Phase I and pharmacokinetic study of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, by twice daily oral administration between meals in patients with advanced solid tumors

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on TSU-68, a novel multiple receptor tyrosine kinase inhibitor, was performed to determine the safety profile, maximum-tolerated dose for Japanese patients with advanced solid tumors and to define the recommended dose of phase II studies. METHODS: Study design was a dose escalation method on a three-patient cohort. TSU-68 was given orally twice daily (bid) between meals without interruption; the estimation of dose escalation was based on the toxicity within 4 week administration at each dose level. RESULTS: Fifteen patients were enrolled into the study. Dose levels studied were 200, 400, 800, and 1,200 mg/m(2) bid. Grade 3 arrhythmia and anemia/thrombocytopenia were observed in 1 patient each at 800 mg/m(2) bid. Three patients discontinued continuous oral administration for 4 weeks at 400 and 800 mg/m(2) bid. At 1,200 mg/m(2) bid, 2 patients discontinued the treatment over 4 weeks for intolerable fatigue and abdominal pain, respectively. No serious drug-related toxicities have been observed. Grade 1–2 toxicity included urinary/feces discoloration, diarrhea, fatigue, anorexia, abdominal/chest pain, and edema. Tumor shrinkage was observed in 1 patient of NSCLC. In the pharmacokinetics, at any dose levels, C(max) and AUC(0–t) after repeated administration of TSU-68 on days 8 and 29 were ~2-fold lower that those after the first administration on day 1; these parameters are similar between days 8 and 28. In addition, no obvious dose-dependent increase in plasma exposure to TSU-68 repeatedly administered was observed over the four dose levels, including the higher dose levels. CONCLUSIONS: The tolerable dose in this administration schedule for continuing treatment is thought to be 800 mg/m(2) or less bid.