1. 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
- Author
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Isamu Okamoto, Noriko Hokoda, Akio Ohyama, Miyako Satouchi, Takashi Seto, Kazuhiko Nakagawa, Masaki Miyazaki, Ryuichi Kitamura, Eiji Yoshihara, Hiroshige Yoshioka, Hiroshi Nakayama, Nobuyuki Yamamoto, Kazuo Kasahara, and Koji Takeda
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Indoles ,Lung Neoplasms ,Maximum Tolerated Dose ,Paclitaxel ,medicine.medical_treatment ,Pharmacology ,Adenocarcinoma ,Gastroenterology ,Carboplatin ,chemistry.chemical_compound ,Young Adult ,Phase I ,Non-small cell lung cancer ,Pharmacokinetics ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Pyrroles ,Tissue Distribution ,Lung cancer ,Adverse effect ,Aged ,Chemotherapy ,business.industry ,Area under the curve ,Middle Aged ,medicine.disease ,Oxindoles ,Treatment Outcome ,chemistry ,Oncology ,Toxicity ,Carcinoma, Squamous Cell ,Feasibility Studies ,Female ,Angiogenesis ,Propionates ,business ,Follow-Up Studies - Abstract
Introduction: TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, 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, 6 mg · 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.
- Published
- 2012
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