Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888; V) in combination with irinotecan (CPT-11; Ir) in patients (pts) with advanced solid tumors.

Abstract

3000 Background: The nuclear enzyme PARP is essential in recognition and repair of DNA damage. In preclinical models, PARP inhibitors work as sensitizing agents for DNA-damaging agents such as Ir. V is an orally bioavailable PARP 1 and 2 inhibitor. This phase I study determined the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), PK and PD of V together with Ir. Methods: Eligibility included patients with performance status 0-2; ≥ age 18; adequate bone marrow, hepatic and renal function. Cycles were 21 days. Ir was given i.v. 100 mg/m2 over 90 min on Days 1 and 8. Twice daily (BID) oral dosing of V (10-50mg) occurred Days 3-14 (Cycle 1) and Days -1-14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Tumor biopsies and matched peripheral blood mononuclear cells (PBMCs) were collected for PD evaluation of PAR, γ-H2AX, PARP1, TOPO1, and ERCC1 after Ir alone and after the combination. Results: 32 pts were treated (2 lung, 14 breast, 4 esophageal, 7 ovarian, 4 colon, 1 anal). Median age was 53 (range 31-73). Most frequent drug-related toxicities included: diarrhea (59%), nausea (56%), leucopenia (50%), fatigue (47%), neutropenia (47%), anemia (34%), and vomiting (31%). DLTs included fatigue, diarrhea, febrile neutropenia (gr 3), leukopenia and, neutropenia (gr 4). Response has been determined for 28 pts. A clinical benefit (CB) rate of 61% (5 PR, 2 MR, 10 SD) was observed. V exhibited linear PK over the dose range of 10 to 50 mg BID; co-administration of Ir did not affect PK of V. Exploratory analysis of pre/post-V treatment changes indicated median ERCC1 levels in tumor tissue and PBMCs differed somewhat by CB status. PAR levels in paired tumor biopsies showed > 50% reduction in 17 of 19 pts and > 90% reduction in 10 of 19 pts. Conclusions: The MTD and recommended phase II dose was established as 100 mg/m2 of Ir given i.v. Days 1 and 8 combined with 40 mg of V given BID 15 days on/6 days off (21 day cycle). Exploratory analysis demonstrated that V reduced PAR levels in tumor. Support: NCI U01-CA062487 and NCI R21-CA135572.