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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 2/2013

01-02-2013 | Original Article

A phase I trial of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer

Authors: M. Michael, J. Zalcberg, P. Gibbs, L. Lipton, M. Gouillou, M. Jefford, G. McArthur, M. Copeman, K. Lynch, N. C. Tebbutt

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2013

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Abstract

Purpose

Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities.

Methods

Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6–bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily.

Results

Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib.

Conclusions

MTD was imatinib 400 mg plus full dose mFOLFOX–bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.
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Metadata
Title
A phase I trial of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer
Authors
M. Michael
J. Zalcberg
P. Gibbs
L. Lipton
M. Gouillou
M. Jefford
G. McArthur
M. Copeman
K. Lynch
N. C. Tebbutt
Publication date
01-02-2013
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 2/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-012-2009-5

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