Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer.

Abstract

BACKGROUND:

TAS-102 is a nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). We investigated the recommended dose (RD) of TAS-102 plus irinotecan for metastatic colorectal cancer refractory to 5-fluorouracil (5-FU) and oxaliplatin.

METHODS:

This study was used a escalated dose of TAS-102 (40-70 mg/m(2)/day, for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest) with a fixed dose of irinotecan (150 mg/m(2) on Days 1 and 15 of a 28-day schedule). The primary endpoints were determination of RD and assessment of safety.

RESULTS:

Ten patients were enrolled; 7 at the Level 1 (50 mg/m(2)/day) and 3 at the Level 2 (60 mg/m(2)/day). One patient at Level 1 was excluded from the analysis of dose-limiting toxicities (DLT) and efficacy. Five DLTs occurred in 3 patients; 1 patient at Level 1 (Grade 3 febrile neutropenia and Grade 4 neutropenia), and 2 patients at Level 2 (Grade 3 febrile neutropenia in two patients and Grade 4 neutropenia in one). Grade 3 or higher treatment-related adverse events were neutropenia (100 %), leukopenia (70 %), febrile neutropenia (30 %) and lymphopenia, anaemia (20 % each). 2 patients (22 %) achieved partial response with the duration of response were 112 and 799 days.

CONCLUSION:

The RD was determined to be 50 mg/m(2)/day of TAS-102 combined with 150 mg/m(2) of irinotecan although further investigation to explore optimal regimen is warranted.

• Authors: Toshihiko Doi, Takayuki Yoshino, Nozomu Fuse, Narikazu Boku, Kentaro Yamazaki, Wasaburo Koizumi, Ken Shimada, Yasutaka Takinishi, Atsushi Ohtsu
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 5 Pg. 1068-77 (Oct 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 26163340 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• KRAS protein, human
• Pyrrolidines
• trifluridine tipiracil drug combination
• Uracil
• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• Proto-Oncogene Proteins p21(ras)
• Thymine
• Trifluridine
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Area Under Curve
• Camptothecin (analogs & derivatives, therapeutic use)
• Colorectal Neoplasms (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Drug Combinations
• Female
• Glucuronosyltransferase (genetics)
• Humans
• Irinotecan
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Metastasis
• Polymorphism, Genetic
• Proto-Oncogene Proteins p21(ras) (genetics)
• Pyrrolidines
• Thymine
• Trifluridine (pharmacokinetics, therapeutic use)
• Uracil (analogs & derivatives, pharmacokinetics, therapeutic use)