WO2025007946A1 - 治疗前列腺癌的方法 - Google Patents

治疗前列腺癌的方法 Download PDF

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Publication number
WO2025007946A1
WO2025007946A1 PCT/CN2024/103772 CN2024103772W WO2025007946A1 WO 2025007946 A1 WO2025007946 A1 WO 2025007946A1 CN 2024103772 W CN2024103772 W CN 2024103772W WO 2025007946 A1 WO2025007946 A1 WO 2025007946A1
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prostate cancer
formula
drug
resistant prostate
pharmaceutically acceptable
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French (fr)
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王文亮
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Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
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Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
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Priority to KR1020267003058A priority Critical patent/KR20260033049A/ko
Priority to CN202480038139.7A priority patent/CN121443295A/zh
Publication of WO2025007946A1 publication Critical patent/WO2025007946A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • 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.
  • Androgen receptor is a ligand-dependent trans-transcriptional regulatory protein, a member of the nuclear receptor superfamily, and is mainly present in the cell nucleus.
  • AR that is not bound to the ligand binds to heat shock protein (HSP); after AR binds to the ligand, it undergoes a conformational change, dissociates from HSP, and increases its affinity for DNA (AR activation).
  • HSP heat shock protein
  • the activated AR binds to a specific DNA sequence in the cell nucleus—androgen response element (ARE)—in the form of a dimer, and interacts with other transcription factors, thereby regulating the expression of related genes and producing biological effects.
  • ARE androgen response element
  • 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.
  • Multiple 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.
  • 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.
  • 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.
  • 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.
  • 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 of Formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CYP3A4 enzyme substrate.
  • a method for treating metastatic castration-resistant prostate cancer described in the present disclosure comprises 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.
  • the CYP3A4 enzyme substrate described herein is midazolam.
  • the metastatic castration-resistant prostate cancer described in the present disclosure is metastatic castration-resistant prostate cancer that has been medically or surgically castrated.
  • 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 previously undergone bilateral orchiectomy (surgical castration), or has maintained effective LHRHA treatment after not undergoing bilateral orchiectomy.
  • LHRHA continuous luteinizing hormone-releasing hormone analogs
  • the testosterone of patients with metastatic castration-resistant prostate cancer described herein is at castrate levels ( ⁇ 50 ng/dL or 1.73 nmol/L).
  • the metastatic castration-resistant prostate cancer described in the present disclosure is metastatic castration-resistant prostate cancer that has failed treatment with at least one novel endocrine drug.
  • the metastatic castration-resistant prostate cancer described in the present disclosure is metastatic castration-resistant prostate cancer that has failed at least one previous endocrine drug treatment.
  • the novel endocrine drug disclosed herein is selected from abiraterone, enzalutamide, apalutamide, revilutamide, and darolutamide.
  • the endocrine drug described in the present disclosure is selected from abiraterone, enzalutamide, apalutamide, revilutamide, and darolutamide.
  • the treatment failure described in the present disclosure refers to the occurrence of disease progression during treatment.
  • 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 not suitable for or intolerant to chemotherapy drugs.
  • the chemotherapeutic drugs disclosed herein are selected from taxane-based chemotherapeutic drugs, and preferably, the taxane-based chemotherapeutic drugs are selected from docetaxel.
  • PSA progression including progression to CRPC during HSPC treatment (defined as PSA value >1 ng/mL at castration level, with an interval of at least 1 week, and 2 consecutive PSA levels increased by >50% compared with the baseline value), and PSA progression during CRPC treatment (according to PCWG3 criteria); for patients treated with flutamide or bicalutamide, PSA must also progress after drug discontinuation ( ⁇ 4 weeks and ⁇ 6 weeks, respectively);
  • 3Bone disease progression as defined by the PCWG3 standard, i.e., ⁇ 2 new lesions found on bone scan.
  • the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is 10 mg-1000 mg, preferably 20 mg-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.
  • the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof according to the present disclosure is 30 mg or 90 mg or 180 mg or 360 mg or 540 mg or 720 mg.
  • 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.
  • 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.
  • the administered dose or unit dose described herein is based on the weight of the compound of Formula I.
  • the administration frequency of the compound of Formula I or a pharmaceutically acceptable salt thereof described in 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.
  • 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, which comprises the compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, excipients, and diluents.
  • 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 enzyme substrate to a patient refers to administering Formula I or a pharmaceutically acceptable salt thereof and at least one CYP3A4 enzyme substrate within a certain time period, and the time period may be within a dosing cycle, and may be selected within 72 hours, within 36 hours, within 48 hours, within 24 hours, within 20 hours, within 18 hours, within 16 hours, within 12 hours, within 10 hours, within 8 hours, within 6 hours, within 4 hours, within 2 hours, within 1 hour, within 0.5 hours, or taken together.
  • Experimental drug 1 Compound represented by formula I, 15 mg/tablet, 60 mg/tablet, prepared with reference to WO2023093845A, produced and provided by Jiangsu Hengrui Medicine Co., Ltd.
  • Test drug 2 Midazolam injection, 1ml: 5mg, Jiangsu Enhua Pharmaceutical Co., Ltd.
  • PK parameters of the compound of Formula I after single/multiple administrations including but not limited to:
  • PK Pharmacokinetics of midazolam: Pharmacokinetic parameters of midazolam after patients took a microdose of midazolam before (D-1) and after (D15) multiple oral administrations of the compound of Formula I, including: Tmax, Cmax, AUC0-t, AUC0- ⁇ , t1/2, CL/F, Vz/F.
  • Efficacy endpoints objective response rate (ORR), disease control rate (DCR), duration of response (DoR), radiographic progression-free survival (rPFS), PSA response rate at the end of 12 weeks, proportion of subjects with PSA reduction of ⁇ 50% and ⁇ 30% from baseline during the entire study treatment period, time to PSA progression, and overall survival (OS);
  • ORR objective response rate
  • DCR disease control rate
  • DoR duration of response
  • rPFS radiographic progression-free survival
  • PSA response rate at the end of 12 weeks proportion of subjects with PSA reduction of ⁇ 50% and ⁇ 30% from baseline during the entire study treatment period, time to PSA progression, and overall survival (OS);
  • Prostate adenocarcinoma confirmed by histological or cytological examination, and not diagnosed as neuroendocrine carcinoma or small cell carcinoma Cell cancer;
  • LHRHA Continuous luteinizing hormone-releasing hormone analog
  • Testosterone at castrate level ( ⁇ 50ng/dL or 1.73nmol/L) at screening;
  • Disease progression is defined as one or more of the following three items occurring to the subject while receiving castration therapy: 1PSA progression, including progression to CRPC during HSPC treatment (defined as PSA value >1 ng/mL at castration level, with an interval of at least 1 week, and 2 consecutive PSA levels increased by >50% compared with the baseline value), and PSA progression during CRPC treatment (according to PCWG3 criteria); for patients treated with flutamide or bicalutamide, PSA must also progress after drug withdrawal ( ⁇ 4 weeks and ⁇ 6 weeks, respectively); 2Disease progression defined in RECIST 1.1; 3Bone disease progression defined in PCWG3 criteria, i.e., ⁇ 2 new lesions found on bone scan;
  • Routine blood test (no blood transfusion or blood products within 14 days before the first administration, 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) ⁇ 90g/L;
  • Liver function tests total bilirubin (TBIL) ⁇ 1.5 ⁇ upper limit of normal (ULN) ( ⁇ 2 ⁇ ULN if liver metastasis); serum transaminase ALT and/or AST ⁇ 3 ⁇ ULN ( ⁇ 5 ⁇ ULN if liver metastasis);
  • Renal function test serum creatinine (Cr) ⁇ 1.5 ⁇ ULN; urine routine test indicates urine protein ⁇ ++, which requires confirmation that the 24-hour urine protein amount is ⁇ 1.0 g;
  • LVEF left ventricular ejection fraction
  • Coagulation function test APTT ⁇ 1.5 ⁇ ULN, and INR or PT ⁇ 1.5 ⁇ ULN.
  • 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;
  • 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;
  • hepatitis B HBsAg positive and HBV DNA ⁇ 500 IU/ml
  • hepatitis C hepatitis C antibody positive and HCV RNA higher than the detection limit of the analytical method
  • the researcher determines that the subject has other factors that may affect the study results or cause the study to be terminated midway, 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.
  • factors 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.
  • Tablets oral administration, preset dose group 30mg or 90mg or 180mg or 360mg or 540mg or 720mg, one treatment cycle every 28 days. Continuous administration until disease progression or unacceptable toxicity occurs. Oral administration within 30 minutes after meals every morning, once a day, continuous medication. If PK intensive blood sampling is performed on the same day, water is prohibited for 1 hour before and after medication, and food is prohibited for 4 hours.
  • DAI Drug interaction assessment phase: Tablets, oral administration, once a day, within 30 minutes after meals in the morning, continuous medication. 100 ⁇ g of midazolam was given once within 30 minutes after meals in the morning on Day -1 and Day 15. Midazolam and the test drug were taken at the same time on Day 15 ( ⁇ 2 minutes).
  • the absorption degree after meal is higher, AUC is 2.54 times higher, Cmax is 3.06 times higher, and the peak time is delayed. After 3 hours (about 6h).
  • DLT dose-limiting toxicity
  • TEAEs 9 subjects (34.6%) experienced TEAEs, of which at least 2 subjects experienced anemia, hypercholesterolemia, increased serum creatinine, and rash (two cases each). Three subjects (11.5%) experienced grade 3 TEAEs, including decreased lymphocyte count, increased blood pressure, decreased neutrophil count, and decreased white blood cell count, each occurring in one subject.

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Abstract

治疗前列腺癌的方法。具体而言，一种式I所示的化合物或其可药用盐在用于制备治疗转移性去势抵抗性前列腺癌的药物中的用途。

Description

治疗前列腺癌的方法 技术领域
本申请涉及医药领域，包含一种式I所示的化合物或其可药用盐在制备治疗前列腺癌药物中的用途。
背景技术
雄激素受体(Androgen Receptor，AR)是一种配体依赖性的反式转录调节蛋白，属于核受体超家族成员，主要存在于细胞核内。未与配体结合的AR与热休克蛋白(Heat Shock Protein，HSP)结合；而AR与配体结合后，发生构象变化，与HSP解离，与DNA亲和力增高(AR的活化)。活化的AR以二聚体形式与细胞核中特定的DNA序列—雄激素反应原件(Androgen Response Element，ARE)结合，并与其它转录因子相互作用，从而调节相关基因的表达，产生生物效应。研究表明，AR信号通路的异常与前列腺癌、良性前列腺增生、肯尼迪病(Kennedy’s Disease)、男性不育、雄激素不敏感征以及男性乳癌等疾病的发生、发展有密切的关系。
前列腺癌是最为常见的恶性肿瘤之一。据统计2018年全球有近130万新发病例和35.9万死亡病例，占男性恶性肿瘤发病率的13.5％，高居第二位；占男性恶性肿瘤死亡率的6.7％，高居第五位。目前，前列腺癌的发病率呈逐年上升趋势，是男性癌症患者死亡的重要原因之一。多个AR拮抗剂已经被批准上市(如第一代AR抑制剂比卡鲁胺，第二代AR抑制剂恩扎卢胺、瑞维鲁胺等)，成功应用于激素敏感性和去势抵抗性前列腺癌治疗，已经成为前列腺癌的主要治疗手段。尽管新型AR靶向药物的发展和应用显著改善了前列腺癌患者的预后，特别是使mCRPC患者在化疗外有了其它治疗选择，但患者仍然会出现对新型AR靶向药物的耐药。
发明内容
本公开提供一种式I所示的化合物或其可药用盐用于治疗转移性去势抵抗性前列腺癌，
在某些实施方案中，本公开提供一种治疗转移性去势抵抗性前列腺癌的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐。
在某些实施方案中，本公开提供一种治疗转移性去势抵抗性前列腺癌的方法，包括在餐后给予患者治疗有效量的式I所示的化合物或其可药用盐。
本公开还提供一种治疗治疗转移性去势抵抗性前列腺癌的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的CYP3A4酶底物。
在某些实施方案中，本公开所述的一种治疗治疗转移性去势抵抗性前列腺癌的方法，包括给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的CYP3A4酶底物，不需要调整式I所示化合物或其可药用盐的给药剂量。
在某些实施方案中，本公开所述的CYP3A4酶底物为咪达唑仑。
在某些实施方案中，本公开所述的转移性去势抵抗性前列腺癌为经药物去势、或手术去势的转移性去势抵抗性前列腺癌。
在某些实施方案中，本公开所述的转移性去势抵抗性前列腺癌选自经持续的黄体生成素释放激素类似物(LHRHA)治疗(药物去势)、或既往接受过双侧睾丸切除术(手术去势)、或未接受双侧睾丸切除术的后维持有效的LHRHA治疗的转移性去势抵抗性前列腺癌。
在某些实施方案中，本公开所述的患有转移性去势抵抗性前列腺癌的患者睾酮处于去势水平(≦50ng/dL或1.73nmol/L)。
在某些实施方案中，本公开所述的转移性去势抵抗性前列腺癌为既往至少一种新型内分泌药物治疗失败的转移性去势抵抗性前列腺癌。
在某些实施方案中，本公开所述的转移性去势抵抗性前列腺癌为既往至少一种内分泌药物治疗失败的转移性去势抵抗性前列腺癌。
在某些实施方案中，本公开所述的新型内分泌药物选自如阿比特龙、恩扎卢胺、阿帕他胺、瑞维鲁胺、达罗他胺。
在某些实施方案中，本公开所述的内分泌药物选自如阿比特龙、恩扎卢胺、阿帕他胺、瑞维鲁胺、达罗他胺。
本公开所述的治疗失败是指治疗过程中发生疾病进展。
在某些实施方案中，本公开所述的转移性去势抵抗性前列腺癌为既往使用过至少一种化疗药物并在化疗过程中或化疗结束后6个月内进展，或不适合、不耐受化疗药物的转移性去势抵抗性前列腺癌。
在某些实施方案中，本公开所述的化疗药物选自紫杉醇类化疗药物，优选所述紫杉醇类化疗药物选自多西他赛。
本公开所述的疾病进展定义为受试者在接受去势治疗的同时，发生了下列3项中的1项或1项以上：
①PSA进展，包括HSPC治疗阶段进展为CRPC(定义为去势水平下，PSA值＞1ng/mL，间隔至少1周，连续2次PSA水平较基础值升高＞50％)，和CRPC治疗阶段出现的PSA进展(依据PCWG3标准)；氟他胺或比卡鲁胺治疗的患者，停药(分别≧4周和≧6周)后的PSA也必须进展；
②RECIST 1.1中定义的疾病进展；
③PCWG3标准定义的骨骼疾病进展，即在骨扫描发现有≧2个以上新发病灶。
在某些实施方案中，本公开所述的式I所示化合物或其可药用盐的给药剂量为10mg-1000mg，优选给药剂量为20mg-500mg，更优选给药剂量为20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、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。
在某些实施方案中，本公开所述的式I所示化合物或其可药用盐的给药剂量为30mg或90mg或180mg或360mg或540mg或720mg。
在某些实施方案中，本公开所述的式I所示化合物或其可药用盐的给药剂量选自10mg-300mg；优选10mg-200mg；更优选为10mg-100mg；更优选为10mg-50mg
在某些实施方案中，本公开所述的式I所示化合物或其可药用盐的单位剂量为10mg-300mg；优选10mg-200mg；更优选为10mg-100mg；更优选为10mg-50mg。
在某些实施方案中，本公开所述的式I所示化合物或其可药用盐的单位剂量为10mg-1000mg，优选单位剂量为20mg-500mg，优选单位剂量为15mg、30mg、60mg或90mg或180mg或360mg或540mg或720mg。
在某些实施方案中，本公开所述的给药剂量或单位剂量以式I化合物的重量计。
在某些实施方案中，本公开所述的式I所示化合物或其可药用盐的的给药频次选自每日三次、每日两次、每日一次、每两日一次、每三日一次、每四日一次、每五日一次、每周一次。
在某些实施方案中，本公开所述的式I所示化合物或其可药用盐的施用对象为人。
在某些实施方案中，本公开所述的式I所示化合物或其可药用盐以药物组合物的形式给药，所述药物组合物包含式I所示化合物或其可药用盐以及一种或多种药用载体、赋形剂、稀释剂。
本公开中所述的“给予患者治疗有效量的式I所示的化合物或其可药用盐和治疗有效量的CYP3A4酶底物，”是指在一定时间期限内给予式I或其可药用盐和至少一种CYP3A4酶底物，所述的时间期限可以是一个给药周期内，可选72小时以内、36小时以内、48小时以内、24小时以内、20小时以内、18小时以内、16小时以内、12小时以内、10小时以内、8小时以内、6小时以内、4小时以内、2小时以内、1小时以内、0.5小时以内或一并服用。优选24小时以内、20小时以内、18小时以内、16小时以内、12小时以内、10小时以内、8小时以内、6小时以内、4小时以内、2小时以内、1小时以内、0.5小时以内或一并服用。
具体实施方式
实施例1式I所示化合物在晚期转移性去势抵抗性前列腺癌受试者中的安全性、耐受性、药代动力学及疗效的I期临床研究
1、研究药物
试验药1：式I所示化合物，15mg/片、60mg/片，参照WO2023093845A制备获得，由江苏恒瑞医药股份有限公司生产并提供。
试验药2：咪达唑仑注射液，1ml：5mg，江苏恩华药业股份有限公司
2、研究目的
主要研究目的：
评价式I所示化合物在晚期转移性去势抵抗性前列腺癌(mCRPC)受试者中的安全性和耐受性。
次要研究目的：
评价式I所示化合物及其主要代谢产物在晚期mCRPC受试者中的药代动力学(PK)特征；
评价式I所示化合物多次给药后对CYP3A4酶底物咪达唑仑的药代动力学的影响；
评价式I所示化合物在晚期mCRPC受试者中的初步疗效。
3、研究终点
主要研究终点
·剂量限制毒性(DLT)发生率
·MTD(如能达到)和RP2D；
次要研究终点
·不良事件(AE)及严重不良事件(SAE)的发生率、严重程度(依据CTCAEv5.0进行评级)以及与研究药物的相关性，还包括生命体征、心电图和实验室检查异常；
·单次/多次给药后式I所示化合物的PK参数，包括但不限于：
单次给药参数：血药峰浓度(Cmax)、达峰时间(Tmax)、从0时至最后一个可测浓度时间点t药时曲线下面积(AUC0-t)、从0时至无穷大时间药时曲线下面积(AUC0-inf)(如适用)、半衰期(t1/2)(如适用)、表观分布容积(Vz/F)(如适用)、表观清除率(CL/F)(如适用)；
多次给药参数：稳态峰浓度(Cmax，ss)、达峰时间(Tmax，ss)、稳态谷浓度(Cmin，ss)、稳态血药浓度－时间曲线下面积(AUCss)、药物蓄积比(Rac)。
·咪达唑仑的药代动力学(PK)：患者在多次口服式I化合物前(D-1)后(D15)服用微剂量咪达唑仑后咪达唑仑的药代动力学参数，包括：Tmax、Cmax、AUC0-t、AUC0-∞、t1/2、CL/F、Vz/F。
·疗效终点：客观缓解率(ORR)、疾病控制率(DCR)、缓解持续时间(DoR)、影像学无进展生存期(rPFS)、12周末PSA应答率、整个研究治疗期间PSA较基线降低≧50％以及≧30％的受试者比例、至PSA进展时间、总生存期(OS)；
4、入组标准
受试者必须满足以下所有入选标准才可进入本研究：
1)自愿参加本项临床研究，理解研究程序且能够书面签署知情同意书；
2)年龄18-80岁(含18和80岁)，男性；
3)东部肿瘤协作组(ECOG)体力状况评分为0 -1分；
4)预计生存时间≥12周；
5)组织学或细胞学检查证实的前列腺腺癌，且未诊断为神经内分泌癌或小细 胞癌；
6)持续的黄体生成素释放激素类似物(LHRHA)治疗(药物去势)或既往接受过双侧睾丸切除术(手术去势)；未接受双侧睾丸切除术的受试者必须计划在整个研究期间维持有效的LHRHA治疗；
7)筛选时睾酮处于去势水平(≦50ng/dL或1.73nmol/L)；
8)既往至少一种新型内分泌药物(如阿比特龙、恩扎卢胺)治疗失败(指治疗过程中发生疾病进展；疾病进展定义同入组标准第10条)；
9)既往使用过至少一种紫杉醇类化疗药物(如多西他赛)并在化疗过程中或化疗结束后6个月内进展(疾病进展定义同入组标准第10条)，或不适合、不耐受化疗药物的患者；
10)疾病进展定义为受试者在接受去势治疗的同时，发生了下列3项中的1项或1项以上：①PSA进展，包括HSPC治疗阶段进展为CRPC(定义为去势水平下，PSA值＞1ng/mL，间隔至少1周，连续2次PSA水平较基础值升高＞50％)，和CRPC治疗阶段出现的PSA进展(依据PCWG3标准)；氟他胺或比卡鲁胺治疗的患者，停药(分别≧4周和≧6周)后的PSA也必须进展；②RECIST 1.1中定义的疾病进展；③PCWG3标准定义的骨骼疾病进展，即在骨扫描发现有≧2个以上新发病灶；
11)经CT/MRI或放射性骨扫描(99mTc)影像学检查证实具有转移性病灶；
12)筛选期需提供足够的血液样本用于基因突变检测；建议同时提供肿瘤组织样本(存档或新鲜活检样本均可；优先新鲜样本或1年内的存档样本)
13)按下述实验室检查定义，有充足的器官功能水平，定义如下：
·血常规检查(首次给药前14天内未输血及血制品，未使用G-CSF或其他造血刺激因子纠正)：中性粒细胞绝对计数(ANC)≥1.5×109/L；血小板计数(PLT)≥100×109/L；血红蛋白(Hb)≥90g/L；
·肝功能检查：总胆红素(TBIL)≤1.5×正常值上限(ULN)(如肝转移则≤2×ULN)；血清转氨酶ALT和/或AST≤3×ULN(如肝转移则≤5×ULN)；
·肾功能检查：血肌酐(Cr)≤1.5×ULN；尿常规提示尿蛋白≥++需证实24小时尿蛋白量≤1.0g；
·心电图检查：Fridericia公式校正QT间期(QTcF)正常(男性≤470ms)；
·心脏彩超检查：左室射血分数(LVEF)≥50％；
·凝血功能检查：APTT≤1.5×ULN，同时INR或PT≤1.5×ULN。
14)伴侣为育龄妇女的男性受试者，需同意从签署知情同意书开始直到试验药物末次给药后3个月内，须避免捐献精子，且采用相应的避孕措施进行避孕。
4、排除标准
受试者若符合下列标准中的任意一条，将不能进入本研究：
1)既往接受过任何AR降解剂的治疗；
2)计划本研究期间接受其他任何抗肿瘤治疗；
3)开始研究治疗前接受化疗、靶向治疗、免疫治疗、减毒活性疫苗接种、放疗或手术治疗等不足4周(若是小分子靶向药物，为首次研究用药前7天或5倍药物半衰期，以较长者为准；比卡鲁胺洗脱期为6周)；开始研究治疗前4周(以末次使用试验性药物或器械时间计算)正在参加其他临床研究；
4)既往任何抗肿瘤治疗造成的损害尚未恢复至≤1级或本研究规定的标准(根据NCI-CTCAE 5.0分级；除外脱发与其他经研究者判断可耐受的不良事件)；
5)既往使用过影响代谢酶CYP3A活性的药物，且结束时间至本研究首次给药的洗脱期短于该药物的5个半衰期；
6)参加QT/QTc研究的患者首次用药前4周内使用过任何具有延长QT/QTc间期或引起尖端扭转性室性心动过速(TdP)风险的药物、既往患有先天性QT间期延长综合症或有QT间期延长家族史、带有植入型起搏器或自动的植入型心律转复除颤器、无法纠正的电解质紊乱等影响QT/QTc研究的因素；
7)控制不良的高血压(在规律抗高血压治疗的情况下，收缩压>150mmHg和/或舒张压>100mmHg)，以及既往具有高血压危象或高血压脑病史的受试者；
8)已知存在肿瘤中枢神经系统转移或脑膜转移或受试者有中枢神经系统原发肿瘤病史；
9)研究者判断的肿瘤骨转移所导致的严重骨损伤，包括控制不佳的严重骨疼痛，最近6个月内发生的或预计近期很可能发生的重要部位病理性骨折和脊髓压迫等；
10)具有影响口服药物的多种因素之一(比如无法吞咽、慢性腹泻和肠梗阻等)或具有活动性胃肠道疾病或其他疾病可能导致明显影响药物吸收分布，代谢或排泄的因素；
11)已知对式I所示化合物或其辅料过敏或不耐受；
12)研究首次给药前6个月内存在活动性的心脏疾病，包括：重度/不稳定性心绞痛、心肌梗死、有症状的充血性心力衰竭和需药物治疗的室性心律失常；
13)研究首次给药前5年内曾患其他恶性肿瘤(已完全缓解的原位癌及研究者判定进展缓慢的恶性肿瘤除外)；
14)存在活动性乙型肝炎(HBsAg阳性且HBV DNA≥500IU/ml)、丙型肝炎(丙肝抗体阳性且HCV RNA高于分析方法检测下限)；或需要抗生素、抗病毒药或抗真菌药控制的严重感染者；
15)有免疫缺陷病史(包括HIV检测阳性，其他获得性、先天性免疫缺陷疾病)或器官移植史；
16)经研究者判断，受试者有其他可能影响研究结果或导致本研究被迫中途终止的因素，如酗酒、药物滥用、患有其他严重疾病(含精神疾病)需要合并治疗、实验室检查值严重异常、家庭或社会因素及其他可能影响到受试者安全或试验资料收集的情况等。
5、给药方式
片剂，口服给药，预设剂量组30mg或90mg或180mg或360mg或540mg或720mg，每28天一个治疗周期。连续给药直至疾病进展或发生不可接受的毒性。每天早上餐后30min内口服，每日1次，连续服药。如当天有PK密集采血，服药前后1h禁水，4h禁食。
药物相互作用(DDI)评估阶段：片剂，口服给药，每天早上餐后30min内口服，每日1次，连续服药。第-1天和第15天早上餐后30min内分别给100μg咪达唑仑各一次。在第15天咪达唑仑和试验药物同时服用(±2min)。
6、初步结果
6.1临床药理
食物影响研究共9例患者，空腹给药180mg的半衰期均值(±标准差)40.8±4.37h，表观分布容积的几何均值(几何变异系数％)为1260(90.7)L，清除率几何均值(几何变异系数％)为21.5(83.4)L/h，达峰时间中位数3h。
餐后相较于空腹的吸收程度更高，AUC高2.54倍，Cmax高3.06倍，达峰时间延 后3小时(约6h)。
6.2临床安全性
本次研究共入组了26例肿瘤受试者，剂量递增阶段13例，其中30mg、90mg、180mg、360mg、540mg分别有1例、4例、4例、3例和1例，均已完成DLT观察，未观察到剂量限制性毒性(DLT)；540mg剂量组入组1例受试者，尚未结束DLT观察，未观察到剂量限制性毒性(DLT)。剂量扩展阶段13例受试者，均为180mg剂量组。
研究期间共9例(34.6％)受试者发生了TEAE，其中至少有2例受试者发生的有：贫血、高胆固醇血症、血肌酐升高、皮疹(各两例)。3例(11.5％)受试者发生了3级的TEAE，包括淋巴细胞计数降低、血压升高，中性粒细胞计数降低、白细胞计数降低，各1例受试者发生。
研究期间共8例(30.8％)受试者发生了与式I相关的AE，其中至少有2例受试者发生的有：贫血、高胆固醇血症、血肌酐升高(各两例)。1例(3.8％)受试者发生了3级的TRAE，为中性粒细胞计数降低、白细胞计数降低。
研究期间未发生4/5级AE。
6.3临床有效性
研究中接受过至少1次基线后PSA检查的受试者共17例，其中30mg、90mg、180mg、360mg分别有1例、4例、9例和3例。17例PSA反应率可评估受试者中，8例受试者出现了PSA下降。特别是180mg剂量组9例受试者中，有6例(66.7％)受试者出现了PSA下降，其中3例受试者达到PSA30(治疗期间血清PSA水平较基线降低≧30％)，包括1例受试者达到PSA90(治疗期间血清PSA水平较基线降低≧90％)。

Claims (8)

  1. 一种式I所示化合物或其可药用盐在制备治疗转移性去势抵抗性前列腺癌的药物中的用途，
  2. 根据权利要求1所述的用途，其中所述的转移性去势抵抗性前列腺癌为经药物去势、或手术去势、或未接受双侧睾丸切除术的后维持有效的LHRHA治疗的转移性去势抵抗性前列腺癌。
  3. 根据权利要求1所述的用途，其中所述的转移性去势抵抗性前列腺癌为既往至少一种内分泌药物治疗失败的转移性去势抵抗性前列腺癌；所述内分泌药物优选为阿比特龙、恩扎卢胺、阿帕他胺、瑞维鲁胺、达罗他胺。
  4. 根据权利要求1所述的用途，其中所述的转移性去势抵抗性前列腺癌为既往使用过至少一种化疗药物并在化疗过程中或化疗结束后6个月内进展，或不适合、不耐受化疗药物的转移性去势抵抗性前列腺癌；所述化疗药物优选为紫杉醇类化疗药物；更优选为多西他赛。
  5. 根据权利要求1所述的用途，其中所述式I所示化合物或其可药用盐施用对象为人。
  6. 根据权利要求1所述的用途，其中所述的式I所示化合物或其可药用盐的给药剂量为10mg-1000mg。
  7. 根据权利要求1所述的用途，其中所述的式I所示化合物或其可药用盐的给药剂量为30mg或90mg或180mg或360mg或540mg或720mg。
  8. 根据权利要求1所述的用途，其中所述的式I所示化合物或其可药用盐的单位剂量为10mg-300mg。
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