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.

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/m(2). No DLTs were seen until 270 mg/m(2), 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/m(2) 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/m(2); 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/m(2) given as an intravenous infusion over 60 minutes on a 21-day cycle. Cardiac toxicity was seen with this schedule.

• Authors: Karen A Gelmon, Karl Belanger, Denis Soulieres, Carolyn Britten, Stephen Chia, Danielle Charpentier, Kim Chi, Jean Powers, Wendy Walsh, Lesley Seymour
• Journal: Investigational new drugs (Invest New Drugs) Vol. 23 Issue 5 Pg. 445-53 (Oct 2005) ISSN: 0167-6997 [Print] United States
• PMID: 16133796 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Sulfonamides
• T 900607

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Fatigue (chemically induced)
• Female
• Heart (drug effects, physiology)
• Humans
• Male
• Middle Aged
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism)
• Sulfonamides (administration & dosage, adverse effects, pharmacokinetics)
• Thrombocytopenia (chemically induced)
• Vomiting (chemically induced)