Carboplatin and Combination Chemotherapy With or Without Veliparib in Treating Patients With Stage IIB-IIIC Breast Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well carboplatin and combination chemotherapy with or without veliparib works in treating patients with stage IIB-IIIC breast cancer. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving carboplatin and combination chemotherapy are more effective with or without veliparib is more effective in treating breast cancer.

Detailed Description
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PRIMARY OBJECTIVE: 1) To compare the pathologic complete response (path CR) in patients with stage IIB or stage III triple negative breast cancer treated with neoadjuvant paclitaxel and carboplatin to the path CR of patients treated with paclitaxel, carboplatin, and veliparib. SECONDARY OBJECTIVES: Relapse free survival (follow-up period of 36 months). Overall clinical response to neoadjuvant therapy. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive paclitaxel intravenously (IV) and carboplatin IV on day 1 (course 1 only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive veliparib orally (PO) twice daily (BID) on days 1-5. Patients also receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 36 months.

Official Title
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An Adaptive, Randomized Phase II Trial to Determine Pathologic Complete Response With the Addition of Carboplatin With and Without Veliparib to Standard Chemotherapy in the Neoadjuvant Treatment of Triple-Negative Breast Cancer

Conditions
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Estrogen Receptor-negative Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-negative Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Triple-negative Breast Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Veliparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained prior to any study-related procedures. Histologically confirmed adenocarcinoma of the breast with the following markers: Estrogen receptor negative (<1%), progesterone receptor negative (<1%), and Her-2/neu negative (Her-2/neu 0-1+ IHC or FISH ratio <1.8 or average HER2 gene copy number of <four signal/nucleus for test systems without internal control probe). Female ≥ 18 years old. Clinical stage IIA (T2N0), IIB (T2N1, T3N0) or stage IIIA (T1N2, T2N2, T3N1, T3N2), IIIB, or IIIC breast cancer with no prior treatment. Complete radiology or tumor assessment within 28 days prior to enrollment Breast MRI Unilateral Breast Ultrasound Distant metastatic work-up completed with PET/CT. If enlarged axillary lymph nodes are found during staging scans, FNA must be performed to determine whether the node is involved with cancer. If axillary lymph nodes are clinically negative during initial work-up, sentinel node biopsy will be performed prior to initiation of chemotherapy. ECOG Performance Status of 0 or 1 Adequate organ and hematologic function as evidenced by the following laboratory studies within 4 weeks of study enrollment: Cardiac Ejection Fraction >/= lower limit of normal as determined by 2-D echo or MUGA scan according to institutional standards. Hematologic function, as follows: Absolute neutrophil count ≥ 1.5 x 109/L, Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L, Hemoglobin ≥ 9 g/dL, PTT and INR < 1.5 x ULN. Renal function, as follows: Serum creatinine </= 1.4 mg/dL). Hepatic function, as follows:Aspartate aminotransferase (AST) ≤ 2.5 x ULN, Alanine aminotransferase (ALT) ≤ 2.5 x ULN , Total bilirubin ≤ 2 x ULN (except for patients with UGT1A1 promoter polymorphism, i.e. Gilbert syndrome, confirmed by genotyping or Invader UGT1A1 molecular assay prior to study enrollment. Patients enrolled with Gilbert syndrome must have total bilirubin < 3 ULN). Patient must be willing and able to undergo MRI as outlined in protocol. Exclusion Criteria: Known hypersensitivity to doxorubicin, cyclophosphamide, paclitaxel, cremophor or medications containing cremophor(miconazole, docetaxel, sandimmune, nelfinavir mesylate, propofol, diazepam injection, vitamin K injection, ixabepilone, aci-jel) or carboplatin. Known HIV or active Hepatitis B or C infection. Prior treatment for the currently diagnosed breast cancer. Prior treatment with doxorubicin up to 400 mg/m2. Pre-existing Grade 3 or 4 sensory neuropathy. History of bleeding diathesis or extensive bleeding requiring blood transfusion within 14 days of enrollment. Major surgical procedure within 4 weeks (28 days) prior to enrollment (port placement is not considered a major surgical procedure). Clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, congestive heart failure, or ongoing arrhythmias requiring medication or pacemaker. Non-healing wound, ulcer or fracture. Ongoing or active infection. Pregnant (i.e., positive beta-human chorionic gonadotropin test) or lactating Not willing to use a highly effective method of birth control (i.e. those which result in low failure rates, less than 1% per year), defined as intrauterine devices, barrier methods (condoms, contraceptive sponges, diaphragms, vaginal rings used with spermicidal jellies or creams), oral contraceptive pills, or sexual abstinence. Contraception must be used during the study. T0 tumors Active dental infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Arm 1 (paclitaxel, carboplatin)<br>Patients receive paclitaxel IV and carboplatin IV on day 1 (course 1 only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: Paclitaxel<br>* Given IV<br>* Other names: Abraxane;Drug: Carboplatin<br>* Given IV<br>* Other names: Paraplatin-AQ;Drug: Doxorubicin<br>* Given IV<br>* Other names: Doxil;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Lyophilizedcytoxan;|
| Experimental: Arm 2 (veliparib, paclitaxel, carboplatin)<br>Patients receive veliparib PO BID on days 1-5. Patients also receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: Paclitaxel<br>* Given IV<br>* Other names: Abraxane;Drug: Carboplatin<br>* Given IV<br>* Other names: Paraplatin-AQ;Drug: Doxorubicin<br>* Given IV<br>* Other names: Doxil;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Lyophilizedcytoxan;Drug: Veliparib<br>* Given PO<br>* Other names: ABT-888;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Participants That Achieve Pathologic Complete Response (PCR) | PCR is defined as the absence of any residual invasive cancer on hematoxylin and eosin (H&E) evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes. | 36 months following surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Clinical Response | The count and percentage of subjects with each category of overall clinical response will be summarized by presence of baseline measureable disease (i.e., complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], unable to evaluate [UE], neurogenerative disease [ND]). Evaluated per Response Evaluation Criteria In Solid Tumors (RECIST v1.0) as assessed b MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Beta will be used as priors for combination regimens in calculating the posterior distribution of the pathologic complete response [pCR] for each respective treatment group. Among subjects with measurable disease, a 95% credible region will be calculated for the odds ratio for each treatment combination relative to each other. | Up to 3 years | 
| Relapse Free Survival | Analyzed using Kaplan-Meier methods, stratified by study group, and the log rank test will be completed. | Up to 3 years |