This phase I trial is studying the side effects and best dose of giving ABT-888 together with gemcitabine hydrochloride in treating patients with advanced solid tumors. ABT-888 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving ABT-888 together with gemcitabine hydrochloride may kill more tumor cells.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
31
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, United States
UPMC-Magee Womens Hospital
Pittsburgh, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States
MTD of ABT-888 and gemcitabine hydrochloride, determined according to incidence of DLT graded using the NCI CTCAE version 4.0
Time frame: 3 weeks
Adverse events as assessed by NCI CTCAE v 4.0
The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category and grade. We will describe all DLTs and other serious (≥ grade 3) on a patient-by-patient basis; descriptions will include dose level and any relevant baseline data. Statistics on the number of cycles received by patients and any dose reductions will be tabulated.
Time frame: Up to 4 weeks after completion of study treatment
Plasma concentrations of gemcitabine hydrochloride and ABT-888
Plasma concentration versus time data will be analyzed non-compartmentally using PK Solutions 2.0. Data may also be analyzed using compartmental methods as implemented by the ADAPT computer program or a suitable commercially available software package. Relationships between pharmacokinetic and pharmacodynamic data will be explored and evaluated using the ADAPT computer program or a suitable commercially available software packages.
Time frame: Pre-drug, 25, 60, and 90 min, 2, 3, 4, 6, and 8 hours post-ABT-888 on day -2; pre-drug, 15, 25 (before end of gemcitabine infusion), 60, and 90 min, 2, 3, 4, 6, 8, 24, and 48 h after the start of gemcitabine hydrochloride infusion on day 1 of course 1
Response (complete or partial response)
Responses and incidence of stable disease will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
Time frame: Up to 4 weeks after completion of study treatment
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