ABT-888 and Gemcitabine Hydrochloride in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. Establish the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the
combination of ABT-888 and gemcitabine (gemcitabine hydrochloride) in patients with advanced
solid tumors.

SECONDARY OBJECTIVES:

I. Establish the safety and tolerability of the combination of ABT-888 and gemcitabine in
patients with solid tumors.

II. Determine the effects of ABT-888 and gemcitabine treatment on DNA damage response by
analysis of markers such as Ataxia telangiectasia mutated (ATM) in peripheral blood
mononuclear cells (PBMCs).

III. Determine the pharmacokinetics of ABT-888 and gemcitabine when administered in
combination.

IV. Determine the generation of gemcitabine triphosphate in PBMCs. V. Document any evidence
of antitumor response.

OUTLINE: This is a dose-escalation study.

Patients receive oral ABT-888 twice daily on days 1-14 and gemcitabine hydrochloride IV over
30 minutes on days 1, 8, and 15. Courses repeat every 21* days in the absence of disease
progression or unacceptable toxicity.

After completion of study therapy, patients are followed up for at least 4 weeks.

NOTE: *Patients previously enrolled on a 4-week schedule (ABT-888 twice daily on days 1-21
with gemcitabine IV over 30 minutes once weekly on days 1, 8, and 15, and courses repeating
every 28 days) will continue on the 4-week schedule.

Inclusion Criteria:

- Histologically confirmed solid tumors meeting 1 of the following criteria:

- Progressive disease following standard therapy

- Disease for which acceptable standard treatment options do not exist

- May have received 0-2 prior chemotherapeutic regimens (single-agent or combination
chemotherapies)

- Willing to undergo BRCA mutation analysis

- Known BRCA mutations allowed

- All patients, at any dose level, without a known BRCA mutation undergo screening
with the BRCAPRO program to assess the likelihood of having a BRCA mutation

- Patients with a BRCAPRO likelihood of gene mutation of ≥ 20% must undergo BRCA
gene testing by the Myriad Genetic Laboratories in order to participate in the
study

- Patients are eligible whether they have a known deleterious BRCA 1 or 2
mutation or a mutation of uncertain significance

- No CNS disease (e.g., brain metastases or glioma)

- No active seizure or history of seizure disorder

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

- Life expectancy > 3 months

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Bilirubin < 2.0 mg/dL

- AST and ALT < 3 times upper limit of normal

- Creatinine normal OR creatinine clearance > 50 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to swallow pills

- HIV-positive patients allowed provided that CD4 counts are < 500 and not on protease
inhibitors

- No uncontrolled diarrhea

- 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 or social situations that would limit compliance with study
requirements

- No other concurrent anticancer therapies or agents

- More than 4 weeks since prior major surgery, radiotherapy, or chemotherapy (6 weeks
for mitomycin C or nitrosoureas) and recovered

- Prior gemcitabine hydrochloride or PARP inhibition therapy, including ABT-888,
allowed

- No prior combination of gemcitabine hydrochloride and any PARP inhibitor

- Concurrent bisphosphonate IV allowed provided treatment was initiated before study
therapy (for patients with bone metastases or hypercalcemia)

- Patients with prostate cancer must continue luteinizing-hormone releasing-hormone
agonist therapy and discontinue antiandrogens (≥ 6 weeks since bicalutamide and ≥ 4
weeks since flutamide)

- No other concurrent investigational agents