A Phase III Trial of Niraparib Versus Physician's Choice in HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients

Ovarian Neoplasms Clinical Trial

— BRAVO  

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 Details — Status: Terminated

Administrative data

• NCT number: NCT01905592
• Other study ID #: 213551
• Secondary ID: 1307-BCG, BIG5-1
• Status: Terminated
• Phase: Phase 3
• Start date: February 25, 2014
• Est. completion date: October 26, 2021

Study information

• Verified date: October 2022
• Source: Tesaro, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 216
• Est. completion date: October 26, 2021
• Est. primary completion date: May 23, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• BRCA1 Gene Mutation
• BRCA2 Gene Mutation
• Breast Neoplasms
• Carcinoma
• Carcinoma of Breast
• Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• Neoplasms
• Neoplasms, Breast
• Ovarian Neoplasms

Intervention

Drug:
• niraparib
300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops
• Physician's choice
Choice of 4 standard of care metastatic breast cancer chemotherapies, until progression or unacceptable toxicity develops

Locations

Country	Name	City	State
Belgium	GSK Investigational Site	Aalst
Belgium	GSK Investigational Site	Brussels
Belgium	GSK Investigational Site	Bruxelles
Belgium	GSK Investigational Site	Edegem
Belgium	GSK Investigational Site	Liège
Belgium	GSK Investigational Site	Namur
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Kelowna	British Columbia
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
France	GSK Investigational Site	Bordeaux
France	GSK Investigational Site	Dijon Cedex
France	GSK Investigational Site	Lille Cedex
France	GSK Investigational Site	Lyon Cedex 08
France	GSK Investigational Site	Montpellier
France	GSK Investigational Site	Nantes cedex
France	GSK Investigational Site	Paris Cedex 5
France	GSK Investigational Site	Saint-Cloud
Greece	GSK Investigational Site	Heraklion,Crete
Greece	GSK Investigational Site	Maroussi
Greece	GSK Investigational Site	Nea Kifissia
Greece	GSK Investigational Site	Neo Faliro
Greece	GSK Investigational Site	Thessaloniki
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Debrecen
Hungary	GSK Investigational Site	Miskolc
Hungary	GSK Investigational Site	Nyiregyhaza
Hungary	GSK Investigational Site	Pécs
Hungary	GSK Investigational Site	Szeged
Iceland	GSK Investigational Site	Reykjavik
Israel	GSK Investigational Site	Haifa
Israel	GSK Investigational Site	Holon
Israel	GSK Investigational Site	Kfar-Saba
Israel	GSK Investigational Site	Rehovot
Israel	GSK Investigational Site	Tel Aviv
Israel	GSK Investigational Site	Tel Hashomer
Italy	GSK Investigational Site	Ancona	Marche
Italy	GSK Investigational Site	Cremona	Lombardia
Italy	GSK Investigational Site	Genova	Liguria
Italy	GSK Investigational Site	Lecce	Puglia
Italy	GSK Investigational Site	Legnago (VR)	Veneto
Italy	GSK Investigational Site	Meldola (FC)	Emilia-Romagna
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Parma	Emilia-Romagna
Italy	GSK Investigational Site	Prato	Toscana
Italy	GSK Investigational Site	Rimini	Emilia-Romagna
Italy	GSK Investigational Site	Viterbo	Lazio
Netherlands	GSK Investigational Site	Leiden, RC
Netherlands	GSK Investigational Site	Limburg
Netherlands	GSK Investigational Site	Zwolle
Poland	GSK Investigational Site	Lodz
Poland	GSK Investigational Site	Raciborz
Portugal	GSK Investigational Site	Coimbra
Portugal	GSK Investigational Site	Lisbon
Portugal	GSK Investigational Site	Porto
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Burgos
Spain	GSK Investigational Site	Cáceres
Spain	GSK Investigational Site	L'Hospitalet de Llobregat
Spain	GSK Investigational Site	Lerida
Spain	GSK Investigational Site	Lugo
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Pamplona
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Valencia
Spain	GSK Investigational Site	Vigo
United Kingdom	GSK Investigational Site	Bebington, Wirral
United Kingdom	GSK Investigational Site	Belfast
United Kingdom	GSK Investigational Site	Edinburgh
United Kingdom	GSK Investigational Site	Glasgow
United Kingdom	GSK Investigational Site	Headington, Oxford	Oxfordshire
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Northwood	Middlesex
United Kingdom	GSK Investigational Site	Nottingham
United Kingdom	GSK Investigational Site	Southampton	Hampshire
United Kingdom	GSK Investigational Site	Sutton	Surrey
United Kingdom	GSK Investigational Site	Whitchurch, Cardiff
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Clifton Park	New York
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Eugene	Oregon
United States	GSK Investigational Site	Everett	Washington
United States	GSK Investigational Site	Fort Myers	Florida
United States	GSK Investigational Site	Fort Worth	Texas
United States	GSK Investigational Site	Green Bay	Wisconsin
United States	GSK Investigational Site	Henderson	Nevada
United States	GSK Investigational Site	Lake Success	New York
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Low Moor	Virginia
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Tucson	Arizona
United States	GSK Investigational Site	Webster	Texas
United States	GSK Investigational Site	Weslaco	Texas

Sponsors (7)

Lead Sponsor	Collaborator
Tesaro, Inc.	Breast International Group, European Organisation for Research and Treatment of Cancer - EORTC, Facing Our Risk of Cancer Empowered, Myriad Genetic Laboratories, Inc., Sarah Cannon, US Oncology Research

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Greece,  Hungary,  Iceland,  Israel,  Italy,  Netherlands,  Poland,  Portugal,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Minimally Clinically Important Difference (MCID) Status in European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-C30 (EORTC-QLQ-C30)	The number of participants with MCID status in EORTC-QLQ-C30 was planned to be evaluated.The EORTC- QLQ-C30 includes 30-items with single and multi-item scales. These include five functional scales (physical functioning, role functioning cognitive functioning, emotional functioning and social functioning), three symptom scales (fatigue, pain and nausea/vomiting), a global health status (GHS)/ Quality-of-Life (QoL) scale, and six single items (constipation, diarrhea, insomnia, dyspnea, appetite loss and financial difficulties). Response options are 1 to 4. The average score can be transformed to 0 to 100, a high score for functional scales/ GHS/QoL represents better functioning ability or health-related quality-of-life (HRQoL), whereas a high score for symptom scales/ single items represents significant symptomatology.	Up to 7 years
Other	Number of Participants With Euroqol 5 Dimension 5 Level (EQ-5D-5L) Dimension Scores by Visit	The number of participants with EQ-5D-5L scores by visit were planned to be evaluated. EQ-5D-5L is self-assessment questionnaire, consisting of 5 items covering 5 dimensions (mobility,self care, usual activities, pain/discomfort and anxiety/depression). Each dimension is measured by 5-point Likert scale(no problems, slight problems, moderate problems, severe problems and extreme problems). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Each of these 5 figure health states were to be converted to a single index score. Range for EQ-5D-5L index score is 0 (worst health) to 100 (best health), higher the score better the health status.	Up to 7 years
Other	Number of Participants With Any Subsequent Therapies Post Discontinuation of Study Treatment and Association With Potential Survival Related Outcomes	The number of participants with any subsequent therapies post-discontinuation of study treatment and association with potential survival related outcomes were planned to be evaluated.	Up to 7 years
Other	Number of Participants With Presence of Genetic and Non-genetic Biomarkers	Biomarkers include germline and tumor mutations 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 were planned to be evaluated.	Up to 7 years
Other	Number of Participants With Germline BRCA1 and BRCA2 Mutation Status in Association With Survival Related Outcomes	Participants with germline BRCA1 and BRCA2 mutation status in association with survival related outcomes were planned to be evaluated.	Up to 7 years
Primary	Progression Free Survival (PFS) - Central Review Assessment	The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded central review, of participants with advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gBRCA mutation 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 (v)1.1 as determined by central review assessment. Progressive Disease is defined as at least a 20 percent (%) increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including Baseline) and an absolute increase of >= 5 millimeter (mm).	From the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier, up to 4 years
Secondary	Overall Survival	Overall Survival (OS) was defined as the time from randomization to the date of death of any causes.	From treatment randomization to date of death of any cause, up to 4 years
Secondary	Number of Participants With Central BRCA Mutation Status	Blood samples were collected to evaluate central BRCA mutation status of participants. Baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug. Number of participants with central BRCA mutation status as BRCA1 positive only, BRCA2 positive only, Rearrangement only, BRCA1 and BRCA2 positive, BRCA1 positive and rearrangement, and BRCA2 positive and rearrangement were reported.	At Baseline (Cycle 1 Day1) (Cycle duration was 21 days)
Secondary	Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events (Non-SAE)	An adverse event (AE) is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. An SAE is defined as any untoward medical occurrence or effect in a participant, whether or not considered related to the protocol treatment, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing participant hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an medically important event or reaction as per medical and scientific judgment. Adverse events which were not serious adverse events were considered as non serious adverse events.	Up to 7 years
Secondary	Progression Free Survival (PFS) - Investigator Assessment	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. Progressive Disease is defined as at least a 20 % increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including Baseline) and an absolute increase of >= 5 mm.	Assessed up to 4 years
Secondary	Time to Treatment Failure	Time to treatment failure was 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.	Date of randomization to discontinuation of treatment for any reason, up to 4 years
Secondary	Overall Response Rate (ORR)	ORR was defined as the percentage of the participants who achieved a complete response (CR) or partial response (PR) to treatment evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR)=disappearance of all target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures <10 mm. Partial Response (PR)= at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the Baseline sum of diameters. Percentage values are rounded off up to 1 decimal.	Up to 4 years
Secondary	Duration of Response (DOR)	Duration of response was defined as the time from first documentation of response (confirmed CR or PR) until the time of first documentation of disease progression by RECIST v1.1 or death by any cause.	Up to 4 years
Secondary	Number of Participants With Serious Adverse Events Related to New Malignancy	The number of participants with serious adverse events related to new malignancy were reported.	Up to 7 years
Secondary	Number of Participants With Subsequent Anticancer Therapies	The number of participants with subsequent anticancer therapies were evaluated. Data has been reported as per following categories: any new anitumoral therapy, any chemotherapy, any radiotherapy, any surgery, any hormonal therapy, any targeted agents, and any other treatment. Participants may have received more than one subsequent therapies.	Up to 7 years

External Links

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