Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. Determine the maximum-tolerated dose of veliparib (ABT-888) (days 1-12 of a 21-day
schedule) in combination with cisplatin (day 3) and gemcitabine (days 3, 10) in patients
with advanced, previously untreated carcinoma of the bile ducts, gallbladder or pancreas,
non-small cell lung cancer, or transitional cell carcinoma of the bladder/urothelial tract.

SECONDARY OBJECTIVES:

I. Describe the dose-limiting toxicity (DLT) and other toxicities associated with veliparib
in combination with cisplatin plus gemcitabine as assessed by CTCAE v4.0.

II. Determine the recommended phase 2 dose of veliparib (ABT-888) (RP2D) in combination with
cisplatin plus gemcitabine.

III. Document anti-tumor activity of veliparib (ABT-888), cisplatin, and gemcitabine as
assessed by RECIST 1.1.

IV. Determine the plasma pharmacokinetics of veliparib (ABT-888), cisplatin, and
gemcitabine.

V. Determine the abundance of gemcitabine triphosphate in PBMCs following gemcitabine
administration.

VI. Measure the abundance of DNA-platinum adducts in tumor tissue following cisplatin
administration.

VII. Measure PARP enzymatic activity in PBMC and tumor tissue following study treatment.

VIII. Perform an exploratory correlation between abundance of BRCA and other proteins
assessed by tumor immunohistochemistry and clinical response.

OUTLINE: This is a multicenter, dose-escalation study of veliparib and gemcitabine
hydrochloride. Patients are stratified according to presence of suspected or known BRCA
mutations (no vs yes).

Patients receive veliparib orally every 12 hours on days 1-12, gemcitabine hydrochloride IV
over 30 minutes on days 3 and 10, and cisplatin IV over 60-120 minutes on day 3. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Patients with suspected or known germline BRCA mutations may continue to receive
single-agent veliparib continuously in the absence of disease progression or unacceptable
toxicity. Patients may undergo blood, tumor tissue, and hair follicle sample collection
periodically for pharmacokinetic and correlative studies.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed advanced
biliary/pancreatic cancer, urothelial cancer, or non-small cell lung cancer that is
metastatic or unresectable

- Patients with known CNS metastases should be excluded from this clinical trial

- ECOG performance status ≤ 2 (Karnofsky ≥ 60%)

- Life expectancy of greater than 12 weeks

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin within normal institutional limits

- AST/ALT ≤ 2.5 times institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min

- QTc interval on ECG ≤ 0.48 seconds by Bazett's calculation (≤ CTCAE v.4 grade 2)

- Not pregnant or nursing

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation

- Patients must be able to swallow pills and have no significant impairment in
gastrointestinal absorption

- Patients with known or suspected germline mutation in BRCA1 or BRCA2 are eligible to
participate

- Patients in study screening (primarily those with pancreatic cancer) who have a
family history that is suspicious for BRCA1 or BRCA2 germline mutation should be
assessed by the BRCAPRO computer program to quantitate the likelihood of
harboring a deleterious BRCA mutation

- Patients found to have a BRCAPRO probability score of ≥ 20% should undergo
formal full-sequence BRCA testing

- Patients in screening with a BRCAPRO probability of ≥ 20% who decline genetic
testing are not eligible to participate in this trial due to the potential to
confound safety assessment

- No uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- HIV-positive patients are eligible

- No active seizure or history of seizure disorder

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to veliparib (ABT-888) or other agents used in this study

- No peripheral neuropathy greater than grade1

- No prior systemic treatment

- No prior cytotoxic chemotherapy (neoadjuvant, adjuvant, or metastatic setting)

- At least 4 weeks since major surgery or radiation therapy

- Patients may not be receiving any other investigational agents