Veliparib, Oxaliplatin, and Capecitabine in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of
ABT-888 (veliparib) in combination with oxaliplatin and capecitabine in advanced solid
tumors.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of ABT-888, oxaliplatin, and capecitabine when
administered concomitantly.

II. To evaluate the safety and tolerability of the ABT-888 in combination with capecitabine
and oxaliplatin.

III. To assess for evidence of anti-tumor activity with this combination, per tumor
measurements using RECIST criteria, in these patients.

TERTIARY OBJECTIVES:

I. To assess the inhibition of poly(ADP-ribose) polymerase (PARP) in peripheral blood
mononuclear cells secondary to treatment with ABT-888.

II. To determine the pharmacokinetics of ABT-888 in combination with oxaliplatin and
capecitabine and the relation to treatment side effects.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive veliparib orally (PO) twice daily and capecitabine PO twice daily on 1-7
and 15-21, and oxaliplatin intravenously (IV) over 2 hours on days 1 and 15. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood and urine sample collection at baseline and periodically during study
for pharmacokinetic and poly (ADP-ribose) polymerase (PARP) inhibition studies.

After completion of study therapy, patients are followed up for 30 days.

Inclusion Criteria:

- Histologically or cytologically confirmed solid tumors that fulfill ≥ 1 of the
following criteria:

- BRCA1/2 mutation and a BRCA-related malignancy

- Patients without a known BRCA mutation must have a probability of harboring
a BRCA gene mutation as assessed by BRCAPRO computer program

- Patients with a probability of having genetic mutation ≥ 20% or a BRCA
mutation based on a non-Myriad test, must have a formal BRCA testing by
Myriad Genetic Laboratories

- Patients with known deleterious BRCA 1 or 2 mutation or a mutation of
uncertain significance

- Patients who refuse BRCA testing not allowed unless they have another
acceptable histology

- First- or second-line metastatic colorectal cancer

- Any-line metastatic mucinous ovarian cancer

- Any line of other metastatic gastrointestinal malignancies in which oxaliplatin
has shown some activity (i.e., gastric or pancreatic adenocarcinoma)

- Patients with uncontrolled CNS metastasis are not eligible; patients with CNS
metastases who have had them treated and are stable for > 3 months will be eligible;
patients must be off steroid treatment prior to study enrollment

- Measurable disease

- Patients with ovarian cancer who have a pre-treatment CA 125 level of at least
twice the upper limit of normal allowed

- ECOG performance status (PS) 0-2 (Karnofsky 60-100%)

- Life expectancy > 3 months

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver metastases)

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Fertile patients must use adequate contraception (i.e., hormonal, barrier method of
birth control, or abstinence)

- Not pregnant or nursing

- Negative pregnancy test

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

- No 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 and/or social situations that would limit compliance with
study requirements

- No history of positive serology for hepatitis A, B, or C, liver disease, or other
forms of hepatitis or cirrhosis

- Patients who have active seizures or history of seizures are ineligible

- No condition that impairs the ability to swallow and retain veliparib capsules,
including any of the following:

- Gastrointestinal tract disease resulting in an inability to take oral medication
or a requirement for IV alimentation

- Prior surgical procedures affecting absorption

- Active peptic ulcer disease

- No malabsorption syndrome, disease significantly affecting gastrointestinal function,
resection of the stomach or small bowel, ulcerative colitis, inflammatory bowel
disease, or a partial or complete small bowel obstruction

- No peripheral neuropathy ≥ grade 2

- No prolonged QTC > 450 msec (male) or QTC > 470 (female)

- No concurrent combination antiretroviral therapy for HIV-positive patients

- Recovered from adverse events of prior therapy or prior surgical procedures

- Patients with chronic grade 1 or 2 adverse events that are not expected to
improve are allowed at investigator's discretion

- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)

- At least 4 weeks since prior radiotherapy with no > 35% of marrow irradiation

- Prior fluoropyrimidine allowed

- Prior veliparib allowed provided it was part of a single- or limited-dosing study,
such as a phase 0 study

- Prior capecitabine allowed provided patient tolerated 3500 mg/m² for 7 days out of 14
days

- No other prior investigational agents

- No prior oxaliplatin