, Volume 23, Issue 5, pp 445-453

A phase I study of T900607 given once every 3 weeks in patients with advanced refractory cancers; National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) IND 130

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Abstract

Background: T900607 is a novel tubulin active agent which disrupts microtubule polymerization by a unique mechanism of action. This phase I trial was conducted to determine the maximum tolerated dose, recommended phase II dose, pharmacokinetic properties and toxicities of this agent. Patients and methods: Patients with advanced and/or metastatic solid malignancies were enrolled, for an open dose escalation of T900607 administered intravenously over 30 minutes every 21-days. Results: Thirty patients were enrolled on 7 dose levels ranging from 15 to 270 mg/m2. No DLTs were seen until 270 mg/m2, the sixth dose level, with 1 patient experiencing Grade 3 thrombocytopenia, 1 grade 4 troponin increase and 1 grade 5 myocardial infarction in an expanded cohort of 6 patients. The dose was decreased to 180 mg/m2 with increased cardiac monitoring and at this dose 3/4 patients experienced cardiac toxicity. Further animal cardiotoxicity studies failed to reveal any cardiac effects and the study was reopened at 130 mg/m2; of 6 enrolled patients, 1 had grade 3 drug related lethargy considered to be a DLT and this dose was considered the RP2D. No objective responses were seen but stable disease was reported in 7/20. Pharmacokinetic analysis showed that AUC and C max increased with dose with considerable intrapatient variability, a short half life of < 1 hour, and no apparent dose dependency clearance. Conclusions: The recommended phase II dose for T900607 is 130 mg/m2 given as an intravenous infusion over 60 minutes on a 21-day cycle. Cardiac toxicity was seen with this schedule.

This study was supported by grants from the National Cancer Institute of Canada and Tularik Inc., 1120 Veterans Blvd, San Francisco, CA 94080.