A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors

Purpose: This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Patients and methods: Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m ². Pharmacokinetic studies were performed in patients at all dose levels. Result: Twentyeight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m ². One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m ², and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m ². Six patients were treated at the 18 mg/m ² dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t1/2) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m ² was 2,768 ng•h/ mL. Conclusion: A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m ² may be a tolerable dose of TTI-237.