This phase I trial studies the side effects and best dose of talazoparib when given together with carboplatin and paclitaxel in treating patients with solid tumors that have spread to other places in the body (advanced) or cannot be removed by surgery. Talazoparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Drugs used in chemotherapy, such as carboplatin and paclitaxel, 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 talazoparib with carboplatin and paclitaxel may kill more tumor cells.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of talazoparib (BMN 673) seven day schedule in combination with carboplatin and paclitaxel. II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of talazoparib (BMN 673) three day schedule in combination with carboplatin and paclitaxel. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity of talazoparib (BMN 673) in combination with carboplatin and paclitaxel. II. To determine whether the pharmacokinetic parameters of talazoparib (BMN 673) when given in combination with carboplatin and paclitaxel correlate with thrombocytopenia. III. To observe and record anti-tumor activity of talazoparib (BMN 673) alone after the combination with carboplatin, paclitaxel and talazoparib (BMN 673). IV. To observe the safety and tolerability of talazoparib (BMN 673) in combination with paclitaxel and carboplatin and talazoparib (BMN 673) alone after the combination therapy. EXPLORATORY OBJECTIVES: I. To serially evaluate pharmacokinetic and pharmacodynamics parameters and use indirect pharmacokinetic/pharmacodynamics models to correlate with tumor response and resistance to the combination talazoparib (BMN 673), carboplatin, and paclitaxel therapy. II. To explore mechanisms of resistance to the combination of talazoparib (BMN 673) with carboplatin and paclitaxel. OUTLINE: This is a dose-escalation study of talazoparib. Patients are assigned to 1 of 2 dosing schedules. SCHEDULE A: Patients receive talazoparib orally (PO) once daily (QD) on days 1-7, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. SCHEDULE B: Patients receive talazoparib PO QD on days 1-3, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. At any time after 4-6 cycles of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician. After completion of study treatment, patients are followed up for 4 weeks.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
43
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
University of Wisconsin Carbone Cancer Center
Madison, Wisconsin, United States
Maximum tolerated dose and recommended phase 2 dose of talazoparib three day schedule
Defined as the highest safely tolerated dose where 0/6 or 1/6 (less than 33%) patients experience a dose-limiting toxicity and two or more patients have experienced a dose-limiting toxicity at the next higher dose level. Adverse events will be evaluated by type and severity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 until March 31, 2018. CTCAE version 5.0 will be utilized beginning April 1, 2018. Adverse events data collection include adverse event diagnosis, date of onset and resolution, whether the event is ongoing, CTCAE grade, whether the event is serious, frequency, and outcome status, and action taken.
Time frame: 21 days
Maximum tolerated dose and recommended phase 2 dose of talazoparib seven day schedule
Defined as the highest safely tolerated dose where 0/6 or 1/6 (less than 33%) patients experience a dose-limiting toxicity and two or more patients have experienced a dose-limiting toxicity at the next higher dose level. Adverse events will be evaluated by type and severity using the National Cancer Institute CTCAE version 4.0 until March 31, 2018. CTCAE version 5.0 will be utilized beginning April 1, 2018. Adverse events data collection include adverse event diagnosis, date of onset and resolution, whether the event is ongoing, CTCAE grade, whether the event is serious, frequency, and outcome status, and action taken.
Time frame: 21 days
Incidence of toxicity
Graded according to NCI CTCAE version 4.0 until March 31, 2018. CTCAE version 5.0 will be utilized beginning April 1, 2018. Toxicities observed will be summarized in terms of types and severities for each schedule and dose level separately. The number and severity of toxicity incidents will be analyzed descriptively in tabular format. Comparisons between dose level arms will be performed using Fisher's exact test. Ninety percent confidence intervals for dose-limiting toxicity rates will be constructed for dose levels with 6 or more patients.
Time frame: Up to 4 weeks after last dose of treatment
Anti-tumor response
Will be determined by Response Evaluation Criteria in Solid Tumors criteria. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease, stratified by treatment schedule. 90% confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed for dose levels with 6 or more patients. Exact logistic regression analysis will be performed to evaluate the dose-response relationship. Chi-square or Fisher's exact test will be used to compare responses between treatment schedules.
Time frame: Up to 4 weeks after last dose of treatment
Pharmacokinetic parameters (area under the curve and concentration) in plasma samples
All pharmacokinetic parameters will be summarized by treatment schedule dose level using standard descriptive statistics: means, medians, ranges, and standard deviations (if numbers and distribution permit). The Jonckheere-Terpstra trend test will be performed to determine the significance of the association between increasing dose level and each of the pharmacokinetic parameters within each treatment schedule. A Spearman rank correlation analysis will be performed to determine the relationship between actual dose administered and the pharmacokinetic parameters.
Time frame: Pre-dose and 4 hours after talazoparib administration on days 1 and 3 or 7 (depending on assigned schedule) of cycle 1 and 0 and 4 hours on day 1 of all subsequent cycles
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