A Phase 3 Randomized, Placebo-controlled Trial of Carboplatin and Paclitaxel With or Without Veliparib (ABT-888) in HER2-negative Metastatic or Locally Advanced Unresectable BRCA-associated 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 veliparib in combination with carboplatin and paclitaxel (C/P) compared to placebo plus C/P in participants with a Breast Cancer Gene 1 or 2 (BRCA1; BRCA2) mutation in Human Epidermal Growth Factor Receptor 2 (HER2)-negative metastatic or locally advanced unresectable breast cancer. The secondary objectives of the study are to assess overall survival (OS), clinical benefit rate (CBR) through the end of Week 24, objective response rate (ORR) and PFS on subsequent therapy (PFS2) in participants treated with veliparib in combination with C/P versus placebo in combination with C/P.

Detailed Description
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This is a Phase 3, randomized, double-blind, multinational, multicenter study to evaluate the efficacy and tolerability of veliparib in combination with C/P compared to placebo in combination with C/P in participants with a BRCA1 or BRCA2 mutation, as documented by the Sponsor core laboratory, with HER2-negative metastatic or locally advanced unresectable breast cancer who received no more than 2 prior lines of cytotoxic therapy for metastatic disease. For the purposes of eligibility, HER2-negative status was based on the most recent tumor biopsy. Participants were randomized in a 2:1 ratio, with a total of approximately 500 participants planned to be randomized. Veliparib 120 mg/placebo twice a day (BID) was dosed Days -2 through 5 with carboplatin target area under the concentration-time curve (AUC) 6 administered on Day 1 and paclitaxel 80 mg/m2 administered weekly on Days 1, 8, and 15 of each 21-day cycle. Safety and efficacy data through the prespecified primary analysis cutoff date of 05 April 2019 are included in the interim analysis.

Official Title
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A Phase 3 Randomized, Placebo-Controlled Trial of Carboplatin and Paclitaxel With or Without the PARP Inhibitor Veliparib (ABT-888) in HER2-Negative Metastatic or Locally Advanced Unresectable BRCA-Associated Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Veliparib Placebo
* Drug: Veliparib
* Drug: Carboplatin
* 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 advanced or metastatic. Locally advanced breast cancer must not be amenable to surgical resection or radiation with curative intent. Suspected deleterious or deleterious Breast Cancer Gene 1 (BRCA1) and/or Breast Cancer Gene 2 (BRCA2) germline mutation. Breast cancer must be Human Epidermal Growth Factor Receptor 2 (HER2)-negative. Measurable or non-measurable (but radiologically evaluable) disease per Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 on computed tomography (CT) scan (within 28 days of randomization) with at least one lesion outside previously irradiated areas. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2. Adequate hematologic, renal, and hepatic function (within 28 days of randomization). Exclusion Criteria: More than two prior lines of cytotoxic chemotherapy (e.g., gemcitabine, doxorubicin, capecitabine) for metastatic disease. Regimens received in the adjuvant/neoadjuvant setting or for locally advanced breast cancer within the past 6 months will also be considered toward the maximum of 2 prior lines of therapy. Adjuvant/neoadjuvant chemotherapy for one cancer event will count as one prior line of therapy, if received within the past 6 months. Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) and signal transduction agents (e.g., erlotinib, gefitinib, everolimus, bevacizumab) are allowed and are not counted towards the prior line of therapy. Progressed or recurred within 12 months of completing platinum therapy or received > 1 prior line of platinum therapy for breast cancer in any setting (adjuvant, neoadjuvant, or metastatic). Prior therapy with Poly(ADP-ribose)-Polymerase (PARP) inhibitors. Prior taxane therapy administered for the treatment of metastatic breast cancer with the below exceptions. Prior taxane therapy for metastatic breast cancer is allowed if the patient received ≤ 1 full cycle (i.e., therapy discontinued within 4 weeks for subjects receiving weekly paclitaxel or Abraxane; therapy discontinued within 3 weeks for subjects receiving paclitaxel or docetaxel every 3 weeks) in the absence of progression or if taxane therapy for metastatic disease was > 12 months prior to Cycle 1 Day-2 (C1D-2). Use of taxanes as adjuvant therapy or to treat locally advanced disease is permitted, if given more than 6 months prior to C1D-2 Known history of allergic reaction to cremophor-paclitaxel, carboplatin, Azo-Colourant Tartrazine (also known as FD&C Yellow 5 or E102), Azo-Colourant Orange Yellow-S (also known as FD&C Yellow 6 or E110) or known contraindications to any study supplied drug. Active CNS metastases or leptomeningeal disease.

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 |
| --- | --- |
| Active Comparator: Veliparib Placebo with Carboplatin and Paclitaxel<br>Placebo capsules for veliparib (120 mg) administered by mouth twice daily (BID) on Days -2 through 5 of a 21-day cycle. Carboplatin administered intravenously over approximately 15 to 30 minutes at AUC 6 mg/ml/min immediately following paclitaxel infusion on Day 1 of every cycle. Paclitaxel administered intravenously over approximately 1 hour at a dose of 80 mg/m² on Days 1, 8, and 15 of every cycle. | Drug: Veliparib Placebo<br>* Supplied as 40 mg, 50 mg, or 100 mg capsules for oral administration twice daily (BID) on Days -2 through 5 of a 21-day cycle.<br>Drug: Carboplatin<br>* Administered intravenously over approximately 15 to 30 minutes at an area under the curve (AUC) of 6 mg/mL/min immediately following paclitaxel infusion on Day 1 of every cycle. The duration of carboplatin infusion may be lengthened according to institutional guidelines.<br>Drug: Paclitaxel<br>* Administered by intravenous infusion over approximately 1 hour at a dose of 80 mg/m² of body-surface area (BSA) on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel is to be infused prior to carboplatin on Day 1. Dosing of veliparib/placebo is to be completed before the carboplatin or paclitaxel infusions.<br>|
| Experimental: Veliparib with Carboplatin and Paclitaxel<br>Veliparib capsules (120 mg) administered by mouth twice daily (BID) on Days -2 through 5 of a 21-day cycle. Carboplatin administered intravenously over approximately 15 to 30 minutes at AUC 6 mg/ml/min immediately following paclitaxel infusion on Day 1 of every cycle. Paclitaxel administered intravenously over approximately 1 hour at a dose of 80 mg/m² on Days 1, 8, and 15 of every cycle. | Drug: Veliparib<br>* Supplied as 40 mg, 50 mg, or 100 mg capsules for oral administration twice daily (BID) on Days -2 through 5 of a 21-day cycle.<br>* Other names: ABT-888;Drug: Carboplatin<br>* Administered intravenously over approximately 15 to 30 minutes at an area under the curve (AUC) of 6 mg/mL/min immediately following paclitaxel infusion on Day 1 of every cycle. The duration of carboplatin infusion may be lengthened according to institutional guidelines.<br>Drug: Paclitaxel<br>* Administered by intravenous infusion over approximately 1 hour at a dose of 80 mg/m² of body-surface area (BSA) on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel is to be infused prior to carboplatin on Day 1. Dosing of veliparib/placebo is to be completed before the carboplatin or paclitaxel infusions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Time to PFS is defined as the number of days from the date the participant was randomized to the date the participant experiences radiographic disease progression (as determined by the investigators), or to the date of death (all causes of mortality) if disease progression is not reached. All events of disease progression occurring on or before the Primary Analysis Cutoff date of 05 April 2019 were to be included, regardless of whether the event occurred while the participant was still taking study drug or had previously discontinued study drug. PFS was estimated for each treatment group using Kaplan-Meier methodology. | From randomization until the primary analysis data cut-off date of 05 April 2019; the median duration of follow-up was 35.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time to death (overall survival) is defined as the number of days from the date the participant was randomized to the date of the participant's death. All events of death which occur up to the analysis cutoff date are to be included, regardless of whether the event occurred while the participant was still taking study drug or after the participant discontinued study drug. If a participant has not died, the data for the participant is to be censored at the date last known to be alive or at the analysis cutoff date if that is earlier. The final analysis of OS will occur when the pre-specified number of events has occurred in the ITT population. | Approximately 8 years from randomization | 
| Clinical Benefit Rate (CBR) | The clinical benefit rate (CBR) for each treatment group was to be obtained from a time-to-event analysis of radiographic disease progression per the investigator. CBR is defined as the progression-free rate at 24 weeks (168 days), estimated for each treatment arm using Kaplan Meier methodology. All events of disease progression in the primary progression free survival analysis database were to be included, regardless of whether the event occurred while the participant was still taking, or had previously discontinued, study drug. If the participant had not yet progressed then their data was to be censored at the date of the last evaluable disease progression assessment. Participants without post-baseline assessments were to be censored at the date of randomization. The final analysis of CBR will occur when the pre-specified number of Overall Survival events have occurred in the ITT population, per the fixed sequence testing procedure. | Through the end of Week 24 | 
| Objective Response Rate (ORR) | The objective response rate (ORR) is calculated as the percentage of participants who have a confirmed partial response (PR) or complete response (CR) based on assessment by the investigators per Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1. All participants who had at least one measurable lesion at baseline were to be included in the ORR calculation. The final analysis of ORR will occur when the pre-specified number of Overall Survival events have occurred in the ITT population, per the fixed sequence testing procedure. | Approximately 8 years from randomization | 
| Progression-Free Survival on Subsequent Therapy (PFS2) | PFS2 is defined as the number of days from the date of randomization to the time of disease progression on subsequent therapy or death from any cause. The distribution of PFS2 was to be estimated for each treatment group using Kaplan-Meier methodology. The final analysis of PFS2 will occur when the pre-specified number of Overall Survival events have occurred in the ITT population, per the fixed sequence testing procedure. | Approximately 8 years from randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PARP Inhibitor, Veliparib, BRCA1, BRCA2, HER2-negative, Locally recurrent, Breast Cancer, Metastatic Breast Cancer, ABT-888, Genetic breast cancer, Paclitaxel, BRCA Mutation, PARP, Carboplatin, BROCADE3