Methods of treating prostate cancer

Abstract

This is a method for treating prostate cancer. Specifically, it involves the use of the compound shown in Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating metastatic castration-resistant prostate cancer. [Formula 1] JPEG2026521901000005.jpg32155

Description

Technical Field

[0001] This application relates to the pharmaceutical field and includes the use of the compound shown in Formula I or its pharmaceutically acceptable salt in the manufacture of a drug for treating prostate cancer.

Background Art

[0002] The androgen receptor (AR) is a ligand-dependent trans-type transcriptional regulatory protein, belonging to the nuclear receptor superfamily and mainly existing in the cell nucleus. AR that is not bound to a ligand binds to a heat shock protein (HSP). After AR binds to a ligand, its conformation changes, dissociates from HSP, and its affinity for DNA increases (activation of AR). The activated AR binds to an androgen response element (ARE), which is a specific DNA sequence in the cell nucleus, in a dimeric form, and regulates the expression of related genes and produces biological effects by interacting with other transcription factors. According to research, it has been shown that abnormalities in the AR signaling pathway are closely related to the occurrence 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. Statistics show that in 2018, there were nearly 1.3 million new cases and 359,000 deaths worldwide, accounting for 13.5% of male malignant tumor incidence (second leading cause) and 6.7% of male malignant tumor mortality (fifth leading cause). Currently, the incidence of prostate cancer is increasing year by year, and it is a significant cause of death among male cancer patients. Many AR antagonists have already been approved for market release (e.g., bicalutamide, a first-generation AR inhibitor; enzalutamide and resvirutamide, second-generation AR inhibitors), and have been successfully applied to the treatment of hormone-sensitive and castration-resistant prostate cancer, becoming a major treatment option for prostate cancer. The development and application of novel AR-targeted drugs have significantly improved the prognosis of prostate cancer patients, particularly providing alternative treatment options to chemotherapy for mCRPC patients; however, resistance to novel AR-targeted drugs still emerges in patients. [Overview of the Initiative]

[0004] This disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof for the treatment of metastatic castration-resistant prostate cancer. [ka]

[0005] In some embodiments, the present disclosure provides a method for treating metastatic castration-resistant prostate cancer, the method comprising administering to a patient a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof.

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

[0007] This disclosure further provides a method for treating metastatic castration-resistant prostate cancer, the method 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.

[0008] In some embodiments, the method for treating metastatic castration-resistant prostate cancer described herein comprises administering to a patient a therapeutically effective amount of the compound shown in Formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CYP3A4 enzyme substrate, without requiring any adjustment of the dosage of the compound shown in Formula I or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the CYP3A4 enzyme substrate described herein is midazolam.

[0010] In some embodiments, the metastatic castration-resistant prostate cancer described herein is metastatic castration-resistant prostate cancer that has been castrated by drug or surgery.

[0011] In some embodiments, the metastatic castration-resistant prostate cancer described herein is selected from metastatic castration-resistant prostate cancer that has received sustained treatment with luteinizing hormone-releasing hormone analogs (LHRHA) (pharmacological castration), or has previously undergone bilateral orchiectomy (surgical castration), or has maintained effective LHRHA treatment after not having undergone bilateral orchiectomy.

[0012] In some embodiments, the testosterone levels of patients with metastatic castration-resistant prostate cancer as described in this disclosure are at castration levels (≤50 ng / dL or 1.73 nmol / L).

[0013] In some embodiments, the metastatic castration-resistant prostate cancer described herein is metastatic castration-resistant prostate cancer that has failed to treat at least one previous novel endocrine drug therapy.

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

[0015] In some embodiments, the novel endocrine drugs described herein are selected from, for example, abiraterone, enzalutamide, apalutamide, resvirutamide, and darolutamide.

[0016] In some embodiments, the endocrine drug described herein is selected from, for example, abiraterone, enzalutamide, apalutamide, resvirutamide, and darolutamide.

[0017] Treatment failure as described in this disclosure refers to disease progression occurring during treatment.

[0018] In some embodiments, the metastatic castration-resistant prostate cancer described herein is metastatic castration-resistant prostate cancer that has previously received at least one chemotherapy agent, progressed during or within six months after the completion of chemotherapy, or is unsuitable for or intolerant to chemotherapy agents.

[0019] In some embodiments, the chemotherapeutic agent described herein is selected from paclitaxel-based chemotherapeutic agents, preferably the paclitaxel-based chemotherapeutic agent is selected from docetaxel.

[0020] The disease progression described in this disclosure is defined as the occurrence of one or more of the following three conditions simultaneously with the subject receiving castration treatment.

[0021] (1) PSA progression, including progression to CRPC during HSPC treatment (defined at the castration level as PSA value >1 ng / mL and two consecutive PSA levels >50% above baseline at least one week apart), and PSA progression that appears during CRPC treatment (according to PCWG3 standards), in patients treated with flutamide or bicalutamide, PSA progression must be confirmed after drug-free periods of (≥4 weeks and ≥6 weeks, respectively). (2) Disease progression as defined in RECIST 1.1, (3) Bone disease progression as defined by the PCWG3 standard, i.e., the detection of ≥2 new lesions on a bone scan.

[0022] In some embodiments, the dosage of the compound shown in Formula I described in the present disclosure or its pharmaceutically acceptable salt is 10 mg to 1000 mg, preferably 20 mg to 500 mg, and 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, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg.

[0023] In some embodiments, the dosage of the compound shown in Formula I described in the present disclosure or its pharmaceutically acceptable salt is 30 mg or 90 mg or 180 mg or 360 mg or 540 mg or 720 mg.

[0024] In some embodiments, the dosage of the compound shown in Formula I described in the present disclosure or its pharmaceutically acceptable salt is selected from 10 mg to 300 mg, preferably 10 mg to 200 mg, more preferably 10 mg to 100 mg, and even more preferably 10 mg to 50 mg.

[0025] In some embodiments, the unit dosage of the compound shown in Formula I described in the present disclosure or its pharmaceutically acceptable salt is 10 mg to 300 mg, preferably 10 mg to 200 mg, more preferably 10 mg to 100 mg, and even more preferably 10 mg to 50 mg.

[0026] In some embodiments, the unit dose of the compound represented by Formula I described in the present disclosure or a pharmaceutically acceptable salt thereof is 10 mg to 1000 mg, a preferred unit dose is 20 mg to 500 mg, and preferred unit doses are 15 mg, 30 mg, 60 mg, or 90 mg, or 180 mg, or 360 mg, or 540 mg, or 720 mg.

[0027] In some embodiments, the dosage or unit dose described in the present disclosure is based on the weight of the compound of Formula I.

[0028] In some embodiments, the dosing frequency of the compound represented by Formula I described in the present disclosure or a pharmaceutically acceptable salt thereof 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, once a week.

[0029] In some embodiments, the administration subject of the compound represented by Formula I described in the present disclosure or a pharmaceutically acceptable salt thereof is a human.

[0030] In some embodiments, the compound represented by Formula I described in the present disclosure or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition, and the pharmaceutical composition includes the compound represented by Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, excipients, diluents.

[0031] "Administering a therapeutically effective amount of the compound shown in Formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CYP3A4 enzyme substrate to a patient" as described in this disclosure means administering Formula I or a pharmaceutically acceptable salt thereof and at least one CYP3A4 enzyme substrate within a certain period of time, which may be within a single administration cycle and may be optionally 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 simultaneous administration. Preferably, it is 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 simultaneous administration. [Modes for carrying out the invention]

[0032] Phase I clinical study of the safety, tolerance, pharmacokinetics, and therapeutic effects of the compound shown in Example 1, Formula I, in subjects with terminal metastatic castration-resistant prostate cancer. 1. Research drug JPEG2026521901000003.jpg18163

[0033] 2. Research purpose Main research objectives: The safety and tolerance of the compound shown in Formula I will be evaluated in subjects with advanced metastatic castration-resistant prostate cancer (mCRPC).

[0034] Secondary research objectives: The pharmacokinetic (PK) characteristics of the compound shown in Formula I and its main metabolites were evaluated in patients with end-stage mCRPC. The effect of multiple administrations of the compound shown in Formula I on the pharmacokinetics of the CYP3A4 enzyme substrate midazolam was evaluated. This study evaluates the preliminary therapeutic effects of the compound shown in Formula I in patients with end-stage mCRPC.

[0035] 3. Research endpoints Key research endpoints • Incidence of dose-limiting toxicity (DLT) • MTD (if achievable) and RP2D,

[0036] Secondary research endpoints In addition to the incidence, severity (graded according to CTCAE v5.0), and correlation with the study drug of adverse events (AEs) and serious adverse events (SAEs), vital signs, electrocardiograms, and laboratory test abnormalities are also included. The PK parameters of the compound shown in Formula I after single / multiple administrations, Single-dose parameters: Maximum blood drug concentration (Cmax), time to peak (Tmax), area under the blood concentration-time curve from 0:00 to the last measurable concentration time point t (AUC0-t), area under the blood concentration-time curve from 0:00 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), Multiple dose parameters include, but are not limited to, the maximum blood concentration at steady state (Cmax, ss), time to peak (Tmax, ss), minimum blood concentration at steady state (Cmin, ss), area under the blood concentration-time curve at steady state (AUCss), and drug accumulation ratio (Rac). • Pharmacokinetics (PK) of midazolam: Pharmacokinetic parameters of midazolam after a small dose of midazolam is administered before (D-1) and after (D15) oral administration of the compound of formula I, including Tmax, Cmax, AUC0-t, AUC0-∞, t1 / 2, CL / F, and Vz / F. Treatment efficacy endpoints: Objective response rate (ORR), disease control rate (DCR), duration of response (DoR), radiographic progression-free survival (rPFS), PSA response rate at 12 weeks, percentage of subjects whose PSA decreased by ≥50% and ≥30% compared to baseline over the entire treatment period, time to PSA progression, and overall survival (OS).

[0037] 4. Eligibility Criteria Participants must meet all of the following selection criteria in order to participate in this study. 1) You are willing to voluntarily participate in this clinical study, understand the research procedures, and sign a written informed consent form. 2) Male, between 18 and 80 years of age (including 18 and 80 years of age) 3) The performance status score by the East Coast Cancer Clinical Group (ECOG) is between 0 and 1. 4) Predicted survival time is ≥ 12 weeks, 5) Prostate adenocarcinoma confirmed by histological or cytological examination, and not diagnosed as neuroendocrine carcinoma or small cell carcinoma, 6) Subjects who have received sustained treatment with luteinizing hormone-releasing hormone (LHRHA) (pharmacological castration) or who have previously undergone bilateral orchiectomy (surgical castration) and have not undergone bilateral orchiectomy must maintain effective LHRHA treatment throughout the entire study period. 7) At the time of screening, testosterone levels are at castration levels (≤50 ng / dL or 1.73 nmol / L), 8) Failure to treat at least one previous novel endocrine drug (e.g., abiraterone, enzalutamide) (meaning disease progression occurs during treatment, the definition of disease progression is the same as in eligibility criterion 10), 9) Patients who have previously received at least one paclitaxel-based chemotherapy agent (e.g., docetaxel), whose disease has progressed during or within 6 months after the completion of chemotherapy (the definition of disease progression is the same as in item 10 of the eligibility criteria), or who are unsuitable for or intolerant to chemotherapy agents, 10) Disease progression is defined as the occurrence of one or more of the following three conditions simultaneously with castration treatment in a subject: (1) PSA progression, including progression to CRPC during the HSPC treatment stage (defined as a PSA value >1 ng / mL at the castration level, with two consecutive PSA levels >50% above baseline at least one week apart), and PSA progression that appears during the CRPC treatment stage (according to PCWG3 standards), and in patients treated with flutamide or bicalutamide, PSA progression must be confirmed after drug-free periods of ≥4 weeks and ≥6 weeks, respectively; (2) disease progression as defined in RECIST 1.1; (3) bone disease progression as defined in PCWG3 standards, i.e., the discovery of ≥2 new lesions on a bone scan. 11) If metastatic lesions are confirmed by CT / MRI or radiographic bone scan (99mTc) imaging, 12) During the screening period, it is necessary to provide sufficient blood samples for gene mutation testing, and at the same time, it is recommended to provide tumor tissue samples (preserved samples or new biopsy samples are acceptable, with new samples or preserved samples within the last year being preferred). 13) According to the definition of the laboratory test below, there is a sufficient level of organ function, and the definition is as follows: • Complete blood count (no blood transfusions or blood products were administered in the 14 days prior to the initial administration, and no correction was made using G-CSF or other hematopoietic stimulants): Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹ / L, platelet count (PLT) ≥ 100 × 10⁹ / L, hemoglobin (Hb) ≥ 90 g / L • Liver function tests: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) (≤ 2 × ULN in cases of liver metastasis), serum transaminase ALT and / or AST ≤ 3 × ULN (≤ 5 × ULN in cases of liver metastasis), • Renal function tests: If serum creatinine (Cr) ≤ 1.5 × ULN and urine protein ≥ ++ are indicated in the urinalysis, the 24-hour urine protein amount ≤ 1.0g must be confirmed. • Electrocardiogram: The corrected QT interval (QTcF) according to the Fridericia formula was normal (male ≤ 470ms). • Cardiac color Doppler ultrasound: Left ventricular ejection fraction (LVEF) ≥ 50% • Coagulation function test: APTT ≤ 1.5 × ULN, and simultaneously INR or PT ≤ 1.5 × ULN. 14) Male test subjects whose partners are women of childbearing age must agree to avoid sperm donation and to use applicable contraceptive measures within three months of signing the informed consent form and after the last dose of the study drug.

[0038] 4, Exclusion criteria Participants will be excluded from this study if they meet any of the following criteria. 1) In the past, have you received treatment with any AR-degrading agent? 2) During the study period, the patient is scheduled to receive any other antitumor treatment. 3) If you have received chemotherapy, targeted therapy, immunotherapy, attenuated active vaccine, radiotherapy, or surgical treatment for less than 4 weeks prior to the start of the study treatment (in the case of small molecule targeted drugs, 7 days before the first administration of the study drug or the longer of the 5 half-lives; in the case of bicalutamide elution period, 6 weeks), and have participated in another clinical study within 4 weeks prior to the start of the study treatment (calculated from the last day of use of the study drug or medical device), 4) Damage from any previous antitumor treatment has not recovered to a grade of 1 or below, or to the criteria defined in this study (graded based on NCI-CTCAE 5.0, excluding alopecia and other adverse events that the researchers deemed tolerable), 5) The patient has previously used a drug that affects the activity of the metabolic enzyme CYP3A, and the dissolution period from the last dose to the first dose in this study is shorter than the 5 half-life of the drug. 6) Patients participating in the QT / QTc study who have used drugs that increase the risk of QT / QTc interval prolongation or torsades de pointe (TdP) within 4 weeks prior to the first dose, who have a history of congenital long QT syndrome or a family history of QT prolongation, who have an implanted pacemaker or automated implantable cardioverter-defibrillator, or who have factors that affect QT / QTc assessment, such as uncorrectable electrolyte abnormalities, 7) Subjects with poorly controlled hypertension (systolic blood pressure > 150 mmHg and / or diastolic blood pressure > 100 mmHg in the case of regular antihypertensive treatment) and a history of hypertensive emergency or hypertensive encephalopathy, 8) Subjects with a history of known central nervous system metastases or meningeal metastases or primary central nervous system tumors, 9) Severe bone disorders caused by metastatic bone tumors as determined by researchers, including severe bone pain that is poorly controlled, pathological fractures of vital sites that have occurred within the past six months or are suspected to occur in the near future, and spinal cord compression. 10) Having one of several factors that affect the administration of oral medications (e.g., difficulty swallowing, chronic diarrhea, intestinal obstruction), or having an active gastrointestinal disease or other disease that may have a significant effect on the absorption, distribution, metabolism, or excretion of the drug, 11) Allergies or intolerances to the compounds shown in Formula I or their excipients are known, 12) Having had active heart disease, including severe / unstable angina, myocardial infarction, symptomatic congestive heart failure, and ventricular arrhythmias requiring drug treatment, within 6 months prior to the first dose of the study, 13) Having a history of other malignancies (excluding carcinoma in situ that has gone into complete remission and malignancies that the researchers judged to be progressing slowly) within 5 years prior to the first dose of the study, 14) Individuals with active hepatitis B (HBsAg positive and HBV DNA ≥ 500 IU / ml), hepatitis C (positive for hepatitis C virus antibody and HCV RNA above the detection limit by analytical method), or severe infections requiring control with antibiotics, antiviral drugs, or antifungal drugs. 15) Having a history of immunodeficiency (including HIV positivity, other acquired or congenital immunodeficiency disorders) or a history of organ transplantation, 16) In the researchers' judgment, subjects have factors that could affect the results of the study or cause the study to be interrupted, such as alcohol dependence, substance abuse, serious comorbidities requiring treatment (including mental illness), significant abnormalities in laboratory test values, family or social factors, and circumstances that could affect the safety of the subject or the collection of test data.

[0039] 5. Method of administration The tablets were administered orally, with predetermined dose groups of 30 mg, 90 mg, 180 mg, 360 mg, 540 mg, or 720 mg, forming one treatment cycle every 28 days. Administration continued until disease progression or unacceptable toxicity occurred. The medication was administered orally once daily within 30 minutes after breakfast. If a concentrated PK blood draw was performed on the day of administration, the patient was instructed to refrain from drinking water for 1 hour before and after administration, and to fast for 4 hours. Drug interaction (DDI) evaluation stage: The tablets were administered orally once daily within 30 minutes after breakfast. - 100 μg of midazolam was administered once each within 30 minutes after breakfast on day 1 and day 15. Midazolam and the test drug were taken simultaneously on day 15 (±2 min).

[0040] 6. Preliminary results 6.1 Clinical Pharmacology In a study on food effects, when 180 mg was administered to a total of nine patients on an empty stomach, the mean half-life (± standard deviation) 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 clearance was 21.5 (83.4) L / h, and the median time to peak was 3 h. After a meal, absorption was higher compared to when the body was fasting, with AUC being 2.54 times higher, Cmax being 3.06 times higher, and the time to reach peak absorption delayed by 3 hours (approximately 6 hours).

[0041] 6.2 Clinical safety In this study, a total of 26 tumor subjects were enrolled. In the dose escalation phase, 13 subjects were enrolled. In this phase, the 30 mg, 90 mg, 180 mg, 360 mg, and 540 mg groups consisted of 1, 4, 4, 3, and 1 subject, respectively. In all cases, DLT observation was completed and no dose-limiting toxicity (DLT) was observed. In the 540 mg dose group, one subject was enrolled, and DLT observation was not completed, but no dose-limiting toxicity (DLT) was observed. In the dose expansion phase, there were 13 subjects, all in the 180 mg dose group. During the study period, a total of nine subjects (34.6%) experienced TEAEs, with at least two subjects experiencing anemia, hypercholesterolemia, elevated serum creatinine, and rash (two of each). Three subjects (11.5%) experienced grade 3 TEAEs, including decreased lymphocyte count and elevated blood pressure, while one subject each experienced decreased neutrophil count and decreased leukocyte count. During the study period, a total of 8 subjects (30.8%) experienced AEs related to formula I, with at least 2 subjects experiencing anemia, hypercholesterolemia, and elevated serum creatinine (2 of each). One subject (3.8%) experienced a grade 3 TRAE, characterized by decreased neutrophil count and decreased white blood cell count. No grade 4 / 5 adverse events occurred during the study period.

[0042] 6.3 Clinical efficacy In the study, a total of 17 subjects underwent at least one PSA test after baseline. The 30 mg, 90 mg, 180 mg, and 360 mg dose groups comprised 1, 4, 9, and 3 subjects, respectively. Of the 17 subjects for whom PSA response rates were evaluable, eight experienced a decrease in PSA levels. In particular, among the nine subjects in the 180 mg dose group, six (66.7%) experienced a decrease in PSA levels. Three subjects reached PSA 30 (serum PSA levels ≥30% lower than baseline during the treatment period), and one subject reached PSA 90 (serum PSA levels ≥90% lower than baseline during the treatment period).

Claims

1. Uses of the compound shown in Formula I or a pharmaceutically acceptable salt thereof in the manufacture of drugs for the treatment of metastatic castration-resistant prostate cancer. 【Chemistry 1】

2. The use according to claim 1, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer that has maintained effective LHRHA treatment after undergoing drug castration, surgical castration, or 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 at least one previous endocrine drug treatment, and the endocrine drug is preferably abiraterone, enzalutamide, apalutamide, resvirutamide, or darolutamide.

4. The use according to claim 1, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer that has previously received at least one chemotherapy drug, progresses during or within six months after the completion of chemotherapy, or is unsuitable for or intolerant to chemotherapy drugs, and the chemotherapy drug is preferably a paclitaxel-based chemotherapy drug, and more preferably docetaxel.

5. The use according to claim 1, wherein the target of administration of the compound shown in formula I or a pharmaceutically acceptable salt thereof is human.

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

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

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

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