standard treatment. a Based on Bayesian optimal interval (BOIN) incremental design. b Part 1B is not present in the Phase 1 dose escalation. c Phase 2 will be initiated once the recommended Phase 2 dose (RP2D) is determined. d In the Phase 2 group, patients will receive compound (I) monotherapy during RP2D in Parts 2A and 2B, compound (I) and carboplatin during RP2D in Part 2C, and compound (I) and ribociclib during RP2D in Part 2D. In the combination therapy groups (Parts 2B, 2C, and 2D), the dose of compound (I) will not exceed the dose of compound (I) monotherapy during RP2D. e For part 2B, fulvestrant will be administered according to local prescribing information and institutional standards. f For Part 2D, ribociclib and fulvestrant will be administered at dose levels determined for a specific dose escalation cohort, based on local prescribing information and institutional standards.

[0012] Figure 2 The mean plasma concentration of compound (I) over time was shown after twice-daily (BID) administration of 50–600 mg.

[0013] Figure 3 The dose-dependent serum TK1 response is shown in patients receiving monotherapy with compound (I) at escalating doses (by dose cohort). The dashed line indicates a 30% reduction in TK1. Other types of tumors include adenocarcinoma, anal neuroendocrine carcinoma, cervical cancer, chondroblastic osteosarcoma, colorectal cancer, fallopian tube cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, prostate cancer, and thyroid cancer.

[0014] Figure 4 The percentage of pRb-positive cells in tumor biopsies of patients treated with screening samples (dark gray bars) and compound (I) monotherapy is shown. Light gray bars are marked below the bar chart at time points, where C represents a cycle and D represents a day. For example, patient 6 was assessed at day 13 of cycle 1 (i.e., 12 hours after the most recent dose of compound (I)). Below the bar chart, the cancer type and the percentage change in pRb percentage between the screening sample (dark gray bar) and the time point (C1DX) sample (light gray bar) are indicated. pRb is phosphorylated retinoblastoma protein (Rb).

[0015] Figure 5 This demonstrates a partial response of target liver lesions in HR+ / HER2- metastatic breast cancer patients to monotherapy with compound (I). Detailed Implementation

[0016] Treatment International application publication number WO 2023 / 278326 discloses a compound (I) having the following structural formula, the entire teaching of which is incorporated herein by reference: Compound (I) is an investigational, orally administered, potent, and selective CDK2 inhibitor. Compound (I) exhibits oral bioavailability. Compound (I) is highly potent and possesses both CDK family selectivity and overall kinase selectivity.

[0017] Preclinical studies have shown that compound (I) in CCNE1 In expanded ovarian cancer models and when used in combination with CDK4 / 6 inhibitors, it demonstrated potent antitumor activity in CDK4 / 6 inhibitor-naïve and platinum-resistant HR+ / HER2- breast cancer (Choi YJ et al., AACR 2021 report; poster number 1279; Brown V et al., AACR 2022 report; poster number 2306; Brown V et al., SABCS 2022 report; poster number P6-10-07).

[0018] In one aspect, this disclosure provides a method of treating a subject with cancer using compound (I) or a pharmaceutically acceptable salt thereof. This disclosure provides a dosing regimen for compound (I) or a pharmaceutically acceptable salt thereof for treating cancer. This disclosure provides a method of treating cancer comprising administering to a subject in need 100 mg to 1600 mg of compound (I), or an amount equivalent to 100 mg to 1600 mg of its pharmaceutically acceptable salt. In some embodiments, the method of treating cancer comprises administering to a subject in need orally daily 100 mg to 1600 mg of compound (I), or an amount equivalent to 100 mg to 1600 mg of its pharmaceutically acceptable salt.

[0019] The term "pharmaceutically acceptable salt" refers to a medicinal salt that, within reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, or allergic responses, and has a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. […]. J. Pharm. Sci. Pharmacologically acceptable salts are described in 1977, 66, 1–19.

[0020] The compound (I) disclosed herein can be used in the form of a free base or a salt. In some embodiments, the pharmaceutically acceptable salt is selected from methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, naphthalene-2-sulfonates, glycine salts, succinates, citrates, tartrates, adipates, aspartate salts, histidine salts, vanillin salts, phosphates, hydrochlorides, hydrobromic acids, nitrates, and sulfates. In some embodiments, the pharmaceutically acceptable salt of compound (I) is selected from salts of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-4-sulfonic acid, naphthalene-2-sulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid.

[0021] In some embodiments, in the treatment methods disclosed herein, compound (I) is administered in the form of a free base. In some embodiments, in the treatment methods disclosed herein, a pharmaceutically acceptable salt of compound (I) is administered.

[0022] Compound (I) is a potent, selective CDK2 inhibitor and is intended for the treatment of various cancers. As used herein, the term "selective CDK2 inhibitor" means a compound that selectively inhibits CDK2 compared to other CDKs and kinases. In other words, a selective CDK2 inhibitor has no or low activity against other CDKs (most notably CDK1) and kinases. The inhibitory activity of a selective CDK2 inhibitor against CDK2 is significantly higher than that against other CDKs and many other kinases in the IC50-900 kinase inhibitory concentration. 50 More effective in terms of value (i.e., IC) 50 (Values ​​below sub-nanomolar). Potency can be measured using known biochemical assays. Advantages associated with this selectivity may include improved efficacy and reduced CDK1-mediated mid-target toxicity. Compound (I) exhibits favorable toxicity profiles relative to other non-kinase targets.

[0023] Compound (I) is selective for CDK2 compared to CDK1. In some such embodiments, compound (I) exhibits at least 10-fold selectivity for CDK2 compared to CDK1. In other embodiments, compound (I) exhibits at least 20-fold selectivity for CDK2 compared to CDK1. In a specific embodiment, compound (I) exhibits at least 30-fold selectivity for CDK2 compared to CDK1. In some embodiments, compound (I) exhibits at least 40-fold selectivity for CDK2 compared to CDK1. In other embodiments, compound (I) exhibits at least 50-fold selectivity for CDK2 compared to CDK1. Compound (I) is selective for CDK2 compared to CDK4 and / or CDK6. In some such embodiments, compound (I) exhibits at least 10-fold selectivity for CDK2 compared to CDK4 and / or CDK6. In other embodiments, compound (I) exhibits at least 20-fold selectivity for CDK2 compared to CDK4 and / or CDK6. In a specific embodiment, compound (I) exhibits at least 30-fold selectivity for CDK2 compared to CDK4 and / or CDK6.

[0024] Compound (I) has the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Hepatic metabolism is the primary pathway for the elimination of small molecule drugs. The clearance of compounds by hepatic metabolism can be assessed in vitro using human liver microsomes (HLM) or human hepatocytes. The compound is incubated with HLMs plus appropriate cofactors or human hepatocytes, and the consumption of the compound is measured to determine the in vitro intrinsic clearance (Clint). Clint is converted to systemic clearance (CL), and the liver extraction rate (ER) is determined by dividing CL by standard human liver blood flow. Compounds with low liver extraction rates are considered to have good metabolic stability. In some embodiments, the compounds of this disclosure have calculated ERs of <0.3, <0.4, <0.5, and <0.6.

[0025] In another embodiment, the cancer is characterized by amplification and / or overexpression of CCNE1 or CCNE2. In some embodiments, the cancer is characterized by elevated or abnormal expression of CCNE1 or CCNE2. Therefore, in some embodiments of the method, it has been previously determined that the cyclin E1 (CCNE1) gene in the subject or patient is elevated, and / or that the expression level of CCNE1 in biological samples obtained from the subject or patient is higher than the control expression level of CCNE1.

[0026] In another embodiment, this disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells in vitro. The method includes contacting tumor (e.g., cancer) cells in vitro with compound (I) or a pharmaceutically acceptable salt thereof. In another embodiment, this disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells with elevated or abnormal CCNE1 expression in a subject or patient. The method includes administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject or patient in need.

[0027] In some embodiments, this disclosure provides the use of 100 mg to 1600 mg of compound (I) or an amount equivalent to 100 mg to 1600 mg of its pharmaceutically acceptable salt in the preparation of a medicament for treating cancer.

[0028] As used herein, “cancer” refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named after the type of cells that form them, blood cancers, myeloma, or lymphomas. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancers originating in a specific site in the body, metastatic cancers that have spread from their origin to other parts of the body, relapses following remission of an initial primary cancer, and second primary cancers that are new primary cancers in individuals with a history of cancer of a different type than the latter. In some such embodiments, the cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is characterized by elevated or abnormal expression of CCNE1 or CCNE2.

[0029] Cancers treated according to the disclosed methods include breast cancer, ovarian cancer, bladder cancer, uterine cancer (e.g., uterine carcinosarcoma), prostate cancer (e.g., androgen receptor (AR) dependent and AR-independent), lung cancer (including NSCLC, SCLC, squamous cell carcinoma (e.g., lung squamous cell carcinoma (LUSC)) or adenocarcinoma (e.g., lung adenocarcinoma (LUAD))), esophageal cancer, head and neck cancer, colorectal cancer (e.g., colon cancer, colorectal adenocarcinoma (COADREAD)), kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer (including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), stomach cancer (i.e., gastric cancer), urothelial carcinoma, brain cancer, mesothelioma (MESO), and skin cancer. Cancer (e.g., melanoma), sarcoma (including osteosarcoma), or thyroid cancer, including metastases (particularly brain metastases) of all listed cancers. In one implementation, the cancer is uterine cancer (including uterine carcinosarcoma (UCS) and uterine corpus endometrial cancer (UCEC)), endometrial cancer (including serous endometrial cancer (SEC)), breast cancer (including invasive breast cancer (BRCA), TNBC (triple-negative breast cancer), HR+ breast cancer (hormone receptor-positive breast cancer), ER+ breast cancer (estrogen receptor-positive breast cancer), HR+ / HER2- breast cancer (hormone receptor-positive, human epidermal growth factor 2-negative breast cancer), ER+ / HER2- breast cancer (estrogen receptor-positive, human epidermal growth factor 2-negative breast cancer), ER+ / HER2- breast cancer (estrogen receptor-positive, human epidermal growth factor 2-negative breast cancer), human epidermal growth factor 2-negative ... Human epidermal growth factor 2 (HGF2) negative breast cancer, PR+ / HER2- breast cancer (progesterone receptor positive, HGF2 negative breast cancer), HER2- breast cancer (HGF2 negative breast cancer), HER2-low breast cancer (HGF2 low breast cancer), and HER2+ breast cancer (HGF2 positive breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma (OV) and high-grade serous ovarian cancer (HGSOC)), gastric cancer (including gastric adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), kidney cancer, head and neck cancer, liver cancer, and prostate cancer. (Including androgen receptor (AR) dependent, AR independent, and castration-resistant prostate cancer (CRPC)), skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myelodysplastic neoplasm (MPN), sarcoma (SARC, including osteosarcoma), esophageal cancer (including esophageal cancer (ESCA)), bladder cancer (including urothelial carcinoma of the bladder), lung cancer (including squamous cell carcinoma of the lung, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), such as EGFRm (epidermal growth factor receptor mutant) + non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma (ACC) or mesothelioma.In some embodiments, the cancer is characterized by overexpression and / or amplification of CCNE1 and / or CCNE2 as described herein. In some embodiments of the methods provided herein, the subject is identified as having a cancer characterized by amplification and / or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is characterized by elevated and / or abnormal expression of CCNE1 and / or CCNE2 as described herein. In some embodiments of the methods provided herein, the subject is identified as having a cancer characterized by elevated and / or abnormal expression of CCNE1 and / or CCNE2.

[0030] In other embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or stomach cancer. In some such embodiments, the cancer is characterized by elevated and / or abnormal expression of CCNE1 and / or CCNE2.

[0031] In further embodiments of the methods provided herein, the cancer is selected from breast cancer (including ER+ / HER2- breast cancer, HR+ / HER2- breast cancer, PR+ / HER2- breast cancer, and triple-negative breast cancer), endometrial cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer (including PDAC), and prostate cancer. In some embodiments of the methods provided herein, the cancer is selected from ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and pulmonary adenosarcoma. In some embodiments of the methods provided herein, the cancer is selected from ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, and breast cancer. In some embodiments, the cancer is characterized by elevated and / or abnormal CCNE1 expression. In some embodiments, the cancer progresses despite platinum-based treatment.

[0032] In some implementations, the cancer is platinum-resistant and / or platinum-refractory. In some implementations, the cancer still progresses despite platinum treatment.

[0033] In some implementations, the cancer is adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0034] In other embodiments, the cancer is breast cancer, including, for example, ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is chemotherapy- or radiation-induced platinum-resistant breast cancer, endocrine platinum-resistant breast cancer, trastuzumab platinum-resistant breast cancer, or breast cancer exhibiting primary or acquired platinum resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by elevated and / or abnormal expression of CCNE1 and / or CCNE2.

[0035] In some embodiments, the cancer is HR-positive breast cancer. In some embodiments, the breast cancer is ER-positive breast cancer. In some embodiments, the breast cancer is HR-positive, HER2-negative breast cancer. In some embodiments, the breast cancer is ER-positive, HER2-negative breast cancer. In some embodiments, the breast cancer is PR-positive, HER2-negative breast cancer. In some embodiments, the breast cancer is responsive to CDK4 / 6 inhibitor therapy. In some embodiments, the breast cancer is platinum-resistant to CDK4 / 6 inhibitor therapy. In some embodiments, the breast cancer progresses despite treatment with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is fulvestrant. In some embodiments, the breast cancer progresses despite initial treatment with palbociclib, ribociclib, and / or fulvestrant, and subsequent treatment with abexilide and / or fulvestrant. In some embodiments, the method further includes administering an effective amount of the CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib and ribociclib, or a combination thereof. In some implementations, the CDK4 / 6 inhibitor is ribociclib. In some implementations, the breast cancer presents with elevated and / or aberrant CCNE expression.

[0036] In some implementations, breast cancer is triple-negative breast cancer.

[0037] In some embodiments, the cancer is ovarian cancer. In some such embodiments, the cancer is ovarian cancer characterized by elevated and / or abnormal expression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) ovarian cancer; (b) characterized by elevated and / or abnormal expression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the ovarian cancer is high-grade serous ovarian cancer (HGSOC).

[0038] In some embodiments, the cancer is endometrial cancer. In some such embodiments, the cancer is endometrial cancer characterized by elevated and / or abnormal expression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) endometrial cancer; (b) characterized by elevated and / or abnormal expression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the endometrial cancer is selected from carcinosarcoma endometrial cancer, clear cell endometrial cancer, grade 3 endometrioid endometrial cancer, and serous endometrial cancer. In some embodiments, the endometrial cancer is serous endometrial cancer (SEC).

[0039] In some implementations, the cancer is CCNE1-amplified ovarian cancer or CCNE1-amplified endometrial cancer.

[0040] In some embodiments, the cancer is lung cancer. In some such embodiments, the cancer is lung cancer characterized by elevated and / or abnormal expression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) lung cancer; (b) characterized by elevated and / or abnormal expression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is small cell lung cancer (SCLC).

[0041] In some embodiments, compound (I) is administered as a first-line therapy. In other embodiments, compound (I) is administered as a second-line (or subsequent) therapy. In some embodiments, compound (I) is administered as a second-line (or subsequent) therapy following treatment with an endocrine therapy agent and / or a CDK4 / CDK6 inhibitor. In some embodiments, compound (I) is administered as a second-line (or subsequent) therapy following treatment with an endocrine therapy agent such as an aromatase inhibitor, SERM, or SERD. In some embodiments, compound (I) is administered as a second-line (or subsequent) therapy following treatment with a CDK4 / CDK6 inhibitor. In some embodiments, compound (I) is administered as a second-line (or subsequent) therapy following treatment with one or more chemotherapy regimens (e.g., including taxanes, platinum-based drugs, pyrimidine antagonists, and / or gemcitabine). In some embodiments, compound (I) is administered as a second-line (or subsequent) therapy following treatment with a HER2-targeting agent (e.g., trastuzumab). In some embodiments, the compounds of this disclosure are administered as second-line (or subsequent) therapy after treatment with an EGFR inhibitor such as osimertinib. In some embodiments, the compounds of this disclosure are administered as second-line (or subsequent) therapy after treatment with a pyrimidine antagonist (e.g., 5-fluorouracil (5-FU)) and / or gemcitabine and / or platinum-based drugs (e.g., carboplatin and cisplatin).

[0042] In some implementations, the cancer is N-myc-amplified neuroblastoma cells (see Molenaar et al., Proc Natl Acad Sci USA 106(31): 12968-12973), K-Ras-mutant lung cancer (see Hu, S. et al., Mol Cancer Ther, 2015. 14(11): 2576-85), and cancer with FBW7 mutation and CCNE1 overexpression (see Takada et al., Cancer Res, 2017. 77(18): 4881-4893).

[0043] Examples of cancers that can be treated with compound (I) include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, adrenal cancer, and soft tissue sarcoma (including...). CIC-DUX4 sarcoma )Urethritis, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including asbestos-induced cancers), and combinations of the aforementioned cancers. Compound (I) may also be used to treat metastatic cancers.

[0044] In some embodiments, cancers treatable with compound (I) include, but are not limited to: melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90-inhibited platinum-resistant melanoma, cutaneous epidermal melanoma (SKCM)), renal cell carcinoma (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer (e.g., head and neck squamous cell carcinoma (NHSC)), urothelial carcinoma (e.g., bladder cancer), and cancers with high microsatellite instability (MSIhigh). Furthermore, this disclosure includes refractory or recurrent malignant tumors whose growth can be inhibited by compound (I).

[0045] In some implementations, the cancers that can be treated with compound (I) include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematologic cancers (e.g., lymphoma, leukemia (such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML)), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including follicular lymphoma, including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, or multiple myeloma), and combinations of said cancers.

[0046] In some implementations, cancers that can be treated with compound (I) include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma (e.g., hepatocellular carcinoma (LIHC)), Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, colon cancer, pancreatic islet cell carcinoma, oral cancer, oral cancer, pharyngeal cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, eye cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0047] In some implementations, cancers that can be treated with compound (I) include genomic identification of important cancer targets (GISTIC) as well as pheochromocytoma and paraganglioma (PCPG).

[0048] In some implementations, the cancers treatable with compound (I) include advanced / recurrent tumors; platinum-resistant or platinum-refractory ovarian cancer; endometrial cancer that has progressed after two or more lines of therapy (previously treated with platinum); gastric cancer that has progressed after two or more lines of therapy (previously treated with platinum); and HR+ / HER2- BC (including ER+ / HER2- BC and PR+ / HER2- BC) that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In some implementations, the cancers treatable with compound (I) include platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer; CCNE1-amplified endometrial cancer that has failed two or more lines of therapy; CCNE1-amplified advanced / recurrent tumors that do not belong to other groups; HR+ / HER2-BC that has progressed despite the presence of CDK4 / 6 inhibitors; and platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer. In one implementation, the subject has an advanced / recurrent tumor with CCNE1 amplification. In one embodiment, the subject has platinum-resistant or platinum-refractory ovarian cancer with CCNE1 amplification. In one embodiment, the subject has endometrial cancer that has progressed after two or more lines of therapy (including platinum therapy) (previously treated with platinum therapy, e.g., where the patient has previously been treated with platinum therapy). In one embodiment, the subject has endometrial cancer with CCNE1 amplification that has failed two or more lines of therapy (possibly including previous platinum therapy). In one embodiment, the subject has gastric cancer that has progressed after two or more lines of therapy (including platinum therapy) (previously treated with platinum therapy, e.g., where the patient has previously been treated with platinum therapy). In one embodiment, the subject has HR+ / HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In one embodiment, the subject's TNBC has progressed despite first- or more lines of therapy. In one embodiment, the subject's AR+ prostate cancer has progressed despite first- or more lines of therapy. In one embodiment, the subject's pancreatic cancer has progressed despite first- or more lines of therapy. In one embodiment, the subject's PDAC has progressed despite first- or more lines of therapy. In one embodiment, the subject has lung cancer with elevated CCNE1. In one implementation, the subject's NSCLC progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib). In another implementation, the subject's non-small cell lung cancer with elevated CCNE1 levels progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib).

[0049] In some implementations, the cancers that can be treated with compound (I) include, but are not limited to, blood cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0050] Exemplary blood cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, myeloproliferative disorders (such as primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0051] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0052] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchial carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma. Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilator intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0053] Exemplary urogenital cancers include kidney cancer (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma (PRAD), sarcoma, AR+ or AR-dependent prostate cancer, AR-independent prostate cancer, and CRPC) and testicular cancer (seminomatous seminoma, teratoma, embryonal carcinoma, teratomatoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma).

[0054] Exemplary liver cancers include hepatocellular carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0055] Exemplary bone cancers include, for example, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromycinoma, osteoid osteoma, and giant cell tumor.

[0056] Exemplary neurological cancers include skull cancers, meningeal cancers (meningioma, meningeal sarcoma, glioma), brain cancers (astrocytoma, medulloblastoma, glioma, low-grade glioma (LGG), ependymoma, germ cell tumors (pineal tumor), glioblastoma, glioblastoma multiforme (GBM), oligodendroglioma, Schwannoma, retinoblastoma, congenital tumors, and spinal cord cancers (neurofibroma, meningioma, glioma, sarcoma)), as well as neuroblastoma and Lhermitte-Duclos disease.

[0057] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical carcinoma, cervical squamous cell carcinoma (CESC), precancerous cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), and fallopian tube cancer (cancer).

[0058] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipomas, hemangiomas, dermatofibromas, and keloids. In some embodiments, cancers that can be treated with compound (I) include, but are not limited to, triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0059] combination Compound (I) can be administered as a single agent or in combination with other anticancer agents, particularly standard care agents suitable for specific cancers.

[0060] As used herein, the term "additional anticancer therapeutic agent" means any one or more therapeutic agents other than compound (I) that are used or can be used to treat cancer. In some embodiments, such additional anticancer therapeutic agents include compounds derived from the following categories: mitosis inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormones and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors (such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases), cell cycle inhibitors, biological response modulators, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxins, immunotumor agents, etc.

[0061] In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, a selective estrogen receptor downregulator (SERD), or a selective estrogen receptor modulator (SERM). In some embodiments, the additional anticancer agent is a SERD. In some embodiments, the SERD is fulvestrant.

[0062] In some implementations, the additional anticancer agent is a PIK3CA inhibitor, including but not limited to alpelisib (PIQRAY), BEBT-908, BPI-21668, buparlisib, inavolisib, TQB-3525, RLY-2608, miransertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolisib, and fimepinostat. In some implementations, the PIK3CA inhibitor is alpelisib.

[0063] In some implementations, the additional anticancer agent is an AKT inhibitor, including but not limited to capivasertib and ipatasertib. In some implementations, the AKT inhibitor is capivasertib.

[0064] In some implementations, the additional anticancer agent is an antibody-drug conjugate, including but not limited to trastuzumab deruxtecan (Enhertu), trastuzumab duocarmazine, trastuzumab emtansine (Kadcyla), upipitamab rilsodotin, mirvetuximab soravtansine, tisotumab vedotin (Tivdak), praluzatamabravtansine, sacituzumab govitecan, or sacituzumab govitecan-hziy. Govitecan-hziy)(Trodelvy), Dapopotamab deruxtecan, Ladiratuzumab vedotin, Patritumab deruxtecan, STRO-002, MORab-202, DS-6000, Anetumab, Avitansine, XMT-2056, Disitamab Vedotin (RC48-ADC, Aidexi).

[0065] In some implementations, additional anticancer agents are PLK1 inhibitors, including but not limited to onvansertib, BI2536, BI6727, GSK461364A, TAK960, and rigosertib.

[0066] In some implementations, the additional anticancer agent is the estrogen PROTAC (ARV-471, H3B-5942).

[0067] In other embodiments, compound (I) may be administered in combination with a standard care agent. In some embodiments, compound (I) may be administered in combination with endocrine therapy, such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, compound (I) may be administered in combination with a chemotherapeutic agent, such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin. In some embodiments, compound (I) may be administered in combination with carboplatin. In other embodiments, compound (I) may be administered in combination with an anti-HER2 agent, such as trastuzumab or pertuzumab.

[0068] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof may be administered in combination with an effective amount of 5-FU, apelips, carboplatin, cisplatin, enzalutamide, fulvestrant, gemcitabine, osimertinib, ribociclib, or a combination thereof. In some embodiments, the compounds disclosed herein may be administered in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

[0069] In some implementations, the additional anticancer agent is an anti-angiogenic agent, including, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (α-v / β-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors. Preferred anti-angiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG13958 (Pfizer). Additional anti-angiogenic agents include vatalanib (CGP 79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdate (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer). Other anti-angiogenic agents include enzastaurin (LY 317615), midostaurin (CGP41251), perifosine (KRX 0401), teprenone (Selbex™), and UCN 01 (Kyowa Hakko).Other examples of anti-angiogenic agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™). Further anti-angiogenic agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Further anti-angiogenic agents include ABT 510 (Abbott), apratastat (TMI005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon).

[0070] Further anti-angiogenic agents (including VEGFR / PDGFR inhibitors) include, but are not limited to, ponatinib (Iclusig), BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib, brolucizumab (Beovu), aflibercept (Eylea), and faricimab.

[0071] Further anti-angiogenic agents include atratin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), compretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), and Vitaxin™ (MEDI). 522) and zoledronicacid (Zometa™).

[0072] In other implementations, additional anticancer agents are so-called signal transduction inhibitors (e.g., inhibitors of how regulatory molecules controlling fundamental processes of cell growth, differentiation, and survival communicate within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyltransferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan-erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors, and so-called multi-target kinase inhibitors. Other examples of signal transduction inhibitors that can be used in combination with the compounds (I) and pharmaceutical compositions described herein include BMS214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumab (Vectibix™), vandetanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene™ (TP 38).Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), getagliflozin (Pfizer), canertinib (CI 1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), and BMS599626 (Bristol-Myers Squibb). Squibb, Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), avocidib (flavopiridol), BMS 387032 (Bristol-Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC200), BIO 112 (Onc Bio), BMS 387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG024322 (Pfizer).

[0073] In other implementations, the additional anticancer agents are so-called classical antitumor agents. Classical antitumor agents include, but are not limited to, hormone modulators (such as hormones, anti-hormones, androgen agonists, androgen antagonists, and anti-estrogen therapies), histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencers or gene activators, ribonucleases, proteases, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (such as talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib), microtubule inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classic antitumor agents used in combination therapy with compound (I), optionally with one or more other agents, include, but are not limited to, glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, and progesterone such as medroxyprogesterone, megace, mifepristone (RU-48). 6) Selective estrogen receptor modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, azoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF)4227 (Cheisi), selective estrogen receptor downregulators (SERDs; such as fulvestrant, LSZ102, G1T48, RAD1901, elacestrant, GDC-9545, girestrant, SAR439859, amcenestrant, AZD9833, camizestrant, LY3484356, Zn-c5, D-0502), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH; also commonly known as luteinizing hormone releaser) LHRH agonists, such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), medroxyprogesterone acetate, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, and saw palmetto (Serenoa). Repens, PHL 00801, abaregrelin, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogens, such as enzalutamide, abiraterone acetate, Casodex; and combinations thereof. Other examples of classic antitumor agents used in combination with compound (I) include, but are not limited to, succinyl aniline hydroxamic acid (SAHA, Merck Inc. / Aton).Pharmaceuticals), phenylbutyrate peptides (FR901228 or FK228), G2M-777, MS-275, neopentyloxymethyl butyrate and PXD-101; onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecone, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan hydrochloride.HCl (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edocaline, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, ananmycin, daunorubicin n), doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxyformamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin n), sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactal, mitomycin CC), mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum therapy, including platinum-coordinated alkylating compounds (such as cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin) and combinations thereof.

[0074] In other implementation schemes, additional anticancer agents include so-called dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin, or trimethotraxa glucuronide), purine antagonists (such as 6-mercaptopurine nucleoside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nerabine, and raltitrexed), and pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta (pemetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytarabine, Gemzar™ (gemcitabine, Eli Lilly), and tegafur (UFT). Orzel or Uforal, and including TS-1 combinations of tegafur, gememstat, and otostat, docefluuridine, carmofluuridine (including cytarabine alkyl phosphate, stearate phosphate, sustained-release and liposomal forms), enoxabin, 5-azacitidine (Vidaza), decitabine, and ethinylcytidine) and other antimetabolites such as efornithine, hydroxyurea, leucovorin, noratrexate (Thymitaq), triapine, trimethyltraxa, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thienocarboxyl)-L-glutamate, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS) Pharmaceuticals) and GPI 18180 (Guilford Pharm Inc.) and combinations thereof. In some embodiments, the additional anticancer agent is a pyrimidine antagonist. In some embodiments, the pyrimidine antagonist is 5-FU.

[0075] Other examples of classic antitumor cytotoxic agents include, but are not limited to, albumin-bound paclitaxel (Abraxis, BioScience, Inc.), batabulin (Amgen), EPO 906 (Novartis), and vinblastine (Bristol-Myers Squibb). Company), Actinomycin D, Bleomycin, Mitomycin C, Zinostatin, Vincristine, Vincristine, Vincristine, Vinorelbine, Docetaxel (Tasocorty), Oxaliplatin, Paclitaxel (including DHA / paclitaxel conjugate Taxoprexin), Cisplatin, Carboplatin, Nedaplatin, Oxaliplatin (Lexadine), Ceterplatin, Camptosar, Capecitabine (Xeloda), Oxaliplatin (Lexadine), Taxocorty avitamin, Telcyta™, DMXAA (Antisoma), Ibandronic acid, L-asparaginase, Oncaspar™, Efaproxyn™ -Radiotherapy), Targretin™, Temilifen (DPPE – enhances the efficacy of cytotoxic drugs), Theratope™ (Biomira), Vesanoid™, Trizaone™, Xcytrin™, Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), Xyotax™, and combinations thereof. Further examples of classic antitumor agents include, but are not limited to, Advexin (ING 201), TNFerade (GeneVec, a compound that expresses TNFα in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Olimerson, Genta), Comparexin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Pravastatin (Pravacol, Bristol-Myers Squibb), Lovastatin (Merconi, Merck Inc.), Simvastatin (Zoconi, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Bayer), Russellvastatin (AstraZeneca), Lovastatin, Nicotinic Acid (Advicor, Kos Pharmaceuticals), Lipitor, Lipitor, Tocher, and combinations thereof.

[0076] In other implementations, additional anticancer agents are epigenetic modulators, such as inhibitors or EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2, or BCL6.

[0077] In another implementation, the additional anticancer agent is an immunomodulatory agent, such as, but not limited to: CTLA-4 inhibitors (e.g., ipilimumab), PD-1 or PD-L1 inhibitors (e.g., pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dosterlimab), and LAG-3 inhibitors (e.g., relatlimab, TIM-3, TIGIT, 4-1BB, OX40, GITR, CD40, or CAR-T cell therapy).

[0078] In some implementations, the additional anticancer agent is an EGFR inhibitor, such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, or gefitinib, or an EGFR antibody, such as cetuximab, panitumumab, or nexituzumab. In some implementations, the EGFR inhibitor is osimertinib.

[0079] Alternatively, the compounds (I) disclosed herein, their pharmaceutically acceptable salts, or pharmaceutical compositions may be administered in combination with other anticancer agents that are not EGFR inhibitors, such as those containing: MEK, including mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (emibetuzumab); mitotic kinase inhibitors (CDK4). CDK4 / 6 inhibitors, such as palbociclib, rebociclib, abemaciclib, lerociclib, trilaciclib, dalpiciclib, and BPI-16350; anti-angiogenic agents, such as bevacizumab and nintedanib; apoptosis inducers, such as Bcl-2 inhibitors, such as venetoclax, obatoclax, and navicola, and Mcl-1 inhibitors, such as AZD-5991, AMG-176, and S-64315; and mTOR inhibitors, such as rapamycin, tesiromoxim, everolimus, and ridoforolimus. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is rebociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some implementations, the CDK4 / 6 inhibitor is lenosicillin.

[0080] The compounds (I) disclosed herein, their pharmaceutically acceptable salts, or pharmaceutical compositions may be administered in combination with CDK4 / 6 inhibitors. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, rebociclib, abeciclib, lenosiclib, triasidib, dalcidib, and BPI-16350. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is rebociclib. In some embodiments, the CDK4 / 6 inhibitor is abeciclib. In some embodiments, the CDK4 / 6 inhibitor is lenosiclib.

[0081] The compound (I) disclosed herein, its pharmaceutically acceptable salts, or pharmaceutical compositions can be administered in combination with CDK4 / 6 inhibitors and SERD. In some embodiments, the compound (I) disclosed herein, its pharmaceutically acceptable salts, or pharmaceutical compositions can be administered in combination with ribociclib and fulvestrant. In some embodiments, the compound (I) disclosed herein, its pharmaceutically acceptable salts, or pharmaceutical compositions can be administered in combination with a pyrimidine antagonist and gemcitabine. In some embodiments, compound (I) can be administered in combination with a pyrimidine antagonist, gemcitabine, and a CDK4 / 6 inhibitor. In some embodiments, the combination further comprises platinum. In some embodiments, compound (I) can be administered in combination with 5-FU, gemcitabine, ribociclib, and optionally cisplatin. In some embodiments, compound (I) can be administered in combination with 5-FU, gemcitabine, palbociclib, and optionally cisplatin. In some embodiments, compound (I) can be administered in combination with 5-FU, gemcitabine, abecibyl, and optionally cisplatin. In some embodiments, the compound (I) disclosed herein, its pharmaceutically acceptable salts, or pharmaceutical compositions may be administered in combination with an EGFR inhibitor. In some embodiments, the compound (I) disclosed herein, its pharmaceutically acceptable salts, or pharmaceutical compositions may be administered in combination with osimertinib. In some embodiments, the compound (I) disclosed herein, its pharmaceutically acceptable salts, or pharmaceutical compositions may be administered in combination with a PARP-1 inhibitor. In some embodiments, the compound (I) disclosed herein, its pharmaceutically acceptable salts, or pharmaceutical compositions may be administered in combination with olaparib.

[0082] The compounds (I) disclosed herein, their pharmaceutically acceptable salts, or pharmaceutical compositions may also be administered in combination with an effective amount of a second agent selected from the following: palbociclib (e.g., ibrance®), ribociclib, abexilide, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., gilotri... f®), osimertinib (e.g., tagrisso®), gefitinib (e.g., iressa®), erlotinib (e.g., tarceva®), ramucirumab (e.g., cyramza®), EGFR inhibitors, pralatinib, ABT-263 (navicola), MK-1775 (adaseti), BAY-1895344, berzoseti, cilasetide, SRA-737, LY2603618 (rapeseti), and trastuzumab (e.g., herceptin®) or combinations thereof. EGFR inhibitors can be selected from afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib, JBJ-04-125-02, azirtinib (AST 2818), omamotinib (formerly ametinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, giritinib, icotinib, JND-3229, lazatinib, and nazatinib (EGF inhibitors). 816), Avitinib, PCC-0208027, Rezitinib (BPI-7711), TQB3804, Zoritinib (AZ-3759) or DZD9008; EGFR antibodies, such as cetuximab, panitumumab, nexituzumab, HLX07, JMT101; or bispecific EGFR and MET antibodies (e.g., Evantuzab (JNJ-61186372, JNJ-372)).

[0083] Biomarkers and pharmacodynamic markers This disclosure also provides predictive markers (e.g., biomarkers and pharmacodynamic markers, such as levels, gene copy numbers, gene sequences, expression levels, phosphorylation levels, or mutations) to identify subjects who have cancer, are suspected of having cancer, or are at risk of developing cancer, to whom administration of a CDK2 inhibitor (“CDK2 inhibitor” as used herein refers to compound (I) or a pharmaceutically acceptable salt thereof) may be effective.

[0084] CCNE1 In one embodiment, the biomarker is CCNE1. In some embodiments, CCNE1 is mutated (e.g., a loss-of-function mutation). In some embodiments, CCNE1 or mutated CCNE1 is functional. In some embodiments, CCNE1 is a biomarker of the salt sensitivity of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels are modulated by treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, changes in CCNE1 levels at two different time points, before and after administration of compound (I) or a pharmaceutically acceptable salt thereof, or during treatment with compound (I) or a pharmaceutically acceptable salt thereof, indicate / predict a response to treatment with compound (I) or a pharmaceutically acceptable salt thereof in subjects with or at risk of developing cancer.

[0085] In some embodiments, the level of CCNE1 changes by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CCNE1 changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CCNE1 changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CCNE1 increases before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some implementations, CCNE1 levels are reduced before and after administration of compound (I) or its pharmaceutically acceptable salt.

[0086] In some embodiments, CCNE1 levels changed by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, CCNE1 levels changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, CCNE1 levels changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, CCNE1 levels increased at two different time points during administration of compound (I) or its pharmaceutically acceptable salts. In some embodiments, CCNE1 levels decreased at two different time points during administration of compound (I) or its pharmaceutically acceptable salts.

[0087] In some embodiments, CCNE1 levels increase by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 20% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 30% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 40% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 50% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 60% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 70% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 80% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 90% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increase by at least 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof, the level of CCNE1 increases by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof, the level of CCNE1 increases by at least 10%. In some embodiments, at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof, the level of CCNE1 increases by at least 20%. In some embodiments, at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof, the level of CCNE1 increases by at least 30%. In some embodiments, at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof, the level of CCNE1 increases by at least 40%. In some embodiments, at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof, the level of CCNE1 increases by at least 50%. In some embodiments, CCNE1 levels increased by at least 60% at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increased by at least 70% at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increased by at least 80% at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increased by at least 90% at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CCNE1 levels increased by at least 100% at two different time points during administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0089] In some implementations, elevated levels of the cyclin E1 (CCNE1) gene and / or abnormal expression levels of CCNE1 in a biological sample would indicate that a patient or subject could benefit from the administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0090] CCNE1 is a cell cycle factor essential for controlling the cell cycle during the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). As a regulatory subunit of CDK2, CCNE1 interacts with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity to the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is composed of cyclin E1 (“…”). CCNE1 The gene (GenBank accession number NM_001238) encodes the human CCNE1. The amino acid sequence of human CCNE1 can be found in GenBank accession number NP_001229 / UniProtKB accession number P24864.

[0091] In one aspect, this disclosure provides a method of treating a subject who has cancer or is at risk of developing cancer, comprising administering to the subject a therapeutically effective amount of the disclosed compound (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the subject has an amplification of the CCNE1 gene (e.g., based on copy number) and / or has a CCNE1 level higher than a CCNE1 control level. In some embodiments, the invention provides a method of treating a subject who has cancer or is at risk of developing cancer, comprising administering to the subject a therapeutically effective amount of the disclosed compound (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the subject has abnormal expression of the CCNE1 gene.

[0092] This article also provides methods for treating patients with increased CCNE1 gene copy number and / or elevated CCNE1 expression levels who have solid tumor cancer or are at risk of developing solid tumor cancer, including administering to the patient a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition disclosed herein.

[0093] In some embodiments, amplification of the CCNE1 gene and / or CCNE1 levels higher than the CCNE1 control level indicate / predict that subjects with cancer or at risk of cancer will respond to an effective dose of a CDK2 inhibitor (i.e., compound (I) or a pharmaceutically acceptable salt thereof). In some embodiments, abnormal CCNE1 levels, different from the CCNE1 control level, indicate / predict that subjects with cancer or at risk of cancer will respond to an effective dose of a CDK2 inhibitor (i.e., compound (I) or a pharmaceutically acceptable salt thereof). In some embodiments, the expression level of CCNE1 may be the level of CCNE1 mRNA. In other embodiments, the expression level of CCNE1 may be the level of CCNE1 protein. In other embodiments, the expression level of CCNE1 may be an indirect measure of CCNE1 mRNA or protein levels. In some embodiments, the level of CCNE1 is regulated in response to administration of an effective dose of compound (I) or a pharmaceutically acceptable salt thereof to the subject.

[0094] Other biomarkers In some embodiments, the intended biomarker is p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, and p16-INK4a encoded by the gene CDKN2A), which acts as a negative regulator of normal cell proliferation by interacting with CDK4 and CDK6. In some embodiments, the level of p16 is regulated in response to administration of an effective dose of compound (I) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, p16 is absent. In some embodiments, the loss of p16 is a biomarker. In some embodiments, p16 is mutated (e.g., a loss-of-function mutation). In some embodiments, p16 or a p16 mutant is functional. In some embodiments, p16 is a biomarker of sensitivity to compound (I). In some implementations, changes in p16 levels at two different time points, before and after administration of compound (I) or its pharmaceutically acceptable salt, or during treatment with compound (I) or its pharmaceutically acceptable salt, indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salt in subjects with or at risk of developing cancer.

[0095] In some embodiments, the p16 level changes by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the p16 level changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the p16 level changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the p16 level increases before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some implementations, p16 levels are reduced before and after administration of compound (I) or its pharmaceutically acceptable salt.

[0096] In some embodiments, the p16 level changes by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, the p16 level changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, the p16 level changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, the p16 level increases at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some implementations, p16 levels are reduced at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt.

[0097] In some embodiments, the anticipated biomarker is the retinoblastoma 1 protein (pRb or RB), encoded by the gene RB transcriptional co-repressor 1 (RB1). In some embodiments, the anticipated biomarker is phosphorylation of Rb at any phosphorylation site. In some embodiments, the biomarker is phosphorylation of serine corresponding to amino acid position 780 (Ser780 or S780) and / or serine corresponding to amino acid position 795 (Ser795 or S795). In some embodiments, the anticipated biomarker is phosphorylation of Rb at serine corresponding to amino acid position 807 (Ser807 or S807) and / or serine corresponding to amino acid position 811 (Ser811 or S811). In some embodiments, the anticipated biomarker is phosphorylation of Rb at threonine corresponding to amino acid position 821 (Thr821 or T821). In some embodiments, the anticipated biomarker is phosphorylation of Rb at a threonine residue corresponding to amino acid position 826 (Thr826 or T826). Rb is a regulator of the cell cycle and acts as a tumor suppressor. Rb is activated by phosphorylation of cyclin D-CDK4 / 6 at Ser780 and Ser795 and / or Ser807 and / or Ser811, and by phosphorylation of cyclin E / CDK2 at Ser807, Ser811, and Thr821. In some embodiments, the level of phosphorylated Rb is regulated in response to administration of an effective dose of compound (I) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, phosphorylated Rb or RB is absent. In some embodiments, the loss of phosphorylated Rb or RB is a biomarker. In some embodiments, RB is mutated (e.g., a loss-of-function mutation). In some embodiments, RB or an RB mutant is functional. In some embodiments, phosphorylated Rb or RB is a biomarker of sensitivity to compound (I).

[0098] In some embodiments, changes in phosphorylated Rb or RB levels before and after administration of compound (I) or a pharmaceutically acceptable salt thereof indicate / predict a response to treatment with compound (I) or a pharmaceutically acceptable salt thereof in a subject with or at risk of developing cancer. In some embodiments, the phosphorylated Rb level at any phosphorylation site changes by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the phosphorylated Rb level at any phosphorylation site changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at any phosphorylation site changes by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated RB or Rb at any phosphorylation site increases before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated RB or Rb at any phosphorylation site decreases before and after application of compound (I) or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, changes in phosphorylated Rb or RB levels at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salt in a subject with cancer or at risk of cancer. In some embodiments, the level of phosphorylated Rb at any phosphorylation site changes by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, the level of phosphorylated Rb at any phosphorylation site changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts, the level of phosphorylated Rb at any phosphorylation site varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts, the level of phosphorylated Rb or RB at any phosphorylation site increased. In some embodiments, at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts, the level of phosphorylated Rb or RB at any phosphorylation site decreased.

[0100] In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 changes by at least 10% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Ser780 and / or Ser795 varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Ser780 and / or Ser795 increased before and after application of compound (I) or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 varies by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 varies by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 varies by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 increases at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 decreases at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts.

[0102] In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 10% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 20% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 30% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 40% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 50% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 60% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 70% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 80% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 90% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 changes by at least 10% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Ser807 and / or Ser811 varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Ser807 and / or Ser811 increased before and after application of compound (I) or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 varies by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 varies by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 varies by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, the levels of phosphorylated Rb at Ser807 and / or Ser811 increase at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, the levels of phosphorylated Rb at Ser807 and / or Ser811 decrease at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts.

[0105] In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 10% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 20% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 30% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 40% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 50% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 60% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 70% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 80% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 90% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the level of phosphorylated Rb at Thr821 changes by at least 10% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some implementations, the level of phosphorylated Rb at Thr821 increases before and after administration of compound (I) or its pharmaceutically acceptable salt.

[0107] In some embodiments, the level of phosphorylated Rb at Thr821 varies by at least 10% at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 varies by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, the level of phosphorylated Rb at Thr821 varies by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, the level of phosphorylated Rb at Thr821 increases at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 decreases at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the level of phosphorylated Rb at Thr821 is reduced before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 10% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 20% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 30% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 40% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 50% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 60% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 70% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 80% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 is reduced by at least 90% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some implementations, the level of phosphorylated Rb at Thr821 is reduced by at least 100% before and after administration of compound (I) or its pharmaceutically acceptable salt.

[0109] In some embodiments, the level of phosphorylated Rb at Thr826 changes by at least 10% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some implementations, the level of phosphorylated Rb at Thr826 increases before and after administration of compound (I) or its pharmaceutically acceptable salt.

[0110] In some embodiments, the level of phosphorylated Rb at Thr826 varies by at least 10% at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 varies by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, the level of phosphorylated Rb at Thr826 varies by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment. In some embodiments, the level of phosphorylated Rb at Thr826 increases at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 decreases at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the level of phosphorylated Rb at Thr826 is reduced before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 10% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 20% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 30% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 40% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 50% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 60% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 70% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 80% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr826 is reduced by at least 90% before and after application of compound (I) or a pharmaceutically acceptable salt thereof. In some implementations, the level of phosphorylated Rb at Thr826 is reduced by at least 100% before and after administration of compound (I) or its pharmaceutically acceptable salt.

[0112] In some embodiments, the intended biomarker is TK1 (thymidine kinase 1). TK1 is a direct downstream target of the Rb-E2F pathway. It participates in cell proliferation through the restoration of thymidine nucleotides in the DNA rescue pathway. TK1 is important for DNA repair following DNA damage because it is essential for the formation of nucleotides outside the S phase. In some embodiments, TK1 levels are regulated in response to administration of an effective dose of compound (I) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, TK1 is absent. In some embodiments, loss of TK1 is a biomarker. In some embodiments, TK1 is mutated (e.g., a loss-of-function mutation or a platinum-resistant mutation). In some embodiments, TK1 or a TK1 mutant is functional. In some embodiments, a TK1 mutant has a platinum-resistant mutation. In some embodiments, TK1 is differentially methylated. In some embodiments, TK1 is serum TK1. In some embodiments, TK1 is a biomarker of sensitivity to compound (I) or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, changes in TK1 levels before and after administration of compound (I) or its pharmaceutically acceptable salts indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salts in subjects with or at risk of developing cancer. In some embodiments, TK1 levels changed by at least 10% before and after administration of compound (I) or its pharmaceutically acceptable salts. In some embodiments, TK1 levels changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or its pharmaceutically acceptable salts. In some embodiments, the level of TK1 varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of TK1 increased before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, changes in TK1 levels at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salt in subjects with or at risk of developing cancer. In some embodiments, TK1 levels change by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, TK1 levels change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, TK1 levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, TK1 levels increased at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts.

[0115] In some embodiments, TK1 levels decrease before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels decrease by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels decrease by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels decrease by at least 20% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels decrease by at least 30% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels decrease by at least 40% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels are reduced by at least 50% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels are reduced by at least 60% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels are reduced by at least 70% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels are reduced by at least 80% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels are reduced by at least 90% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, TK1 levels are reduced by at least 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, TK1 levels decrease at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels decrease by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels decrease by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels decrease by at least 20% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels decrease by at least 30% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels decrease by at least 40% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels are reduced by at least 50% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels are reduced by at least 60% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels are reduced by at least 70% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels are reduced by at least 80% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels are reduced by at least 90% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, TK1 levels are reduced by at least 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline.

[0117] In one embodiment, the biomarker is the cell proliferation marker Ki-67 (Ki-67 or MKI67). In some embodiments, Ki-67 levels are modulated by treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, Ki-67 is absent. In some embodiments, the loss of Ki-67 is the biomarker. In some embodiments, Ki-67 is mutated (e.g., a loss-of-function mutation). In some embodiments, Ki-67 or a Ki-67 mutant is functional. In some embodiments, Ki-67 is a compound of formula (I) or a pharmaceutically acceptable salt-sensitive biomarker thereof.

[0118] In some embodiments, changes in Ki-67 levels before and after administration of compound (I) or a pharmaceutically acceptable salt thereof indicate / predict a response to treatment with compound (I) or a pharmaceutically acceptable salt thereof in subjects with or at risk of developing cancer. In some embodiments, Ki-67 levels changed by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, Ki-67 levels changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, Ki-67 levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, Ki-67 levels increased before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, Ki-67 levels decreased before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, changes in Ki-67 levels at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salt in subjects with or at risk of developing cancer. In some embodiments, Ki-67 levels change by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, Ki-67 levels change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, Ki-67 levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, Ki-67 levels decreased at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts.

[0120] In one embodiment, the biomarker is cancer antigen 125 or (CA-125). In some embodiments, the cancer is ovarian cancer. In some embodiments, the level of CA-125 is modulated by treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 is absent. In some embodiments, the loss of CA-125 is the biomarker. In some embodiments, CA-125 is mutated (e.g., a loss-of-function mutation). In some embodiments, CA-125 or a CA-125 mutant is functional. In some embodiments, CA-125 is a compound of formula (I) or a pharmaceutically acceptable salt-sensitive biomarker thereof.

[0121] In some embodiments, changes in CA-125 levels before and after administration of compound (I) or a pharmaceutically acceptable salt thereof indicate / predict a response to treatment with compound (I) or a pharmaceutically acceptable salt thereof in subjects with or at risk of developing cancer. In some embodiments, CA-125 levels changed by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 increased before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, changes in CA-125 levels at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salt in subjects with or at risk of developing cancer. In some embodiments, CA-125 levels change by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, CA-125 levels change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, CA-125 levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, CA-125 levels increased at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts.

[0123] In some embodiments, CA-125 levels are reduced before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 20% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 30% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 40% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 50% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 60% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 70% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 80% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 90% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CA-125 levels are reduced by at least 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, CA-125 levels are reduced at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 20% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 30% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 40% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 50% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 60% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 70% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 80% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 90% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, CA-125 levels are reduced by at least 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline.

[0125] In one embodiment, the biomarker is carcinoembryonic antigen (CEA). In some embodiments, the cancer is selected from breast cancer, colorectal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer. In some embodiments, CEA levels are regulated by treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA is absent. In some embodiments, loss of CEA is the biomarker. In some embodiments, CEA is mutated (e.g., a loss-of-function mutation). In some embodiments, CEA or a CEA mutant is functional. In some embodiments, CEA is a biomarker of compound (I) or a pharmaceutically acceptable salt-sensitive compound thereof.

[0126] In some embodiments, changes in CEA levels before and after administration of compound (I) or its pharmaceutically acceptable salts indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salts in subjects with or at risk of developing cancer. In some embodiments, CEA levels change by at least 10% before and after administration of compound (I) or its pharmaceutically acceptable salts. In some embodiments, CEA levels change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or its pharmaceutically acceptable salts. In some embodiments, CEA levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels increased before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, changes in CEA levels at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salt in subjects with or at risk of developing cancer. In some embodiments, CEA levels change by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, CEA levels change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, CEA levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, CEA levels increased at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, CEA levels decreased at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts.

[0128] In some embodiments, CEA levels are reduced before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 20% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 30% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 40% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 50% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 60% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 70% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 80% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 90% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, CEA levels are reduced by at least 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0129] In one embodiment, the biomarker is prostate-specific antigen (PSA). In some embodiments, the cancer is prostate cancer. In some embodiments, PSA levels are regulated by treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA is absent. In some embodiments, the loss of PSA is the biomarker. In some embodiments, PSA has a mutation (e.g., a loss-of-function mutation). In some embodiments, PSA or a PSA mutant is functional. In some embodiments, PSA is a biomarker of compound (I) or a pharmaceutically acceptable salt-sensitive compound thereof.

[0130] In some embodiments, changes in PSA levels before and after administration of compound (I) or its pharmaceutically acceptable salts indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salts in subjects with or at risk of developing cancer. In some embodiments, PSA levels changed by at least 10% before and after administration of compound (I) or its pharmaceutically acceptable salts. In some embodiments, PSA levels changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or its pharmaceutically acceptable salts. In some embodiments, PSA levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels increased before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, changes in PSA levels at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salt in subjects with or at risk of developing cancer. In some embodiments, PSA levels change by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, PSA levels change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, PSA levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, PSA levels increased at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts.

[0132] In some embodiments, PSA levels decrease before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels decrease by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels decrease by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels decrease by at least 20% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels decrease by at least 30% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels decrease by at least 40% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels are reduced by at least 50% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels are reduced by at least 60% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels are reduced by at least 70% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels are reduced by at least 80% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels are reduced by at least 90% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PSA levels are reduced by at least 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, PSA levels decrease at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels decrease by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels decrease by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels decrease by at least 20% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels decrease by at least 30% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels decrease by at least 40% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels are reduced by at least 50% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels are reduced by at least 60% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels are reduced by at least 70% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels are reduced by at least 80% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels are reduced by at least 90% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, PSA levels are reduced by at least 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline.

[0134] In one embodiment, the biomarker is a Kirsten rat sarcoma virus oncogene homolog (KRAS). In some embodiments, the cancer is colon cancer, lung cancer, or pancreatic cancer. In some embodiments, KRAS levels are modulated by treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS is absent. In some embodiments, loss of KRAS is the biomarker. In some embodiments, KRAS is mutated (e.g., a loss-of-function mutation). In some embodiments, KRAS or a KRAS mutant is functional. In some embodiments, KRAS is a compound of formula (I) or a pharmaceutically acceptable salt-sensitive biomarker thereof.

[0135] In some embodiments, changes in KRAS levels before and after administration of compound (I) or a pharmaceutically acceptable salt thereof indicate / predict a response to treatment with compound (I) or a pharmaceutically acceptable salt thereof in subjects with or at risk of developing cancer. In some embodiments, KRAS levels changed by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels increased before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, changes in KRAS levels at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt indicate / predict a response to treatment with compound (I) or its pharmaceutically acceptable salt in subjects with or at risk of developing cancer. In some embodiments, KRAS levels change by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, KRAS levels change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salt. In some embodiments, KRAS levels varied by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts. In some embodiments, KRAS levels increased at two different time points during treatment with compound (I) or its pharmaceutically acceptable salts.

[0137] In some embodiments, KRAS levels are reduced before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 10% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 20% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 30% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 40% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 50% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 60% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 70% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 80% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 90% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, KRAS levels are reduced by at least 100% before and after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, KRAS levels are reduced at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 10% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 20% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 30% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 40% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 50% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 60% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 70% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 80% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 90% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline. In some embodiments, KRAS levels are reduced by at least 100% at two different time points during treatment with compound (I) or its pharmaceutically acceptable saline.

[0139] The intended biomarkers may also be selected from the group consisting of: RB1, RBL1, RBL2, CA-125, CDKN2A (or p16), CDKN1A, CDKN1B, FBXW7, CCNE1, CCNE2, CCNA1, CCNA2, CCND1, CCND2, CCND3, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK18, CEA, CHK1, E2F1, E2F2, E2F3, KRAS, MIK67 (or Ki-67), MYC, MYCL, MYCN, EZH2, ER, HER2, HER3, PSA, TK1, and EGFR. In some embodiments, the level of any of the biomarkers disclosed herein may be modulated in response to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0140] On the other hand, this article provides a method for determining changes in the levels of one or more biomarkers after administering a compound (I) in amounts from 100 mg to 1600 mg or a pharmaceutically acceptable salt of the equivalent amount of compound (I) to a subject who has cancer or is at risk of developing cancer, wherein treatment with compound (I) alters the levels of one or more biomarkers. In some embodiments, this document provides a method for determining changes in biomarker levels, said biomarker being selected from cancer antigen 125 or (CA-125), cyclin E1 (CCNE1), carcinoembryonic antigen (CEA), cyclin-dependent kinase inhibitor 2A (CDKN2A or p16), Kirsten rat sarcoma virus oncogene homolog (KRAS), cell proliferation marker Ki-67 (MKI67 or Ki-67), phosphorylated retinoblastoma 1 protein (Rb), and prostate-specific antigen (PSA); and administering, to a subject with cancer or at risk of cancer, an amount of compound (I) from 100 mg to 1600 mg or an amount of its pharmaceutically acceptable salt equivalent to 100 mg to 1600 mg, wherein the biomarker levels are altered by treatment with compound (I). In some implementations, the levels of the biomarker varied by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0141] On the other hand, this article provides a method for determining the sensitivity of a subject with cancer to compound (I) or a pharmaceutically acceptable salt thereof, including: i. Measuring the levels of one or more biomarkers in biological samples obtained from subjects; ii. Compare the levels of one or more biomarkers from step i with the levels of one or more biomarkers measured in subjects with normally functioning pathways; and iii. Based on the comparison in step ii, determine whether the cancer subject is sensitive to compound (I) or its pharmaceutically acceptable salt.

[0142] On the other hand, this article provides a method for determining the resistance of a subject with cancer to compound (I) or a pharmaceutically acceptable salt thereof, comprising: i. Measuring the levels of one or more biomarkers in biological samples obtained from subjects; ii. Compare the levels of one or more biomarkers from step i with the levels of one or more biomarkers measured in subjects with normally functioning pathways; and iii. Based on the comparison in step ii, determine whether the subject has tolerance to compound (I) or a pharmaceutically acceptable salt thereof.

[0143] On the other hand, this article provides a method for treating cancer in subjects in need, including: i. Testing or having tested a first biological sample obtained from the subject who has cancer to measure the level of one or more biomarkers in the subject's cancer; ii. Compare the levels of one or more biomarkers from step i. with the levels of one or more biomarkers measured in subjects with normal functional pathways; iii. In response to determining that the subject's cancer will be sensitive to compound (I) or a pharmaceutically acceptable salt thereof, the subject is treated with a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0144] The method also includes testing, or having already tested, a second biological sample obtained from a subject with cancer to determine whether the levels of one or more biomarkers change after administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0145] In another aspect, this article provides methods for monitoring the response of subjects who have cancer or are at risk of developing cancer, including: i. Administer to the subject in need a dose of 100 mg to 1600 mg of compound (I), or a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1600 mg of compound (I); ii. A first biological sample obtained from the subject has been tested or has been tested to measure the level of one or more biomarkers in the biological sample; iii. Compare the levels of one or more biomarkers from step ii. with the levels of one or more biomarkers measured in subjects with normally functioning pathways; and iv. If the comparison in step iii shows a change in the level of one or more biomarkers, determine whether the subject with cancer or at risk of cancer responded to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, additional biological samples are obtained from the subject and compared with the levels of biomarkers measured in subjects with normally functioning pathways for continued monitoring.

[0147] In some embodiments, the levels of one or more biomarkers in biological samples obtained from subjects with cancer or at risk of cancer differ by at least 10% compared to the levels of one or more biomarkers measured in subjects with normally functioning pathways. In some embodiments, the comparison shows a difference of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the comparison shows a difference of approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0148] In some embodiments, one or more biomarkers are selected from CA-125, CDKN2A (or p16), CDKN1A, CDKN1B, FBXW7, CCNE1, CCNE2, CCNA1, CCNA2, CCND1, CCND2, CCND3, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK18, CEA, CHK1, E2F1, E2F2, E2F3, EGFR, KRAS, MKI67 (or Ki-67), MYC, MYCL, MYCN, EZH2, ER, HER2, HER3, PSA, RB1, RBL1, RBL2, and TK1. In some embodiments, one or more biomarkers are selected from CA-125, CDKN2A (or p16), CCNE1, CEA, MKI67 (or Ki-67), PSA, phosphorylated Rb, and TK1.

[0149] In some implementation schemes, the cancer is selected from breast cancer, endometrial cancer, esophageal cancer, stomach cancer, ovarian cancer, pancreatic cancer, prostate cancer, and thyroid cancer.

[0150] In some embodiments, the levels of one or more of CA-125, CDKN2A (or p16), CCNE1, CEA, phosphorylated Rb, MKI67 (or Ki-67), PSA, and TK1 change. In some embodiments, after treatment with compound (I) or a pharmaceutically acceptable salt thereof, the levels of one or more of CA-125, CDKN2A (or p16), CCNE1, CEA, KRAS, MKI67 (or Ki-67), PSA, phosphorylated Rb, and TK1 decrease. In some embodiments, the level of CA-125 decreases. In some embodiments, the level of CCNE1 decreases. In some embodiments, the level of KRAS decreases. In some embodiments, the level of MKI67 or Ki-67 decreases. In some embodiments, the level of PSA decreases. In some embodiments, the level of phosphorylated Rb decreases. In some embodiments, the level of phosphorylated Rb decreases. In some embodiments, the level of TK1 enzyme activity decreases.

[0151] In some implementations, one or more biomarkers are measured based on a selection of DNA (including cDNA), RNA (including messenger ribonucleic acid (mRNA) and microribonucleic acid (miRNA)), protein expression (including protein overexpression), enzyme activity (e.g., for TK1), gene copy number, gene expression, gene sequence, mutation, and phosphorylation levels.

[0152] biological samples Suitable biological samples for use in the methods described herein include any sample containing blood or tumor cells obtained from or derived from a human subject in need of treatment. For example, a biological sample may contain tumor cells from a biopsy of a patient with a solid tumor. Tumor biopsies can be obtained through a variety of methods known in the art. Alternatively, a blood sample may be obtained from a patient with a blood cancer.

[0153] Biological samples can be obtained from subjects who have, are suspected of having, or are at risk of having CDK2-related diseases or conditions.

[0154] Methods for obtaining and / or storing samples while maintaining the activity or integrity of molecules (e.g., nucleic acids or proteins) in the sample are well known to those skilled in the art. For example, biological samples may be further contacted with one or more additional agents such as buffers and / or inhibitors, including one or more inhibitors of nucleases, proteases, and phosphatases that retain or minimize changes in the molecules in the sample.

[0155] Pharmaceutical Composition The pharmaceutical compositions disclosed herein (also referred to herein as “the disclosed pharmaceutical compositions”) comprise one or more pharmaceutically acceptable carriers or diluents and compound (I) or a pharmaceutically acceptable salt thereof.

[0156] "Pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents" refer to substances that facilitate the formulation and / or administration to and / or absorption by a subject of an active agent, and may be included in the pharmaceutical compositions disclosed herein without causing significant adverse toxicological effects on the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, physiological saline solutions, lactated Ringer's solution, physiological sucrose, physiological glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), hydroxymethyl cellulose, fatty acid esters, polyvinylpyrrolidone, and colorants, etc. Such formulations can be sterilized and, if necessary, mixed with excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or aromatic substances, which do not adversely react with or interfere with the activity of compound (I). Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with compound (I) or its pharmaceutically acceptable salts.

[0157] The pharmaceutical compositions disclosed herein optionally include one or more pharmaceutically acceptable carriers and / or diluents, such as lactose, starch, cellulose, and glucose. Other excipients may also be included, such as flavoring agents, sweeteners, and preservatives, such as methylparaben, ethylparaben, propylparaben, and butylparaben. A more complete list of suitable excipients is available in the Handbook of Pharmaceutical Excipients (5th edition, Pharmaceutical Press (2005)). Those skilled in the art will recognize how to prepare formulations suitable for various routes of administration. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003–20th edition) and the United States Pharmacopeia: National Formulary (USP 24NF19), published in 1999. Carriers, diluents, and / or excipients are “acceptable” in the sense that they are compatible with the other components of the pharmaceutical composition and harmless to the recipient.

[0158] Application method and dosage form The precise amount of compound administered to provide an “effective dose” to a subject will depend on the route of administration, the type and severity of the cancer, and the subject’s characteristics, such as general health, age, sex, weight, and tolerance to the drug. Technicians will be able to determine the appropriate dose based on these and other factors. When administered in combination with other therapeutic agents, such as when administered in combination with an anticancer agent, the “effective dose” of any additional therapeutic agent will depend on the type of drug used. Appropriate doses of approved therapeutic agents are known and can be determined by technicians based on the subject’s condition, the type of condition being treated, and the amount of the compound of formula (I) used, as reported in, for example, the literature. Physician's Desk Reference The dosage recommended in (57th edition, 2003) has been adjusted.

[0159] "Treatment" refers to achieving the desired pharmacological and / or physiological effect. The effect can be therapeutic and may include partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of cancer; alleviating or improving cancer-related clinical symptoms or indicators; delaying, inhibiting, or reducing the likelihood of cancer progression; or reducing the likelihood of cancer recurrence.

[0160] The term "effective dose" means the amount that, when administered to a subject, produces a beneficial or desired outcome, including clinical outcomes such as inhibition, prevention, or reduction of symptoms of the treated disorder in the subject compared to a control. For example, an effective therapeutic dose may be administered in unit dosage forms (e.g., 0.1 mg / day to about 50 g / day, or 1 mg / day to about 5 g / day; and in another alternative, 10 mg / day to 1 g / day).

[0161] As used herein, the term "administer / administering / administration" refers to a method that can be used to deliver a composition to a desired site of biological action. These methods include, but are not limited to, intra-articular, intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, local, intrathecal, inhalation, transdermal, and rectal administration. Administration techniques applicable to the agents and methods described herein can be found at, for example, Goodman and Gilman. The Pharmacological Basis of Therapeutics Current version; Pergamon; and Remington's, Pharmaceutical Sciences (Current edition), Mack Publishing Co., Easton, Pa.

[0162] As used herein, the terms "patient" or "subject" refer to an organism that will be treated by the methods of this disclosure. Non-limiting examples of organisms include mammals such as rodents, apes, horses, cattle, pigs, dogs, cats, etc. In some embodiments, the organism is a human.

[0163] In some implementations, a total daily dose of 50 mg to 1600 mg of compound (I), or a pharmaceutically acceptable salt of compound (I) equivalent to a total daily dose of 50 mg to 1600 mg, is administered to the subject in need.

[0164] In some implementations, a total daily dose of compound (I) of 100 mg to 1600 mg, or a pharmaceutically acceptable salt of compound (I) of an amount equivalent to a total daily dose of 100 mg to 1600 mg, is administered to the subject in need.

[0165] In some implementations, a total daily dose of compound (I) of 100 mg to 1400 mg, or a pharmaceutically acceptable salt of compound (I) of an amount equivalent to a total daily dose of 100 mg to 1400 mg, is administered to the subject in need.

[0166] In some implementations, the subject in need is administered with amounts of compound (I) in the form of 50 mg to 250 mg, 100 mg to 300 mg, 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, 600 mg to 800 mg, 700 mg to 900 mg, 800 mg to 1000 mg, 900 mg to 1100 mg, 1000 mg to 1200 mg, 1100 mg to 1300 mg, 1200 mg to 1400 mg, 1300 mg to 1500 mg, or 1400 mg to 1600 mg, or equivalent amounts of 50 mg to 250 mg, 100 mg to 300 mg, 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, or 600 mg to 800 mg. The amount of compound (I) of its pharmaceutically acceptable salt in mg, 700 mg to 900 mg, 800 mg to 1000 mg, 900 mg to 1100 mg, 1000 mg to 1200 mg, 1100 mg to 1300 mg, 1200 mg to 1400 mg, 1300 mg to 1500 mg or 1400 mg to 1600 mg.

[0167] In some implementations, subjects in need are administered a dose selected from 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, etc. Compound (I) in amounts of 50 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg and 1600 mg, or equivalent to 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, or 1600 mg, or equivalent to 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, or 675 mg. 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg or 1600 mg of a pharmaceutically acceptable salt of compound (I).

[0168] In some implementations, the subject in need is given an amount of compound (I) of 100 mg to 1200 mg or an amount of its pharmaceutically acceptable salt equivalent to 100 mg to 1200 mg of compound (I).

[0169] In some implementations, the subject in need is administered a compound (I) in amounts of 100 mg to 300 mg, 200 mg to 400 mg, 300 mg to 500 mg, 300 mg to 600 mg, 400 mg to 600 mg, 500 mg to 700 mg, 600 mg to 800 mg, 700 mg to 900 mg, 800 mg to 1000 mg, 900 mg to 1100 mg, or 1000 mg to 1200 mg, or an amount equivalent to 100 mg to 300 mg, 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, 600 mg to 800 mg, 700 mg to 900 mg, 800 mg to 1000 mg, 900 mg to 1100 mg, or 1000 mg to 1200 mg. In some embodiments, a pharmaceutically acceptable salt of compound (I) in the amount of mg is administered to the subject in need. In some embodiments, a pharmaceutically acceptable salt of compound (I) in the amount of 300 mg to 600 mg is administered to the subject in need. In some embodiments, a pharmaceutically acceptable salt of compound (I) in the amount of 400 mg to 600 mg is administered to the subject in need.

[0170] In some implementations, subjects in need are administered a dose selected from 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, and 1200 mg. mg of compound (I), or equivalent to 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg and 1200 mg of compound (I) in the amount of its pharmaceutically acceptable salt.

[0171] In some implementations, a pharmaceutically acceptable salt of compound (I) in an amount of 100 mg to 1000 mg or equivalent to 100 mg of compound (I) is administered to a subject in need.

[0172] In some implementations, a 50 mg amount of compound (I) or an equivalent amount of its pharmaceutically acceptable salt is administered to the subject in need.

[0173] In some implementations, a 100 mg amount of compound (I) or a pharmaceutically acceptable salt equivalent to 100 mg of compound (I) is administered to the subject in need.

[0174] In some implementations, a dose of 150 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 150 mg is administered to a subject in need.

[0175] In some implementations, a 200 mg amount of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 200 mg is administered to the subject in need.

[0176] In some implementations, a dose of 250 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 250 mg is administered to the subject in need.

[0177] In some implementations, a dose of 300 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 300 mg is administered to the subject in need.

[0178] In some implementations, a dose of 350 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 350 mg is administered to the subject in need.

[0179] In some implementations, a dose of 400 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 400 mg is administered to the subject in need.

[0180] In some implementations, a dose of 450 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 450 mg is administered to the subject in need.

[0181] In some implementations, a dose of 500 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 500 mg is administered to the subject in need.

[0182] In some implementations, a dose of 550 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 550 mg is administered to the subject in need.

[0183] In some implementations, a dose of 600 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 600 mg is administered to the subject in need.

[0184] In some implementations, a dose of 650 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 650 mg is administered to the subject in need.

[0185] In some implementations, a dose of 700 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 700 mg is administered to the subject in need.

[0186] In some implementations, a dose of 750 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 750 mg is administered to the subject in need.

[0187] In some implementations, an amount of 800 mg of compound (I) or an amount of its pharmaceutically acceptable salt equivalent to 800 mg of compound (I) is administered to the subject in need.

[0188] In some implementations, an amount of 850 mg of compound (I) or an amount of its pharmaceutically acceptable salt equivalent to 850 mg of compound (I) is administered to the subject in need.

[0189] In some implementations, a 900 mg amount of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 900 mg is administered to the subject in need.

[0190] In some implementations, a dose of 950 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 950 mg is administered to the subject in need.

[0191] In some implementations, a 1000 mg amount of compound (I) or a pharmaceutically acceptable salt equivalent to 1000 mg of compound (I) is administered to a subject in need.

[0192] In some implementations, the subject in need is given 1100 mg of compound (I) or an amount of its pharmaceutically acceptable salt equivalent to 1100 mg of compound (I).

[0193] In some implementations, a dose of 1200 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 1200 mg is administered to the subject in need.

[0194] In some implementations, a dose of 1300 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 1300 mg is administered to the subject in need.

[0195] In some implementations, a dose of 1400 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 1400 mg is administered to the subject in need.

[0196] In some implementations, a dose of 1500 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 1500 mg is administered to the subject in need.

[0197] In some implementations, a dose of 1600 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 1600 mg of compound (I) is administered to the subject in need.

[0198] In some implementations, the subject in need is given an amount of compound (I) of 800 mg to 1200 mg or an amount of its pharmaceutically acceptable salt equivalent to 800 mg to 1200 mg of compound (I).

[0199] In some implementations, the determined amount of compound (I) or a pharmaceutically acceptable salt thereof is administered orally to a subject in need once daily (QD).

[0200] In some implementations, a 100 mg dose of compound (I) or a pharmaceutically acceptable salt equivalent to 100 mg of compound (I) is administered once daily to a subject in need.

[0201] In some implementations, a dose of 200 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 200 mg of compound (I) is administered once daily to a subject in need.

[0202] In some implementations, a dose of 300 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 300 mg is administered once daily to a subject in need.

[0203] In some implementations, a dose of 400 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 400 mg is administered once daily to a subject in need.

[0204] In some implementations, a dose of 500 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 500 mg of compound (I) is administered to a subject in need once daily.

[0205] In some implementations, a dose of 600 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 600 mg of compound (I) is administered once daily to the subject in need.

[0206] In some implementations, a dose of 700 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 700 mg of compound (I) is administered once daily to a subject in need.

[0207] In some implementations, an amount of 800 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 800 mg of compound (I) is administered to a subject in need once daily.

[0208] In some implementations, a dose of 900 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 900 mg of compound (I) is administered once daily to a subject in need.

[0209] In some implementations, a dose of 1000 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 1000 mg of compound (I) is administered once daily to a subject in need.

[0210] In some implementations, a dose of 1100 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 1100 mg of compound (I) is administered once daily to a subject in need.

[0211] In some implementations, a dose of 1200 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 1200 mg of compound (I) is administered once daily to a subject in need.

[0212] In some implementations, a dose of 1300 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 1300 mg of compound (I) is administered once daily to a subject in need.

[0213] In some implementations, a dose of 1400 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 1400 mg of compound (I) is administered once daily to a subject in need.

[0214] In some implementations, a dose of 1500 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 1500 mg of compound (I) is administered once daily to a subject in need.

[0215] In some implementations, a dose of 1600 mg of compound (I) or a pharmaceutically acceptable salt equivalent to 1600 mg of compound (I) is administered once daily to a subject in need.

[0216] In some implementations, the determined amount of compound (I) or a pharmaceutically acceptable salt thereof is administered orally to the subject in need twice daily (BID).

[0217] In some implementations, a 50 mg dose of compound (I) or a pharmaceutically acceptable salt equivalent to 50 mg of compound (I) is administered twice daily to the subject in need.

[0218] In some implementations, a 100 mg dose of compound (I) or a pharmaceutically acceptable salt equivalent to 100 mg of compound (I) is administered twice daily to the subject in need.

[0219] In some implementations, a dose of 150 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 150 mg is administered twice daily to the subject in need.

[0220] In some implementations, a 200 mg dose of compound (I) or a pharmaceutically acceptable salt equivalent to 200 mg of compound (I) is administered twice daily to the subject in need.

[0221] In some implementations, a dose of 250 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 250 mg is administered twice daily to the subject in need.

[0222] In some implementations, a dose of 300 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 300 mg is administered twice daily to the subject in need.

[0223] In some implementations, a dose of 350 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 350 mg is administered twice daily to the subject in need.

[0224] In some implementations, a dose of 400 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 400 mg is administered twice daily to the subject in need.

[0225] In some implementations, a dose of 450 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 450 mg is administered twice daily to the subject in need.

[0226] In some implementations, a 500 mg dose of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 500 mg is administered twice daily to the subject in need.

[0227] In some implementations, a dose of 550 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 550 mg is administered twice daily to the subject in need.

[0228] In some implementations, a dose of 600 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 600 mg is administered twice daily to the subject in need.

[0229] In some implementations, a dose of 650 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 650 mg is administered twice daily to the subject in need.

[0230] In some implementations, a dose of 700 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 700 mg is administered twice daily to the subject in need.

[0231] In some implementations, a dose of 750 mg of compound (I) or a pharmaceutically acceptable salt of compound (I) equivalent to 750 mg is administered twice daily to the subject in need.

[0232] In some implementations, the subject in need is given 800 mg of compound (I) or an equivalent amount of its pharmaceutically acceptable salt twice daily.

[0233] In some implementations, the subject in need is given twice daily an amount of 300 mg to 600 mg of compound (I) or an amount of its pharmaceutically acceptable salt equivalent to 300 mg to 600 mg of compound (I).

[0234] In some implementations, a pharmaceutically acceptable salt of compound (I) or an amount equivalent to 400 mg to 600 mg of compound (I) is administered to the subject in need twice daily.

[0235] Additionally, the compound (I), its pharmaceutically acceptable salt, or pharmaceutical composition disclosed herein may be administered co-administered with other therapeutic agents. As used herein, the terms “co-administered,” “administered in conjunction with,” and their grammatical equivalents are intended to cover the administration of two or more therapeutic agents to a single subject and are intended to include treatment regimens in which said agents are administered via the same or different routes of administration or at the same or different times. In some embodiments, the compound (I), its pharmaceutically acceptable salt, or the pharmaceutical composition disclosed herein will be administered co-administered with other agents. These terms cover the administration of two or more agents to a subject such that both agents and / or their metabolites are simultaneously present in the subject's body. These include simultaneous administration in separate compositions, administration in separate compositions at different times, and / or administration in a composition in which two agents are present. Thus, in some embodiments, the compound (I) and one or more other agents are administered as a single composition. In some embodiments, the compound (I) and other agents are mixed in a composition.

[0236] The specific administration method and dosage regimen will be selected by the attending clinician based on the specific circumstances (e.g., the subject, the cancer, the specific treatment). Treatment may involve daily, multiple-day, or less-than-daily dosing (e.g., weekly or monthly dosing) over a period of days to months or even years. In some embodiments, compound (I) and other agents are administered in a 28-day cycle. In some embodiments, the 28-day cycle is continuous. However, those skilled in the art will readily recognize suitable and / or equivalent dosages by referring to the dosages of approved compositions using disclosed CDK2 inhibitors for the treatment of cancer.

[0237] In some embodiments, the subject in need is given an amount of compound (I) or a pharmaceutically acceptable salt thereof described in any of the above embodiments (e.g., any one of paragraphs

[00165] -

[00236] ) in combination with an effective amount of platinum therapy. In some embodiments, the platinum therapy is carboplatin. In some embodiments, the subject in need is given a combination of compound (I) or a pharmaceutically acceptable salt thereof with an effective amount (e.g., area under the plasma concentration-time curve (AUC) of 4 mg / mL·min at the starting dose). In one embodiment, carboplatin is co-administered once on day 1 of each 28-day cycle. In one embodiment, carboplatin with an initial AUC of 4 mg / mL·min is co-administered intravenously once on day 1 of each 28-day cycle. In some embodiments, the subject is given 4, 5, or 6 cycles of carboplatin.

[0238] In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof described in any of the above embodiments (e.g., any one of paragraphs

[00165] -

[00236] ) is administered to the subject in need, in combination with an effective amount of SERD. In some embodiments, SERD is fulvestrant. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject in need in combination with an effective amount (e.g., 500 mg) of fulvestrant. In one embodiment, fulvestrant is co-administered on days 1 and 15 of the first cycle and on day 1 of each subsequent cycle. In one embodiment, 500 mg of fulvestrant is co-administered intramuscularly on days 1 and 15 of the first cycle and on day 1 of each subsequent cycle.

[0239] In some embodiments, the subject in need is administered the amount of compound (I) or a pharmaceutically acceptable salt thereof described in any of the above embodiments (e.g., any one of paragraphs

[00165] -

[00236] ), in combination with an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the subject in need is administered compound (I) or a pharmaceutically acceptable salt thereof in combination with an effective amount (e.g., 400 mg or 600 mg) of ribociclib and an effective amount (e.g., 500 mg) of fulvestrant. In one embodiment, ribociclib is co-administered once daily on days 1 to 21 of a 28-day cycle, and fulvestrant is co-administered on days 1 and 15 of the first cycle and on day 1 of each subsequent cycle. In one implementation, 400 mg or 600 mg of ribociclib is administered orally once daily from day 1 to day 21 of a 28-day cycle, and 500 mg of fulvestrant is administered intramuscularly on day 1 and day 15 of cycle 1 and on day 1 of each subsequent cycle.

[0240] As those skilled in the art will understand, compound (I) or its pharmaceutically acceptable salts can be administered to patients in various forms, depending on the chosen route of administration. Compound (I) can be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, via patch, pump, or transdermally, and the pharmaceutical composition is formulated accordingly. Parenterally administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local administration. Parenterally administration can be performed by continuous infusion over a selected time period.

[0241] The pharmaceutical compositions disclosed herein are formulated to be compatible with their intended route of administration. In one embodiment, the composition is formulated according to conventional procedures to be suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to a human. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration.

[0242] Typically, for oral therapeutic use, compound (I) or its pharmaceutically acceptable salt can be mixed with excipients and used in the form of ingestible tablets, buccal tablets, sugar tablets, capsules, elixirs, suspensions, syrups, rice paper capsules, etc.

[0243] For parenteral administration, solutions of compound (I) or its pharmaceutically acceptable salts are typically prepared in water, suitably mixed with surfactants such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as in oils. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0244] Generally, for injection applications, sterile aqueous solutions or dispersions and sterile powders of compound (I) for the temporary preparation of sterile injectable solutions or dispersions are appropriate.

[0245] The following examples are intended to illustrate the point and are not intended to limit the scope of this disclosure in any way.

[0246] Example Example 1: Phase 1 / 2 study of patients with advanced solid tumors This is an ongoing Phase 1 / 2, open-label, first-in-human study (NCT05252416) to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of compound (I) (a selective CDK2 inhibitor).

[0247] Phase 1: Dosage escalation This study included dose escalation periods in patients with the following cancers: advanced / recurrent solid tumors (Part 1A; 50–70 patients); platinum-resistant or platinum-refractory ovarian cancer, endometrial cancer that had progressed after 2 or more lines of therapy (previously treated with platinum), and gastric cancer that had progressed after 2 or more lines of therapy (previously treated with platinum) (Part 1C; 25–40 patients); and HR+ / HER2- BC that had progressed despite CDK4 / 6i therapy (Part 1D; 25–40 patients). Figure 1 In the Phase 1 dose escalation, there is no Part 1B.

[0248] This study includes an initial Phase 1 portion for determining the maximum tolerated dose (MTD) and / or recommended Phase 2 dose (RP2D) of compound (I) as a monotherapy (initially with a BID (twice daily) regimen, with the option to evaluate QD (once daily) dosing if new PK and safety data support it; Part 1A), and two additional dose escalation portions for determining the RP2D of compound (I) in combination with carboplatin (Part 1C) and the RP2D of compound (I) in combination with ribociclib and fulvestrant (Part 1D).

[0249] Dosage escalation Part 1A: Compound (I) monotherapy Phase 1 dose escalation employed a Bayesian optimal interval (BOIN) design to determine the median dose (MTD) of compound (I) when administered via BID and QD dosing regimens. Patients with advanced recurrent / relapsed tumors (regardless of CCNE1 status) were enrolled during the dose escalation period, with priority given to patients with CCNE1-amplified solid tumors at the potential therapeutic dose. At each dose level, slots may be reserved for patients with CCNE1 amplification.

[0250] Patients in the first cohort were treated with a starting dose of compound (I) orally at a dose of 50 mg BID. To limit the number of patients receiving potentially subtherapeutic doses, the study initially used a cohort size of 1–3 patients, with dose increments between cohorts increasing by approximately 100%. During the first 28 days of treatment, dose escalation increments were reduced to approximately 50% if one patient at any dose level experienced a dose-limiting toxicity (DLT), or if any two patients at any dose level experienced a grade ≥ 2 adverse event (AE) considered likely to be related to compound (I). Each dose level was rounded down or up to the nearest multiple of 25 mg to accommodate available dose intensities (25 mg and 100 mg). Patients who experienced a DLT or received at least 75% of the prescribed compound (I) dose (21 days) and completed the 28-day DLT assessment period were eligible for DLT evaluation. Recruitment, dose escalation, descent, and dose elimination for each cohort followed the BOIN rule. The Safety Review Committee (SRC) met to review accumulated safety data and agree on the decision to open each cohort and the specific doses selected for each cohort. All cohorts at dose levels ≥100 mg BID (or ≥200 mg QD) consisted of at least 3 evaluable patients. To provide a more robust characterization of safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity, additional patients may be recruited at a previously tested lower dose level if the dose level cohort includes fewer than 12 patients with evaluable DLTs and has been approved by the SRC for further escalation. For patients enrolled at previously tested dose levels, dose escalation is permitted, provided the dose does not exceed the SRC-approved dose level for further escalation, the patient has completed ≥8 weeks of treatment, and has not experienced grade 3 / 4 AEs or DLTs related to compound (I).

[0251] For any given dose level, the total number of patients evaluable for DLT should not exceed 12. Dose escalation is considered complete when 12 patients are evaluable for DLT at any dose level. MTD is determined based on isotonic regression, while RP2D can be selected based on all clinical data, including safety, PK, pharmacodynamics, and antitumor activity.

[0252] Furthermore, if new PK data for BID dose escalation are available to support it, the same BOIN dose escalation design described above should be used to evaluate QD dosing regimens. The initial total daily dose level for QD dose escalation should not exceed the highest dose level of the BID regimen for which the SRC has approved further dose escalation. For example, if QD dosing is initiated after it is believed that a further escalation to a 100 mg BID dose is safe, the QD dosing cohort will begin with a 100 mg QD dose.

[0253] Dosage escalation, Part 1C: Compound (I) and Carboplatin Dose escalation of the combination of compound (I) and carboplatin was performed in patients with platinum-resistant or platinum-refractory ovarian cancer, patients with gastric cancer that had progressed after at least two prior lines of therapy (including platinum-based chemotherapy), and patients with endometrial cancer that had progressed after at least two prior lines of therapy (including platinum-based chemotherapy). The first cohort received no more than 50% of the monotherapy RP2D of compound (I) in combination with carboplatin, with the starting dose of carboplatin being an area under the plasma concentration-time curve (AUC) of 4 mg / mL·min, administered intravenously once on day 1 of each 28-day cycle. Further dose escalations or descents were performed according to the rules of the BOIN design. The dose of compound (I) in the combination cohort did not exceed the monotherapy RP2D. Patients who underwent DLT or received at least 75% of the prescribed compound (I) dose (21 days), received the full prescribed carboplatin dose, and completed the 28-day DLT assessment period were eligible for DLT evaluation.

[0254] Part 1D of dose escalation: Combinations of compound (I) with ribociclib and fulvestrant Dose escalation of the combination of compound (I) and ribociclib was performed in patients with HR+ / HER2- breast cancer whose disease had progressed. The first cohort included at least six patients receiving compound (I) at a dose of ~25% of the monotherapy RP2D (or, if the RP2D has not been determined, ~25% of the highest monotherapy dose deemed safe for further escalation; doses may be rounded up or down to account for available tablet strength), in combination with ribociclib at a 400 mg oral QD (days 1-21 of a 28-day cycle) and the approved dose of fulvestrant (500 mg intramuscularly on days 1 and 15 of the first cycle and on day 1 of each subsequent cycle). Patients who underwent DLT or received at least 75% of the prescribed compound (I) dose (21 days), at least 75% of the prescribed ribociclib dose (16 days), or the full dose of the prescribed fulvestrant and completed the 28-day DLT assessment period were eligible for DLT evaluation. Further dose escalation or de-escalation was performed according to the rules of the BOIN design. In the combination cohort, the dose of compound (I) does not exceed that of the single therapy RP2D.

[0255] Phase 1 assessment The maximum tolerated dose (MTD) will be determined based on dose-limiting toxicity (DLT) and safety profile.

[0256] R2PD will be determined based on DLT, PK, PD, and preliminary security data.

[0257] result Compound (I) is currently undergoing dose escalation evaluation in a Phase 1 clinical trial. To date, patients treated with compound (I) at doses ranging from 50 mg BID to 800 mg BID have all shown evidence of clinical benefit, and no patients have discontinued treatment due to adverse events (AEs).

[0258] Example 2 Dosage Extensions: Part 2A (Compound (I) monotherapy), Part 2B (Combination of Compound (I) with fulvestrant), Part 2C (Combination of Compound (I) with carboplatin), and Part 2D (Combination of Compound (I) with ribociclib and fulvestrant). The Phase 2 expansion groups for compound (I) monotherapy (Part 2A) and combination therapy with fulvestrant (Part 2B) were initiated after completion of dose escalation of compound (I) monotherapy and determination of RP2D (dose level and regimen). Approximately 45 patients with platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer (Group 1), approximately 45 patients with CCNE1-amplified endometrial cancer (Group 2), and approximately 25 patients with CCNE1-amplified solid tumors in a basket group (Group 3) received compound (I) RP2D. For Group 4 of Part 2B, at least 9 patients with HR+ / HER2- breast cancer who had progressed on CDK4 / 6i therapy in the lead cohort received compound (I) RP2D monotherapy in combination with fulvestrant. If this was tolerable, an additional 24 patients with HR+ / HER2- breast cancer who had progressed on CDK4 / 6i therapy would receive fulvestrant and compound (I) monotherapy RP2D.

[0259] The Phase 2 expansion group for the combination of compound (I) and carboplatin (Part 2C) was initiated after Part 1C was completed and the RP2D of compound (I) and carboplatin was determined. Approximately 45 patients with platinum-resistant or platinum-refractory ovarian cancer with CCNE1 amplification were treated with compound (I) and carboplatin.

[0260] The Phase 2 extension group (Part 2D) for compound (I) in combination with ribociclib and fulvestrant was initiated after Part 1D was completed and RP2D for compound (I) in combination with ribociclib and fulvestrant was determined. Approximately 33 patients with HR+ / HER2- breast cancer whose disease had progressed during CDK4 / 6i therapy received ribociclib and fulvestrant, along with compound (I) in RP2D.

[0261] Research on treatment Compound (I) is administered orally daily (at the dose levels and regimens applicable to the study period and cohort [BID or QD]), with no food or concomitant medications for 2 hours before and 1 hour after administration. It is preferred to take the medication at approximately the same time each day. Dosage adjustments are made based on specific criteria for observed toxicity.

[0262] For patients in Part 2B, fulvestrant is used in combination with compound (I) for patients with HR+ / HER2- breast cancer. Fulvestrant is administered according to local prescribing information and institutional standards.

[0263] For patients in Parts 1C and 2C, carboplatin AUC 4-5 mg / mL·min is administered intravenously over 15-60 minutes every 28 days, according to local prescribing information and institutional standards, for 4-6 cycles.

[0264] For patients in Part 1D and Part 2D, ribociclib and fulvestrant were administered at dose levels determined for the specific dose escalation cohort, based on local prescribing information and institutional standards.

[0265] Phase 2 assessment The efficacy was assessed using the RECIST (Responsive Clinical Trial and Evaluation Criteria in Solid Tumors) version (v) 1.1 criteria (Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (1.1)). Eur J Cancer. 2009; 45:228–247.

[0266] Example 3: Data summary from a phase 1 / 2 study of patients with advanced solid tumors In the phase 1 dose-escalation study described in Example 1, patients were enrolled and received compound (I) treatment. The primary eligibility criteria for patients included i) adults diagnosed with unresectable advanced solid tumors; ii) ECOG PS 0-2; and iii) progression despite standard treatment. CCNE1 Patients can enroll regardless of their condition.

[0267] As of the data cutoff date (January 22, 2024), 53 patients were treated with compound (I) monotherapy in the Phase 1 (Part 1A) study, divided into 7 escalating dose cohorts with a total daily dose ranging from 100 mg to 1600 mg (50 mg to 800 mg twice daily), and included in the safety population (Table 1). Patients had received substantial prior therapy, with the majority (71.7%) having received 4 or more prior therapies.

[0268] Table 1: Demographic and Baseline Characteristics (as of January 22, 2024)

[0269] a ECOG PS, Eastern Cooperative Oncology Group Performance Status: Grade 0 - Fully active, able to perform all pre-illness activities without restriction; Grade 1 - Limited strenuous physical activity, but able to walk and perform light or sedentary work, such as light housework or office work; Grade 2 - Able to walk and fully self-sufficient, but unable to perform any work activities, with approximately more than 50% of waking time. b Ovarian cancer subtypes: 10 cases of high-grade serous carcinoma, 1 case of other cancers; c Endometrial carcinoma subtypes: 2 cases of endometrioid carcinoma and 2 cases of serous carcinoma; d Subtypes of uterine cancer: 2 cases of carcinosarcoma, 2 cases of leiomyosarcoma; e Other cancers included prostate cancer (n=3), fallopian tube cancer (2), adenocarcinoma, anal neuroendocrine carcinoma, cervical cancer, chondroblastic osteosarcoma, colorectal cancer, primary extraovarian cancer, gastric cancer, hepatocellular carcinoma, lung cancer, pancreatic cancer, thyroid cancer, and urothelial carcinoma, with one case of each cancer. f One patient completed the sub-study but did not receive monotherapy with compound (I) at a dose level of 400 mg BID.

[0270] Pharmacokinetics (Deadline is December 14, 2023) The plasma concentration of compound (I) increases proportionally up to 600 mg BID. Figure 2 The mean effective half-life of compound (I) is 12 hours (calculated based on cumulative effect). Effective concentration (C) eff The range represents the single-therapeutic concentration of the effective compound (I) that induced tumor arrest in preclinical OVCAR-3, MKN-1, and T47D models, and corresponds to 25%, 25%, and 60% inhibition of phosphorylated Rb at Ser807 and / or Ser811 sites in these models, respectively.

[0271] Pharmacodynamics (Deadline is January 22, 2024) Evidence of targeting activity was observed at serum TK1 levels during dose escalation, with patients receiving monotherapy with compound (I) showing decreased TK1 activity at higher study dose levels. Figure 3 Patients who discontinued treatment at the time of sampling (n=3) or lacked baseline samples (n=1) were excluded. Confirmed partial responses (PRs) were observed according to RECIST v1.1.

[0272] A decrease in phosphorylated Rb (pRb) was observed in three patients treated with compound (I) at 400 mg BID and 500 mg BID. Figure 4 Patients 5, 6, and 7). The tumor biopsy during treatment in patient 6 (as described in the patient profile below) likely underestimated the extent of pRb suppression because the biopsy occurred late (12 hours after the most recent administration of compound (I)) and pRb has been confirmed to recover over time.

[0273] Security (Deadline is January 22, 2024) As of the data cutoff date of January 22, 2024, monotherapy with compound (I) was generally well tolerated. Dose escalation is ongoing. Table 2 shows the most frequently reported treatment-related adverse events (TRAEs). Two patients discontinued study treatment due to AEs. Two patients experienced dose-limiting toxicities (DLTs): one experienced grade 3 nausea at 800 mg BID, and the other experienced grade 3 blurred vision / photophobia at 600 mg BID. Both patients improved after dose reduction. No cardiac TRAEs or QTc prolongation were observed. Hematological TRAEs were generally mild and primarily occurred in patients with a history of cytopenia and / or baseline cytopenia. Four patients experienced grade 3 anemia, one of which was treatment-related; no ≥ grade 4 anemia was reported. Three patients experienced grade 1 or 2 neutropenia; no ≥ grade 3 neutropenia was reported. One patient experienced grade 3 thrombocytopenia. In two patients receiving the 800 mg BID dose, TRAEs improved after dose reduction.

[0274] Fifteen (28.3%) patients reported visual adverse events (AEs), with some experiencing >1 event. The most common were photophobia (17.0% [9 / 53]) and blurred vision (11.3% [6 / 53]). Except for one patient who experienced grade 3 blurred vision and photophobia (DLT), the other symptoms were generally tolerable. Events were intermittent (ranging from seconds to hours), occurred shortly after administration, and most resolved spontaneously or completely after dose interruption / reduction. Comprehensive ophthalmological examinations (including optical coherence tomography) performed on all patients revealed no abnormalities, and no acute abnormalities were found.

[0275] Forty-one (77.4%) patients receiving compound (I) monotherapy experienced treatment-related adverse events (TRAEs) (Table 2). The most common TRAEs (≥15%) included nausea (49.1%), diarrhea (49.1%), fatigue (32.1%), vomiting (30.2%), anemia (17.0%), and photophobia (15.1%). DLT was observed in two patients. Two patients discontinued treatment due to TRAEs.

[0276] Table 2. Treatment-related adverse events reported in ≥5% of patients receiving compound (I) monotherapy (safety population N=53) (as of January 22, 2024) In addition, as of January 22, 2024, at least one patient in each of the 200 mg BID, 400 mg BID, 500 mg BID and 600 mg BID cohorts had stable disease (one patient had stable disease for 6 months at 400 mg BID and another patient had stable disease for about 1 year at 600 mg BID), and a partial remission was observed in one patient in the 800 mg BID cohort (dose was reduced to 400 mg BID after 4 days).

[0277] Patient Profile (Part 1) A 57-year-old woman with HR+ / HER2- breast cancer that had metastasized to the liver and bones experienced progression despite receiving the following treatments: 1) doxorubicin, cyclophosphamide, and paclitaxel; 2) tamoxifen; 3) palbociclib and fulvestrant; 4) abecilibi and anastrozole; and 5) capecitabine.

[0278] The patient participated in the phase 1 portion of the study and started with compound (I) monotherapy at 800 mg BID for 4 days. Due to grade 3 nausea (DLT), which improved after dose reduction, the dose was reduced to 400 mg BID on day 8 of cycle 1.

[0279] According to the PR report of RECIST v1.1, a 43% reduction in single liver metastases was observed after two cycles, which was confirmed after four cycles. See also Figure 5 .

Claims

1. A method for treating cancer, said method comprising orally administering, daily, an amount of compound (I) of 100 mg to 1600 mg to a subject in need. (I), or a pharmaceutically acceptable salt of compound (I) in an amount equivalent to 100 mg to 1600 mg.

2. The method of claim 1, wherein the subject in need is given an amount of compound (I) of 100 mg to 1400 mg or a pharmaceutically acceptable salt thereof of an amount equivalent to 100 mg to 1400 mg of compound (I).

3. The method of claim 1, wherein the subject in need is administered with a concentration selected from 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, or 1050 mg. Compound (I) in amounts of 50 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg and 1600 mg, or equivalent to 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, or 1600 mg. 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg or 1600 mg of a pharmaceutically acceptable salt of compound (I).

4. The method of claim 1, wherein the subject in need is given an amount of compound (I) of 800 mg to 1200 mg, or an amount of its pharmaceutically acceptable salt equivalent to 800 mg to 1200 mg of compound (I).

5. The method of claim 1, wherein the subject in need is given twice daily an amount of 300 mg to 600 mg of compound (I), or an amount of its pharmaceutically acceptable salt equivalent to 300 mg to 600 mg of compound (I).

6. The method of any one of claims 1 to 5, wherein the cancer has elevated and / or abnormal expression of CCNE1.

7. The method of any one of claims 1 to 6, wherein the cancer is platinum-resistant and / or platinum-refractory.

8. The method of any one of claims 1 to 7, wherein the cancer is selected from ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, and breast cancer.

9. The method of any one of claims 1 to 8, wherein the cancer is selected from advanced / recurrent tumors; platinum-resistant or platinum-refractory ovarian cancer; endometrial cancer that has progressed after two or more lines of therapy (previously treated with platinum); gastric cancer that has progressed after two or more lines of therapy (previously treated with platinum); and HR+ (hormone receptor positive) / HER2- (human epidermal growth factor 2 negative) breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors.

10. The method of any one of claims 1 to 9, wherein the cancer is CCNE1-amplified ovarian cancer or CCNE1-amplified endometrial cancer.

11. The method of any one of claims 1 to 10, wherein the method further comprises administering to the subject an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

12. The method of any one of claims 1 to 11, wherein the cancer is CCNE1-amplified ovarian cancer.

13. The method of any one of claims 1 to 12, wherein the method further comprises administering an effective amount of platinum therapy to the subject.

14. The method of claim 13, wherein the platinum therapy is carboplatin.

15. The method of any one of claims 9-14, wherein a single intravenous administration of carboplatin at an initial dose of 4 mg / mL·min is given on day 1 of each 28-day cycle.

16. The method of any one of claims 9-14, wherein the subject is administered carboplatin for 4, 5, or 6 cycles.

17. The method of any one of claims 1 to 9, wherein the cancer is breast cancer.

18. The method of claim 17, wherein the breast cancer is HR+ / HER2- breast cancer.

19. The method of claim 18, wherein the HR+ / HER2- breast cancer progresses despite treatment with a CDK4 / 6 inhibitor.

20. The method of any one of claims 1 to 19, wherein the method further comprises administering an effective amount of a selective estrogen receptor downregulator (SERD) to the subject.

21. The method of claim 20, wherein the SERD is fulvestrant.

22. The method of any one of claims 11 or 17-21, wherein 500 mg of fulvestrant is administered intramuscularly on day 1 and day 15 of the first cycle and on day 1 of each subsequent cycle.

23. The method of any one of claims 1 to 22, wherein the method further comprises administering an effective amount of a CDK4 / 6 inhibitor to the subject.

24. The method of claim 23, wherein the CDK4 / 6 inhibitor is ribociclib.

25. The method of any one of claims 11 or 17-24, wherein 400 mg or 600 mg of ribociclib is administered orally once daily from day 1 to day 21 of a 28-day cycle, and 500 mg of fulvestrant is administered intramuscularly on day 1 and day 15 of cycle 1 and on day 1 of each subsequent cycle.

26. A method of treating a subject with amplified CCNE1 expression levels and who has or is at risk of developing solid tumor cancer, said method comprising orally administering, daily, an amount of compound (I) of about 100 mg to about 1600 mg to the subject in need. (I), or a pharmaceutically acceptable salt of compound (I) in an amount equivalent to 100 mg to 1600 mg.

27. The method of claim 26, wherein the solid tumor cancer is at least one of the following: uterine cancer (including uterine carcinosarcoma (UCS) and uterine corpus endometrial cancer (UCEC)), endometrial cancer (including carcinosarcoma endometrial cancer, clear cell endometrial cancer, grade 3 endometrioid endometrial cancer, and serous endometrial cancer (SEC)), breast cancer (including invasive breast cancer (BRCA), TNBC (triple-negative breast cancer), HR (hormone receptor)+ breast cancer, ER (progesterone receptor)+ breast cancer, HR+ / HER2 (human epidermal growth factor 2)- breast cancer, ER+ / HER2- breast cancer, PR+ (Progesterone receptor positive) / HER2- breast cancer, HER2- breast cancer, HER2-low breast cancer and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma (OV) and high-grade serous ovarian cancer (HGSOC)), gastric cancer (including gastric adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML) (Acute myeloid leukemia), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myelodysplastic neoplasm (MPN), sarcoma (including osteosarcoma), esophageal cancer (including esophageal cancer), bladder cancer (including bladder urothelial carcinoma (BCLA)), lung cancer (including squamous cell carcinoma of the lung, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), such as EGFRm (epidermal growth factor receptor mutant + non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma (ACC) or mesothelioma.

28. A method for treating cancer in a subject of need, the method comprising: i. Testing or having tested a first biological sample obtained from the subject who has cancer to measure the level of one or more biomarkers in the subject's cancer; ii. Compare the levels of one or more biomarkers from step i. with the levels of one or more biomarkers measured in subjects with normal functional pathways; iii. In response to determining that the subject's cancer will be sensitive to compound (I) or a pharmaceutically acceptable salt thereof, the subject is treated with a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, further comprising testing, or having tested, a second biological sample obtained from the subject suffering from cancer to determine whether the levels of one or more biomarkers have changed after administration of compound (I) or a pharmaceutically acceptable salt thereof.

30. A method for monitoring the response of a subject who has cancer or is at risk of developing cancer, the method comprising: i. Administer to the subject in need a dose of 100 mg to 1600 mg of compound (I), or a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1600 mg of compound (I); ii. A first biological sample obtained from the subject has been tested or has been tested to measure the level of one or more biomarkers in the biological sample; iii. Compare the levels of one or more biomarkers from step ii. with the levels of one or more biomarkers measured in subjects with normally functioning pathways; and iv. If the comparison in step iii shows a change in the level of one or more biomarkers, determine whether the subject with cancer or at risk of cancer responded to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

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