A phase II clinical trial with proteomic profiling of imatinib mesylate in patients with refractory or relapsed epithelial ovarian cancer (EOC)

Abstract

9651 Background: PDGFR-β and c-kit expression have been described in EOC and imatinib is an inhibitor of both. A phase II clinical trial with proteomic signal pathway profiling is underway to elucidate both the clinical and biological activity of this new agent in EOC. Methods: Patients with relapsed or refractory EOC and no more than 4 prior regimens received imatinib at 400 mg bid; the starting dose was lowered to 600 mg daily due to toxicity. Patients were treated continuously in 28 day cycles and examined every 4 weeks, with imaging every 8 weeks. Tumors were biopsied prior to and after 4 weeks of treatment. Cytokine and growth factor concentrations were measured by ELISA in plasma and fluid samples. Results: Sixteen patients with a median of 4 prior regimens have been enrolled with 15 evaluable. Seven patients (47%) started treatment at 400 mg bid; 4 withdrew within 1 month. The remainder (9) started at 600 mg qd. Five patients (33%) without evidence of disease progression experienced unacceptable toxicities. Eleven patients (73%) experienced grade 3/4 toxicities. Fluid related toxicities included the following events: ascites 40% (6/15), pleural effusion 27% (4/15), and/or peripheral edema 13% (2/15). Non-fluid related grade 3 toxicities included nausea 27% (4/15), vomiting 20% (3/15), constipation, anorexia, hypoalbuminemia, anemia, and leucopenia (1 each); Median time on study was 63 days. Disease stabilization was observed for 4 and 5 months in 2 patients, respectively. Plasma VEGF and PDGF-AB increases were greater in patients who developed symptomatic ascites (p= 0.0012 and 0.04, respectively). Ascites reversed with cessation of imatinib. Profiling by tumor lysate arrays of proliferation, survival, and angiogenesis signaling pathways in tumor and stroma, and a potential mechanism for imatinib-related ascites accumulation will be presented. Conclusions: Imatinib has significant fluid related toxicity in patients with EOC precluding assessment of clear benefit. Based on this data there may be potential benefits from combination therapy with angiogenesis inhibitors. No significant financial relationships to disclose.