A Safety and Efficacy Study of SHR3680 in Metastatic Castration-Resistant Prostate Cancer Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hormone Refractory Prostate Cancer, Metastatic Prostate Carcinoma

Intervention / Treatment
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* Drug: SHR3680


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECOG performance scale 0 - 1. 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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR3680<br>Tablet | Drug: SHR3680<br>* SHR3680 is administrated orally, qd, 28 days as one cycle. Patients may continue SHR3680 until disease progression or unacceptable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | 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 | 12 weeks | 
| Radiological progression-free survival | For Phase 2 portion of study | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events | Adverse events are assessed by CTCAE v4.0 | 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 | Prostate specific antigen (PSA) progression is defined by the Prostate Cancer Clinical Trials Working Group (PCWG2) criteria. | 24 months | 
| Objective response rate |  | 24 months | 
| Quality of life | Brief Pain Inventory (Short Form), Functional Assessment of Cancer Therapy-Prostate (v4.0) | 24 months | 
| Peak plasma concentration (Cmax) |  | 12 weeks | 
| Area under the plasma concentration versus time curve (AUC） |  | 12 weeks | 
| T1/2 (Half-life) | The time required for the plasma concentration of a drug to be reduced by 50% | 12 weeks |