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

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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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Acknowledgments

I would like to thank the analytical staff of the Translational Research Laboratory, Peter MacCallum Cancer Centre for the oxaliplatin and 5FU analysis. I would also thank the analytical staff of the Royal Adelaide Hospital for the imatinib analysis. This work was supported by funding from Novartis Australia.

Conflict of interest

J. Zalcberg: Travel and Research Funding and Honorarium; K. Lynch: Previous employee of Novartis Australia; M. Copeman: Employee of Novartis Australia, G. McArthur: Research funding from Novartis; M. Michael, M. Jefford, M. Gouillou, P. Gibbs, L. Lipton, N.C. Tebbutt: No conflict of interest.

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Authors and Affiliations

  1. Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, Victoria, 8006, Australia

    M. Michael, J. Zalcberg, M. Jefford & G. McArthur

  2. Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, VIC, 3050, Australia

    P. Gibbs & L. Lipton

  3. Department of Medical Oncology, Western Hospital, Gordon St, Footscray, VIC, Australia

    L. Lipton

  4. Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, Victoria, 8006, Australia

    M. Gouillou

  5. Novartis Pharmaceuticals, Australia, Pty Ltd, 54 Waterloo Rd, North Ryde, NSW, Australia

    M. Copeman

  6. Celgene Australia (ex-employee Novartis Pharmaceuticals, Australia), Level 7, 607 St Kilda Road, Melbourne, 3004, Australia

    K. Lynch

  7. Department of Medical Oncology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia

    N. C. Tebbutt

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  1. M. Michael
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Correspondence to M. Michael.

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Michael, M., Zalcberg, J., Gibbs, P. et al. A phase I trial of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer. Cancer Chemother Pharmacol 71, 321–330 (2013). https://doi.org/10.1007/s00280-012-2009-5

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  • DOI: https://doi.org/10.1007/s00280-012-2009-5

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