A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours

摘要

Background Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. Methods Patients received veliparib (10–270?mg BID, days 1–5, 15–19) and FOLFIRI (days 1–3, 15–17) in three regimens containing 5-fluorouracil 2,400?mg/m~(2): irinotecan 150?mg/m~(2)and folinic acid 400?mg/m~(2)(part 1); irinotecan 180?mg/m~(2), folinic acid 400?mg/m~(2), and 5-fluorouracil 400?mg/m~(2)bolus (part 2), or irinotecan 180?mg/m~(2)(part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed. Results Ninety-two patients received ≥1 veliparib dose. MTD was not reached; RP2D was set at 200?mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities ( n ?=?4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%). Conclusions The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.