A phase i trial of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer

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

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9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)321-330
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number2
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

Keywords

  • Bevacizumab
  • Colorectal cancer
  • FOLFOX
  • Imatinib
  • Platelet-derived growth factor
  • Tumoral interstitial hypertension

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