Phase I Clinical Study of the Angiogenesis Inhibitor TSU-68 Combined with Carboplatin and Paclitaxel in Chemotherapy-Naive Patients with Advanced Non-small Cell Lung Cancer

Introduction: TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor beta, and fibroblast growth factor receptor 1. An open-label, single-arm, phase I study was performed to evaluate escalating doses of TSU-68 in combination with standard chemotherapy in patients with advanced non-small cell lung cancer. Methods: Eligible patients received TSU-68 at 200 or 400 mg twice daily and continuously in combination with carboplatin (area under the curve, 6mg . min/mL) plus paclitaxel (200 mg/m(2)) on day 1 every 21 days. Results: Thirty-seven patients were enrolled at the two dose levels of TSU-68. No dose-limiting toxicities were observed with TSU-68 at the 200 mg twice a day dose level. At 400 mg twice a day, one of six patients experienced a dose-limiting toxicity (anorexia of grade 3) during the first cycle. The 400 mg twice a day dose level was determined to be the recommended dose, and a total of 34 patients were treated at this dose. Overall, adverse events were mild to moderate in severity, with the most frequently observed such events being myelosuppression, neuropathy, and gastrointestinal disorders. No drug-related bleeding was observed. The objective response rate was 39.4% (95% confidence interval, 22.9-57.9%), and median progression-free survival was 5.6 months (95% confidence interval, 3.6-7.2 months). Coadministration of TSU-68, carboplatin, and paclitaxel had no substantial impact on the pharmacokinetics of these drugs. Conclusions: TSU-68 can be safely combined with standard doses of carboplatin-paclitaxel, with the combination manifesting promising antitumor activity.