Weekly Paclitaxel with Intermittent Imatinib Mesylate (Gleevec®>): Tolerance and Activity in Recurrent Epithelial Ovarian Cancer

Objective: Imatinib mesylate (IM, Gleevec), a potent PDGF/PDGFR tyrosine kinase inhibitor, affects stroma and vascular endothelial cells. Our study sought to determine the safety and activity of paclitaxel with an intermittent schedule of IM. Materials and Methods: rEOC patients previously treated with platinum/paclitaxel and ≤2 regimens for recurrence were enrolled. Paclitaxel 80 mg/m 2 was given on days 3, 10, 17 every 28 days and oral IM 300 mg bid on days 1-4, 8-11, and 13-18. Results: Between 2007- 2009, 14 patients enrolled, 12 were evaluable. Nine patients were on study at 12 weeks. Objective responses (by RECIST and/or CA125) occurred in 4 patients. There were no grade 4, and only four grade 3 toxic events: diarrhea, edema and 2 cases of neutropenia. Early study closure was due to sufficient safety information with preliminary encouraging efficacy results. Conclusion: This weekly paclitaxel regimen with intermittent IM is tolerable with anti-tumor activity, making it suitable as part of future studies. Most patients with epithelial ovarian cancer (EOC) will relapse and undergo treatment with 'second-line' drugs, such as taxanes, topotecan, pegylated liposomal doxorubicin and/or gemcitabine (1). Greater understanding of the mechanisms of action and resistance pathways of these drugs may lead to more long-term control of disease. Weekly administration of paclitaxel provides a pharmaco- logically-based continuous exposure that is more effective and less toxic than administration every three weeks (2-3). Inhibition of angiogenesis may contribute to the antitumor effects of paclitaxel beyond direct cytotoxicity (4-6). Imatinib mesylate (IM, Gleevec ® ), a 2-phenylamino- pyrimidine derivative, is a selective inhibitor of ABL, c-KIT, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases (7). Platelet-derived growth factor (PDGF)