Abstract
BackgroundVeliparib 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.MethodsPatients 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.ResultsNinety-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%).ConclusionsThe acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.
Highlights
Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are abundant nuclear enzymes that recognise DNA damage, enable DNA repair, and prevent cellular cytotoxicity.[1,2] PARPs play a vital role in maintaining genomic stability as part of normal cellular physiology
All 92 patients were discontinued from the study; 77 (83.7%) patients discontinued primarily due to progressive disease (PD)
Tumour cell reliance on PARPmediated DNA repair provides the rationale for development of PARP inhibitors both as monotherapy and in combination with DNA-damaging chemotherapy and radiation therapy.[24,27]
Summary
Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are abundant nuclear enzymes that recognise DNA damage, enable DNA repair, and prevent cellular cytotoxicity.[1,2] PARPs play a vital role in maintaining genomic stability as part of normal cellular physiology. These enzymes are overexpressed in several cancer types and are implicated in tumourigenesis. 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. CONCLUSIONS: The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination
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