Phase I study of trifluridine/tipiracil plus irinotecan and bevacizumab in advanced gastrointestinal tumors

Purpose: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). Patients and Methods: Dose escalation (3þ3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m² twice daily; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m²; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. Results: Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m² twice daily plus irinotecan 180 mg/m². In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months). Conclusions: Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecan-bevacizumab combination in previously treated mCRC.