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

OBJECTIVES:

Primary

- 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. (Stratum I)

- 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

- To define the dose-limiting toxicity and other toxicities associated with the use of
this combination.

- To obtain preliminary evidence of antitumor activity in patients treated with this
combination.

- To evaluate the pharmacokinetic parameters of veliparib, carboplatin, and paclitaxel
when administered as a combination.

- 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 IV over 30 minutes and paclitaxel IV over 3 hours on day 3
and oral veliparib 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.

DISEASE CHARACTERISTICS:

- 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 brain metastasis should have stable disease ≥ 4 weeks following therapy
for brain metastasis (i.e., surgery, radiotherapy, stereotactic radiosurgery)

PATIENT CHARACTERISTICS:

Inclusion criteria:

- 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

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

- History of seizure disorder

- Evidence of bleeding diathesis

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

- 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:

- 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