Description:
The purpose of this study is to compare progression-free survival (PFS) in patients with
advanced/metastatic breast cancer who have a BRCA mutation when treated with niraparib as
compared to those treated with physician's choice
Title
- Brief Title: A Phase III Trial of Niraparib Versus Physician's Choice in HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients
- Official Title: A Phase III, Randomized, Open Label, Multicenter, Controlled Trial of Niraparib Versus Physician's Choice in Previously-treated, HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients
Clinical Trial IDs
- ORG STUDY ID:
213551
- SECONDARY ID:
1307-BCG, BIG5-13
- SECONDARY ID:
PR-30-5010-C
- NCT ID:
NCT01905592
Conditions
- Neoplasms, Breast
- Carcinoma of Breast
- Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
- BRCA1 Gene Mutation
- BRCA2 Gene Mutation
- Ovarian Neoplasms
Interventions
| Drug | Synonyms | Arms |
|---|
| niraparib | formerly MK-4827 | niraparib |
| Physician's choice | | Physician's choice |
Purpose
The purpose of this study is to compare progression-free survival (PFS) in patients with
advanced/metastatic breast cancer who have a BRCA mutation when treated with niraparib as
compared to those treated with physician's choice
Detailed Description
This is a phase III, randomized, open label, multicenter, controlled trial of niraparib
versus physician's choice in previously-treated, HER2 negative, germline BRCA
mutation-positive breast cancer patients. Niraparib is an orally active PARP inhibitor.
Niraparib (in a 2:1 ratio) will be administered once daily continuously during a 21-day
cycle. Physician's choice will be administered on a 21-day cycle. Health-related quality of
life will be measured. The safety and tolerability will be assessed by clinical review of
adverse events (AEs), physical examinations, electrocardiograms (ECGs), and safety laboratory
values.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Physician's choice | Active Comparator | Physician may select from 4 active comparators | |
| niraparib | Experimental | Patients will be randomized 2:1 to receive niraparib 300 mg (3x100 mg capsules) once daily for 21 continuous days | |
Eligibility Criteria
Inclusion Criteria:
1. Germline BRCA1 or BRCA2 mutation; patients with unknown BRCA status who meet NCCN BRCA
screening criteria will be screened for BRCA mutation.
2. Histologically or cytologically confirmed HER2-negative metastatic or locally advanced
disease that is not amenable to resection or radiation with curative intent.
3. 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.
4. 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; either
relapsed while on adjuvant endocrine treatment, or within one year of completing
adjuvant endocrine treatment, or progression on at least one line of endocrine
treatment for advanced cancer.
5. ECOG performance status 0-2
6. Adequate bone marrow, kidney and liver function
Exclusion Criteria:
1. Patients with platinum resistant cancer
2. Symptomatic uncontrolled brain metastases
3. 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
4. Known hypersensitivity to the components of niraparib
5. Invasive cancer other than breast cancer within 2 years (except basal or squamous cell
carcinoma of the skin that has been definitely treated)
6. Pregnant or breast feeding patients
7. Immunocompromised patients
8. Known active Hepatitis B or C
9. Prior treatment with a PARP inhibitor
10. Known history of myelodysplastic syndrome (MDS).
11. known and persistent (>4 weeks) >/= grade 3 toxicity or fatigue from prior cancer
treatment.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Progression Free Survival (PFS) - Central Review Assessment |
| Time Frame: | From the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier, up to 4 years |
| Safety Issue: | |
| Description: | The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded central review, of patients with advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gBRCAmut breast cancer when treated with niraparib as compared to those treated with physician's choice single agent chemotherapy standards (eribulin, vinorelbine, gemcitabine or capecitabine). PFS is defined as the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier as per Response evaluation criteria in solid tumors (RECIST) version 1.1 as determined by central review assessment. |
Secondary Outcome Measures
| Measure: | Overall Survival |
| Time Frame: | From treatment randomization to date of death of any cause, up to 4 years |
| Safety Issue: | |
| Description: | To compare overall survival of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer who have a gBRCAmut when treated with niraparib as compared to those treated with physician's choice. Overall Survival (OS) is defined as the time from randomization to the date of death of any causes. |
| Measure: | Determine Concordance Between gBRCAmut Tests for the Purpose of Developing a Commercial Companion Diagnostic Test |
| Time Frame: | End of study |
| Safety Issue: | |
| Description: | To establish germline BRCA (gBRCA) mutation status of screened patients using a centrally provided, validated test as well as future tests, and determine concordance between tests for the purpose of developing a commercial companion diagnostic test. The concordance of the candidate companion diagnostic test with the centralized gBRCA mutation test with respect to identifying gBRCA mutated patients will be evaluated using a separate blood sample. The sensitivity and specificity of the companion diagnostic test to the centralized validated test with respect to gBRCA status will be determined along with the corresponding 95% confidence intervals. |
| Measure: | Safety and Tolerability |
| Time Frame: | End of Study |
| Safety Issue: | |
| Description: | To evaluate safety and tolerability as measured by all adverse events (AEs). Safety and tolerability will be described using frequency of AEs and AEs of Common Terminology Criteria for Adverse Events (CTCAE) grade >=3. Safety analyses will include all patients who have received at least one dose of study drug and will be evaluated descriptively. |
| Measure: | Progression Free Survival (PFS) - Investigator Assessment |
| Time Frame: | Assessed up to 4 years |
| Safety Issue: | |
| Description: | PFS is defined as the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier as per RECIST version 1.1 as determined by Investigator assessment. |
| Measure: | Time to Treatment Failure |
| Time Frame: | Date of randomization to discontinuation of treatment for any reason, up to 4 years |
| Safety Issue: | |
| Description: | To evaluate time to treatment failure (discontinuation of treatment for any reason). Time to treatment failure is defined from the date of randomization to progression or discontinuation of treatment for any reason, including but not restricted to disease progression, treatment toxicity, and death. If progressive disease occurred earlier than treatment discontinuation, the date of progressive disease was considered the date of treatment failure. At the time of analysis, patients who were continuing to receive treatment were censored on the date of last contact. |
| Measure: | Response Rate and Duration of Response |
| Time Frame: | End of Study |
| Safety Issue: | |
| Description: | To compare response rate and duration of response. The best response (complete response [CR], partial response [PR], stable disease [SD] or disease progression [PD]) for each patient will be summarized by treatment arm. The overall response rate (ORR) (ORR = CR+PR) will be summarized by treatment arm along with the corresponding exact 2-sided 95% confidence interval. A chi-square test will be used to compare ORR between the treatment arms. Duration of response will be summarized for the subgroup of patients that obtained objective response (CR or PR) using the Kaplan-Meier method and be displayed graphically where appropriate. The median duration and 2-sided 95% confidence interval for the median will be provided for each treatment arm. |
| Measure: | To Compare Time to Deterioration of Health-related Quality of Life: QLQ-C30 and EQ-5D-5L |
| Time Frame: | 13 months |
| Safety Issue: | |
| Description: | To compare time to deterioration of health-related quality of life (HRQoL): European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EuroQol 5 Dimension 5 Level (EQ-5D-5L). Patient reported outcomes were collected via questionnaires (EORTC QLQ-C30 and EQ-5D-5L). These had to be completed within 4 weeks prior to randomization and subsequent questionnaires were filled in every 2 cycles (ie. 6 weeks) while on-treatment and every 3 months while in follow- up. Collection of HRQoL data was limited to the first 12 months after randomization. The primary HRQoL endpoint considered relevant for this study is time to HRQoL deterioration (TTQ). TTQ is defined as the time from randomization to death, progression or clinical relevant deterioration in pre-specified QLQ-C30 scales. Patients who had not experienced an event at the time of analysis were censored at the time of the last completed HRQoL assessment. |
| Measure: | Subsequent Therapies and Potential Relationships With Outcomes |
| Time Frame: | End of Study |
| Safety Issue: | |
| Description: | To describe subsequent therapies and potential relationships with outcomes |
| Measure: | Assess Genetic and Non-genetic Biomarkers |
| Time Frame: | End of Study |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Assess Outcomes by Germline Mutation BRCA1 vs BRCA2 |
| Time Frame: | End of Study |
| Safety Issue: | |
| Description: | To assess outcomes by germline mutation BRCA1 vs BRCA2 |
| Measure: | Post-treatment Data |
| Time Frame: | End of Study |
| Safety Issue: | |
| Description: | Descriptive summary statistics will be used to summarize post- treatment data (.i.e subsequent anticancer therapies and any new malignancy) |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Tesaro, Inc. |
Trial Keywords
- Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
- BRCA1 Gene Mutation
- BRCA2 Gene Mutation
- PARP Inhibitor
- BRCA
Last Updated
November 16, 2020
