Selective kinase inhibition with daily imatinib intensifies toxicity of chemotherapy in patients with solid tumours Suzanne George*, Jayesh Desai, J. Paul Eder, Judith Manola, David P. Ryan, Leonard J. Appleman, George D. Demetri Dana-Farber Cancer Institute, Massachusetts General Hospital, Ludwig Center for Cancer Research at Dana-Farber/Harvard, Harvard Medical School, Boston, MA, United States ARTICLE INFO Article history: Received 4 December 2005 Accepted 6 December 2005 Available online 28 February 2006 Keywords: Targeted therapy Kinase inhibition Clinical trial Chemotherapy ABSTRACT The aim of this study was to determine the safety and maximum-tolerated doses of imati- nib combined with cytotoxic chemotherapy (either gemcitabine or doxorubicin). Patients with advanced solid tumours were enrolled separately in two different combinations of imatinib with chemotherapy (imatinib + gemcitabine or imatinib + doxorubicin). A stan- dard modified Fibonacci inter-cohort dose escalation was planned for each combination. Sixteen patients were accrued. Seven patients received gemcitabine and imatinib. A sepa- rate cohort of nine patients received imatinib and doxorubicin. In both groups, dose-limit- ing toxicity (DLT) was observed at the initial dose level requiring dose reductions for subsequent cohorts. Further DLTs were observed necessitating closure of the protocol. Daily dosing of imatinib with concurrent administration of cytotoxic chemotherapy (either gemcitabine or doxorubicin) at standard doses was associated with toxicity that was clin- ically unacceptable. It remains unclear whether addition of growth factors might improve tolerability for imatininb in combination with cytotoxic chemotherapy. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Despite the development of newer molecular targeted ap- proaches to cancer therapy, cytotoxic chemotherapy remains a major modality for treatment of patients with common so- lid tumours. Emergence of resistance to these drugs remains a common problem and limits the effectiveness of chemo- therapy. A number of mechanisms underlying chemoresis- tance have been proposed, including the development of genetic mutations preventing chemotherapy-induced apopto- sis, or the high interstitial pressures that exist within the tu- mour matrix, 1 resulting in suboptimal drug delivery to cancer cells resident within large tumours. The molecular mecha- nisms underlying changes in interstitial pressures are depen- dent on a number of influences. Signalling through the platelet-derived growth factor (PDGF) receptor and ligand sys- tem is believed to play a central role in modulating intratumo- ural interstitial fluid pressures, particularly via the PDGFb receptor. 2–4 Deregulation of PDGF-receptor signalling has also been implicated in several types of cancers including prostate, 5,6 lung, 7 breast, 8 sarcomas, 9 gliomas, 10–12 and ovarian cancers. 13 Imatinib mesylate (Glivec Ò , also known as Gleevec TM in North America; Novartis Pharmaceuticals) is a small molecule phenylaminopyrimidine derivative that selectively inhibits a number of protein tyrosine kinases involved in cellular 0959-8049/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2005.12.010 * Corresponding author: Present address: Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, SW530, 44 Binney Street, Boston, MA 02115, United States. Tel.: +1 617 632 5204; fax: +1 617 632 3408. E-mail address: Suzanne_George@dfci.harvard.edu (S. George). EUROPEAN JOURNAL OF CANCER 42 (2006) 864 – 870 available at www.sciencedirect.com journal homepage: www.ejconline.com