This phase I clinical trial studies the side effects and the best dose of veliparib when given together with carboplatin and paclitaxel in treating patients with locally advanced or metastatic solid tumors. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by blocking them from dividing. Giving veliparib with carboplatin and paclitaxel may work better in treating patients with solid tumors.
PRIMARY OBJECTIVE: I. To determine the maximum-tolerated dose (MTD) of the combination of weekly carboplatin, paclitaxel, and veliparib. SECONDARY OBJECTIVES: I. To assess the safety, tolerability, and MTD of the combination of weekly carboplatin, paclitaxel, and veliparib. II. To assess the safety and toxicity of this combination as determined by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0) and to determine the dose-limiting toxicity (DLT). III. To determine the pharmacokinetic and pharmacodynamic effects of this combination, including determinations of poly (adenosine diphosphate \[ADP\]-ribose) polymerase (PAR) in tumor specimens when available, assessment of deoxyribonucleic acid (DNA) damage as measured by gamma H2A histone family, member X (g-H2AX) in skin biopsies and tumor specimens will be obtained. IV. To assess characteristics of primary tumor specimens that may contribute to efficacy of this combination including breast cancer, early onset (BRCA) by immunohistochemistry, gene analysis of PARP 1, PARP 2, BRCA, and triple negative and homologous recombination repair (HRR) deficiency gene expression signatures. V. To document any anti-tumor response. OUTLINE: This is a dose-escalation study of veliparib. DOSE-ESCALATION: Patients receive veliparib orally (PO) twice daily (BID) on days 1-5, 8-12, and 15-19 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes in course 1 and 3 hours in subsequent courses on days 3, 10, and 17. After 4 courses, patients receive paclitaxel and carboplatin on days 3 and 10 only. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. (Completed as of 12/2012) EXPANSION COHORT: Patients receive veliparib PO BID on days 1-21 and paclitaxel IV over 1 hour and carboplatin IV over 3 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up for 4 weeks.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Given IV
Correlative studies
Given IV
Correlative studies
Given PO
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, United States
UPMC-Magee Womens Hospital
Pittsburgh, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
MTD defined as the dose level one level below the lowest dose where greater than or equal to 2 patients experience a DLT assessed by National Cancer Institute (NCI) CTCAE v. 4.0
Time frame: 21 days
Change in BRCA protein levels by immunohistochemistry
Calculated and compared using the Wilcoxon rank sum test.
Time frame: Baseline to day 4 of course 2
Change in PAR and g-H2AX in tumor tissue
Assessed with Wilcoxon signed rank tests.
Time frame: Baseline to day 4 of course 2
Grade >= 3 non-hematological or any grade 5 DLTs as graded by the NCI CTCAE v. 4.0
Statistics on the number of cycles received by patients and any dose reductions will be tabulated.
Time frame: 21 days
Incidence of adverse events as graded by the NCI CTCAE v. 4.0
The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category and grade.
Time frame: Up to 4 weeks post-treatment
Plasma concentration of carboplatin, paclitaxel, and veliparib using liquid chromatography-mass spectrometry (LC-MS) assay and spectrometry assay
Time frame: Baseline, at 30 minutes and at 1, 2, 4, and 8 hours on day 3 of course 1
Response complete response [Cr], partial response [PR], and stable disease [SD]) using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)
CR, PR, and incidence of SD will be tabulated by disease diagnosis and by dose level.
Time frame: Up to 4 weeks post-treatment
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