This phase I trial studies the side effects and best dose of veliparib when given together with cisplatin and vinorelbine ditartrate in treating patients with breast cancer that has returned or spread to other parts of the body. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin and vinorelbine ditartrate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving veliparib together with combination chemotherapy may be a better treatment for breast cancer.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of ABT-888 (veliparib) when administered daily for 14 days out of a 21 day cycle in combination with cisplatin and vinorelbine (vinorelbine ditartrate) in subjects with metastatic triple negative breast cancer (TNBC) and breast cancer (BRCA) mutation associated breast cancer. SECONDARY OBJECTIVES: I. Assess the pharmacokinetic profile of ABT-888 when combined with cisplatin and vinorelbine and the safety/tolerability profile of the combination. II. Evaluate the level of poly ADP ribose polymerase (PARP) inhibition at each dose level to determine whether maximal PARP inhibition is achieved. III. Identify the subgroup of triple negative breast cancer patients who will potentially derive the most benefits from PARP inhibition combined with platinum-based chemotherapy. OUTLINE: This is a dose-escalation study of veliparib. Patients receive veliparib orally (PO) twice daily (BID) on days 1-14 (days 0-13 of course 1 only). Patients also receive cisplatin intravenously (IV) over 1 hour on day 1 and vinorelbine ditartrate IV over 10-20 minutes on days 1 and 8. Treatment repeats every 21 days for 6-10 courses in the absence of disease progression or unacceptable toxicity. Treatment with veliparib alone may continue in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for up to 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States
MTD of veliparib, defined as the highest dose tested in which fewer than 33% of patients experienced dose-limiting toxicity attributable to the study regimen, when at least 6 patients were treated at that dose and were evaluable for toxicity
Time frame: Day 21
Toxicity profile, defined by the incidence of toxicity, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time frame: Up to 30 days post-treatment
Pharmacokinetic (PK) parameters of veliparib in plasma and urine samples
The PK parameters determined will be: AUC0-t (the area under the concentration-time curve over a dosing interval), Cmax (maximal concentration), Tmax (time to maximal concentration), Vd (volume of distribution), CL/F (oral clearance for veliparib), CL (clearance for cisplatin), and t1/2 (elimination half-life). To improve understanding of systemic bioavailability, the amount of veliparib excreted in the urine for each collection interval will be calculated by the product of urinary drug concentration and urine volume.
Time frame: Baseline and day 1 of courses 1 and 4
Pharmacokinetic (PK) parameters of cisplatin in plasma samples
The PK parameters determined will be: AUC0-t, Cmax, Tmax, Vd, CL/F, CL, and t1/2 .
Time frame: Baseline and day 1 of courses 1 and 4
Pharmacodynamic parameters of PARP inhibition
Assessed by measuring changes in PAR levels in peripheral blood mononuclear cells and in tumor tissue (if available).
Time frame: Baseline and day 1 of courses 1 and 4
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