Phase Ib trial of intravenous recombinant humanized monoclonal antibody tovascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: Pharmacologic and long-term safety data

Purpose: Tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) is inhibited by the recombinant humanized (rhu) monoclonal antibody (MAb) rhuMAbVEGF, which has synergy with chemotherapy in animal models. The present study was designed to assess the safety and pharmacokinetics of we ekly intravenous (IV) rhuMAbVEGF with one of three standard chemotherapy re gimens. Patients and Methods: Twelve adult patients were enrolled four on each comb ination, rhuMAbVEGF, 3 mg/kg IV, was administered weekly for 8 weeks with ( 1) doxarubicin 50 mg/m(2) every 4 weeks; (2) carboplatin at area under the curve of 6 plus paclitaxel 175 mg/m(2) every 4 weeks; and (3) fluorouracil (5-FU) 500 mg/m(2) with leucovorin 20 mg/m(2) weekly, weeks 1 to 6 every 8 weeks. Results: The median number of rhuMAbVEGF doses delivered was eight (range, four to eight doses). Grade 3 toxicities were diarrhea [one 5-FU patient], thrombo-cytopenia (two patients on carboplatin plus paclitaxel) and leukope nia (one patient on carboplatin plus paclitaxel). These toxicities were lik ely attributable to the chemotherapy component of the regimen. The mean (+/ -SD) peak serum revel of rhuMAbVEGF was 167 +/- 46 mug/ml, and the mean ter minal half-life was 13 days. Total (free plus bound) serum VEGF levers incr eased from 51 +/- 39 pg/mL (day 0) to 211 +/- 112 (day 49) pg/mL. Three res ponding patients continued treatment with rhuMAbVEGF and chemotherapy, rece iving the equivalent of 36, 20, and 40 total rhuMAbVEGF doses with no cumul ative or late toxicities. Conclusion: rhuMAbVEGF can be safely combined with chemotherapy at doses as sociated with VEGF blockade and without apparent synergistic toxicity. Its contribution to the treatment of advanced solid tumors should be evaluated in randomized treatment trials. (C) 2001 by American Society of Clinical On cology.