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

Phase 1

Completed

• Conditions: Adult Solid Neoplasm; BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Hereditary Breast and Ovarian Cancer Syndrome
• Interventions: Drug: Carboplatin; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel; Other: Pharmacological Study; Drug: Veliparib

• Registration Number: NCT00535119
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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

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.

Study Timeline

• Study Start: 2007-09
• Study First Submitted: 2007-09-25
• Study First Submitted QC: 2007-09-25
• Study First Posted: 2007-09-26
• Primary Completion: 2012-10
• Status Verified: 2015-04
• Last Update Submitted: 2015-05-21
• Last Update Posted: 2015-05-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 107

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (enzyme inhibitor therapy and chemotherapy)	Pharmacological Study	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.
Treatment (enzyme inhibitor therapy and chemotherapy)	Laboratory Biomarker Analysis	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.
Treatment (enzyme inhibitor therapy and chemotherapy)	Carboplatin	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.
Treatment (enzyme inhibitor therapy and chemotherapy)	Paclitaxel	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.
Treatment (enzyme inhibitor therapy and chemotherapy)	Veliparib	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.

Primary Outcome Measures

Name	Time	Method
Recommended phase II dose (RP2D) for each stratum	Up to 4 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Frequency of platinum-DNA adducts	At baseline and 4 weeks post-treatment	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.
Incidence of stable disease (SD)	Measured from the start of the treatment until the criteria for progression are met, assessed up to 4 weeks post-treatment	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.
Toxicities as assessed by CTCAE v.4.0	From the time of their first treatment with veliparib to up to 4 weeks post-treatment	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.
Dose-limiting toxicity (DLT)	During course 1	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
Responses to veliparib in combination with carboplatin and paclitaxel	Up to 4 weeks post-treatment	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.
PAR levels	Up to 4 weeks post-treatment	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.
Time to progression (TTP)	Time from start of treatment to time of progression, assessed up to 4 weeks post-treatment	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.

Trial Locations

Locations (7)

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, United States

USC / Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Emory University/Winship Cancer Institute; 🇺🇸 Atlanta, Georgia, United States

Penn State Milton S Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

University of Pittsburgh Cancer Institute (UPCI); 🇺🇸 Pittsburgh, Pennsylvania, United States

University of Pittsburgh Cancer Institute; 🇺🇸 Pittsburgh, Pennsylvania, United States