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


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.


RESULTS
Twenty-eight 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 (t(1/2)) 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.


CONCLUSIONS
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.
Wang-Gillam
Andrea
A
Department of Internal Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Arnold
Susanne M
SM
Bukowski
Ronald M
RM
Rothenberg
Mace L
ML
Cooper
Wendy
W
Wang
Kenneth K
KK
Gauthier
Eric
E
Lockhart
A Craig
AC
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D005260:Female; D006207:Half-Life; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D006846:Hydrocarbons, Halogenated; D014230:Triazoles; D050257:Tubulin Modulators; C521494:cevipabulin