Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors

Purpose. Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors. Experimental design. Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/mlxmin. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/mlxmin. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed. Results. The administered regimen of paclitaxel (225 mg/m(2) i.v. over 3 h) and carboplatin (AUC 6 mg/mlxmin i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m(2) i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease. Conclusions. The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors.