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1B-13-11-A Phase III, Randomized, Open Label, Multicenter, Controlled Trial of Niraparib versus Physicians Choice In Previously-Treated, HER2 Negative, Germline BRCA Mutation-Positive Breast Cancer Patients

Description

This study is for individuals that have breast cancer that has progressed under the current best standard treatment and because you were also found to be a carrier of an inherited BRCA1 or BRCA2 gene mutation (change).Niraparib is a PARP inhibitor. These drugs selectively kill cancer cells by affecting the DNA repair mechanism (DNA contains our unique hereditary information, the genetic code). A harmful mutation in a BRCA gene is a defect in the DNA repair mechanism. Individuals carrying such mutation are more prone to respond to the experimental drug niraparib. Niraparib has been developed to address DNA repair defects, and has been shown to be effective in previous tests.The purpose of this study is to compare the effects, both good and/or bad, of treating subjects with either niraparib or with the standard chemotherapy for this type of breast cancer to find out which is better.The endpoints for this study are: progression free survival (PFS) assessed by blinded, review between participants randomized to the study drug versus the physician's choice.; overall survival between participants randomized to the study drug versus physician's choice; safety and tolerability, described using frequency of AEs and AEs of more that grade 3. Safety analysis will include all participants who have received at least one dose of study drug and will be evaluated descriptively.The primary analysis of PFS and OS will be analyzed using a non-stratified log- rank. Futility analyses are planned after 35 and 96 PFS events. If the results cross the pre-specified futility boundary, the IDMC may recommend stopping the study.This is a phase 3 superiority trial study. No crossover to the study drug is permitted following discontinuation from physician's choice treatment.Randomization will be 2:1 (treatment control). At least 306 participants will participate in this study. Approximately 204 of them will receive treatment with niraparib and the rest, approximately 102 will be allocated to receive a standard chemotherapy drug which is already approved for breast cancer that has progressed. The intent-to-treat population, defined as all randomized participants, is the primary analysis population for the efficacy analysis.The study drug, niraparib, 300 mg (3x100 mg niraparib capsules) will be administered orally QD continuously in an open- label fashion. Patients will be required to fast for at least 2 hours before each daily dose and for 2 hours after each daily dose.The Physician's choice (eribulin, vinorelbine, gemcitabine or capecitabine) chemotherapy will be administered in 3 week cycles. The physicians choice chemotherapy must be designated prior to randomization of each participant. 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.

Phase

Phase 3 - a treatment has shown activity against a particular disease, where it is either added to existing treatment or compared to the standard treatment.

Inclusion and Exclusion Criteria

  • Germline BRCA1 or BRCA2 mutation; patients with unknown BRCA status who meet NCCN BRCA screening criteria will be screened for BRCA mutation.
  • Metastatic or locally advanced disease that is not amenable to resection or radiation with curative intent.
  • Up to 2 prior cytotoxic regimens for advanced or metastatic breast cancer 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.
  • 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.
  • ECOG performance status 0-2
  • Adequate bone marrow, kidney and liver function

  • Patients with platinum resistant cancer
  • Symptomatic uncontrolled brain metastases
  • Prior diagnosis of Stage IV ovarian cancer; Stage III ovarian cancer must have a 5-year disease-free interval; Stage II ovarian cancer must have a 2-year disease-free interval
  • Known hypersensitivity to the components of niraparib
  • Invasive cancer other than ovarian cancer within 2 years (except basal or squamous cell carcinoma of the skin that has been definitely treated)
  • Pregnant or breast feeding patients
  • Immunocompromised patients
  • Known active Hepatitis B or C
  • Prior treatment with a PARP inhibitor
  • Known history of myelodysplastic syndrome (MDS).
  • known and persistent (>4 weeks) >/= grade 3 toxicity or fatigue from prior cancer treatment.

Sites

  • California

    • Unknown facility, San Jose, California, 95124
  • South Dakota

    • Unknown facility, Sioux Falls, South Dakota, 57105
  • Israel

    • Unknown facility, Tel Hashomer, 52621
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