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


Authors: Varghese, A. M.; Cardin, D. B.; Hersch, J.; Benson, A. B.; Hochster, H. S.; Makris, L.; Hamada, K.; Berlin, J. D.; Saltz, L. B.
Article Title: Phase I study of trifluridine/tipiracil plus irinotecan and bevacizumab in advanced gastrointestinal tumors
Abstract: 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. © 2020 American Association for Cancer Research Inc.. All rights reserved.
Keywords: adult; treatment response; aged; middle aged; major clinical study; constipation; drug tolerability; fatigue; neutropenia; bevacizumab; area under the curve; cancer combination chemotherapy; diarrhea; drug efficacy; drug safety; drug withdrawal; hypertension; side effect; cancer patient; progression free survival; multiple cycle treatment; pain; anemia; leukopenia; nausea; stomatitis; vomiting; dehydration; cohort analysis; antineoplastic activity; irinotecan; abdominal pain; backache; chill; coughing; drug dose escalation; dyspnea; fever; hypokalemia; multicenter study; peripheral edema; open study; flu like syndrome; headache; maximum plasma concentration; time to maximum plasma concentration; maximum tolerated dose; phase 1 clinical trial; dyspepsia; muscle spasm; alopecia; epistaxis; proteinuria; tachycardia; dysgeusia; decreased appetite; gastrointestinal tumor; metastatic colorectal cancer; infusion related reaction; human; male; female; priority journal; article; volume of distribution; elimination half-life; treatment interruption; tipiracil plus trifluridine; oral clearance
Journal Title: Clinical Cancer Research
Volume: 26
Issue: 7
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2020-04-01
Start Page: 1555
End Page: 1562
Language: English
DOI: 10.1158/1078-0432.Ccr-19-2743
PUBMED: 31924737
PROVIDER: scopus
DOI/URL:
Notes: Article -- Source: Scopus
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MSK Authors
  1. Leonard B Saltz
    680 Saltz
  2. Jonathan T Hersch
    5 Hersch