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

Anna M. Varghese, Dana B. Cardin, Jonathan Hersch, Al B. Benson, Howard S. Hochster, Lukas Makris, Kensuke Hamada, Jordan D. Berlin, Leonard B. Saltz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1555-1562
Number of pages8
JournalClinical Cancer Research
Issue number7
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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