CDK2 inhibitor BLU-222 for the treatment of cancer

Abstract

The present disclosure provides improved methods of treating cancer using N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine, or a pharmaceutically acceptable salt thereof. In one aspect, the present disclosure provides a method of treating a subject suffering from cancer with Compound (I) or a pharmaceutically acceptable salt thereof. The present disclosure provides a dosing regimen of Compound (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to 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 disclosures of each of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that play a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and selective activation of specific CDKs allows for the proper sequencing of steps in cell cycle progression. CDK activation requires heterodimerization with regulatory subunits known as cyclins. Cell cycle deregulation is a common feature of human cancers.

[0003] Cyclin-dependent kinase 2 (Cdk2) is involved in a range of biological activities. CDK2 is a key cell cycle regulator, active throughout late G1 and S phases. CDK2 participates in the DNA damage response (DDR) via the homologous recombination (HR) pathway. CDK2 also regulates aspects of the apoptotic pathway. Cyclin E1 (CCNE1), cyclin E2 (CCNE2), cyclin A1 (CCNA1), and cyclin A2 (CCNA2), as well as p21Cip1 / Waf1, p27Kip1, and p57Kip2 (cyclin-dependent kinase inhibitors of the cyclin-CDK2 complex), are key regulators of CDK2 activity. Dysregulation of CDK2 binding by cyclin E1, E2, A1, or A2, or the activity of cyclin-dependent kinase inhibitor proteins, can occur in cancer. (See S. Tadesse et al., Drug Discovery Today, Volume 25, Number 2, February 2020)

[0004] Dysregulation of CDK2 can occur through several mechanisms. Amplification and / or overexpression of CCNE1 has been observed 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 overexpression and / or amplification of CCNE1 (see Ooi et al., Hum Pathol. (2017) 61:58-67 and Noske et al., Oncotarget (2017) 8:14794-14805).

[0005] These findings indicate that CDK2 is a potential target for cancers with unregulated CDK2 activity, but no drugs that selectively target CDK2 are currently approved, necessitating the development of new selective CDK2 inhibitors.

[0006] The structure of one of the CDK2 inhibitors, 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: [ka] There is a need to develop improved methods, including dosing regimens, for treating subjects suffering from cancer with Compound (I). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] S. Tadesse et al.,Drug Discovery Today,Volume 25,Number 2 February 2020 [Non-patent document 2] Scaltriti,M.et al.,Proc.Natl Acad.Sci.USA 108,3761-3766(2011) [Non-patent document 3] Etemadmoghadam,D.et al. Proc.Natl Acad.Sci.USA 110,19489-19494(2013) [Non-patent document 4] Ooi et al. Hum Pathol.(2017)61:58-67 [Non-patent document 5] Noske et al, Oncotarget(2017)8:14794-14805 Summary of the Invention [Means for solving the problem]

[0008] In one aspect, the present disclosure provides a method for treating a subject suffering from cancer with Compound (I) or a pharmaceutically acceptable salt thereof. The present disclosure provides a dosing regimen of Compound (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer. More specifically, the present disclosure provides a method for treating cancer, the method comprising administering to a subject in need of treatment an amount of Compound (I) in an amount of 100 mg to 1600 mg per day: [ka] or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1600 mg of Compound (I). The objective of the present disclosure is to provide a novel method for treating a subject suffering from cancer at a safe and effective daily dose. Compound (I) is orally bioavailable. Compound (I) is highly potent and has CDK family selectivity and overall kinome selectivity.

[0009] In some embodiments, the cancer is selected from the group consisting of breast cancer, endometrial cancer, esophageal cancer, gastric cancer, lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

[0010] Also provided herein is a method for treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing solid tumor cancer, the method comprising administering to a subject in need thereof an amount of 100 mg to 1600 mg per day of Compound (I): [ka] Or, it comprises administering a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1600 mg of compound (I).

[0011] Contemplated solid tumor cancers may be at least one of the following: uterine cancer (including uterine carcinosarcoma and uterine endometrial cancer (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 tumor), colorectal cancer (C RC), 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), myeloproliferative neoplasms (MPN), sarcoma (including osteosarcoma), esophageal cancer (including esophageal carcinoma and esophageal adenocarcinoma), bladder cancer (including bladder urothelial carcinoma (BLCA)), lung cancer (including squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.

[0012] In another aspect, the disclosure provides a method of measuring a change in the level of one or more biomarkers after administering to a subject suffering from or at risk of developing cancer an amount of Compound (I) in the range of 100 mg to 1600 mg, or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1600 mg of Compound (I), wherein treatment with Compound (I) results in a change in the level of one or more biomarkers. [Brief explanation of the drawings]

[0013] [Figure 1] The study design for the ongoing Phase 1 / 2, open-label, first-in-human study (NCT05252416) is shown. BC, breast cancer; CCNE1, cyclin 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 of care. aBased on a Bayesian optimal interval (BOIN) escalation study design. bFor Phase 1 dose escalation, there is no Part 1B. cPhase 2 will begin after the recommended Phase 2 dose (RP2D) is determined. d Phase 2 cohorts will be treated with Compound (I) at the RP2D for Compound (I) monotherapy in Parts 2A and 2B, Compound (I) and carboplatin at the RP2D for Part 2C, and Compound (I) and ribociclib at the RP2D for Part 2D. In the combination therapy cohorts (Parts 2B, 2C, and 2D), the dose of Compound (I) will not exceed the Compound (I) monotherapy RP2D dose. 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 according to local prescribing information and institutional standards at the dose levels determined for the specific dose escalation cohorts.

[0014] [Figure 2] 1 shows the mean plasma concentrations of Compound (I) versus time following twice-daily (BID) dosing of 50-600 mg.

[0015] [Figure 3]Figure 1 shows the dose-dependent serum TK1 response in patients treated with Compound (I) monotherapy at dose escalation by dose cohort. The dotted line represents a 30% decrease in TK1. *Other tumor types include adenocarcinoma, anal neuroendocrine carcinoma, cervical carcinoma, chondroblastic osteosarcoma, colorectal carcinoma, fallopian tube carcinoma, gastric carcinoma, hepatocellular carcinoma, pancreatic carcinoma, prostate carcinoma, and thyroid carcinoma.

[0016] [Figure 4] The percentage of pRb-positive cells in tumor biopsies from patients for screening samples (dark gray bars) and patients for compound (I) monotherapy treatment is shown. Light gray bars are for the time points listed below the bar graph, where C is the cycle and D is the number of days. For example, patient 6 was evaluated 12 hours after the most recent compound (I) administration, at cycle 1 on day 13. The cancer type and the percentage change in pRb between the screening sample (dark gray bar) and the time point (C1DX) sample (light gray bar) are shown below the bar graph. pRb is phosphorylated retinoblastoma protein (Rb).

[0017] [Figure 5] Partial response to Compound (I) monotherapy in target liver lesions in patients with HR+ / HER2- metastatic breast cancer. DETAILED DESCRIPTION OF THE INVENTION

[0018] Treatment method International Application Publication No. WO2023 / 278326, the teachings of which are incorporated herein by reference in their entirety, discloses compound (I) having the following structural formula: [ka] Compound (I) is an investigational, oral, potent, and selective CDK2 inhibitor. Compound (I) is orally bioavailable. Compound (I) is highly potent and possesses CDK family selectivity and global kinome selectivity.

[0019] In preclinical studies, compound (I), in combination with CDK4 / 6 inhibitors, has been shown to exhibit potent antitumor activity in CCNE1-amplified ovarian cancer models, as well as CDK4 / 6 inhibitor-naïve and -resistant HR+ / HER2- breast cancer (Choi YJ et al. AACR 2021 Presentation; Poster #1279; Brown V et al. AACR 2022 Presentation; Poster #2306; Brown V et al. SABCS 2022 Presentation; Poster #P6-10-07).

[0020] In one aspect, the present disclosure provides a method of treating a subject suffering from cancer with Compound (I) or a pharmaceutically acceptable salt thereof. The present disclosure provides a dosing regimen of Compound (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer. The present disclosure provides a method of treating cancer comprising administering to a subject in need thereof an amount of Compound (I) in the range of 100 mg to 1600 mg, or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1600 mg of Compound (I). In some embodiments, the method of treating cancer comprises daily oral administration to a subject in need thereof of an amount of Compound (I) in the range of 100 mg to 1600 mg, or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1600 mg of Compound (I).

[0021] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic reaction, within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmacologically acceptable salts in J.Pharm.Sci., 1977, 66, 1-19.

[0022] Compound (I) disclosed herein can be useful in the form of a free base or a salt. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of methanesulfonate, ethanesulfonate, benzenesulfonate, tosylate, naphthalene-2-sulfonate, glycine, succinate, citrate, tartrate, adipate, aspartate, histidine, vanillin, phosphate, hydrochloride, hydrobromide, nitrate, and sulfate. In some embodiments, the pharmaceutically acceptable salt of Compound (I) is selected from the group consisting of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-4-sulfonic acid, naphthalene-2-sulfonic acid, hydrochloric acid, hydrobromide, nitric acid, and sulfuric acid salts.

[0023] In some embodiments, Compound (I) is administered as the free base in the methods of treatment disclosed herein. In some embodiments, a pharmaceutically acceptable salt of Compound (I) is administered in the methods of treatment disclosed herein.

[0024] Compound (I) is an effective, potent, and selective CDK2 inhibitor and can be used to treat various cancers. As used herein, the term "selective CDK2 inhibitor" refers to a compound that selectively inhibits CDK2 over other CDKs and kinomes. In other words, a selective CDK2 inhibitor has no or low activity against other CDKs, particularly CDK1, and kinomes. The inhibitory activity of a selective CDK2 inhibitor against CDK2 is higher than that against other CDKs and many other kinases, with an IC 50 value( すなわち Compound (I) is more potent in terms of selectivity (e.g., subnanomolar IC50 values). Efficacy can be measured using known biochemical assays. Advantages associated with such selectivity may include facilitating effective administration and reducing toxicity on CDK1-mediated targets. Compound (I) has a favorable toxicity profile relative to other non-kinase targets.

[0025] Compound (I) is selective for CDK2 over CDK1. In some such embodiments, Compound (I) exhibits at least 10-fold selectivity for CDK2 over CDK1. In other embodiments, Compound (I) exhibits at least 20-fold selectivity for CDK2 over CDK1. In certain embodiments, Compound (I) exhibits at least 30-fold selectivity for CDK2 over CDK1. In certain embodiments, Compound (I) exhibits at least 40-fold selectivity for CDK2 over CDK1. In other embodiments, Compound (I) exhibits at least 50-fold selectivity for CDK2 over CDK1. Compound (I) is selective for CDK2 over CDK4 and / or CDK6. In some such embodiments, Compound (I) exhibits at least 10-fold selectivity for CDK2 over CDK4 and / or CDK6. In other embodiments, compound (I) exhibits at least 20-fold selectivity for CDK2 over CDK4 and / or CDK6. In certain embodiments, compound (I) exhibits at least 30-fold selectivity for CDK2 over CDK4 and / or CDK6.

[0026] Compound (I) has the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Hepatic metabolism is the predominant excretion route for small molecule drugs. The clearance of a compound via hepatic metabolism can be evaluated in vitro using human liver microsomes (HLM) or human hepatocytes. The compound is incubated with HLM plus appropriate cofactors or human hepatocytes, and the compound depletion is measured to determine the in vitro intrinsic clearance (Cl). The Cl is scaled to the total body clearance (CL) and the hepatic extraction ratio (ER) is determined by dividing the CL by the standard hepatic blood flow rate in humans. Compounds with low hepatic extraction ratios are considered to have good metabolic stability. In some embodiments, the compounds of the present disclosure have a calculated ER of <0.3, <0.4, <0.5, or <0.6.

[0027] 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 aberrant expression of CCNE1 or CCNE2. Thus, in some embodiments of the method, the subject or patient has previously been determined to have elevated Cyclin E1 (CCNE1) gene expression and / or a CCNE1 expression level higher than a control expression level of CCNE1 in a biological sample obtained from the subject or patient.

[0028] In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells in vitro. The method comprises contacting tumor (e.g., cancer) cells in vitro with Compound (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method for suppressing the growth of tumor (e.g., cancer) cells associated with elevated or aberrant expression of CCNE1 in a subject or patient. The method comprises administering a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, to a subject or patient in need thereof.

[0029] In some embodiments, the present disclosure provides the use of 100 mg to 1600 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1600 mg of Compound (I), to prepare a medicament for treating cancer.

[0030] As used herein, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell proliferation. Cancers include solid tumors, named for the type of cell that forms them, and cancers of the blood, bone marrow, or lymphatic system. 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 that begin at a specific site in the body, metastatic cancers that have spread from their original location to other parts of the body, recurrence of a first primary cancer after remission, and second primary cancers (new primary cancers in people with a history of a previous cancer of a different type from the latter). In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is characterized by elevated or aberrant expression of CCNE1 or CCNE2.

[0031] Cancers that may be 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)), gastric cancer (i.e., cancer of the stomach), urothelial carcinoma, brain cancer, mesothelioma (MESO), skin cancer (e.g., melanoma), sarcoma (including osteosarcoma), or thyroid cancer, as well as metastases (especially brain metastases) of all of the cancers listed.In one embodiment, the cancer is uterine cancer (including uterine carcinosarcoma (UCS) and uterine corpus endometrial cancer (UCEC)), endometrial cancer (including serous endometrial carcinoma (SEC)), breast cancer (including invasive carcinoma of the breast (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), PR+ / HER2- breast cancer (progesterone receptor-positive, human epidermal growth factor 2-negative breast cancer), HER2- breast cancer (human epidermal growth factor 2-negative breast cancer), HER2- low breast cancer (human epidermal growth factor 2-low level breast cancer), and HER2+ breast cancer (human epidermal growth factor 2-positive breast cancer)), ovarian cancer (e.g., ovarian serous cystadenocarcinoma (OV), and high-grade Hepatocellular carcinoma (HGSOC), gastric cancer (including gastric adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), kidney cancer, head and neck cancer, liver cancer, prostate cancer (including androgen receptor (AR)-dependent, AR-independent, and castration-resistant prostate cancer (CRPC)), skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (B-cell lymphoma) 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 expression and / or aberrant expression of CCNE1 and / or CCNE2 as described herein.In some embodiments of the methods provided herein, the subject has been identified as having a cancer characterized by elevated and / or aberrant expression of CCNE1 and / or CCNE2.

[0032] In further 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 gastric cancer. In some such embodiments, the cancer is characterized by elevated and / or aberrant expression of CCNE1 and / or CCNE2.

[0033] In further embodiments of the methods provided herein, the cancer is selected from the group consisting of 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 the group consisting of 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 the group consisting of ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, and breast cancer. In some embodiments, the cancer is characterized by elevated and / or aberrant expression of CCNE1. In some embodiments, the cancer is progressing despite platinum therapy.

[0034] In some embodiments, the cancer is platinum-resistant and / or platinum-refractory, hi some embodiments, the cancer is progressing despite platinum therapy.

[0035] In some embodiments, the cancer is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0036] 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-resistant breast cancer, endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired 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 expression and / or aberrant expression of CCNE1 and / or CCNE2.

[0037] 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 treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer has progressed 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 breast cancer has progressed despite a first treatment with palbociclib, ribociclib, and / or fulvestrant and a second treatment with abemaciclib and / or fulvestrant. In some embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib and ribociclib, or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In one embodiment, the breast cancer has elevated and / or aberrant expression of CCNE.

[0038] In some embodiments, the breast cancer is triple-negative breast cancer.

[0039] In some embodiments, the cancer is ovarian cancer. In some such embodiments, the cancer is ovarian cancer characterized by elevated and / or aberrant expression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) ovarian cancer; (b) a cancer characterized by elevated and / or aberrant 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).

[0040] In some embodiments, the cancer is endometrial cancer. In some such embodiments, the cancer is endometrial cancer characterized by elevated and / or aberrant expression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) endometrial cancer; (b) a cancer characterized by elevated and / or aberrant expression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the endometrial cancer is selected from the group consisting of carcinosarcoma endometrial cancer, clear cell endometrial cancer, and grade 3 endometrial cancer, serous endometrial cancer. In some embodiments, the endometrial cancer is serous endometrial carcinoma (SEC).

[0041] In some embodiments, the cancer is CCNE1-amplified ovarian cancer or CCNE1-amplified endometrial cancer.

[0042] In some embodiments, the cancer is lung cancer. In some such embodiments, the cancer is lung cancer characterized by elevated and / or aberrant expression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) lung cancer; (b) a cancer characterized by elevated and / or aberrant 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 lung cancer is small cell lung cancer (SCLC).

[0043] In some embodiments, compound (I) is administered as a first-line therapy. In other embodiments, compound (I) is administered as a second (or later) line therapy. In some embodiments, compound (I) is administered as a second (or later) line therapy following treatment with an endocrine therapy and / or a CDK4 / CDK6 inhibitor. In some embodiments, compound (I) is administered as a second (or later) line therapy following treatment with an endocrine therapy, e.g., an aromatase inhibitor, a SERM, or a SERD. In some embodiments, compound (I) is administered as a second (or later) line therapy following treatment with a CDK4 / CDK6 inhibitor. In some embodiments, compound (I) is administered as a second (or later) line therapy following treatment with one or more chemotherapy regimens including, e.g., a taxane, a platinum agent, a pyrimidine antagonist, and / or gemcitabine. In some embodiments, compound (I) is administered as a second (or later) line therapy following treatment with a HER2-targeted agent (e.g., trastuzumab). In some embodiments, a compound of the present disclosure is administered as a second (or later) line therapy following treatment with an EGFR inhibitor, e.g., osimertinib. In some embodiments, a compound of the present disclosure is administered as a second (or later) line therapy following treatment with a pyrimidine antagonist (e.g., 5-fluorouracil (5-FU)) and / or gemcitabine, and / or a platinum agent (e.g., carboplatin and cisplatin).

[0044] In some embodiments, the cancer is N-myc amplified neuroblastoma cells (see Molenaar, et al., Proc Natl Acad Sci USA 106(31):12968-12973), K-Ras mutated 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).

[0045] Examples of cancers treatable with Compound (I) include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, 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 intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma (including CIC-DUX4 sarcoma), urethral cancer, penile cancer, chronic or acute leukemia including acute myeloid leukemia, and ovarian cancer. Compound (I) is also useful in the treatment of metastatic cancers, including, but not limited to, leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, cancer of the kidney or urethra, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, including asbestos-induced cancer, and combinations of the foregoing cancers. Compound (I) is also useful in the treatment of metastatic cancers.

[0046] In some embodiments, cancers treatable with Compound (I) include, but are not limited to, melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma, cutaneous melanoma (SKCM)), renal cancer (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), and cancers with high microsatellite instability (MSI high). Furthermore, the present disclosure includes refractory or recurrent malignant tumors whose growth can be inhibited using Compound (I).

[0047] In some embodiments, cancers treatable 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.), blood cancers (e.g., lymphoma, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML)), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (relapsed or refractory NHL and follicular lymphoma, including relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of the foregoing cancers.

[0048] In some embodiments, cancers treatable with Compound (I) include, but are not limited to, cholangiocarcinoma, bile duct carcinoma, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma (e.g., liver 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, intestinal cancer, islet cell carcinoma, oral cavity cancer, mouth cancer, throat 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, paranasal sinus cancer, spinal cancer, tongue cancer, tubular adenocarcinoma, urethral cancer, and ureteral cancer.

[0049] In some embodiments, cancers treatable with Compound (I) include Genomic Identification of Key Targets in Cancer (GISTIC) and Pheochromocytoma and Paraganglioma (PCPG).

[0050] In some embodiments, 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 therapy), gastric cancer that has progressed after two or more lines of therapy (previously treated with platinum therapy), and HR+ / HER2-BC (including both ER+ / HER2-BC and PR+ / HER2-BC) that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In some embodiments, 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 not belonging to other groups, HR+ / HER2-BC that has progressed despite a CDK4 / 6i, and platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer. In one embodiment, the subject has a CCNE1-amplified advanced / recurrent tumor. In one embodiment, the subject is suffering from CCNE1-amplified platinum-resistant or platinum-refractory ovarian cancer. In one embodiment, the subject has endometrial cancer that has progressed after two or more lines of therapy (including platinum therapy) (has previously received platinum therapy, e.g., the patient has previously been treated with platinum therapy). In one embodiment, the subject has CCNE1-amplified endometrial cancer that has failed two or more lines of therapy (which may include previous platinum therapy). In one embodiment, the subject has gastric cancer that has progressed after two or more lines of therapy (including platinum therapy) (has previously received platinum therapy, e.g., 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 has TNBC that has progressed despite one or more lines of therapy. In one embodiment, the subject has AR+ prostate cancer that has progressed despite one or more lines of therapy. In one embodiment, the subject has pancreatic cancer that has progressed despite one or more lines of therapy. In one embodiment, the subject has PDAC that has progressed despite one or more lines of therapy. In one embodiment, the subject has lung cancer with elevated CCNE1.In one embodiment, the subject has NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib). In one embodiment, the subject has CCNE1 elevated NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib).

[0051] In some embodiments, cancers treatable with Compound (I) include, but are not limited to, hematological cancers, sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0052] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0053] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0054] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchial carcinoma, squamous cell, small cell undifferentiated, large cell undifferentiated, adenocarcinoma, alveolar epithelial (bronchiolar) carcinoma, bronchial adenoma, chondroid hamartoma, and mesothelioma. Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0055] Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilms' 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 (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoroid tumor, lipoma).

[0056] Exemplary liver cancers include hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0057] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0058] Exemplary nervous system cancers include skull cancer, meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, brain low-grade glioma (LGG), ependymoma, germ cell tumor (pinealoma), glioblastoma, glioblastoma multiforme (GBM), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cancer (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

[0059] Exemplary gynecological cancers include uterine cancer (endometrial carcinoma), cervical cancer (cervical carcinoma, cervical squamous cell carcinoma (CESC), preneoplastic cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma)), and fallopian tube cancer (epithelial carcinoma).

[0060] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, cancers treatable with Compound (I) include, but are not limited to, triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma. combination

[0061] Compound (I) may be administered as a single agent or in combination with other anti-cancer therapeutic agents, particularly standard of care agents appropriate for the particular cancer.

[0062] As used herein, the term "additional anti-cancer therapeutic agent" refers to any one or more therapeutic agents other than Compound (I) that are used or may be used in the treatment of cancer. In some embodiments, such additional anti-cancer therapeutic agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents 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 modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immuno-oncology agents, and the like.

[0063] In some embodiments, the additional anticancer agent is an endocrine agent such as an aromatase inhibitor, a selective estrogen receptor degrader (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.

[0064] In some embodiments, 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, milansertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolicib, and fimepinostat. In some embodiments, the PIK3CA inhibitor is alpelisib.

[0065] In some embodiments, the additional anticancer agent is an AKT inhibitor, including but not limited to capivasertib and ipatasertib, hi some embodiments, the AKT inhibitor is capivasertib.

[0066] In some embodiments, the additional anti-cancer agent includes, but is not limited to, trastuzumab deruxtecan (Enhertu), trastuzumab duocarmazine, trastuzumab emtansine (Kadcyla), upifitamab rxodotin (Upifitamab Antibody-drug conjugates include rilsodotin, mirvetuximab sorafutansine, tisotumab vedotin (Tivdak), pralzatamaravtansine, sacituzumab govitecan or sacituzumab govitecan-hziy (Trodelvy), datopotamab deruxtecan, ladiratuzumab vedotin, patritumab deruxtecan, STRO-002, MORab-202, DS-6000, anetumab, avatansine, XMT-2056, and dicitamab vedotin (RC48-ADC, Aidexi).

[0067] In some embodiments, the additional anti-cancer agent is a PLK1 inhibitor, including but not limited to onvansertib, BI2536, BI6727, GSK461364A, TAK960, rigosertib.

[0068] In some embodiments, the additional anti-cancer agent is an estrogen PROTAC (ARV-471, H3B-5942).

[0069] In other embodiments, Compound (I) may be administered in combination with standard of care agents. In some embodiments, Compound (I) may be administered in combination with endocrine therapy, such as drugs such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, Compound (I) may be administered in combination with a chemotherapeutic agent (e.g., 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 (e.g., trastuzumab or pertuzumab).

[0070] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, may be administered in combination with an effective amount of 5-FU, alpelisib, carboplatin, cisplatin, enzalutamide, fulvestrant, gemcitabine, osimertinib, ribociclib, or a combination thereof. In some embodiments, the compounds of the present disclosure may be administered in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

[0071] In some embodiments, the additional anti-cancer agent is an anti-angiogenic agent, such as a VEGF inhibitor, a VEGFR inhibitor, a TIE-2 inhibitor, a PDGFR inhibitor, an angiopoietin inhibitor, a PKCb inhibitor, a COX-2 (cyclooxygenase II) inhibitor, an integrin (αv / β3), an MMP-2 (matrix metalloproteinase 2) inhibitor, and an MMP-9 (matrix metalloproteinase 9) inhibitor. Preferred anti-angiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG13736), SU14813 (Pfizer), and AG13958 (Pfizer). Additional antiangiogenic agents include vatalanib (CGP79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU14843 (Pfizer), AZD2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE941), tetrathiomolybdate (Coprexa™), AMG706 (Amgen), VEGF Trap (AVE0005), CEP7055 (Sanofi-Aventis), XL880 (Exelixis), telatinib (BAY57-9352), and CP-868,596 (Pfizer). Other antiangiogenic agents include enzastaurin (LY317615), midostaurin (CGP41251), perifosine (KRX0401), teprenone (Selbex™), and UCN01 (Kyowa Hakko). Other examples of antiangiogenic agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™).Still further anti-angiogenic agents include exilind (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™). Additional anti-angiogenic agents include ABT510 (Abbott), aplatastat (TMI005), AZD8955 (AstraZeneca), incyclinide (Metastat™), and PCK3145 (Procyon).

[0072] Still other antiangiogenic 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.

[0073] Additional antiangiogenic agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengitide (EMD121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), revimastat (BMS275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC631570), Vitaxin™ (MEDI522), and zoledronic acid (Zometa™).

[0074] In other embodiments, the additional anticancer agent is a so-called signal transduction inhibitor (e.g., an agent that inhibits the intracellular transmission of regulatory molecules that govern fundamental processes of cell proliferation, differentiation, and survival). 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, farnesyl protein transferase 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, inhibitors of the WNT pathway, and so-called multi-targeted kinase inhibitors. Additional examples of signal transduction inhibitors that may be used in conjunction with Compound (I) and the pharmaceutical compositions described herein include BMS214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), peritrexol (AG2037), matuzumab (EMD7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vandetanib (Zactima™), pazopanib (SB786034), ALT110 (Alteris Therapeutics), BIBW2992 (Boehringer Ingelheim), and Cervene™ (TP38).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), gedatricisib (Pfizer), canertinib (CI1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB569), miltefosine (Miltefosin™), BMS599626 (Bristol-Myers Squibb), and others. Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP23573 (ARIAD), and VX680 (Vertex), XL647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT751 (Abbott), alvocidib (flavopiridol), BMS387032 (Bristol Myers), EM1421 (Erimos), indisulam (E7070), seliciclib (CYC200), BIO112 (Onc Bio), BMS387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG024322 (Pfizer).

[0075] In other embodiments, the additional anticancer agent is a so-called classical antitumor agent. Classical antitumor agents include, but are not limited to, hormone regulators, such as hormones, antihormones, androgen agonists, androgen antagonists, and antiestrogenic therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing or gene activating agents, ribonucleases, proteomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (e.g., talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib, etc.), microtubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins.Examples of classical anti-tumor agents used in combination therapy with Compound (I) (which may be used in combination with one or more other drugs) include, but are not limited to, glucocorticoids (dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), progestins such as medroxyprogesterone, megestrol acetate (MegaAce), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, CHF4227 (Cheisi), etc.), selective estrogen receptor downregulators (SERDs; fulvestrant, LSZ102, G1T48, RAD1901, Eraser, etc.). Trant, GDC-9545, Gildestrant, SAR439859, Amsenestrant, AZD9833, Camizetrant, LY3484356, Zn-c5, D-0502), Exemestane (Aromasin), Anastrozole (Arimidex), Atamestane, Fadrozole, Letrozole (Femara), Formestane; Gonadotropin-Releasing Hormone (GnRH; commonly luteinizing hormone-releasing hormone [ LHRH [also known as LHRH] agonists (such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar)), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandrone), and osaterone, dutasteride, epristeride, finasteride, saw palmetto, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogens such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof.Other examples of classical antitumor agents that may be used in combination with Compound (I) include suberanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101; onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCl (Camptosar), lurtotecan, olathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pisantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine Platinum therapy including busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds (e.g., cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin), and combinations thereof.

[0076] In still other embodiments, the additional anticancer agent is a so-called dihydrofolate reductase inhibitor (such as methotrexate and Nutrexin (trimetresate glucuronate)), a purine antagonist (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), a pyrimidine antagonist (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), tegafur (UFT Orzel or Uforal, and the TS-1 combination of tegafur, gimestat, and otostat), doxifluridine, carmofur, cytarabine (including ocphosphate, phosphate stearate, sustained-release, and liposomal forms), enocitabine, 5-azacytidine (Vidaza), decitabine, and ethinylcytidine), and other antimetabolites, such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid, 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.

[0077] Other examples of classical antitumor cytotoxic agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), vatabulin (Amgen), EPO906 (Novartis), vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere), ortataxel, paclitaxel (including Taxoplexin, a DHA / paclitaxel conjugate), cisplatin, carboplatin, nedaplatin, oxaliplatin (Eloxatin), satraplatin, camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, and the like. cyclophosphamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar™), efaproxiral (Efaproxyn™ - radiation therapy), bexarotene (Targretin™), tesmilifene (DPPE - enhances the effectiveness of cytotoxic drugs), Theratope™ (Biomira), tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™), Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), polyglutamic acid-paclitaxel (Xyotax™) and combinations thereof.Further examples of classical antitumor agents include Advexin (ING201), TNFerade (GeneVec, a compound that induces TNFα expression in response to radiation therapy), RB94 (Baylor College of Medicine), Genasense (Oblimmersen, Genta), combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), provastatin (Pravachol, Bristol-Myers Squibb), lovastatin (Mevacor, Merck Inc.), simvastatin (Zocor, Merck Inc.), fluvastatin (Lescol, Novartis), cerivastatin (Baycol, Bayer), rosuvastatin (Crestor, AstraZeneca), lovostatin, niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

[0078] In other embodiments, the additional anticancer agent is an epigenetic modulator, such as an inhibitor or EZH2, Smalca4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2, or BCL6.

[0079] In further embodiments, the additional anti-cancer agent is an immunomodulatory agent such as, but not limited to, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 or PD-L1 inhibitor (e.g., pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dostarlimab), a LAG-3 inhibitor (e.g., leratolimab), a TIM-3 inhibitor, a TIGIT inhibitor, a 4-1BB inhibitor, an OX40 inhibitor, a GITR inhibitor, a CD40 inhibitor, or a CAR-T cell therapy.

[0080] In some embodiments, 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 necitumumab. In some embodiments, the EGFR inhibitor is osimertinib.

[0081] Alternatively, compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein may be administered in combination with other anticancer agents that are not EGFR inhibitors, such as MEK inhibitors, for example, mutant MEK inhibitors (trametinib, cobimutetinib, binimetinib, selumetinib, refametinib); c-MET inhibitors, for example, mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (emibetuzumab); mitotic kinase inhibitors (palbociclib, ribociclib, abemaciclib, reloxicillin); CDK4 / 6 inhibitors such as cyclosporine, trilaciclib, dalpiciclib, and BPI-16350; antiangiogenic agents such as bevacizumab and nintedanib; apoptosis inducers such as Bcl-2 inhibitors (e.g., venetoclax, obatoclax, and navitoclax) and Mcl-1 inhibitors (e.g., AZD-5991, AMG-176, and S-64315); and mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, and lidofolimus). 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 abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is relociclib.

[0082] Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be administered in combination with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, relociclib, trilaciclib, dalpiciclib, and BPI-16350. 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 abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is relociclib.

[0083] Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be administered in combination with a CDK4 / 6 inhibitor and a SERD. In some embodiments, Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be administered in combination with ribociclib and fulvestrant. In some embodiments, Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein 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 a platinum agent. 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, abemaciclib, and optionally cisplatin. In some embodiments, Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be administered in combination with an EGFR inhibitor. In some embodiments, Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be administered in combination with osimertinib. In some embodiments, Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be administered in combination with a PARP-1 inhibitor. In some embodiments, Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be administered in combination with olaparib.

[0084] Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be administered in combination with palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarg®), afatinib (e.g., Gilotrif®), osimertinib (e.g., Tag and trastuzumab (e.g., Herceptin®), or a combination thereof. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinibJBJ-04-125-02, alflutinib (AST2818), aumoretinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, lazertinib, It may be selected from nazartinib (EGF816), avitinib, PCC-0208027, resivertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759), or DZD9008, from EGFR antibodies such as cetuximab, panitumumab, necitumumab, HLX07, JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372)).

[0085] Biomarkers and Pharmacodynamic Markers The present disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, e.g., levels, gene copy number, gene sequence, expression levels, phosphorylation levels, or mutations) for identifying human subjects suffering from, suspected of suffering from, or at risk of developing cancer that is likely to benefit from the administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to Compound (I) or a pharmaceutically acceptable salt thereof).

[0086] 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 for sensitivity to Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof modulates the level of CCNE1. In some embodiments, a change in the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof, or at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof, indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

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

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

[0089] In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased 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, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 10%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 20%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 30%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 40%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 50%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 60%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 70%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 80%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 90%. In some embodiments, the level of CCNE1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 100%.

[0090] In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased 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, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 10%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 20%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 30%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 40%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 50%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 60%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 70%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 80%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 90%. In some embodiments, the level of CCNE1 at two different time points during administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased by at least 100%.

[0091] In some embodiments, elevated levels of the Cyclin E1 (CCNE1) gene and / or abnormal expression levels of CCNE1 in a biological sample may indicate that a patient or subject may benefit from administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0092] CCNE1 is a cell cycle factor essential for cell cycle regulation at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2 and interacts with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity for the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 ("CCNE1") gene (GenBank accession number NM_001238). The amino acid sequence of human CCNE1 can be found in GenBank accession number NP_001229 / UniProtKB accession number P24864).

[0093] In one aspect, the present disclosure provides a method of treating a subject suffering from or at risk of developing cancer, the method comprising administering to the subject a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the subject has an amplified (e.g., copy number-based) CCNE1 gene and / or a level of CCNE1 that is higher than a control level of CCNE1. In some embodiments, the present disclosure provides a method of treating a subject suffering from or at risk of developing cancer, the method comprising administering to the subject a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the subject has aberrantly expressed CCNE1 gene.

[0094] Also provided herein is a method for treating a patient having an increased copy number of the CCNE1 gene and / or an elevated expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0095] In some embodiments, amplification of the CCNE1 gene and / or a level of CCNE1 higher than a control level of CCNE1 indicates / predicts that a human subject suffering from or at risk of developing cancer will respond to an effective dose of a CDK2 inhibitor, i.e., Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, an abnormal level of CCNE1 that is different from a control level of CCNE1 indicates / predicts that a human subject suffering from or at risk of developing 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 modulated in response to administration of an effective dose of Compound (I) or a pharmaceutically acceptable salt thereof to a subject.

[0096] Other biomarkers In some embodiments, a contemplated 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 CDKN2A gene), which acts as a negative regulator of normal cell proliferation by interacting with CDK4 and CDK6. In some embodiments, the level of p16 is modulated 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, loss of p16 is a biomarker. In some embodiments, p16 has a mutation (e.g., a loss-of-function mutation). In some embodiments, p16 or a p16 mutant is functional. In some embodiments, p16 is a biomarker for Compound (I) sensitivity. In some embodiments, a change in the level of p16 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof, or at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof, indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the level of p16 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of p16 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of p16 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of p16 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is increased. In some embodiments, the level of p16 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is decreased.

[0098] In some embodiments, the level of p16 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of p16 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of p16 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of p16 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of p16 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0099] In some embodiments, a contemplated biomarker is the retinoblastoma 1 protein (pRb or RB), which is encoded by the gene RB transcriptional corepressor 1 (RB1). In some embodiments, a contemplated biomarker is phosphorylation of Rb at any phosphorylation site. In some embodiments, the biomarker is phosphorylation at the serine corresponding to amino acid position 780 (Ser780 or S780) and / or the serine corresponding to amino acid position 795 (Ser795 or S795). In some embodiments, a contemplated biomarker is phosphorylation of Rb at the serine corresponding to amino acid position 807 (Ser807 or S807) and / or the serine corresponding to amino acid position 811 (Ser811 or S811). In some embodiments, a contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 821 (Thr821 or T821). In some embodiments, a potential biomarker is phosphorylation of Rb at threonine (Thr826 or T826) corresponding to amino acid position 826. Rb is a cell cycle regulator and acts as a tumor suppressor. Rb is activated when phosphorylated by cyclin D-CDK4 / 6 at Ser780 and Ser795 and / or Ser807 and Ser811, and by 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, loss of phosphorylated Rb or RB is a biomarker. In some embodiments, RB has a mutation (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 for Compound (I) sensitivity.

[0100] In some embodiments, a change in the level of phosphorylated Rb or RB before and after administration of compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at any phosphorylation site before and after administration of compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of phosphorylated Rb at any phosphorylation site before and after administration of compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of phosphorylated Rb at any phosphorylation site before and after administration of compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of phosphorylated Rb or RB at any phosphorylation site before and after administration of compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of phosphorylated Rb or RB at any phosphorylation site before and after administration of compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0101] In some embodiments, a change in the level of phosphorylated Rb or RB at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at any phosphorylation site at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of phosphorylated Rb at any phosphorylation site at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of phosphorylated Rb at any phosphorylation site at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of phosphorylated Rb or RB at any phosphorylation site at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of phosphorylated Rb or RB at any phosphorylation site at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof decreases.

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

[0103] In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of phosphorylated Rb at Ser780 and / or Ser795 at two different time points during treatment changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0104] In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%.In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

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

[0106] In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of phosphorylated Rb at Ser807 and / or Ser811 at two different time points during treatment changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0107] In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%.In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

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

[0109] In some embodiments, the level of phosphorylated Rb at Thr821 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of phosphorylated Rb at Thr821 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of phosphorylated Rb at Thr821 at two different time points during treatment changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of phosphorylated Rb at Thr821 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of phosphorylated Rb at Thr821 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0110] In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the level of phosphorylated Rb at Thr821 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

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

[0112] In some embodiments, the level of phosphorylated Rb at Thr826 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of phosphorylated Rb at Thr826 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of phosphorylated Rb at Thr826 at two different time points during treatment changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of phosphorylated Rb at Thr826 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of phosphorylated Rb at Thr826 at two different time points during treatment with compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0113] In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the level of phosphorylated Rb at Thr826 before and after administration of compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0114] In some embodiments, a contemplated biomarker is TK1 (thymidine kinase 1). TK1 is a direct downstream target of the Rb-E2F pathway. TK1 is involved in cell proliferation through the salvage of the nucleotide thymidine in the DNA salvage pathway. TK1 is required for nucleotide formation outside of S phase and is therefore important for DNA repair after DNA damage. In some embodiments, the level of TK1 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, TK1 is absent. In some embodiments, loss of TK1 is a biomarker. In some embodiments, TK1 has a mutation (e.g., a loss-of-function mutation or a resistance mutation). In some embodiments, TK1 or a TK1 mutant is functional. In some embodiments, a TK1 mutant has a resistance mutation. In some embodiments, TK1 is differentially methylated. In some embodiments, TK1 is serum TK1. In some embodiments, TK1 is a biomarker for sensitivity to Compound (I) or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, a change in the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof increases.

[0116] In some embodiments, a change in the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is increased.

[0117] In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the level of TK1 before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0118] In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the level of TK1 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0119] In one embodiment, the biomarker is a marker of cell proliferation Ki-67 (Ki-67 or MKI67). In some embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof modulates the level of Ki-67. In some embodiments, Ki-67 is absent. In some embodiments, loss of Ki-67 is a biomarker. In some embodiments, Ki-67 has a mutation (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 biomarker for sensitivity to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, a change in Ki-67 levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the Ki-67 levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change by at least 10%. In some embodiments, the Ki-67 levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change 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, the Ki-67 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the Ki-67 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the Ki-67 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0121] In some embodiments, a change in the level of Ki-67 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of Ki-67 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of Ki-67 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of Ki-67 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of Ki-67 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of Ki-67 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0122] In one embodiment, the biomarker is cancer antigen 125 or (CA-125). In some embodiments, the cancer is ovarian cancer. In some embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof modulates the level of CA-125. In some embodiments, CA-125 is absent. In some embodiments, loss of CA-125 is a biomarker. In some embodiments, CA-125 has a mutation (e.g., a loss-of-function mutation). In some embodiments, CA-125 or a CA-125 variant is functional. In some embodiments, CA-125 is a biomarker for sensitivity to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, a change in CA-125 levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the CA-125 levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change by at least 10%. In some embodiments, the CA-125 levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change 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, the CA-125 levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the CA-125 levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof are increased.

[0124] In some embodiments, a change in CA-125 levels at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the CA-125 levels at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof change by at least 10%. In some embodiments, the CA-125 levels at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof change 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, the level of CA-125 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of CA-125 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is increased.

[0125] In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the CA-125 level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0126] In some embodiments, the level of CA-125 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the level of CA-125 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the level of CA-125 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the level of CA-125 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the CA-125 level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the CA-125 level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the CA-125 level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the CA-125 level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the CA-125 level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the CA-125 level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of CA-125 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the level of CA-125 at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0127] In one embodiment, the biomarker is carcinoembryonic antigen (CEA). In some embodiments, the cancer is selected from the group consisting of breast cancer, colorectal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer. In some embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof modulates the level of CEA. In some embodiments, CEA is absent. In some embodiments, loss of CEA is a biomarker. In some embodiments, CEA has a mutation (e.g., a loss-of-function mutation). In some embodiments, CEA or a CEA mutant is functional. In some embodiments, CEA is a biomarker for sensitivity to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, a change in CEA levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the CEA levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change by at least 10%. In some embodiments, the CEA levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change 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, the level of CEA before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of CEA before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof increases.

[0129] In some embodiments, a change in the level of CEA at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CEA at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of CEA at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of CEA at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of CEA at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of CEA at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof decreases.

[0130] In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the CEA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0131] In one embodiment, the biomarker is prostate-specific antigen (PSA). In some embodiments, the cancer is prostate cancer. In some embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof modulates the level of PSA. In some embodiments, PSA is absent. In some embodiments, loss of PSA is a 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 for sensitivity to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, a change in PSA levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the PSA levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change by at least 10%. In some embodiments, the PSA levels before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof change 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, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof increases.

[0133] In some embodiments, a change in PSA levels at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the PSA levels at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof change by at least 10%. In some embodiments, the PSA levels at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof change 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, the level of PSA at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of PSA at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is increased.

[0134] In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the PSA level before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0135] In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof 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%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 10%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 20%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 30%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the PSA level at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0136] In one embodiment, the biomarker is Kirsten rat sarcoma viral oncogene homolog (KRAS). In some embodiments, the cancer is colon cancer, lung cancer, or pancreatic cancer. In some embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof modulates the level of KRAS. In some embodiments, KRAS is absent. In some embodiments, loss of KRAS is a biomarker. In some embodiments, KRAS has a mutation (e.g., a loss-of-function mutation). In some embodiments, KRAS or a KRAS mutant is functional. In some embodiments, KRAS is a biomarker for sensitivity to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, a change in the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof increases.

[0138] In some embodiments, a change in the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject suffering from or at risk of developing cancer has responded to treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes 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, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof changes by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is increased.

[0139] In some embodiments, the KRAS level is reduced before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS level 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 administration of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS level is reduced by at least 10% before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS level is reduced by at least 20% before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS level is reduced by at least 30% before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the level of KRAS before and after administration of Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0140] In some embodiments, the level of KRAS is reduced at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of KRAS is reduced at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof 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, the level of KRAS is reduced at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof by at least 10%. In some embodiments, the level of KRAS is reduced at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof by at least 20%. In some embodiments, the level of KRAS is reduced at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof by at least 30%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 40%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 50%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 60%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 70%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 80%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 90%. In some embodiments, the level of KRAS at two different time points during treatment with Compound (I) or a pharmaceutically acceptable salt thereof is reduced by at least 100%.

[0141] Contemplated 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 one of the biomarkers disclosed herein may be modulated in response to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0142] In another aspect, provided herein is a method of measuring a change in the level of one or more biomarkers after administering to a subject suffering from or at risk of developing cancer an amount of Compound (I) in the range of 100 mg to 1600 mg, or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1600 mg of Compound (I), wherein treatment with Compound (I) results in a change in the level of one or more biomarkers. In some embodiments, provided herein are methods of measuring an altered level of a biomarker selected from the group consisting of cancer antigen 125 or (CA-125), cyclin E1 (CCNE1), carcinoembryonic antigen (CEA), cyclin-dependent kinase inhibitor 2A (CDKN2A or p16), Kirsten sarcoma viral oncogene homolog (KRAS), cell proliferation marker Ki-67 (MKI67 or Ki-67), phosphorylated retinoblastoma 1 protein (Rb), and prostate-specific antigen (PSA), comprising administering to a subject suffering from or at risk of developing cancer an amount of Compound (I) in the range of 100 mg to 1600 mg, or a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1600 mg of Compound (I), wherein treatment with Compound (I) alters the level of the biomarker. In some embodiments, the level of the biomarker is changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0143] In another aspect, provided herein is a method for determining sensitivity to Compound (I) or a pharmaceutically acceptable salt thereof in a subject suffering from cancer, the method comprising: i. measuring the level of one or more biomarkers in a biological sample obtained from the subject; ii. comparing the level of the one or more biomarkers in step i to the level of the one or more biomarkers measured in a subject in which the pathway is functioning normally; iii. determining whether the subject is sensitive to compound (I) or a pharmaceutically acceptable salt thereof based on the comparison in step ii.

[0144] In another aspect, provided herein is a method for determining resistance to Compound (I) or a pharmaceutically acceptable salt thereof in a subject suffering from cancer, the method comprising: i. measuring the level of one or more biomarkers in a biological sample obtained from the subject; ii. comparing the level of the one or more biomarkers in step i to the level of the one or more biomarkers measured in a subject in which the pathway is functioning normally; iii. Based on the comparison in step ii, determining whether the subject with cancer is resistant to compound (I) or a pharmaceutically acceptable salt thereof.

[0145] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising: i. testing or having tested a first biological sample obtained from a subject suffering from cancer to measure the level of one or more biomarkers in the subject's cancer; ii. comparing the level of the one or more biomarkers in step i to the level of the one or more biomarkers measured in a subject in which the pathway is functioning normally; iii. In response to determining that the subject's cancer is sensitive to compound (I) or a pharmaceutically acceptable salt thereof, treating the subject with a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0146] The method further includes testing, or having tested, a second biological sample obtained from the subject suffering from cancer, to determine whether the level of one or more biomarkers changes following administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0147] In another aspect, provided herein is a method of monitoring a response in a subject suffering from or at risk of developing cancer, the method comprising: i. administering to a subject in need thereof an amount of Compound (I) in an amount of 100 mg to 1600 mg, or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1600 mg of Compound (I); ii. testing or has tested a first biological sample obtained from the subject, thereby measuring the level of one or more biomarkers in the biological sample; iii. comparing the level of the one or more biomarkers in step ii to the level of the one or more biomarkers measured in a subject in which the pathway is functioning normally; iv. If the comparison in step iii indicates an alteration in the level of one or more biomarkers, determining whether the subject suffering from or at risk of developing cancer has responded to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, monitoring continues by obtaining an additional biological sample from the subject and comparing the level of the biomarker measured in the subject in which the pathway is functioning normally, hi some embodiments, monitoring continues by obtaining an additional biological sample from the subject and comparing the level of the biomarker measured in the first biological sample.

[0149] In some embodiments, the level of one or more biomarkers in a biological sample obtained from a subject suffering from or at risk of developing cancer is at least 10% different from the level of one or more biomarkers measured in a subject in which the pathway is functioning normally. 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 about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0150] In some embodiments, the one or more biomarkers are selected from the group consisting of 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, the one or more biomarkers are selected from the group consisting of CA-125, CDKN2A (or p16), CCNE1, CEA, MKI67 (or Ki-67), PSA, phosphorylated Rb, and TK1.

[0151] In some embodiments, the cancer is selected from the group consisting of breast cancer, endometrial cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, prostate cancer, and thyroid cancer.

[0152] 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 are altered. 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 are decreased. In some embodiments, the level of CA-125 is decreased. In some embodiments, the level of CCNE1 is decreased. In some embodiments, the level of KRAS is decreased. In some embodiments, the level of MKI67 or Ki-67 is decreased. In some embodiments, the level of PSA is decreased. In some embodiments, the level of phosphorylated Rb is decreased. In some embodiments, the level of phosphorylated Rb is decreased. In some embodiments, the level of TK1 enzyme activity is decreased.

[0153] In some embodiments, one or more biomarkers are measured based on levels selected from the group consisting of DNA (including cDNA), RNA (including messenger ribonucleic acid (mRNA) and microribonucleic acid (miRNA)), protein expression (including protein overexpression), enzyme activity (e.g., TK1), gene copy number, gene expression, gene sequence, mutation, and phosphorylation.

[0154] biological samples Biological samples suitable for 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, biological samples can include tumor cells obtained by biopsy from a patient suffering from a solid tumor.Tumor biopsies can be obtained by various means known in the art.Alternatively, blood samples can be collected from patients suffering from blood cancer.

[0155] Biological samples can be obtained from human subjects suffering from, suspected of suffering from, or at risk of developing cancer (eg, as described above).

[0156] Methods of obtaining and / or storing samples that preserve the activity or integrity of molecules (e.g., nucleic acids or proteins) in the sample are well known to those of skill in the art. For example, a biological sample may be further contacted with one or more additional agents, such as buffers and / or inhibitors (including one or more of nuclease, protease, and phosphatase inhibitors), that preserve or minimize alteration of the molecules in the sample.

[0157] Pharmaceutical Composition The pharmaceutical compositions of the present disclosure (also referred to herein as "disclosed pharmaceutical compositions") comprise one or more pharmaceutically acceptable carrier(s) or diluent(s) and Compound (I) or a pharmaceutically acceptable salt thereof.

[0158] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation and / or administration of, and / or absorption by, an active agent in a subject and that can be included in the pharmaceutical compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, saline, lactated Ringer's solution, regular sucrose, regular glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if necessary, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not deleteriously react with Compound (I) or interfere with its activity. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with Compound (I) or its pharmaceutically acceptable salts.

[0159] Pharmaceutical compositions of the present disclosure may contain one or more pharmaceutically acceptable carriers and / or diluents therefor, examples of which include lactose, starch, cellulose, and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens, may also be included.

[0042] The Handbook of Pharmaceutical Excipients (5 th A more complete list of suitable excipients can be found in Remington's Pharmaceutical Sciences (2003-20th edition), Pharmaceutical Press (2005). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences (2003-20th edition), and The United States Pharmacopeia: The National Formulary, 1999 (USP 24 NF19). A carrier, diluent, and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0160] Administration method and dosage form The exact amount of compound administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the cancer, and the subject's characteristics (such as overall health, age, sex, weight, and tolerance to drugs). Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with anti-cancer drugs, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Appropriate dosages of approved therapeutic agents are known and can be adjusted by those skilled in the art depending on the subject's condition, the type of pathology(s) being treated, and the amount of Compound (I) used, for example, by following the dosages reported in the literature and recommended in the Physician's Desk Reference (57th Ed., 2003).

[0161] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect, which may be therapeutic, including partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of cancer; ameliorating or improving clinical symptoms or indicators associated with cancer; delaying, inhibiting, or reducing the likelihood of cancer progression; or reducing the likelihood of cancer recurrence.

[0162] The term "effective amount" refers to an amount that, when administered to a subject, produces a beneficial or desired result (including a clinical result), e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively 1 mg to about 5 grams per day, and further alternatively 10 mg to 1 gram per day).

[0163] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0164] As used herein, the term "patient" or "subject" refers to an organism treated by the methods of the present disclosure. Non-limiting exemplary organisms include mammals, such as mice, monkeys, horses, cows, pigs, dogs, cats, etc. In some embodiments, the organism is a human.

[0165] In some embodiments, the method for treating cancer comprises daily orally administering to a subject in need thereof an amount of Compound (I) in an amount between 50 mg and 1600 mg, or a pharmaceutically acceptable salt thereof in an amount equivalent to 50 mg and 1600 mg of Compound (I).

[0166] In some embodiments, the method for treating cancer comprises daily orally administering to a subject in need thereof an amount of Compound (I) in an amount between 100 mg and 1600 mg, or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg and 1600 mg of Compound (I).

[0167] In some embodiments, the method for treating cancer comprises daily orally administering to a subject in need thereof an amount of Compound (I) in an amount between 100 mg and 1400 mg, or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg and 1400 mg of Compound (I).

[0168] In some embodiments, 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 of Compound (I) or a pharmaceutically acceptable salt thereof. The salt is administered to a subject in need thereof in an amount equivalent to 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 of Compound (I).

[0169] In some embodiments, the saturation levels are 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, 950 mg, 960 mg, 975 mg, 980 mg, 990 mg, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, 1230 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, 1280 mg, 1290 mg, 1300 mg, 1310 mg, 1320 mg, 1330 mg, 1340 mg, 1350 mg, 1360 mg, 13 25 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, and 1600 mg of Compound (I) or a pharmaceutical composition thereof and administering to a subject in need thereof 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, or 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.

[0170] In some embodiments, 100 mg to 1200 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1200 mg of Compound (I), is administered to a subject in need thereof.

[0171] In some embodiments, 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 of Compound (I) or a pharmaceutical In some embodiments, a subject in need thereof is administered 300 mg to 600 mg of Compound (I), or a pharmaceutically acceptable salt thereof, in an amount equivalent to 300 mg to 600 mg of Compound (I). In some embodiments, a subject in need thereof is administered 400 mg to 600 mg of Compound (I), or a pharmaceutically acceptable salt thereof, in an amount equivalent to 400 mg to 600 mg of Compound (I).

[0172] In some embodiments, the doses are 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 g, 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) or a pharmaceutical composition thereof or a salt thereof, which is acceptable for the purpose of administering to a subject in need thereof 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, Administer in amounts equivalent to 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, or 1200 mg.

[0173] In some embodiments, 100 mg to 1000 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1000 mg of Compound (I), is administered to a subject in need thereof.

[0174] In some embodiments, 50 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 50 mg of Compound (I), is administered to a subject in need thereof.

[0175] In some embodiments, 100 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg of Compound (I), is administered to a subject in need thereof.

[0176] In some embodiments, 150 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 150 mg of Compound (I), is administered to a subject in need thereof.

[0177] In some embodiments, 200 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 200 mg of Compound (I), is administered to a subject in need thereof.

[0178] In some embodiments, 250 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 250 mg of Compound (I), is administered to a subject in need thereof.

[0179] In some embodiments, 300 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 300 mg of Compound (I), is administered to a subject in need thereof.

[0180] In some embodiments, 350 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 350 mg of Compound (I), is administered to a subject in need thereof.

[0181] In some embodiments, 400 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 400 mg of Compound (I), is administered to a subject in need thereof.

[0182] In some embodiments, 450 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 450 mg of Compound (I), is administered to a subject in need thereof.

[0183] In some embodiments, 500 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 500 mg of Compound (I), is administered to a subject in need thereof.

[0184] In some embodiments, 550 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 550 mg of Compound (I), is administered to a subject in need thereof.

[0185] In some embodiments, 600 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 600 mg of Compound (I), is administered to a subject in need thereof.

[0186] In some embodiments, 650 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 650 mg of Compound (I), is administered to a subject in need thereof.

[0187] In some embodiments, 700 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 700 mg of Compound (I), is administered to a subject in need thereof.

[0188] In some embodiments, 750 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 750 mg of Compound (I), is administered to a subject in need thereof.

[0189] In some embodiments, 800 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 800 mg of Compound (I), is administered to a subject in need thereof.

[0190] In some embodiments, 850 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 850 mg of Compound (I), is administered to a subject in need thereof.

[0191] In some embodiments, 900 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 900 mg of Compound (I), is administered to a subject in need thereof.

[0192] In some embodiments, 950 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 950 mg of Compound (I), is administered to a subject in need thereof.

[0193] In some embodiments, 1000 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1000 mg of Compound (I), is administered to a subject in need thereof.

[0194] In some embodiments, 1100 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1100 mg of Compound (I), is administered to a subject in need thereof.

[0195] In some embodiments, 1200 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1200 mg of Compound (I), is administered to a subject in need thereof.

[0196] In some embodiments, 1300 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1300 mg of Compound (I), is administered to a subject in need thereof.

[0197] In some embodiments, 1400 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1400 mg of Compound (I), is administered to a subject in need thereof.

[0198] In some embodiments, 1500 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1500 mg of Compound (I), is administered to a subject in need thereof.

[0199] In some embodiments, 1600 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1600 mg of Compound (I), is administered to a subject in need thereof.

[0200] In some embodiments, 800 mg to 1200 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 800 mg to 1200 mg of Compound (I), is administered to a subject in need thereof.

[0201] In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is orally administered to a subject in need thereof once daily (QD) in the amounts specified above.

[0202] In some embodiments, 100 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg of Compound (I), is administered once daily to a subject in need thereof.

[0203] In some embodiments, 200 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 200 mg of Compound (I), is administered once daily to a subject in need thereof.

[0204] In some embodiments, 300 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 300 mg of Compound (I), is administered once daily to a subject in need thereof.

[0205] In some embodiments, 400 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 400 mg of Compound (I), is administered once daily to a subject in need thereof.

[0206] In some embodiments, 500 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 500 mg of Compound (I), is administered once daily to a subject in need thereof.

[0207] In some embodiments, 600 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 600 mg of Compound (I), is administered once daily to a subject in need thereof.

[0208] In some embodiments, 700 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 700 mg of Compound (I), is administered once daily to a subject in need thereof.

[0209] In some embodiments, 800 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 800 mg of Compound (I), is administered once daily to a subject in need thereof.

[0210] In some embodiments, 900 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 900 mg of Compound (I), is administered once daily to a subject in need thereof.

[0211] In some embodiments, 1000 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1000 mg of Compound (I), is administered once daily to a subject in need thereof.

[0212] In some embodiments, 1100 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1100 mg of Compound (I), is administered once daily to a subject in need thereof.

[0213] In some embodiments, 1200 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1200 mg of Compound (I), is administered once daily to a subject in need thereof.

[0214] In some embodiments, 1300 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1300 mg of Compound (I), is administered once daily to a subject in need thereof.

[0215] In some embodiments, 1400 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1400 mg of Compound (I), is administered once daily to a subject in need thereof.

[0216] In some embodiments, 1500 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1500 mg of Compound (I), is administered once daily to a subject in need thereof.

[0217] In some embodiments, 1600 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 1600 mg of Compound (I), is administered once daily to a subject in need thereof.

[0218] In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is orally administered to a subject in need thereof twice daily (BID) in the amounts specified above.

[0219] In some embodiments, 50 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 50 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0220] In some embodiments, 100 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0221] In some embodiments, 150 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 150 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0222] In some embodiments, 200 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 200 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0223] In some embodiments, 250 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 250 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0224] In some embodiments, 300 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 300 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0225] In some embodiments, 350 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 350 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0226] In some embodiments, 400 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 400 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0227] In some embodiments, 450 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 450 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0228] In some embodiments, 500 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 500 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0229] In some embodiments, 550 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 550 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0230] In some embodiments, 600 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 600 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0231] In some embodiments, 650 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 650 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0232] In some embodiments, 700 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 700 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0233] In some embodiments, 750 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 750 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0234] In some embodiments, 800 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 800 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0235] In some embodiments, 300 mg to 600 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 300 mg to 600 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0236] In some embodiments, 400 mg to 600 mg of Compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 400 mg to 600 mg of Compound (I), is administered twice daily to a subject in need thereof.

[0237] Additionally, Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure can be co-administered with other therapeutic agents. As used herein, the terms "co-administered," "administered in combination with," and their grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject, and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, Compound (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure is co-administered with other agents. These terms encompass administering two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. These include co-administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, Compound (I) and other agent(s) are administered in a single composition. In some embodiments, Compound (I) and other agent(s) are mixed in the composition.

[0238] The particular mode of administration and dosage regimen will be selected by the attending clinician, taking into account the specifics of the case (e.g., subject, cancer, particular treatment). Treatment may involve daily or multiple daily or less-than-daily (weekly, monthly, etc.) administration over a period ranging from several days to several months, or even years. In some embodiments, Compound (I) and other agent(s) are administered in a 28-day cycle. In some embodiments, the 28-day cycle is consecutive. However, one of ordinary skill in the art will readily recognize appropriate and / or equivalent dosages, looking at the dosages of approved compositions for treating cancer using CDK2 inhibitors disclosed as guidance.

[0239] In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in combination with an effective amount of platinum therapy in an amount described in any one of the above embodiments (e.g., any of paragraphs

[0165] to

[0236] ). In some embodiments, the platinum therapy is carboplatin. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in combination with an effective amount (e.g., a starting dose of an area under the plasma concentration-time curve (AUC) of 4 mg / mL·min) of carboplatin. In one embodiment, carboplatin is co-administered once on day 1 of each 28-day cycle. In one embodiment, a starting dose of carboplatin with an AUC of 4 mg / mL·min is co-administered once intravenously on day 1 of each 28-day cycle. In some embodiments, the subject is administered 4, 5, or 6 cycles of carboplatin.

[0240] In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in combination with an effective amount of a SERD in the amount described in any one of the above embodiments (e.g., any of paragraphs

[0165] to

[0236] ). In some embodiments, the SERD is fulvestrant. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof 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 cycle 1 and on day 1 of each cycle thereafter. In one embodiment, 500 mg of fulvestrant is co-administered intramuscularly on days 1 and 15 of cycle 1 and on day 1 of each cycle thereafter.

[0241] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in combination with an effective amount of a CDK4 / 6 inhibitor in the amount described in any one of the above embodiments (e.g., any of paragraphs

[0165] to

[0236] ). In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need 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 cycle 1 and on day 1 of each cycle thereafter. In one embodiment, 400 mg or 600 mg of ribociclib are co-administered orally once daily on days 1-21 of a 28-day cycle with 500 mg of fulvestrant co-administered intramuscularly on days 1 and 15 of cycle 1 and day 1 of each cycle thereafter.

[0242] As will be understood by those skilled in the art, Compound (I) or its pharmaceutically acceptable salts can be administered to patients in various forms depending on the selected administration route. Compound (I) may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and by pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, transepithelial administration, intranasal administration, intrapulmonary administration, intrathecal administration, rectal administration, and topical administration modes. Parenteral administration can be by continuous infusion over a selected period of time.

[0243] The pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration.In one embodiment, the composition is formulated according to conventional procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In some embodiments, the pharmaceutical composition is formulated for oral administration.In some embodiments, the pharmaceutical composition is formulated for intravenous administration.

[0244] Typically, for oral therapeutic administration, Compound (I) or a pharmaceutically acceptable salt thereof may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0245] Typically, for parenteral administration, solutions of Compound (I) or its pharmaceutically acceptable salts can be prepared in water, generally in a suitable mixture with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof, with or without alcohol, and in oils. These preparations contain a preservative to prevent the growth of microorganisms under ordinary storage and use conditions.

[0246] Typically, for injectable use, sterile aqueous solutions or dispersions and sterile powders of Compound (I) for the extemporaneous preparation of sterile injectable solutions or dispersions are suitable.

[0247] The following examples are intended to be illustrative and not to limit the scope of the present disclosure in any way. [Example]

[0248] Example 1 Phase 1 / 2 Study in 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 inhibitor of CDK2.

[0249] Phase 1: Dose escalation

[0250] This study included dose-escalation phases in patients with advanced / recurrent solid tumors (Part 1A; 50–70 patients); platinum-resistant or platinum-refractory ovarian cancer, endometrial cancer that had progressed after two or more lines of therapy (previously received platinum therapy), and gastric cancer that had progressed after two or more lines of therapy (previously received platinum therapy) (Part 1C; 25–40 patients); and HR+ / HER2- BC that had progressed despite CDK4 / 6i (Part 1D; 25–40 patients) (Figure 1). There was no Part 1B in the phase 1 dose-escalation phase.

[0251] The study included an initial Phase 1 portion to determine the maximum tolerated dose (MTD) and / or recommended Phase 2 dose (RP2D) of compound (I) as monotherapy (initially a BID regimen, with the option to evaluate QD dosing if supported by new PK and safety data; Part 1A), as well as two additional dose-escalation portions to determine 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).

[0252] Dose Escalation Part 1A: Compound (I) Monotherapy

[0253] Phase 1 dose escalation used a Bayesian optimal interval (BOIN) design to identify the MTD of Compound (I) when administered in BID and QD dosing regimens. During dose escalation, patients with advanced recurrent / recurrent tumors were included (regardless of CCNE1 status), and at potentially therapeutic doses, priority was given to patients with CCNE1-amplified solid tumors. At each dose level, slots may be reserved for patients with CCNE1 amplification.

[0254] Patients in the first cohort were treated with a starting dose of 50 mg orally twice daily. To limit the number of patients receiving treatment at potentially subtherapeutic dose levels, the study initially used cohort sizes of 1 to 3 patients, with dose escalation between cohorts at approximately 100%. If one patient at any dose level experienced a dose-limiting toxicity (DLT) or any two patients at any dose level experienced a grade 2 or higher adverse event (AE) considered potentially related to Compound (I) within 28 days of treatment, dose escalation increments were reduced to approximately 50%. Each dose level was rounded down or up to the nearest multiple of 25 mg to accommodate available dose strengths (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 evaluation period were evaluable for DLT assessment. Enrollment into each cohort, dose escalation, de-escalation, and dose discharge followed BOIN rules. A Safety Review Committee (SRC) met to review accumulated safety data and reached consensus on the decision to open each cohort and the specific dose selected for each cohort. All cohorts at dose levels ≥ 100 mg BID (or ≥ 200 mg QD) consisted of at least three evaluable patients. To allow for more robust characterization of safety, PK, pharmacodynamics, and preliminary clinical activity, additional patients may be enrolled at a previously tested lower dose level if that dose level cohort contains fewer than 12 evaluable patients for DLT and further escalation is approved by the SRC. For patients enrolled at a previously tested dose level, intrapatient dose escalation was permitted, provided the dose was not increased beyond the dose level approved for further dose escalation by the SRC and the patient completed ≥ 8 weeks of treatment without experiencing a grade 3 / 4 AE related to Compound (I) or the DLT.

[0255] The total number of patients evaluable for DLT at any given dose level should not exceed 12, and dose escalation was considered complete when 12 patients were evaluable for DLT at any dose level. While the MTD is determined based on monotonic regression, the RP2D may be selected taking into account all clinical data, including safety, PK, pharmacodynamics, and antitumor activity.

[0256] Additionally, if supported by new PK data from the BID dose escalation, a QD dosing schedule will be evaluated using the same BOIN dose escalation design as above. The total daily dose level at the start of the QD dose escalation will not exceed the highest dose level of the BID schedule approved for further dose escalation by the SRC. For example, if QD dosing is initiated after a 100 mg BID dose is deemed safe for further escalation, the QD dose cohort will begin at a dose of 100 mg QD.

[0257] Dose Escalation Part 1C: Compound (I) in Combination with Carboplatin

[0258] Dose escalation of the combination of Compound (I) and carboplatin includes patients with platinum-resistant or platinum-refractory ovarian cancer, gastric cancer that has progressed after at least two prior lines of therapy, including platinum-based chemotherapy, and endometrial cancer that has progressed after at least two prior lines of therapy, including platinum-based chemotherapy. The first cohort will receive a single intravenous dose of Compound (I) on Day 1 of each 28-day cycle, in combination with carboplatin at a starting area under the plasma concentration-time curve (AUC) of 4 mg / mL·min at ≤50% of the monotherapy RP2D. Further dose escalation or deescalation will be performed according to the BOIN design rules. The dose of Compound (I) in the combination cohort will not exceed the monotherapy RP2D. Patients who experience a DLT or receive at least 75% (21 days) of the prescribed Compound (I) dose, receive the full prescribed dose of carboplatin, and complete the 28-day DLT evaluation period will be evaluable for DLT assessment.

[0259] Dose Escalation Part 1D: Compound (I) in Combination with Ribociclib and Fulvestrant

[0260] Dose escalation of Compound (I) in combination with ribociclib includes patients with HR+ / HER2- breast cancer with disease progression. The first cohort includes at least six patients receiving Compound (I) in combination with ribociclib at 400 mg orally QD on days 1-21 of a 28-day cycle at approximately 25% of the monotherapy RP2D (or, if the RP2D has not yet been determined, at approximately 25% of the highest monotherapy dose at which further escalation is deemed safe; doses may be rounded up or down to account for available tablet strengths), and fulvestrant at its approved dose (500 mg intramuscular injection on days 1 and 15 of cycle 1 and day 1 of each cycle thereafter). Patients who experience a DLT or receive at least 75% of the prescribed dose of Compound (I) (for 21 days), at least 75% of the prescribed dose of ribociclib (for 16 days), receive the full prescribed dose of fulvestrant, and complete the 28-day DLT evaluation period will be evaluable for DLT assessment. Further dose escalation or deescalation will be performed according to the BOIN design rules. The dose of Compound (I) in the combination cohort will not exceed the RP2D of monotherapy.

[0261] Phase 1 evaluation

[0262] The maximum tolerated dose (MTD) will be determined based on dose-limiting toxicities (DLTs) and the safety profile.

[0263] The R2PD will be determined based on DLT, PK, PD, and preliminary safety data.

[0264] result

[0265] Compound (I) is currently being evaluated in a Phase 1 dose-escalation clinical trial. To date, patients have been treated with Compound (I) at doses ranging from 50 mg BID to 800 mg BID, with evidence of clinical benefit and no discontinuations due to adverse events (AEs).

[0266] Example 2 Dose Expansion Part 2A (Compound (I) as Monotherapy), Part 2B (Compound (I) in Combination with Fulvestrant), Part 2C (Compound (I) in Combination with Carboplatin), and Part 2D (Compound (I) in Combination with Ribociclib and Fulvestrant) Upon completion of dose escalation of Compound (I) monotherapy and determination of the RP2D (dose level and schedule), Phase 2 expansion arms of Compound (I) monotherapy (Part 2A) and the combination of Compound (I) with fulvestrant (Part 2B) will be initiated. Approximately 45 patients with platinum-resistant or platinum-refractory ovarian cancer harboring CCNE1 amplification (Arm 1), approximately 45 patients with endometrial cancer harboring CCNE1 amplification (Arm 2), and approximately 25 patients from a basket group with solid tumors harboring CCNE1 amplification (Arm 3) will be treated with Compound (I) at the RP2D. For Part 2B, Arm 4, an advance cohort of at least nine patients with HR+ / HER2- breast cancer that has progressed on CDK4 / 6i will be treated with Compound (I) in combination with fulvestrant as monotherapy at the RP2D. If this is tolerated, an additional 24 patients with HR+ / HER2- breast cancer that has progressed on CDK4 / 6i will be treated with fulvestrant and Compound (I) at the RP2D as monotherapy.

[0267] Upon completion of Part 1C and determination of the RP2D for Compound (I) and carboplatin, a Phase 2 expansion arm (Part 2C) of Compound (I) in combination with carboplatin will be initiated. Approximately 45 patients with platinum-resistant or platinum-refractory ovarian cancer harboring CCNE1 amplification will be treated with Compound (I) and carboplatin.

[0268] Upon completion of Part 1D and determination of RP2D for Compound (I) in combination with ribociclib and fulvestrant, a Phase 2 expansion arm (Part 2D) of Compound (I) in combination with ribociclib and fulvestrant will be initiated. Approximately 33 patients with HR+ / HER2- breast cancer who have progressed on CDK4 / 6i will be treated with ribociclib and fulvestrant and Compound (I) at RP2D.

[0269] Test treatment

[0270] Compound (I) will be administered orally daily (at a dose level and schedule [BID or QD] defined for the relevant study phase and cohort) without food or concomitant medications from 2 hours before dosing until 1 hour after dosing. The drug is preferably administered at approximately the same time(s) each day. Dose modifications will be made according to specific criteria based on observed toxicity.

[0271] For patients in Part 2B, fulvestrant will be used in combination with Compound (I) in patients with HR+ / HER2- breast cancer. Fulvestrant will be administered according to local prescribing information and institutional standards.

[0272] For patients in Parts 1C and 2C, carboplatin AUC 4–5 mg / mL·min will be administered as an intravenous infusion over 15–60 minutes every 28 days for 4–6 cycles according to local prescribing information and institutional standards.

[0273] For patients in Parts 1D and 2D, ribociclib and fulvestrant will be administered at dose levels determined for specific dose escalation cohorts according to local prescribing information and institutional standards.

[0274] Phase 2 evaluation

[0275] Efficacy will be assessed using standard Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria (Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247).

[0276] Example 3. Summary of Data from a Phase 1 / 2 Study in Patients with Advanced Solid Tumors Patients were enrolled in a Phase 1 dose-escalation study described in Example 1 and treated with Compound (I). Primary patient eligibility criteria included: i) adulthood with unresectable, advanced solid tumors; ii) ECOG PS 0-2; and iii) progression after standard of care. Patients were eligible for enrollment regardless of CCNE1 status.

[0277] As of data cutoff (January 22, 2024), 53 patients were treated with Compound (I) monotherapy in Phase 1 (Part 1A) in seven ascending dose cohorts at total daily doses ranging from 100 mg to 1600 mg (50 mg to 800 mg twice daily) and were included in the safety population (Table 1). Patients were heavily pretreated, with 71.7% having received four or more prior therapies.

[0278] [Table 1-1] [Table 1-2]

[0279] Pharmacokinetics (cutoff date: December 14, 2023)

[0280] Plasma concentrations of Compound (I) increased proportionally up to 600 mg BID (Figure 2). The mean effective half-life of Compound (I) was 12 hours (calculated from the extent of accumulation).eff ) ranges represent effective Compound (I) monotherapy concentrations that result in tumor congestion in preclinical OVCAR-3, MKN-1, and T47D models, corresponding to 25%, 25%, and 60% inhibition of phosphorylated Rb at Ser807 and / or Ser811, respectively, in these models.

[0281] Pharmacodynamics (cutoff date January 22, 2024)

[0282] During dose escalation, evidence of on-target activity via serum TK1 levels was observed, with patients treated with compound (I) monotherapy showing decreased TK1 activity at the higher dose levels tested (Figure 3). Patients who were off treatment at the time of sample collection (n=3) or for whom baseline samples could not be obtained (n=1) were excluded. A partial response (PR) was confirmed by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).

[0283] A decrease in phosphorylated Rb (pRb) was observed in three patients treated with Compound (I) at 400 mg and 500 mg twice daily (Figure 4, patients 5, 6, and 7). The mid-treatment tumor biopsy of patient 6 (described in the patient vignette below) most likely underestimates the extent of pRb inhibition, as the biopsy was performed late (12 hours after the most recent Compound (I) dose), demonstrating recovery of pRb over time.

[0284] Safety (Cut-off date: January 22, 2024)

[0285] Compound (I) monotherapy was generally well tolerated through the data cutoff of January 22, 2024. Dose escalation is ongoing. The most frequently reported treatment-related adverse events (TRAEs) are shown in Table 2. Two patients discontinued study treatment due to AEs. Two patients experienced dose-limiting toxicities (DLTs): one patient experienced grade 3 nausea at 800 mg BID, and one patient experienced grade 3 blurred vision / nyctophobia at 600 mg BID. Both patients improved after dose reduction. No cardiac TRAEs or QTc prolongation were observed. Hematologic TRAEs were generally mild and were primarily observed in patients with a history of cytopenias and / or baseline cytopenias. Four patients experienced grade 3 anemia, one of which was treatment-related; no grade 4 or higher anemia was reported. Three patients experienced grade 1 or grade 2 neutropenia, but no grade 3 or higher neutropenia was reported. One patient experienced grade 3 thrombocytopenia. Two patients receiving 800 mg BID experienced improvement in TRAEs after dose reduction.

[0286] Visual AEs were reported in 15 (28.3%) patients (some experienced >1 event), with photophobia (17.0% [9 / 53]) and blurred vision (11.3% [6 / 53]) being the most frequently reported. Symptoms were generally well tolerated, except for one patient with grade 3 blurred vision and photophobia (DLT). Events were intermittent (intervals ranging from seconds to hours), occurred shortly after dosing, and most resolved completely either spontaneously or with dose interruption / reduction. Comprehensive ophthalmologic examinations, including optical coherence tomography, were normal in all patients, with no acute abnormal findings.

[0287] 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 phobia (15.1%). DLTs were observed in two patients. Two patients discontinued due to TRAEs.

[0288] [Table 2]

[0289] Additionally, 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 remained stable (one patient in the 400 mg BID cohort remained stable for 6 months, and another patient in the 600 mg BID cohort remained stable for approximately 1 year), and one patient in the 800 mg BID cohort experienced a partial response (the dose was reduced to 400 mg BID after 4 days).

[0290] Part 1 Patient Vignette

[0291] A 57-year-old woman with HR+ / HER2- breast cancer that had metastasized to the liver and bone and had progressed after treatment with 1) doxorubicin, cyclophosphamide, and paclitaxel, 2) tamoxifen, 3) palbociclib and fulvestrant, 4) abemaciclib and anastrozole, and 5) capecitabine.

[0292] Patients were enrolled in the Phase 1 portion of the study and initiated Compound (I) monotherapy at 800 mg BID for 4 days. Grade 3 nausea (DLT) improved after dose reduction, so the dose was reduced to 400 mg BID on Day 8 of Cycle 1.

[0293] A PR by RECIST v1.1 was observed as a 43% reduction in solitary liver metastasis after 2 cycles, which was confirmed after 4 cycles. See Figure 5.

Claims

1. A subject in need of treatment is administered an amount of 100 mg to 1600 mg of Compound (I) per day. 【Chemistry 1】 or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 1600 mg of compound (I).

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

3. A subject in need of such treatment is administered 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, or 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, and 1600 mg of compound (I) or a pharmaceutical composition thereof. A therapeutically acceptable salt of Compound (I) is administered in an amount of 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, 90 ...180 mg, 1825 mg, 1850 mg, 1875 mg, 190 mg, 200 mg, 210 mg, 225 mg, 230 mg, 230 mg, 240 10. The method of claim 1, wherein the compound is administered in an amount equivalent to 0 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.

4. 10. The method of claim 1, wherein the subject in need of said treatment is administered 800 mg to 1200 mg of compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 800 mg to 1200 mg of compound (I).

5. 10. The method of claim 1, wherein the subject in need of said treatment is administered 300 mg to 600 mg of compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 300 mg to 600 mg of compound (I), twice a day.

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 the group consisting of ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, and breast cancer.

9. 9. The method of any one of claims 1 to 8, wherein the cancer is selected from the group consisting of advanced / recurrent tumors, platinum-resistant or platinum-refractory ovarian cancer, endometrial cancer that has progressed after two or more lines of treatment (previously received platinum therapy), gastric cancer that has progressed after two or more lines of treatment (previously received platinum therapy), 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. 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 to the subject an effective amount of platinum therapy.

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

15. 15. The method of any one of claims 9 to 14, wherein carboplatin is co-administered intravenously as a single dose at a starting area under the plasma concentration-time curve dose of 4 mg / mL min on day 1 of each 28-day cycle.

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

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

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

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

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

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

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

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

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

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

26. 1. A method for treating a subject having an amplified expression level of CCNE1 and suffering from or at risk of developing solid tumor cancer, comprising administering to a subject in need thereof an amount of about 100 mg to about 1600 mg per day of Compound (I): 【Chemistry 2】 【change】 or orally administering an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1600 mg of compound (I).

27. The solid tumor cancers include uterine cancer (including uterine carcinosarcoma (UCS) and uterine corpus endometrial cancer (UCEC)), endometrial cancer (including carcinosarcoma endometrial cancer, clear cell endometrial cancer, and grade 3 endometrioid endometrial cancer, and serous endometrial cancer (SEC)), breast cancer (including breast invasive carcinoma (BRCA), TNBC (triple-negative breast cancer), HR (hormone receptor)+ breast cancer, ER (estrogen 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 (gastric adenocarcinoma 27. The method of claim 26, wherein the cancer is at least one of: 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 syndromes (MDS), myeloproliferative neoplasms (MPN), sarcoma (including osteosarcoma), esophageal cancer (including esophageal carcinoma), 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), e.g., EGFRm (epidermal growth factor receptor mutant)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma (ACC), or mesothelioma.

28. 1. A method of treating cancer in a subject in need thereof, comprising: i. testing or has tested a first biological sample obtained from said subject suffering from cancer, thereby measuring the level of one or more biomarkers in said subject's cancer; ii. comparing the level of the one or more biomarkers in step i to the level of the one or more biomarkers measured in a subject in which the pathway is functioning normally; iii. In response to determining that the subject's cancer is sensitive to compound (I) or a pharmaceutically acceptable salt thereof, the method comprises treating the subject with a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

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

30. 1. A method for monitoring a response in a subject suffering from or at risk of developing cancer, said method comprising: i. administering to said subject in need thereof an amount of 100 mg to 1600 mg of compound (I), or an amount of a pharmaceutically acceptable salt thereof equivalent to 100 mg to 1600 mg of compound (I); ii. testing or has tested a first biological sample obtained from said subject, thereby measuring the level of one or more biomarkers in said biological sample; iii. Comparing the level of the one or more biomarkers in step ii to the level of the one or more biomarkers measured in a subject in which the pathway is functioning normally; iv. If the comparison in step iii indicates a change in the level of one or more biomarkers, determining whether the subject suffering from or at risk of developing cancer has responded to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

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