Studieoverzicht - 2014-02 BRAVO

Niraparib versus single agent chemotherapy (eribulin or vinorelbine or gemcitabine or capecitabine)

Randomization will be 2:1 (treatment: control).

Patients will continue on study
medication until disease progression as long as in the investigator's opinion
they are benefiting from treatment and do not meet any other treatment
discontinuation criteria.

Primary objective: To compare progression-free survival (PFS) as assessed by blinded, central review between patients randomized to niraparib versus physician's choice.

Key secondary objective: To compare overall survival between patients randomized to niraparib versus physician's choice.

Secondary objectives:

1. Establish germline BRCA mutation status of screened patients using a centrally provided, validated test. Additional tests will be performed in order to determine concordance between tests for the purpose of developing a commercial companion diagnostic test.

2. To evaluate safety and tolerability as measured by all AEs

3. To compare PFS using investigator assessment of progression.

4. To evaluate time to treatment failure (discontinuation of treatment for any reason).

5. To compare response rate and duration of response.

6. To compare time to deterioration of health-related quality of life: QLQ-C30 and EQ-5D-5L.

7. To describe subsequent therapies and potential relationships with outcomes.

8. To assess genetic and non-genetic biomarkers relating to treatment efficacy. Germline and tumor mutations may be explored including somatic BRCA1 and 2 mutations, reversion mutations, loss of
heterozygosity as well as genome landscape and transcriptional or functional measures of homologous recombination (HR) deficiency.

9. To assess outcomes by germline mutation BRCA1 vs BRCA2.

The primary objective of this study is to determine the efficacy of niraparib compared to physician's choice
amongst four single agent chemotherapy agents (eribulin, vinorelbine, gemcitabine or capecitabine) in treatment of patients with germline BRCA mutation with advanced/ metastatic HER2 negative breast cancer who have been treated with up to 2 prior lines of chemotherapy for advanced/ metastatic disease. This objective will be assessed by the primary endpoint of PFS as assessed by blinded, central review.

Key secondary endpoint is evaluation of overall survival. 

Safety and tolerability will be described using frequency of AEs and AEs of CTCAE grade ≥3. Safety analyses will include all patients who have received at least one dose of study drug and will be evaluated descriptively.

1. Histologically or cytologically confirmed HER2-negative metastatic or locally advanced breast cancer that is not amenable to resection or radiation with curative intent.

2. Female and male patients age at least 18 years.

3. Germline BRCA1 or BRCA2 mutation that is considered deleterious or suspected deleterious (include those mutations or translocations termed "deleterious" or "suspected deleterious" according to Myriad reporting) by analysis at a reference laboratory (Myriad Genetic Laboratories, Salt Lake City, UT, USA,). Testing under the context of this protocol may be performed at any time prior to randomization. Patients who have a prior BRCA test done by Myriad may enroll into the study based at the result of the prior test as long as it is verified that their prior test is identical to the one used in the study.

4. Measurable disease by RECIST v1.1 or non- measurable disease that is clinically evaluable (except sclerotic-only bone disease; bone-only disease that has a lytic component is allowed); there must evidence of disease progression within 3 months prior to enrollment without change of therapy.

5. Patients must not have symptomatic uncontrolled brain metastases. To be considered controlled, central nervous system (CNS) disease must have undergone treatment (whole brain radiation, radiosurgery or equivalent) at least 1 month previously and the patient has no new or progressive signs or symptoms related to the CNS disease, and are off steroid therapy two weeks. A post- treatment brain CT/MRI obtained at least 7 days off of steroids that shows no evidence of progression is needed.

6. Up to 2 prior cytotoxic regimens for advanced or metastatic breast cancer (not including adjuvant or
neo-adjuvant therapy); patients with no prior cytotoxic regimens for advanced or metastatic disease will only be allowed if they relapsed during or within 12 months of (neo-) adjuvant cytotoxic therapy that included a taxane and/or anthracycline , if not contraindicated.

7. Prior therapy should have included a taxane and/ or anthracycline (unless contraindication to those) in
the neoadjuvant, adjuvant, or advanced/metastatic setting.

a. Hormone receptor positive patients must also have hormone resistant disease (progression during at least one prior hormonal therapy) for which chemotherapy is indicated.

8. Patients must not have received anticancer chemotherapy, radiotherapy, hormonal therapy, biological therapy, or any other investigational therapy within 3 weeks prior to the start of study treatment. Patients with persistent toxicity (except alopecia) > grade 1 from prior cancer therapy will also be excluded. Bisphosphonate and denosumab  is allowed.

9. No prior treatment with a known or putative PARP inhibitor (except iniparib). No other anticancer agent (chemotherapy, hormonal therapy, or other agent) is to be permitted during the course of the study for any patient.

See protocol for more criteria.