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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.

SUBMITTER: Berlin J

PROVIDER: S-EPMC5933261 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Berlin Jordan J Ramanathan Ramesh K RK Strickler John H JH Subramaniam Deepa S DS Marshall John J Kang Yoon-Koo YK Hetman Robert R Dudley Matthew W MW Zeng Jiewei J Nickner Caroline C Xiong Hao H Komarnitsky Philip P Shepherd Stacie Peacock SP Hurwitz Herbert H Lenz Heinz-Josef HJ

British journal of cancer 20180312 7

<h4>Background</h4>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.<h4>Methods</h4>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<sup>2</sup>: irinotecan 150 mg/m<sup>2</sup> and folinic acid 400 mg ...[more]

PMID: 29527010

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Project description:BACKGROUND:NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions. PATIENTS AND METHODS:This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3?+?3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity. RESULTS:Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100?mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose. CONCLUSIONS:Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients. CLINCALTRIALS.GOV NUMBER:NCT02122913.

Dataset Information

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

Publications

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

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