A Phase I Study of ABT-888 in Combination With Topotecan Hydrochloride in Adults With Refractory Solid Tumors and Lymphomas
- The PARP family of enzymes is characterized by the ability to poly (ADP-ribosyl)ate
protein substrates. PARP-1 and PARP-2 play a critical role in the maintenance of
genomic stability by regulating a variety of DNA repair mechanisms.
- Poly (ADP-ribosylated) PARP-1 has been shown to block the formation of topo 1-DNA
cleavage and accelerate the removal of camptothecin-stabilized topo 1-DNA complexes.
PARP-1 inhibition may therefore prevent efficient repair of DNA damage induced by
topoisomerase 1 inhibitors. ABT-888 is an oral PARP inhibitor and topotecan is a
topoisomerase I inhibitor.
- Establish the safety and tolerability of the combination of ABT-888 with topotecan
hydrochloride in patients with refractory solid tumors and lymphomas.
- Establish the maximum tolerated dose of the combination of ABT-888 with topotecan
- Evaluate the pharmacokinetics of each agent alone and in combination.
- Determine the effects of the study treatment on the level of PARP inhibition and DNA
damage in PBMCs and tumor samples.
- Patients with histologically documented solid tumors and lymphoid malignancies
(lymphoma and CLL) whose disease has progressed following standard therapy or who have
no acceptable standard treatment options.
- No major surgery, radiation or chemotherapy within four weeks prior to study
enrollment, and recovered from toxicities of prior therapies to at least eligibility
- Cycle 1, dose levels -1 to 7 and 1B: Topotecan (TPT) will be administered intravenously
over 30 minutes as a single dose on days 1-5. Starting on day 2, ABT-888 will be
administered orally twice a day on a q12 hour schedule for 4 days (D2-5). Following the
completion of study drug administration on day 5, no further treatment will be
administered for the rest of this 21-day cycle. Growth factors will be administered
prophylactically starting Cycle 1 to patients on dose level 1B only.
- Cycle 2 and beyond, dose levels -1 to 7 and 1B: ABT-888 will be administered twice a
day on a q12 hour schedule orally on days 1-5. TPT will be given IV daily from days
1-5, in a 21-day cycle. Growth factors will be administered prophylactically to
patients on dose level 1B only.
- All cycles, dose levels -2 and 1A to 5A: ABT-888 will be administered on day 1 only for
dose levels -2 and 1A, 2A, 3A, and 4A. For dose level 5A, ABT-888 will be administered
on days 1 and 2 of each cycle. TPT will be given IV daily from days 1-5, in a 21-day
- Dose escalation will proceed as outlined below. Once maximum tolerated dose (MTD) is
established, 6 additional patients will be enrolled at the MTD to further define the
dose and evaluate PD studies at this dose level.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and tolerability of the combination of ABT-888 with topotecan hydrochloride in patients with refractory solid tumors and lymphomas; Establish the maximum tolerated dose of ABT-888 with topotecan hydrochloride.
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|