A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumours
Jordan Berlin, Ramesh K Ramanathan, John H Strickler, Deepa S Subramaniam, John Marshall, Yoon-Koo Kang, Robert Hetman, Matthew W Dudley, Jiewei Zeng, Caroline Nickner, Hao Xiong, Philip Komarnitsky, Stacie Peacock Shepherd, Herbert Hurwitz, Heinz-Josef Lenz, Jordan Berlin, Ramesh K Ramanathan, John H Strickler, Deepa S Subramaniam, John Marshall, Yoon-Koo Kang, Robert Hetman, Matthew W Dudley, Jiewei Zeng, Caroline Nickner, Hao Xiong, Philip Komarnitsky, Stacie Peacock Shepherd, Herbert Hurwitz, Heinz-Josef Lenz
Abstract
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/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (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.
Trial registration: ClinicalTrials.gov NCT01123876.
Conflict of interest statement
H.-J.L., R.K.R., and J.H.S.: research funding from AbbVie. J.B.: research funding from AbbVie and AbbVie ad board. S.P.S.: former employee of AbbVie. May hold AbbVie stock or options. Holds Abbott and Corcept stocks. D.S.S.: No disclosure pertaining to this study. Advisory board member for BMS, AstraZeneca, Takeda Oncology. H.H.: research funding from AbbVie. H.X., R.H., J.Z., P.K., C.N., and M.W.D.: employed by AbbVie. May hold AbbVie stock or options. The remaining authors declare that they have no competing financial interests.
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