A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)

Study Overview
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Brief Summary
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The purpose of this open-label, 2:1 randomized phase III trial is to compare the safety and efficacy of talazoparib (also known as BMN 673) versus protocol-specific physician's choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations.

Official Title
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A PHASE 3, OPEN-LABEL, RANDOMIZED PARALLEL,2-ARM,MULTI-CENTER STUDY OF TALAZOPARIB(BMN 673) VERSUS PHYSICIAN'S CHOICE IN GERMLINE BRCA MUTATION SUBJECTS WITH LOCALLY ADVANCED AND/OR METASTATIC BREAST CANCER, WHO HAVE RECEIVED PRIOR CHEMOTHERAPY REGIMENS FOR METASTATIC DISEASE

Conditions
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Breast Neoplasms, BRCA 1 Gene Mutation, BRCA 2 Gene Mutation

Intervention / Treatment
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* Drug: talazoparib
* Drug: Physician's-Choice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed carcinoma of the breast Locally advanced breast cancer that is not amenable to curative radiation or surgical cure and/or metastatic disease appropriate for systemic single cytotoxic chemotherapy Documentation of a deleterious, suspected deleterious, or pathogenic germline BRCA1 or BRCA2 mutation from Myriad Genetics or other laboratory approved by the Sponsor No more than 3 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic disease (no limit on prior hormonal therapies or targeted anticancer therapies such as mechanistic target of rapamycin (mTOR) or CDK4/6 inhibitors, immune-oncology agents, tyrosine kinase inhibitors, or monoclonal antibodies against CTL4 or VEGF) Prior treatment with a taxane and/or anthracycline in the neoadjuvant, adjuvant, locally advanced, or metastatic setting unless medically contraindicated Have measurable or non-measurable, evaluable disease by the revised response evaluation criteria in solid tumors (RECIST) v.1.1 Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Exclusion Criteria: First-line locally advanced and/or metastatic breast cancer with no prior adjuvant chemotherapy unless the Investigator determines that one of the 4 cytotoxic chemotherapy agents in the control arm would otherwise be offered to the subject Prior treatment with a PARP inhibitor (not including iniparib) Not a candidate for treatment with at least 1 of the treatments of protocol-specific physician's choice (ie, capecitabine, eribulin, gemcitabine, vinorelbine) Subjects who had objective disease progression while receiving platinum chemotherapy administered for locally advanced or metastatic disease; subjects who received low-dose platinum therapy administered in combination with radiation therapy are not excluded Subjects who have received platinum in the adjuvant or neoadjuvant setting are eligible; however, subjects may not have relapsed within 6 months of the last dose of prior platinum therapy Cytotoxic chemotherapy within 14 days before randomization Radiation or anti-hormonal therapy or other targeted anticancer therapy within 14 days before randomization HER2 positive breast cancer Active inflammatory breast cancer CNS metastases Exception: Adequately treated brain metastases documented by baseline CT or MRI scan that has not progressed since previous scans and that does not require corticosteroids (except prednisone ≤ 5 mg/day or equivalent) for management of CNS symptoms. A repeat CT or MRI following the identification of CNS metastases (obtained at least 2 weeks after definitive therapy) must document adequately treated brain metastases. Subjects with leptomeningeal carcinomatosis are not permitted Prior malignancy except for any of the following: Prior BRCA-associated cancer as long as there is no current evidence of the cancer Carcinoma in situ or non-melanoma skin cancer A cancer diagnosed and definitively treated ≥ 5 years before randomization with no subsequent evidence of recurrence Known to be human immunodeficiency virus positive Known active hepatitis C virus, or known active hepatitis B virus Known hypersensitivity to any of the components of talazoparib

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: talazoparib<br>Patient will be randomized 2:1 to receive talazoparib oral capsules (1.0 mg) once daily for 21 continuous days | Drug: talazoparib<br>* Until progression or unacceptable toxicity develops<br>|
| Active Comparator: Physician's-Choice<br>Capecitabine, Eribulin, Gemcitabine or Vinorelbine | Drug: Physician's-Choice<br>* Capecitabine, Eribulin, Gemcitabine or Vinorelbine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS): Independent Radiological Facility (IRF) Assessment | IRF assessed PFS was defined as time (in months) from randomization until the date of first documented radiologic progressive disease per response evaluation criteria in solid tumors (RECIST) version 1.1 or death from any cause, whichever occurs first. As per RECIST v1.1, progression defined as 1) for target lesions: at least a 20% increase in the sum of target lesion measurements, compared to the smallest sum on study (including baseline), the absolute increase in the sum has to be at least 5 millimeter (mm); 2) for non-target lesions: unequivocal progression of non-target lesions, evaluated as a whole, such that it is clear that treatment has failed and disease is progressing, regardless of the status of the target lesions; 3) and/or appearance of one or more new lesions. The analysis was performed by Kaplan-Meier method. | Baseline until radiologic progressive disease or death due to any cause (up to maximum duration of 36.9 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response: Investigator Assessment | Investigator assessed objective response was defined as the percentage of participants with a partial response (PR) or complete response (CR) as defined by RECIST v1.1. For target lesions: 1) CR: disappearance of all non-nodal target lesions. Target lymph nodes must reduce to less than 10 mm in short axis. 2) PR: At least a 30% decrease in the sum of diameters of target lesions, compared to the sum at baseline. For non-target lesions, CR: disappearance of all non-target lesions. Percentage of participants with objective response reported are based upon unconfirmed CR/PR. | Baseline until radiologic progressive disease or death due to any cause (up to a maximum duration of 36.9 months) | 
| Overall Survival (OS) | OS was defined as the time (in months) from randomization to death due to any cause. If death was not observed at the time of study cut-off date or permanently lost to follow-up, OS was censored at the date the participant was last known to be alive on or before the study cut-off date, whichever was earlier. The analysis was performed by Kaplan-Meier method. | Baseline until death due to any cause or analysis cut-off, up to a maximum duration of 61.4 months | 
| Trough Plasma Talazoparib Concentrations | A predose PK sample was considered dose-compliant based on the following criteria: A participant must have received 21 consecutive days of 1 mg talazoparib without dosing interruption prior to sample collection; and the predose PK sample must have been collected 24 hours +/- 10 percent (2 hours and 24 minutes) after the previous day's dose and no more than 5 minutes (0.083 hours) after the administration of the dose on the day of PK sample collection. | Predose on Day 1 of Cycle 2, 3 and 4 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse events (AE) was any untoward medical occurrence (e.g., sign, symptom, illness, disease or injury) in a participant administered study drug or other protocol-imposed intervention, regardless of attribution. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug or the day before initiation of a new antineoplastic therapy or 30 days after the date of the last dose date of study drug, whichever occurred first, that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and all non-SAEs. | Talazoparib: Baseline up to a maximum duration of 71.3 months; Physician's Choice Treatment: Baseline up to maximum duration of 46.1 months | 
| Number of Participants With Grade 3 or 4 Post-baseline Toxicities in Laboratory Parameters: Hematology | Toxicity grades were evaluated based on as National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). NCI CTCAE v4.03 defined the severity grade as: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (potentially life threatening) and grade 5 (death related to AE) for each parameter. Key hematology parameters included hemoglobin (gram per liter [g/L]), leukocytes (10^6 cells per liter), lymphocytes (10^6 cells per liter), neutrophils (10^6 cells per liter), and platelets (10^9 cells per liter). Low value indicated lower values than the baseline values and high value indicated higher values than the baseline values. Only those categories in which at least 1 participant had data were reported. | Talazoparib: Baseline up to a maximum duration of 71.3 months; Physician's Choice Treatment: Baseline up to maximum duration of 46.1 months. | 
| Number of Participants With Grade 3 or 4 Post-baseline Toxicities in Laboratory Parameters: Chemistry | Toxicity grades were evaluated based on as NCI CTCAE v4.03. NCI CTCAE v4.03 defined the severity grade as: grade 1 (mild), grade 2 (moderate), grade 3 (severe) and grade 4 (potentially life threatening) and grade 5 (death related to AE) for each parameter. Key chemistry parameters included alanine aminotransferase (units per liter), alkaline phosphatase (units per liter), aspartate aminotransferase (units per liter) and bilirubin (micromole per liter). High value indicated higher values than the baseline values and low value indicated lower values than the baseline values. Only those categories in which at least 1 participant had data were reported. | Talazoparib: Baseline up to a maximum duration of 71.3 months; Physician's Choice Treatment: Baseline up to maximum duration of 46.1 months | 
| Number of Participants With Potentially Clinically Significant Changes From Baseline in Vital Signs | Criteria for potentially clinically significant changes in vital signs included a) Systolic blood pressure: 1) absolute results (AB) greater than (>) 180 millimeter of mercury (mmHg) and increase from baseline (IFB) greater than or equal to (>=) 40 mmHg, 2) absolute results less than (<) 90 mmHg and decrease from baseline (DFB) >30 mmHg; b) Diastolic blood pressure: 1) absolute results >110 mmHg and >=30 mmHg increase from baseline, 2) absolute results <50 mmHg and >20 mmHg decrease from baseline 3) >=20 mmHg increase from baseline; c) Heart rate: 1) absolute results>120 beats per minute [bpm] and >30 bpm increase from baseline, 2) absolute results <50 bpm and >20 bpm decrease from baseline and d) Weight: >10 percent [%] decrease from baseline. | Talazoparib: Baseline up to a maximum duration of 71.3 months; Physician's Choice Treatment: Baseline up to maximum duration of 46.1 months | 
| Number of Participants Taking At-least One Concomitant Medication | Any medication (other than study drug) which was administered to participants during study after first dose of study drug were considered as concomitant medications. | Talazoparib: Baseline up to a maximum duration of 71.3 months; Physician's Choice Treatment: Baseline up to maximum duration of 46.1 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRCA 1, Breast cancer, BRCA mutation, PARP inhibitor, BRCA 2