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.
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.


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.
Gelmon
Karen A
KA
British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, BC, Canada, V5Z 4E6. kgelmon@bccancer.bc.ca
Belanger
Karl
K
Soulieres
Denis
D
Britten
Carolyn
C
Chia
Stephen
S
Charpentier
Danielle
D
Chi
Kim
K
Powers
Jean
J
Walsh
Wendy
W
Seymour
Lesley
L
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D013921:Thrombocytopenia / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
D000970:Antineoplastic Agents; D013449:Sulfonamides; C508276:T 900607