Study Evaluating Efficacy And Tolerability Of Veliparib in Combination With Temozolomide (TMZ) or In Combination With Carboplatin and Paclitaxel Versus Placebo in Participants With Breast Cancer Gene (BRCA)1 and BRCA2 Mutation and Metastatic Breast Cancer

Study Overview
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Brief Summary
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The primary objective of the study is to assess the progression-free survival (PFS) of oral veliparib in combination with TMZ or in combination with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 mutation and locally recurrent or metastatic breast cancer.

Official Title
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A Randomized, Phase 2 Study of the Efficacy and Tolerability of Veliparib in Combination With Temozolomide or Veliparib in Combination With Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Subjects With BRCA1 or BRCA2 Mutation and Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Placebo
* Drug: Veliparib
* Drug: Carboplatin
* Drug: Temozolomide
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed breast cancer that is either locally recurrent or metastatic. Locally recurrent disease must not be amenable to surgical resection or radiation with curative intent. Must have a documented deleterious Breast Cancer Gene BRCA1 or BRCA2 germline mutation. If Human Epidermal Growth Factor Receptor (HER2) positive, subjects must have received and progressed on at least one prior standard HER2 directed therapy or the subject must be ineligible to receive anti-HER2 therapy. Measurable or non-measurable (but radiologically evaluable) disease by RECIST (Response Evaluation Criteria in Solid Tumors) criteria 1.1. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-2. Subject must have adequate bone marrow, renal and hepatic function. Subject must not be pregnant or plan to conceive a child. Exclusion Criteria: Received anticancer agent(s) or an investigational agent within 21 days prior to C1D1, or radiotherapy within 28 days prior Cycle 1 Day 1. More than 2 prior lines of cytotoxic chemotherapy. Prior treatment of breast cancer with temozolomide, a platinum agent, or a Poly (ADP ribose) Polymerase (PARP) inhibitor. Prior taxane therapy for metastatic breast cancer. A history of or evidence of brain metastases or leptomeningeal disease. A history of uncontrolled seizure disorder. Pre-existing neuropathy from any cause in excess of Grade 1. Known history of allergic reaction to cremophor/paclitaxel. Clinical significant uncontrolled conditions, active infection, myocardial infarction, stroke, or transient ischemic attack, psychiatric illness/social situations that would limit compliance. Pregnant or breastfeeding.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Veliparib with Temozolomide<br>Veliparib 40 mg twice daily (BID) Days 1 through 7 plus TMZ 150 to 200 mg/m^2 QD Days 1 through 5 in each 28-day cycle. | Drug: Veliparib<br> <br> * Other names: ABT-888;Drug: Temozolomide<br> <br> * Other names: Temodal;|
| Placebo Comparator: Placebo with Carboplatin and Paclitaxel<br>Placebo BID Days 1 through 7 plus carboplatin target area under the curve (mg•min/mL) (AUC) 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m^2 administered on Day 3 of each 21-day cycle. | Drug: Placebo<br> <br> Drug: Carboplatin<br> <br> Drug: Paclitaxel<br> <br> * Other names: Taxol;|
| Experimental: Veliparib with Carboplatin and Paclitaxel<br>Veliparib 80 mg BID Days 1 through 7 plus carboplatin target AUC 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m^2 administered on Day 3 of each 21-day cycle. | Drug: Veliparib<br> <br> * Other names: ABT-888;Drug: Carboplatin<br> <br> Drug: Paclitaxel<br> <br> * Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the number of months from the date the participant was randomized to the date of radiographic progression as determined by the central imaging center, or to the date of all cause deaths within 63 days of last tumor assessment if disease progression was not reached. | Radiographic evaluation every 9 weeks, clinical evaluation every cycle (data cutoff date: 04 March 2016); maximum duration of follow up for PFS was 34 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time to death for a given participant was defined as the number of months from the day the participant is randomized to the date of the participant's death. All events of death were included, regardless of whether the event occurs while the participant was still taking study drug, or after the participant discontinued study drug. If a participant had not died, then the data will be censored at the date when the participant was last known to be alive. | From Cycle 1 Day 1 until participant's death or 3 years post discontinuation (data cutoff date: 04 March 2016); maximum duration of follow up for OS was 72 months. | 
| Clinical Benefit Rate (CBR) at Week 18 | CBR: percentage of participants who were progression-free at 18 weeks, defined as complete response (CR), partial response (PR), stable disease (SD) or non-CR/non-disease progression (PD) per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1. CR: The disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 0 mm. PR: >= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (SOD). PD: >= 20% increase in the SOD of target lesions, taking as reference the smallest SOD recorded since the treatment started (baseline or after) or the appearance of >=1 new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD since the treatment started (baseline or after). | Week 18 | 
| Objective Response Rate (ORR) | The objective response rate, defined as percentage of participants with a confirmed CR or PR based on RECIST 1.1 criteria. CR: The disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 0 mm. PR: >= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline SODs. | Radiographic evaluation every 9 weeks, clinical evaluation every cycle (data cutoff date: 04 March 2016); maximum duration of follow up for ORR was 34 months. | 
| Change From Baseline at Week 18 in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy Module (EORTC QLQ-CIPN20) Sensory Subscale Score | EORTC QLQ-CIPN20 sensory subscale score was calculated following the standard scoring algorithm, transformed to a 0 (low quality of life) to 100 (best quality of life) scale. A positive change from baseline indicates improvement. | Baseline, Week 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PARP, TMZ, Temodal, Carboplatin, veliparib, BRCA2 mutation carrier, Breast cancer, Metastatic breast cancer, temozolomide, BRCA1 mutation carrier, ABT-888, Paclitaxel, Recurrent breast cancer, Temodar, Locally recurrent