Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors

Abstract

Background Poly (ADP-ribose) polymerase (PARP) is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor-mediated DNA damage. This Phase I study determined the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) and pharmacodynamics (PD) of veliparib, an orally-bioavailable PARP 1/2 inhibitor, in combination with irinotecan. Methods Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily (BID) oral dosing of veliparib (10–50 mg) 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. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1). Results Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1, 8) combined with veliparib 40 mg BID (days −1–14) on a 21-day cycle. Of 31 response-evaluable patients there were 6 (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared to irinotecan alone. Conclusions Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination.

The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity

“…Clofarabine is known to induce DNA damage response signaling (27); therefore, we evaluated the effects of these treatments on markers of DNA damage by immunofluorescence analysis of tumor segments using a validated assay (20,21). The combination yielded a significantly greater induction of γH2AX compared to both bortezomib alone and clofarabine alone at the 6 h time point (Fig.…”

“…Analyses of apoptosis (19) and DNA damage response biomarkers (20,21) were performed as described previously (see Supplementary Methods for details).…”

Synthetic Lethality Exploitation by an Anti–Trop-2-SN-38 Antibody–Drug Conjugate, IMMU-132, Plus PARP Inhibitors in BRCA1/2–wild-type Triple-Negative Breast Cancer

“…Singleagent olaparib toxicities include grade 3-4 fatigue and thrombocytopenia (5). In clinical studies evaluating the combination of either olaparib or veliparib with irinotecan, doselimiting toxicities included fatigue, anorexia, diarrhea, nausea, vomiting, febrile neutropenia, neutropenia, and thrombocytopenia (31,49). A hallmark in these clinical trials was that the amount of irinotecan and PARPi administered was reduced below the single-agent MTDs in order to gain acceptable tolerability.…”

Pilot trial of CRLX101 in patients with advanced, chemotherapy-refractory gastroesophageal cancer

“…As such, the combination of CRLX101 with mFOLFOX6 could be promising in gastroesophageal cancer patients. Other combinatorial opportunities include poly(ADP-ribose) polymerase (PARP) inhibitors potentiating the activity of Topo I inhibitors which have led to phase I studies combining irinotecan with PARP inhibitors in solid tumors (22,23). However, these studies to date have reported significant gastrointestinal and hematologic toxicities limiting PARP inhibitor and chemotherapy combinations to RP2D lower than their established monotherapy prescribing.…”