NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors

Abstract

Purpose: Veliparib is a Poly (ADP-ribose) polymerase inhibitor (PARPi) with activity in BRCA 1/2/PALB2 deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic with PARPi irrespective of homologous recombination deficiency (HRD), potentially expanding the role for PARPi. Patients and Methods NCI 7977 was a multi-cohort phase 1 clinical trial evaluating the safety and efficacy of multiple dose schedules of veliparib with irinotecan for solid tumors. In the intermittent veliparib cohort, escalating doses of veliparib were given twice daily at dose level (DL) 1 (50 mg) and DL 2 (100 mg) days 1-4 and 8-11 with irinotecan 100 mg/m2 days 3 and 10 in 21-day cycles. Results Fifteen patients enrolled, 8/15 (53%) received ≥ 4 prior systemic treatments. At DL1, 1/6 patients experienced a dose limiting toxicity (DLT) of diarrhea. At DL2, 9 patients were treated, with 3 unevaluable for DLT, and 2/6 evaluable patients experienced a DLT of grade 3 neutropenia. Irinotecan 100 mg/m2 and veliparib 50 mg twice daily was the maximum tolerated dose (MTD). No objective responses were observed, although 4 patients had progression free survival > 6 months. Conclusions The MTD of intermittent veliparib is 50 mg twice daily days 1-4 and 8-11 with weekly irinotecan 100 mg/m2 days 3 and 10 every 21 days. Multiple patients experienced prolonged stable disease irrespective of HRD and prior irinotecan. However, due to the toxicities with higher dose intermittent veliparib and irinotecan, this schedule was determined too toxic for further development and the arm was closed prematurely.

Targeted Treatment against Cancer Stem Cells in Colorectal Cancer

“…However, this treatment combination showed limited safety and poor tolerability in trials of escalating doses. The most common toxicities observed were diarrhea, GI toxicities, and neutropenia [ 104 ]. In a phase 2 randomized clinical trial [ 105 ], veliparib was compared to placebo, each with FOLFIRI +/− bevacizumab.…”