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Open Access 01-11-2015 | Original Article

Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer

Authors: Johanna C. Bendell, Lee S. Rosen, Robert J. Mayer, Jonathan W. Goldman, Jeffrey R. Infante, Fabio Benedetti, Donghu Lin, Hirokazu Mizuguchi, Christopher Zergebel, Manish R. Patel

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2015

Abstract

Purpose

To evaluate safety of TAS-102 administered twice daily (bid) on days 1–5 and 8–12 of a 4-week cycle, confirm feasibility of the Japanese recommended dose (RD), 35 mg/m², in Western patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies, and describe preliminary antitumor activity.

Methods

This open-label, dose-escalation phase 1 study was conducted at four US centers. Patients were enrolled into two sequential cohorts [30 (cohort 1) or 35 mg/m²/dose bid (cohort 2)]; dose-limiting toxicities (DLT) were evaluated during cycle 1 in dose-escalation cohorts. At RD, 15 additional patients were enrolled in an expansion cohort.

Results

Patients (N = 27) with refractory mCRC received TAS-102; 74 % had received ≥4 prior regimens. DLT was not observed in three patients in cohort 1, and was in one out of nine patients in cohort 2 (grade 3 febrile neutropenia). Therefore, RD was identified as 35 mg/m² bid. At RD, fatigue (63 %), gastrointestinal disturbances and nausea (46 %), vomiting (46 %), and diarrhea (42 %) were common but rarely grade 3/4. Grade 3/4 nausea, vomiting, and diarrhea occurred at 4 % each. Grade 3/4 toxicity was predominantly hematologic [neutropenia (71 %), anemia (25 %)]; febrile neutropenia was observed in two patients. Stable disease lasting ≥6 weeks was achieved by 16 evaluable patients (70 %); median progression-free survival and overall survival were 5.3 and 7.5 months, respectively.

Conclusions

TAS-102 has an acceptable safety profile and preliminary evidence of disease stabilization in Western patients with refractory mCRC. Results from a randomized phase 3 study have shown survival benefit with disease stabilization evidence in this population.

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Title: Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer
Authors: Johanna C. Bendell
Lee S. Rosen
Robert J. Mayer
Jonathan W. Goldman
Jeffrey R. Infante
Fabio Benedetti
Donghu Lin
Hirokazu Mizuguchi
Christopher Zergebel
Manish R. Patel
Publication date: 01-11-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2015
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2850-4

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