Veliparib and Carboplatin in Treating Patients With HER2-Negative Metastatic Breast Cancer
|BRCA1 Mutation Carrier BRCA2 Mutation Carrier Estrogen Receptor Negative Estrogen Receptor Positive HER2/Neu Negative Progesterone Receptor Negative Progesterone Receptor Positive Recurrent Breast Carcinoma Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Triple-Negative Breast Carcinoma||Drug: Carboplatin Other: Fluorothymidine F-18 Other: Laboratory Biomarker Analysis Other: Pharmacological Study Procedure: Positron Emission Tomography Drug: Veliparib||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Phase 1 Dose-Escalation Study of ABT-888 (Veliparib) in Combination With Carboplatin in HER2 Negative Metastatic Breast Cancer|
- Incidence of adverse events to measure the safety and tolerability of this treatment combination [ Time Frame: Up to 12 weeks post-treatment ]Number and severity of toxicity incidents will be tabulated. Non-hematologic toxicities will be evaluated via the ordinal Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization via CTCAE standard toxicity grading. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.
- Clinical response (complete and partial response as well as stable and progressive disease) [ Time Frame: Up to 12 weeks post-treatment ]Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors guideline (version 1.1).
- Circulating tumor cell markers [ Time Frame: Up to 5 years ]Analysis will be descriptive and exploratory in nature. Potential relationships and differences will be explored using graphical analyses and quantitative summaries of this marker.
- PARP-1 activity [ Time Frame: Up to 5 years ]Analysis will be descriptive and exploratory in nature. Potential relationships and differences will be explored using graphical analyses and quantitative summaries of this marker.
- Thymidine kinase uptake on FLT-PET scans [ Time Frame: Up to 18 weeks (after course 3) ]Analysis will be descriptive and exploratory in nature. Potential relationships and differences will be explored using graphical analyses and quantitative summaries of this marker.
|Actual Study Start Date:||November 16, 2010|
|Primary Completion Date:||June 30, 2016 (Final data collection date for primary outcome measure)|
Experimental: Treatment (veliparib, F 18 fluorothymidine, carboplatin)
Patients receive carboplatin IV over 1 hour on day 1 and veliparib PO twice daily on days 1-7 or 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may undergo fluorothymidine PET scan and peripheral blood cell and tumor tissue collection periodically for correlative studies.
Given IVOther: Fluorothymidine F-18
Correlative studiesOther: Laboratory Biomarker Analysis
Correlative studiesOther: Pharmacological Study
Correlative studiesProcedure: Positron Emission Tomography
Correlative studiesDrug: Veliparib
I. To determine the recommended phase II dose of veliparib along with carboplatin on a 14-day and 21-day schedule in patients with Her2 negative metastatic breast cancer that are estrogen receptor (ER)/progesterone receptor(PR) negative or ER and/or PR positive with defects in Fanconi Anemia (FA) pathway repair genes.
II. To determine the safety and tolerability of combining veliparib on a 14-day and 21-day schedule with carboplatin in this patient population.
III. To determine the preliminary efficacy of this combination in this patient population.
I. To determine the pharmacodynamic endpoints of poly(ADP-ribose) polymerase (PARP) inhibition in the tumor by using, A) 3'-[F-18]fluoro-3'-deoxythymidine positron emission tomography (FLT-PET) of the target lesions, B) circulating tumor cells to detect the induction of the histone variant gamma H2AX, and C) peripheral blood mononuclear cells to assess poly ADP-Ribose (PAR) levels.
II. To determine biomarkers in the primary tumor that may predict antitumor responses to PARP inhibition such as breast cancer 1/2, early onset (BRCA)1/2 protein, Fanconi anemia, complementation group D2 (FANCD2) nuclear foci formation and expression of micro-ribonucleic acid (RNA) 155 (miR 155).
OUTLINE: This is a dose-escalation study of veliparib.
Patients receive carboplatin intravenously (IV) over 1 hour on day 1 and veliparib orally (PO) twice daily (BID) on days 1-7 or 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 12 weeks.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01251874
|United States, New York|
|Montefiore Medical Center-Einstein Campus|
|The Bronx, New York, United States, 10461|
|Montefiore Medical Center - Moses Campus|
|The Bronx, New York, United States, 10467-2490|
|United States, Ohio|
|Ohio State University Comprehensive Cancer Center|
|Columbus, Ohio, United States, 43210|
|Principal Investigator:||Bhuvaneswari Ramaswamy||Ohio State University Comprehensive Cancer Center|