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: 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. 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.
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: 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. 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.
Authors: Nan Zhang; Semiramis Ayral-Kaloustian; Thai Nguyen; Jay Afragola; Richard Hernandez; Judy Lucas; James Gibbons; Carl Beyer Journal: J Med Chem Date: 2007-01-25 Impact factor: 7.446
Authors: Eric Van Cutsem; Vladimir M Moiseyenko; Sergei Tjulandin; Alejandro Majlis; Manuel Constenla; Corrado Boni; Adriano Rodrigues; Miguel Fodor; Yee Chao; Edouard Voznyi; Marie-Laure Risse; Jaffer A Ajani Journal: J Clin Oncol Date: 2006-11-01 Impact factor: 44.544
Authors: Ian F Tannock; Ronald de Wit; William R Berry; Jozsef Horti; Anna Pluzanska; Kim N Chi; Stephane Oudard; Christine Théodore; Nicholas D James; Ingela Turesson; Mark A Rosenthal; Mario A Eisenberger Journal: N Engl J Med Date: 2004-10-07 Impact factor: 91.245
Authors: Carl F Beyer; Nan Zhang; Richard Hernandez; Danielle Vitale; Thai Nguyen; Semiramis Ayral-Kaloustian; James J Gibbons Journal: Cancer Chemother Pharmacol Date: 2009-01-10 Impact factor: 3.333
Authors: Killian Oukoloff; Bobby Lucero; Karol R Francisco; Kurt R Brunden; Carlo Ballatore Journal: Eur J Med Chem Date: 2019-01-14 Impact factor: 6.514
Authors: Killian Oukoloff; Goodwell Nzou; Carmine Varricchio; Bobby Lucero; Thibault Alle; Jane Kovalevich; Ludovica Monti; Anne-Sophie Cornec; Yuemang Yao; Michael J James; John Q Trojanowski; Virginia M-Y Lee; Amos B Smith; Andrea Brancale; Kurt R Brunden; Carlo Ballatore Journal: J Med Chem Date: 2021-01-07 Impact factor: 7.446
Authors: Daniil N Lyapustin; Svetlana K Kotovskaya; Ilya I Butorin; Evgeny N Ulomsky; Vladimir L Rusinov; Denis A Babkov; Alexander A Pokhlebin; Alexander A Spasov; Vsevolod V Melekhin; Maria D Tokhtueva; Anna V Shcheglova; Oleg G Makeev Journal: Molecules Date: 2022-08-17 Impact factor: 4.927