A Study of Fluzoparib±Apatinib Versus Chemotherapy Treatment of Physician's Choice in HER2-negative Metastatic Breast Cancer Patients With Germline BRCA Mutation

Study Overview
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Brief Summary
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This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate the efficacy and safety of Fluzoparib alone or with Apatinib versus Physicians Choice Chemotherapy, as treatment, in patients with a Germline BRCA Mutation and HER2-negative Metastatic Breast Cancer. The study contains a Safety Lead-in Phase in which the safety and tolerability of Fluzoparib+Apatinib will be assessed prior to the Phase 3 portion of the study.

Official Title
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A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to Assess the Efficacy and Safety of Fluzoparib±Apatinib Versus Physicians Choice Chemotherapy in the Treatment of HER2-negative Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations

Conditions
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Treatment in HER2-negative Metastatic Breast Cancer Patients With Germline BRCA Mutation

Intervention / Treatment
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* Drug: Fluzoparib; Apatinib
* Drug: Fluzoparib
* Drug: Physician's choice chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: （Saftey Lead-in + phase 3）Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious （Saftey Lead-in + phase 3）human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer （Saftey Lead-in + phase 3）had received ≤2 lines of chemotherapy for mBC （Saftey Lead-in + phase 3）Prior therapy with an anthracycline and a taxane in either an adjuvant or metastatic setting. ER/PR breast cancer positive patients must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy. ECOG performance status 0-1. Adequate bone marrow, kidney and liver function. Exclusion Criteria: Prior treatment with a poly (ADP-ribose) polymerase (PARP) inhibitor or Apatinib Prior malignancy unless curatively treated and disease-free for > 5 years prior to study entry. Prior adequately treated non-melanoma skin cancer, in situ cancer of the cervix, DCIS or stage I grade 1 endometrial cancer allowed Radiation or anti-hormonal therapy or other targeted anticancer therapy within 14 days before randomization Known to be human immunodeficiency virus positive Known active hepatitis C virus, or known active hepatitis B virus Untreated and/or uncontrolled brain metastases Pregnant or breast-feeding women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead-in, Doublet Arm<br>Fluzoparib+Apatinib | Drug: Fluzoparib; Apatinib<br>* Fluzoparib Orally twice daily; Apatinib Orally once daily<br>|
| Experimental: Single Arm<br>Fluzoparib | Drug: Fluzoparib<br>* Fluzoparib Orally twice daily<br>|
| Active Comparator: Physician's choice chemotherapy<br>Capecitabine or Vinorelbine | Drug: Physician's choice chemotherapy<br>* Investigators will declare one of the following regimens: Capecitabine Vinorelbine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Safety Lead-in) dose limited toxicity (DLT) | dose limited toxicity (DLT) of Fluzoparib+Apatinib in the first cycle | up to 21 days | 
| (Safety Lead-in) Recommended Phase II Dose (RP2D) | Recommended Phase II Dose (RP2D) of Fluzoparib+Apatinib | up to 21 days | 
| (Phase 3) Progression free survival(PFS) in HER2-negative Metastatic Breast Cancer patients | Defined as progression free survival per RECIST 1.1 criteria according to BIRC criteria | Radiological scans performed at baseline then every  6 weeks up to 30 weeks, then every   9 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AEs+SAEs | Adverse Events and Serious Adverse Events | from the first drug administration to within 30 days for the last treatment dose | 
| PFS by investigator's assessment | Progression-Free-Survival | up to 30 months | 
| OS | OS is the time interval from the start of treatment to death due to any reason or lost of follow-up | up to 30 months | 
| Patient Reported Outcomes (PROs) assessed by EORTC QLQ C30 questionnaire | Comparison of the Quality of Life in study arms assessed by EORTC QLQ C30 questionnaire | up to 30 months | 
| Time to progression on the next anticancer therapy (PFS2) | From date of start of next anticancer therapy to date of first documented progression of date of death from any cause, whichever comes first | up to 30 months | 
| Objective Response Rate (ORR) | Number of responders Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) for target lesions assessed by CT or MRI | up to 30 months | 
| Disease control rate (DCR) | Complete response + Partial response + Stable disease (CR+PR+SD) based on RECIST 1.1 | up to 30 months | 
| Duration of response (DoR) | Time from documentation of tumor response to disease progression assessed among patients who had an objective response | up to 30 months |