Pamiparib in mCRPC With HRD or BRCA1/2 Mutation

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy of a PARP inhibitor, Pamiparib, in metastatic castration-resistant prostate cancer patients with homologous recombination deficiency or BRCA 1 or 2 somatic/germline mutation.

Detailed Description
-----------------
This is a single arm, open-label, single center, phase II trial, assessing the efficacy of a PARP inhibitor, Pamiparib, in 50 progressing metastatic castration-resistant prostate cancer patients with at least one line of androgen deprivation therapy or chemotherapy at the metastatic setting, and homologous recombination deficiency or BRCA 1 or 2 somatic or germline mutation.

Official Title
-----------------
A Single Arm, Open-label, Phase II Study to Assess the Efficacy of Pamiparib in Metastatic Castration-Resistant Prostate Cancer Patients With Homologous Recombination Deficiency (HRD) or BRCA1/2 Mutation

Conditions
-----------------
Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Pamiparib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ≥18 years old, male Have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma without neuroendocrine differentiation of the prostate. Mixed histology is accepted, except for small cell carcinoma. Have a deleterious mutation in BRCA1/2 , or HRD score ≥ 9. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 BPI<4 Metastatic Castration-resistant Prostate Cancer (mCRPC): Presence of measurable target lesion according to RECIST criteria v1.1 Male subject has been surgically or medically sterilized and has serum testosterone level ≤1.73nmol/L. Unsterilized male subject uses an acceptable method of contraception (defined as a barrier method with spermicide) to prevent pregnancy during the duration of the study and for 6 months after the last dose of Pamiparib. Experienced disease progression after having received at least 1 prior next-generation androgen receptor-targeted therapies, for metastatic castration-resistant disease. Capable of swallowing the whole capsule. Subjects must have normal organ and bone marrow function at baseline, as defined below: Hemoglobin ≥ 9.0 g/dL at least 28 days after transfusion . Absolute neutrophil count ≥ 1.5 × 10^9/L. Platelet count ≥ 100 × 10^9/L. Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) specified. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase) ≤ 3 × the specified ULN, unless liver metastases are present, in which case it must be ≤ 5 × ULN. Agree to sign informed consent form Agree not to participate in other interventional trials during this trial. Exclusion Criteria: Subjects should not enter the study if any of the following exclusion criteria are fulfilled: Acute toxicity (CTCAE > grade 2) due to prior cancer therapy. Received chemotherapy, endocrine therapy, biotherapy, radionuclide therapy, immunotherapy, experimental drugs, proprietary anticancer drugs or Chinese herbal medicines within 5 (if known) half-lives or 14 days(if unknown) prior to the first day of taking Pamiparib; For bisphosphonates or approved bone targeting therapy, Pamiparib must be administered at a steady dose for ≥28 days prior to the first day of taking Pamiparib. Received radiation therapy within 21 days. Prior treatment with any PARP inhibitor. Prior chemotherapy with mitoxantrone or platinum-based chemotherapy or cyclophosphamide. Prior treatment with sipuleucel-T or immune check point inhibitors are allowed. Subjects with major surgery within 2 weeks before starting study treatment. Subjects expected to receive major surgery during the trial. Active second malignancy, with the exception of curatively treated non-melanoma skin cancer, carcinoma in situ, or superficial bladder cancer Symptomatic and/or untreated central nervous system metastases Immunocompromised subjects, such as those with positive human immunodeficiency virus (HIV) serology. Subjects with known active hepatitis (e.g. hepatitis B or C). The subject has a serious cardiovascular disease. ( For example, but not limited to: uncontrolled arrhythmia, myocardial infarction) Concomitant use of strong CYP3A inducers or moderate CYP3A inducers . If half-lives is known, a 5 half-lives washout period is required before the start of Pamiparib therapy and a 2-week washout period is required when the half-lives is unknown. History of intolerance to Pamiparib capsule excipients Excluded by investigators

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pamiparib<br>Tablets 20mg per os : 40 mg / bid every day in continuous. Patients will be treated with Pamiparib. Cycles are defined in 28-day periods. Disease response will be assessed every 8 weeks (RECIST 1.1). Safety will be assessed continuously. | Drug: Pamiparib<br>* 40 mg bid per os , 28 day cycle, number of cycles: until progression or unacceptable toxicity develops.<br>* Other names: BGB-290;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiologic Progression-free Survival (rPFS) | Radiologic progression-free survival will be assessed from the time of the first dose to radiologic disease progression or death from any cause, whichever comes first. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Proportion of patients in complete remission (CR) plus partial remission (PR) | From enrollment to primary completion of study (up to approximately 3 years) | 
| Duration of Response (DOR) | Time from the start of the first assessment of the tumor as CR or PR to the first assessment of PD (Progressive Disease) or death from any cause. | From enrollment to primary completion of study (up to approximately 3 years) | 
| Time to Response (TTR) | Time from initiation of treatment to first assessment of tumor as CR or PR. | From enrollment to primary completion of study (up to approximately 3 years) | 
| Clinical Benefit Rate | according to RECIST, is either complete response (CR), partial response (PR) or stable disease (SD) lasting for at least 16 weeks | 3 years | 
| Prostate Specific Antigen (PSA) Response Rate | Proportion of patients with a 50% decrease in PSA from baseline | From enrollment to primary completion of study (up to approximately 3 years) | 
| Time to PSA Progression | Time from initiation of treatment to two consecutive 50% PSA increases from baseline level | From enrollment to primary completion of study (up to approximately 3 years) | 
| Overall Survival (OS) | Time between the start of treatment and death from any cause | From enrollment to primary completion of study (up to approximately 3 years) | 
| Adverse events | Adverse events are graded according to the CTCAE V4.03 | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic Castration-resistant Prostate Cancer, PARP inhibitor, Homologous Recombination Deficiency, BRCA1/2 Mutation