A Phase I/II, Open-Label, Dose-Escalation and -Expansion, Safety, Pharmacokinetics and Efficacy Study of SHR3680 in Patients With Metastatic Castration-Resistant Prostate Cancer
试验速览
- 阶段
- 1 期
- 入组人数
- 197
- 试验地点
- 12
- 主要终点
- Radiological progression-free survival
研究概览
简要总结
This study evaluates the tolerability, safety, pharmacokinetics and efficacy of SHR3680 in patients with metastatic castration-resistant prostate cancer (mCPRC). All participants will receive SHR3680.
详细描述
Androgenic signaling plays a pivotal role in the development of prostate cancer. Androgen deprivation therapy is the mainstay treatment for this cancer in the metastatic setting, but the disease eventually develops to castration-resistant prostate cancer (CRPC) mainly due to the overexpression of androgen receptors (AR) and continued AR activation.
SHR3680 is a novel strong AR antagonist. By competitively binding to AR, SHR3680 inhibits androgen-mediated translocation of AR to the nucleus, binding of AR to Deoxyribonucleic acid (DNA), and finally the transcription of AR target genes, thus possibly resulting in a specific and strong anti-tumor effect on prostate cancer. Unlike first-generation AR antagonists (e.g. bicalutamide), which undergoes an antagonist-to-agonist switch to stimulate AR in the setting of AR overexpression in CRPC, SHR3680 is a full antagonist of AR and thus it is supposed to be more effective for the treatment of CRPC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •ECOG performance scale 0 -
- •Life expectancy of more than 6 months.
- •Histologically or cytologic confirmed prostate adenocarcinoma without neuroendocrine differentiation or small cell features
- •Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or orchiectomy
- •Evidence of prostate cancer progression by radiographic or PSA criteria
- •Radiological evidence of distant metastatic lesions
- •Serum testosterone level < 1.7 nmol/L (50 ng/dL) at the screening visit
- •Adequate hepatic, renal, heart, and hematologic functions (platelets > 80 × 10e9/L, neutrophil > 1.5 × 10e9/L, Hb >90 g/L,total bilirubin and creatinine within upper limit of normal(ULN), and serum transaminase≤1.5×the ULN).
- •Signed and dated informed consent.Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedure.
排除标准
- •Treatment with androgen receptor antagonists, 5-alpha reductase inhibitors, estrogens, or chemotherapy within 4 weeks of enrollment or plans to initiate treatment with any of these drugs during the study
- •Prior treatment with enzalutamide, abiraterone, or ketoconazole for prostate cancer
- •History of seizure or any conditions that may predispose to seizure
- •Concurrent or planned treatment with corticosteroids, medications known to have seizure potential, or herbal products known to decrease PSA levels
- •Planned to initiate any other anti-tumor therapies during the study
- •Less than 4 weeks from the last clinical trial
- •Evidence of brain metastasis or primary tumors
- •Clinically significant cardiovascular diseases
- •Abuse of alcohol or drugs
- •Severe concurrent disease, infection, or bone metastasis that, in the judgment of the investigator, would make the patient inappropriate for enrollment
研究组 & 干预措施
SHR3680
Tablet
干预措施: SHR3680 (Drug)
结局指标
主要结局
Radiological progression-free survival
时间窗: 24 months
For Phase 2 portion of study
Maximum tolerated dose (MTD)
时间窗: 12 weeks
For Phase 1 portion of study; maximum-tolerated dose (MTD) will be defined as the maximum dose level at which no more than one out of three subjects experience a dose-limiting toxicity (DLT) within the first 12 weeks of multiple dosing
次要结局
- Objective response rate(24 months)
- Number of participants with treatment-related adverse events(24 months)
- The percentage of patients reaching at least a 50% reduction in prostate specific antigen (PSA) as compared to baseline at 12 weeks(12 weeks)
- Time to prostate specific antigen (PSA) progression(24 months)
- Quality of life(24 months)
- Peak plasma concentration (Cmax)(12 weeks)
- Area under the plasma concentration versus time curve (AUC）(12 weeks)
- T1/2 (Half-life)(12 weeks)