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