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

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.

Figures

Fig. 1

Study design. a Veliparib was administered in all three study parts 1 h prior to FOLFIRI infusion. b Reduced FOLFIRI = reduced dose of irinotecan 150 mg/m2 (90-min infusion) + folinic acid 400 mg/m2 (2-h infusion during irinotecan administration) + 5-FU 2,400 mg/m2 (46-h continuous infusion immediately following irinotecan administration). c Standard FOLFIRI = standard dose of irinotecan 180 mg/m2 (90-min infusion) + folinic acid 400 mg/m2 (2-h infusion during irinotecan administration) + 5-FU 400 mg/m2 (bolus immediately following irinotecan administration) and 2,400 mg/m2 (46-h continuous infusion). d Modified FOLFIRI = modified dose of irinotecan 180 mg/m2 (90-min infusion) + 5-FU 2,400 mg/m2 (46-h continuous infusion immediately following irinotecan administration). e The 400 mg/m2 bolus 5-FU dose was not tolerated during the first 2 weeks of cycle 1, before veliparib administration. Therefore, in part 1 of the study, only 4/67 patients received 400 mg/m2 of 5-FU bolus infusions starting cycle 2. For the remaining 63 patients, bolus administration of 5-FU was removed to reduce the toxic effects of 5-FU. Part 2 dose escalation was consequently discontinued and, although patients could continue veliparib, they were considered not evaluable. Data from part 2 were combined with those from part 3. 5-FU 5-fluorouracil, BID twice daily, DLT dose-limiting toxicity, FOLFIRI 5-fluorouracil plus folinic acid plus irinotecan, RP2D recommended phase 2 dose

Fig. 2

Evaluation of veliparib dose proportionality in part 1 of the study: mean (+SD) veliparib Cmax and AUC (top) and dose-normalized Cmax and AUC (bottom) presented vs increasing doses of veliparib (measured after the first administered dose of veliparib). Numbers of patients for each veliparib BID dose presented in the figure: n = 10 for 10 mg; n = 6 for 100 mg; n = 5 for 20 mg, 40 mg, and 200 mg; n = 4 for 80 mg and 130 mg; n = 7 for 160 mg; n = 9 for 270 mg Cmax, and n = 8 for 270 mg AUC0-8. AUC0–8 area under the plasma or serum concentration-time curve from time zero to hour 8, BID twice daily, Cmax maximum plasma concentration, SD standard deviation

Fig. 3

Kaplan–Meier curves for time to disease progression in a, all dosed patients, and b, expanded safety cohort. The number and percentage of patients with disease progression and the median number of days (and 95% CIs) to disease progression are detailed per cancer type. Censored events are depicted within each graph, and the numbers of patients at risk per cancer type are listed for each depicted timepoint. CI confidence interval, NR not reached