Method for treating prostate cancer

Abstract

A method for treating prostate cancer; specifically, the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating metastatic castration-resistant prostate cancer.

Description

Treatments for prostate cancer Technical Field

[0001] The present application relates to the field of medicine and includes the use of a compound represented by Formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating prostate cancer. Background Art

[0002] The androgen receptor (AR) is a ligand-dependent, transactivating transcriptional regulatory protein belonging to the nuclear receptor superfamily, primarily located in the cell nucleus. Unliganded AR binds to heat shock protein (HSP). Upon ligand binding, AR undergoes a conformational change, dissociating from HSP and increasing its affinity for DNA (AR activation). Activated AR binds as a dimer to a specific DNA sequence in the cell nucleus—the androgen response element (ARE)—and interacts with other transcription factors, thereby regulating the expression of related genes and producing biological effects. Studies have shown that abnormalities in the AR signaling pathway are closely associated with the development and progression of diseases such as prostate cancer, benign prostatic hyperplasia, Kennedy's disease, male infertility, androgen insensitivity, and male breast cancer.

[0003] Prostate cancer is one of the most common malignant tumors. According to statistics, there were nearly 1.3 million new cases and 359,000 deaths worldwide in 2018, accounting for 13.5% of the incidence of male malignant tumors, ranking second; accounting for 6.7% of the mortality rate of male malignant tumors, ranking fifth. At present, the incidence of prostate cancer is increasing year by year, and it is one of the important causes of death in male cancer patients. Several AR antagonists have been approved for marketing (such as the first-generation AR inhibitor bicalutamide, the second-generation AR inhibitor enzalutamide, reviluamide, etc.), and have been successfully used in the treatment of hormone-sensitive and castration-resistant prostate cancer, and have become the main treatment for prostate cancer. Although the development and application of new AR targeted drugs have significantly improved the prognosis of prostate cancer patients, especially providing mCRPC patients with other treatment options besides chemotherapy, patients still develop resistance to new AR targeted drugs.

[0004] Summary of the Invention

[0005] The present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof for use in treating metastatic castration-resistant prostate cancer.

[0006] In certain embodiments, the present disclosure provides a method for treating metastatic castration-resistant prostate cancer, comprising administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0007] In certain embodiments, the present disclosure provides a method for treating metastatic castration-resistant prostate cancer, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient after a meal.

[0008] The present disclosure also provides a method for treating metastatic castration-resistant prostate cancer, comprising administering to a patient a therapeutically effective amount of a compound represented by Formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CYP3A4 enzyme substrate.

[0009] In certain embodiments, the present disclosure provides a method for treating metastatic castration-resistant prostate cancer, comprising administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CYP3A4 enzyme substrate, without the need to adjust the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0010] In certain embodiments, the CYP3A4 enzyme substrate described herein is midazolam.

[0011] In certain embodiments, the metastatic castration-resistant prostate cancer described herein is metastatic castration-resistant prostate cancer that has been subjected to medical castration or surgical castration.

[0012] In certain embodiments, the metastatic castration-resistant prostate cancer described in the present disclosure is selected from metastatic castration-resistant prostate cancer that has been treated with continuous luteinizing hormone-releasing hormone analogs (LHRHA) (medical castration), or has undergone bilateral orchiectomy (surgical castration), or has maintained effective LHRHA treatment after not undergoing bilateral orchiectomy.

[0013] In certain embodiments, the patients described herein with metastatic castration-resistant prostate cancer have castrate levels of testosterone (≦50 ng / dL or 1.73 nmol / L).

[0014] In certain embodiments, the metastatic castration-resistant prostate cancer described herein is metastatic castration-resistant prostate cancer that has failed treatment with at least one novel endocrine drug.

[0015] In certain embodiments, the metastatic castration-resistant prostate cancer described herein is metastatic castration-resistant prostate cancer that has failed prior treatment with at least one endocrine drug.

[0016] In certain embodiments, the novel endocrine drug disclosed herein is selected from abiraterone, enzalutamide, apalutamide, revilutamide, and darolutamide.

[0017] In certain embodiments, the endocrine drug described in the present disclosure is selected from abiraterone, enzalutamide, apalutamide, revilutamide, and darolutamide.

[0018] The treatment failure described in the present disclosure refers to the occurrence of disease progression during treatment.

[0019] In certain embodiments, the metastatic castration-resistant prostate cancer described in the present disclosure is metastatic castration-resistant prostate cancer that has been previously treated with at least one chemotherapy drug and progressed during chemotherapy or within 6 months after the end of chemotherapy, or is unsuitable for or intolerant to chemotherapy drugs.

[0020] In certain embodiments, the chemotherapy drugs disclosed herein are selected from taxane chemotherapy drugs, and preferably, the taxane chemotherapy drugs are selected from docetaxel.

[0021] Disease progression in this disclosure is defined as one or more of the following three items occurring while the subject is receiving castration therapy:

[0022] ① PSA progression, including progression to CRPC during HSPC treatment (defined as a PSA value >1 ng / mL at castration-resistant levels, with two consecutive PSA levels >50% above the baseline value separated by at least one week), and PSA progression during CRPC treatment (according to PCWG3 criteria). For patients treated with flutamide or bicalutamide, PSA progression must also occur after discontinuation of the drug (≥4 weeks and ≥6 weeks, respectively).

[0023] ②Disease progression as defined in RECIST 1.1;

[0024] ③Skeletal disease progression as defined by the PCWG3 standard, i.e., ≥2 new lesions found on bone scan.

[0025] In certain embodiments, the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof is 10 mg to 1000 mg, preferably 20 mg to 500 mg, more preferably 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 2 10mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg.

[0026] In certain embodiments, the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof according to the present disclosure is 30 mg, 90 mg, 180 mg, 360 mg, 540 mg, or 720 mg.

[0027] In certain embodiments, the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 10 mg to 300 mg; preferably 10 mg to 200 mg; more preferably 10 mg to 100 mg; more preferably 10 mg to 50 mg.

[0028] In certain embodiments, the unit dose of the compound of Formula I or a pharmaceutically acceptable salt thereof according to the present disclosure is 10 mg-300 mg; preferably 10 mg-200 mg; more preferably 10 mg-100 mg; more preferably 10 mg-50 mg.

[0029] In certain embodiments, the unit dose of the compound of Formula I or a pharmaceutically acceptable salt thereof according to the present disclosure is 10 mg-1000 mg, preferably 20 mg-500 mg, and preferably 15 mg, 30 mg, 60 mg, 90 mg, 180 mg, 360 mg, 540 mg, or 720 mg.

[0030] In certain embodiments, the administered dose or unit dose described herein is based on the weight of the compound of Formula I.

[0031] In certain embodiments, the administration frequency of the compound of Formula I or a pharmaceutically acceptable salt thereof according to the present disclosure is selected from three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, and once a week.

[0032] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof described in the present disclosure is administered to a human.

[0033] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof described in the present disclosure is administered in the form of a pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0034] As used herein, "administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CYP3A4 substrate to a patient" means administering Formula I or a pharmaceutically acceptable salt thereof and at least one CYP3A4 substrate within a certain time period, which may be within a dosing cycle, and may be within 72 hours, 36 hours, 48 ​​hours, 24 hours, 20 hours, 18 hours, 16 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 0.5 hours, or taken together. Preferably, administering within 24 hours, 20 hours, 18 hours, 16 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 0.5 hours, or taken together. DETAILED DESCRIPTION

[0035] Example 1 Phase I clinical study of the safety, tolerability, pharmacokinetics and efficacy of the compound represented by Formula I in subjects with advanced metastatic castration-resistant prostate cancer

[0036] 1. Study Drug

[0037] Experimental drug 1: Compound represented by Formula I, 15 mg / tablet, 60 mg / tablet, prepared according to WO2023093845A, produced and provided by Jiangsu Hengrui Medicine Co., Ltd.

[0038] Test drug 2: Midazolam injection, 1ml: 5mg, Jiangsu Enhua Pharmaceutical Co., Ltd.

[0039] 2. Research Objectives

[0040] Main research objectives:

[0041] To evaluate the safety and tolerability of the compound represented by Formula I in subjects with advanced metastatic castration-resistant prostate cancer (mCRPC).

[0042] Secondary study objectives:

[0043] To evaluate the pharmacokinetic (PK) characteristics of the compound of Formula I and its major metabolites in subjects with advanced mCRPC;

[0044] To evaluate the effect of multiple administration of the compound of formula I on the pharmacokinetics of midazolam, a substrate of CYP3A4;

[0045] To evaluate the preliminary efficacy of the compound represented by Formula I in subjects with advanced mCRPC.

[0046] 3. Study Endpoints

[0047] Primary study endpoint

[0048] Incidence of dose-limiting toxicity (DLT)

[0049] MTD (if achievable) and RP2D;

[0050] Secondary study endpoints

[0051] The incidence, severity (rated according to CTCAE v5.0) and relationship to study drug of adverse events (AEs) and serious adverse events (SAEs), including vital sign, electrocardiogram, and laboratory abnormalities;

[0052] PK parameters of the compound of Formula I after single / multiple administrations, including but not limited to:

[0053] Single-dose parameters: peak plasma concentration (Cmax), time to peak concentration (Tmax), area under the drug-dose curve from 0 to the last measurable concentration time point t (AUC0-t), area under the drug-dose curve from 0 to infinity (AUC0-inf) (if applicable), half-life (t1 / 2) (if applicable), apparent volume of distribution (Vz / F) (if applicable), apparent clearance (CL / F) (if applicable);

[0054] Multiple-dose parameters: steady-state peak concentration (Cmax, ss), time to peak (Tmax, ss), steady-state trough concentration (Cmin, ss), area under the steady-state plasma concentration-time curve (AUCss), and drug accumulation ratio (Rac).

[0055] Midazolam pharmacokinetics (PK): Pharmacokinetic parameters of midazolam after patients took a microdose of midazolam before (D-1) and after (D15) multiple oral doses of the compound of Formula I, including: Tmax, Cmax, AUC0-t, AUC0-∞, t1 / 2, CL / F, and Vz / F.

[0056] Efficacy endpoints: objective response rate (ORR), disease control rate (DCR), duration of response (DoR), radiographic progression-free survival (rPFS), PSA response rate at week 12, proportion of subjects with a PSA reduction of ≥50% and ≥30% from baseline during the entire study treatment period, time to PSA progression, and overall survival (OS);

[0057] 4. Inclusion criteria

[0058] Subjects must meet all of the following inclusion criteria to enter this study:

[0059] 1) Voluntarily participate in this clinical study, understand the research procedures and be able to sign the written informed consent;

[0060] 2) Age 18-80 years (inclusive), male;

[0061] 3) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0062] 4) expected survival time ≥12 weeks;

[0063] 5) Prostate adenocarcinoma confirmed by histological or cytological examination and not diagnosed as neuroendocrine carcinoma or small cell carcinoma;

[0064] 6) Continuous luteinizing hormone-releasing hormone analog (LHRHA) treatment (medical castration) or previous bilateral orchiectomy (surgical castration); subjects who have not undergone bilateral orchiectomy must plan to maintain effective LHRHA treatment throughout the study period;

[0065] 7) Testosterone at castrate level (≤50 ng / dL or 1.73 nmol / L) at screening;

[0066] 8) Patients who have failed treatment with at least one new endocrine drug (such as abiraterone and enzalutamide) (referring to disease progression during treatment; the definition of disease progression is the same as that in inclusion criteria 10);

[0067] 9) Patients who have previously used at least one taxane chemotherapy drug (such as docetaxel) and have progressed during chemotherapy or within 6 months after chemotherapy (the definition of disease progression is the same as that in inclusion criteria 10), or are unsuitable for or intolerant to chemotherapy drugs;

[0068] 10) Disease progression is defined as the occurrence of one or more of the following three items while the subject is receiving castration therapy: ① PSA progression, including progression to CRPC during HSPC treatment (defined as a PSA value >1 ng / mL at castration level, with a PSA level increase of >50% over the baseline value for two consecutive times at least one week apart), and PSA progression during CRPC treatment (according to the PCWG3 criteria); for patients treated with flutamide or bicalutamide, PSA must also progress after discontinuation of the drug (≥4 weeks and ≥6 weeks, respectively); ② Disease progression defined in RECIST 1.1; ③ Bone disease progression defined in the PCWG3 criteria, i.e., the presence of ≥2 new lesions on bone scan;

[0069] 11) Metastatic lesions confirmed by CT / MRI or radioactive bone scan (99mTc);

[0070] 12) During the screening period, sufficient blood samples must be provided for gene mutation detection; it is recommended to also provide tumor tissue samples (archived or fresh biopsy samples are acceptable; fresh samples or archived samples within 1 year are preferred)

[0071] 13) Adequate organ function as defined by the following laboratory tests:

[0072] Routine blood test (no blood transfusion or blood products within 14 days before the first dose, no use of G-CSF or other hematopoietic stimulating factors for correction): absolute neutrophil count (ANC) ≥ 1.5 × 109 / L; platelet count (PLT) ≥ 100 × 109 / L; hemoglobin (Hb) ≥ 90 g / L;

[0073] Liver function tests: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) (≤ 2 × ULN if liver metastasis occurs); serum transaminases ALT and / or AST ≤ 3 × ULN (≤ 5 × ULN if liver metastasis occurs);

[0074] Renal function test: Serum creatinine (Cr) ≤ 1.5 × ULN; urine protein ≥++ with confirmation of 24-hour urine protein ≤ 1.0 g;

[0075] Electrocardiogram: Fridericia-corrected QT interval (QTcF) is normal (≤470 ms for men);

[0076] Echocardiography: left ventricular ejection fraction (LVEF) ≥ 50%;

[0077] Coagulation function tests: APTT ≤ 1.5 × ULN, with INR or PT ≤ 1.5 × ULN.

[0078] 14) Male subjects whose partners are women of childbearing age must agree to refrain from sperm donation and use appropriate contraceptive measures from the time they sign the informed consent form until 3 months after the last dose of the trial drug.

[0079] 4. Exclusion criteria

[0080] Subjects who meet any of the following criteria will not be eligible for this study:

[0081] 1) Patients who have received any AR degraders before;

[0082] 2) Plan to receive any other anti-tumor treatment during this study;

[0083] 3) Patients who have received chemotherapy, targeted therapy, immunotherapy, active attenuated vaccination, radiotherapy, or surgery for less than 4 weeks before the start of study treatment (for small molecule targeted drugs, the duration is 7 days before the first dose of the study drug or 5 times the half-life of the drug, whichever is longer; the washout period for bicalutamide is 6 weeks); Patients who are participating in other clinical studies 4 weeks before the start of study treatment (calculated based on the time of the last use of the investigational drug or device);

[0084] 4) Damage caused by any previous anti-tumor treatment has not recovered to ≤ Grade 1 or the criteria specified in this study (according to NCI-CTCAE 5.0 classification; excluding alopecia and other adverse events judged to be tolerable by the investigator);

[0085] 5) Patients who have previously used drugs that affect the activity of the metabolic enzyme CYP3A, and the washout period from the end of the study to the first dose of this study is shorter than 5 half-lives of the drug;

[0086] 6) Patients participating in the QT / QTc study had used any drugs that have the risk of prolonging the QT / QTc interval or causing torsade de pointes (TdP) within 4 weeks before the first medication, had a history of congenital long QT syndrome or a family history of QT prolongation, had an implanted pacemaker or automatic implantable cardioverter-defibrillator, or had uncorrectable electrolyte disorders, etc., which may affect the QT / QTc study;

[0087] 7) Subjects with poorly controlled hypertension (systolic blood pressure > 150 mmHg and / or diastolic blood pressure > 100 mmHg under regular antihypertensive treatment), and subjects with a history of hypertensive crisis or hypertensive encephalopathy;

[0088] 8) The patient is known to have central nervous system metastasis or meningeal metastasis, or the subject has a history of primary central nervous system tumor;

[0089] 9) Severe bone damage caused by tumor bone metastasis as determined by the investigator, including poorly controlled severe bone pain, pathological fractures of important parts and spinal cord compression that occurred within the last 6 months or are expected to occur in the near future;

[0090] 10) Having one of the multiple factors that affect oral medication (such as inability to swallow, chronic diarrhea and intestinal obstruction, etc.) or having active gastrointestinal diseases or other diseases that may significantly affect drug absorption, distribution, metabolism or excretion;

[0091] 11) Known allergy or intolerance to the compound of Formula I or its excipients;

[0092] 12) Active heart disease within 6 months before the first dose of the study, including severe / unstable angina, myocardial infarction, symptomatic congestive heart failure, and ventricular arrhythmia requiring drug treatment;

[0093] 13) Suffering from other malignant tumors within 5 years before the first administration of the study (except for carcinoma in situ that has completely remitted and malignant tumors that are judged to be slowly progressing by the researcher);

[0094] 14) Patients with active hepatitis B (HBsAg positive and HBV DNA ≥ 500 IU / ml) or hepatitis C (hepatitis C antibody positive and HCV RNA higher than the detection limit of the analytical method); or those with severe infections that require antibiotics, antivirals, or antifungal drugs;

[0095] 15) History of immunodeficiency (including HIV positive test, other acquired or congenital immunodeficiency diseases) or organ transplantation;

[0096] 16) The researcher determines that the subject has other factors that may affect the study results or force the termination of the study, such as alcoholism, drug abuse, other serious illnesses (including mental illness) requiring combined treatment, serious abnormalities in laboratory test values, family or social factors, and other situations that may affect the safety of the subject or the collection of trial data.

[0097] 5. Dosage

[0098] Tablets, for oral administration, are pre-specified doses of 30 mg, 90 mg, 180 mg, 360 mg, 540 mg, or 720 mg, with a 28-day treatment cycle. Continue until disease progression or unacceptable toxicity occurs. Administer orally once daily within 30 minutes after a meal in the morning. If intensive PK blood sampling is scheduled that day, avoid drinking water for 1 hour and eating for 4 hours before and after dosing.

[0099] Drug-drug interaction (DDI) assessment phase: Oral tablets were administered once daily in the morning within 30 minutes after a meal. 100 μg of midazolam was administered once in the morning on Days -1 and 15, within 30 minutes after a meal. On Day 15, midazolam and the test drug were administered simultaneously (± 2 minutes).

[0100] 6. Preliminary Results

[0101] 6.1 Clinical Pharmacology

[0102] The food effect study included 9 patients. The mean half-life (± standard deviation) of 180 mg dosed on an empty stomach was 40.8±4.37 h, the geometric mean (geometric coefficient of variation %) of the apparent volume of distribution was 1260 (90.7) L, the geometric mean (geometric coefficient of variation %) of the clearance was 21.5 (83.4) L / h, and the median time to peak concentration was 3 h.

[0103] The degree of absorption after meals is higher than that after fasting, with AUC 2.54 times higher, Cmax 3.06 times higher, and peak time delayed by 3 hours (about 6 hours).

[0104] 6.2 Clinical Safety

[0105] A total of 26 tumor patients were enrolled in this study, including 13 in the dose-escalation phase, including 1 in the 30mg, 4 in the 90mg, 4 in the 180mg, 3 in the 360mg, and 1 in the 540mg dose group. All patients have completed DLT observation and no dose-limiting toxicity (DLT) has been observed. One patient was enrolled in the 540mg dose group, and DLT observation has not yet been completed, with no dose-limiting toxicity (DLT) observed. Thirteen subjects were enrolled in the dose-expansion phase, all at the 180mg dose group.

[0106] During the study, 9 subjects (34.6%) experienced TEAEs, including anemia, hypercholesterolemia, increased blood creatinine, and rash (two cases each) in at least two subjects. Three subjects (11.5%) experienced Grade 3 TEAEs, including decreased lymphocyte count, increased blood pressure, decreased neutrophil count, and decreased white blood cell count (one case each).

[0107] During the study, 8 subjects (30.8%) experienced AEs related to Formula I, including anemia, hypercholesterolemia, and increased serum creatinine (two cases each) in at least two subjects. One subject (3.8%) experienced a Grade 3 TRAE, which was decreased neutrophil count and decreased white blood cell count.

[0108] No grade 4 / 5 AEs occurred during the study.

[0109] 6.3 Clinical effectiveness

[0110] A total of 17 subjects in the study underwent at least one post-baseline PSA test, including 1, 4, 9, and 3 subjects in the 30 mg, 90 mg, 180 mg, and 360 mg doses, respectively. Of the 17 subjects evaluable for PSA response, 8 experienced a PSA decrease. Specifically, 6 of the 9 subjects in the 180 mg dose group (66.7%) experienced a PSA decrease, including 3 subjects who achieved PSA30 (a decrease in serum PSA level ≥30% from baseline during treatment), and 1 subject who achieved PSA90 (a decrease in serum PSA level ≥90% from baseline during treatment).

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating metastatic castration-resistant prostate cancer, 2. The use according to claim 1, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer that has been treated with effective LHRHA after medical castration, surgical castration, or not receiving bilateral orchiectomy.

3. The use according to claim 1, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer that has failed to be treated with at least one endocrine drug in the past; the endocrine drug is preferably abiraterone, enzalutamide, apalutamide, revilutamide, and darolutamide.

4. The use according to claim 1, wherein the metastatic castration-resistant prostate cancer is a metastatic castration-resistant prostate cancer that has been previously treated with at least one chemotherapy drug and progresses during chemotherapy or within 6 months after the end of chemotherapy, or is not suitable for or intolerant to chemotherapy drugs; the chemotherapy drug is preferably a paclitaxel chemotherapy drug; more preferably docetaxel.

5. The use according to claim 1, wherein the compound represented by formula I or a pharmaceutically acceptable salt thereof is administered to a human.

6. The use according to claim 1, wherein the dosage of the compound of formula I or its pharmaceutically acceptable salt is 10 mg-1000 mg.

7. The use according to claim 1, wherein the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is 30 mg or 90 mg or 180 mg or 360 mg or 540 mg or 720 mg.

8. The use according to claim 1, wherein the unit dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 10 mg-300 mg.

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