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

Andrea Wang-Gillam, Susanne M. Arnold, Ronald M. Bukowski, Mace L. Rothenberg, Wendy Cooper, Kenneth K. Wang, Eric Gauthier, Albert Lockhart

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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: Twentyeight 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 (t1/2) 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.

Original languageEnglish (US)
Pages (from-to)266-272
Number of pages7
JournalInvestigational New Drugs
Volume30
Issue number1
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

Fingerprint

Neoplasms
Maximum Tolerated Dose
Neutropenia
Pharmacokinetics
Tubulin
cevipabulin
Half-Life
Fever
Pharmaceutical Preparations

Keywords

  • Anti-tubulin drugs
  • Phase I study
  • TTI-237

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Wang-Gillam, A., Arnold, S. M., Bukowski, R. M., Rothenberg, M. L., Cooper, W., Wang, K. K., ... Lockhart, A. (2012). A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors. Investigational New Drugs, 30(1), 266-272. https://doi.org/10.1007/s10637-010-9506-3

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors. / Wang-Gillam, Andrea; Arnold, Susanne M.; Bukowski, Ronald M.; Rothenberg, Mace L.; Cooper, Wendy; Wang, Kenneth K.; Gauthier, Eric; Lockhart, Albert.

In: Investigational New Drugs, Vol. 30, No. 1, 01.02.2012, p. 266-272.

Research output: Contribution to journalArticle

Wang-Gillam, A, Arnold, SM, Bukowski, RM, Rothenberg, ML, Cooper, W, Wang, KK, Gauthier, E & Lockhart, A 2012, 'A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors', Investigational New Drugs, vol. 30, no. 1, pp. 266-272. https://doi.org/10.1007/s10637-010-9506-3
Wang-Gillam A, Arnold SM, Bukowski RM, Rothenberg ML, Cooper W, Wang KK et al. A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors. Investigational New Drugs. 2012 Feb 1;30(1):266-272. https://doi.org/10.1007/s10637-010-9506-3
Wang-Gillam, Andrea ; Arnold, Susanne M. ; Bukowski, Ronald M. ; Rothenberg, Mace L. ; Cooper, Wendy ; Wang, Kenneth K. ; Gauthier, Eric ; Lockhart, Albert. / A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors. In: Investigational New Drugs. 2012 ; Vol. 30, No. 1. pp. 266-272.
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abstract = "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: Twentyeight 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 (t1/2) 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.",
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