Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of veliparib when given together with carboplatin and paclitaxel in treating patients with advanced solid cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 or by stopping them from dividing. Giving veliparib together with carboplatin and paclitaxel may help kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the recommended dose for phase II studies of veliparib (ABT-888 ) that can be administered in combination with carboplatin and paclitaxel in patients with advanced solid malignancies. (Stratum I) II. To determine the recommended dose for phase II studies of veliparib that can be administered in combination with carboplatin and paclitaxel in patients with advanced solid malignancies that harbor a germline BRCA1/2 mutation. (Stratum II) (added 04/07/09) SECONDARY OBJECTIVES: I. To define the dose-limiting toxicity and other toxicities associated with the use of this combination. II. To obtain preliminary evidence of antitumor activity in patients treated with this combination. III. To evaluate the pharmacokinetic parameters of veliparib, carboplatin, and paclitaxel when administered as a combination. IV. To conduct correlative science studies. OUTLINE: This is a multicenter, dose-escalation study of veliparib. Patients are stratified according to BRCA status (no [stratum I] vs yes [stratum II]). Patients receive carboplatin intravenously (IV) over 30 minutes and paclitaxel IV over 3 hours on day 3 and veliparib orally (PO) twice daily on days 1-7 until the recommended phase II dose is determined. Treatment repeats every 3 weeks for at least 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo peripheral blood mononuclear cell collection periodically for pharmacokinetic and biomarker studies. After completion of study treatment, patients are followed up for 4 weeks.

Official Title
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A Phase 1 Study of ABT-888 in Combination With Carboplatin and Paclitaxel in Advanced Solid Malignancies

Conditions
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Adult Solid Neoplasm, BRCA1 Mutation Carrier, BRCA2 Mutation Carrier, Hereditary Breast and Ovarian Cancer Syndrome

Intervention / Treatment
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* Drug: Carboplatin
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Other: Pharmacological Study
* Drug: Veliparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced solid malignancy Patients enrolled in stratum II of the study must have BRCA1/2 mutation (added 04/07/09) Patients with CNS metastases must be stable after therapy for CNS metastases (such as surgery, radiotherapy or stereotactic radiosurgery) for > 3 months and must be off steroid treatment prior to study enrollment ECOG performance status 0-2 Life expectancy > 12 weeks ANC ≥ 1,500/μL Platelet count ≥ 100,000/μL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Creatinine normal OR creatinine clearance ≥ 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) More than 3 weeks since prior radiotherapy Prior veliparib allowed Exclusion Criteria: Known history of allergic reactions to veliparib, carboplatin, or Cremophor-paclitaxel Uncontrolled intercurrent illness, including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that would preclude compliance with study requirements Peripheral neuropathy > grade 1 Inability to take oral medications on a continuous basis Active seizure or history of seizure disorder Evidence of bleeding diathesis Received > 3 prior chemotherapy regimens for advanced stage disease for patients enrolled in stratum I (there is no upper limit on the number of prior regimens for patients enrolled in stratum II) (added 04/07/09) Adjuvant chemotherapy administered ≥ 2 years prior to enrollment to the study does not count as a prior chemotherapy regimen Other concurrent investigational agents Concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy and chemotherapy)<br>Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 3 and veliparib PO twice daily on days 1-7 until the recommended phase II dose is determined. Treatment repeats every 3 weeks for at least 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Veliparib<br>* Given PO<br>* Other names: PARP-1 inhibitor ABT-888;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose (RP2D) for each stratum | The RP2D for each cohort will be defined by the study separately. Standard up & down dose-escalation scheme to determine the RP2D will be use, and toxicities will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | Toxicities should be attributable to the study drug(s) to constitute DLT. Patients will be considered evaluable for DLT if they are eligible, and if they receive any amount of treatment and experience DLT or complete the first course of treatment | During course 1 | 
| Frequency of platinum-DNA adducts | Changes will be summarized as means and standard deviations. A statistical test of the null hypothesis of no change in each variable will be done using the Wilcoxon signed-ranks procedure. Measurements of the two variables at additional time points will be analyzed in a descriptive fashion using tables and plots. | At baseline and 4 weeks post-treatment | 
| Incidence of stable disease (SD) | SD is defined as neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter (LD) since the treatment started. | Measured from the start of the treatment until the criteria for progression are met, assessed up to 4 weeks post-treatment | 
| PAR levels | Changes will be summarized as means and standard deviations. A statistical test of the null hypothesis of no change in each variable will be done using the Wilcoxon signed-ranks procedure. Measurements of the two variables at additional time points will be analyzed in a descriptive fashion using tables and plots. | Up to 4 weeks post-treatment | 
| Responses to veliparib in combination with carboplatin and paclitaxel | Response will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. | Up to 4 weeks post-treatment | 
| Time to progression (TTP) | Progression will be evaluated in this study using the new international criteria proposed by RECIST. TTP will be displayed for all patients and for patients who have responded; no formal statistical analysis is planned. | Time from start of treatment to time of progression, assessed up to 4 weeks post-treatment | 
| Toxicities as assessed by CTCAE v.4.0 | Toxicities will be defined as regimen-related if they are possibly, probably or definitely related to treatment. 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, grade and dose level. Serious (≥ Grade 3) toxicities will be described on a patient-by-patient basis and will include any relevant baseline data. | From the time of their first treatment with veliparib to up to 4 weeks post-treatment |