Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, given weekly to advanced solid tumor patients for 3 weeks.

Abstract

TZT-1027 is a novel synthetic dolastatin 10 derivative that inhibits tubulin polymerization. A phase I study was conducted to determine the maximum tolerated dose (MTD) of TZT-1027, and to assess its pharmacokinetic profile in Japanese patients with advanced solid tumors following administration of the drug weekly for 3 weeks. Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and met the following criteria: performance status ≤2 and acceptable organ function. The MTD was defined as the highest dose at which more than two-thirds of the patients experienced grade 4 hematological toxicity or grade 3/4 non-hematological toxicity during weekly TZT-1027 administration for 3 weeks. Forty patients were enrolled in the present study. Twelve doses between 0.3 and 2.1 mg/m2 were evaluated. Grade 4 neutropenia was the principal dose-limiting toxicity (DLT). At a dose of 2.1 mg/m2, two patients developed DLT: one patient developed grade 4 neutropenia, grade 3 myalgia, and grade 4 constipation, and the other one developed grade 4 neutropenia and grade 3 constipation. At a dose level of 1.8 mg/m2, toxicity was acceptable and no DLT was observed. The area under the curve and maximum concentration of TZT-1027 tended to increase linearly with the dose. The DLT observed were neutropenia, myalgia, and constipation, and the MTD was 2.1 mg/m2. The recommended dose for a phase II study was determined to be 1.8 mg/m2 for the drug administered weekly for 3 weeks.

• Authors: Nobuyuki Yamamoto, Masahiro Andoh, Masaaki Kawahara, Masahiro Fukuoka, Hisanobu Niitani
• Journal: Cancer science (Cancer Sci) Vol. 100 Issue 2 Pg. 316-21 (Feb 2009) ISSN: 1349-7006 [Electronic] England
• PMID: 19068085 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Depsipeptides
• Oligopeptides
• Tubulin
• Tubulin Modulators
• soblidotin
• dolastatin 10

Topics

• Adult
• Aged
• Antineoplastic Agents (therapeutic use)
• Depsipeptides (chemistry)
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, metabolism, pathology)
• Oligopeptides (chemistry, therapeutic use)
• Polymerization
• Survival Rate
• Treatment Outcome
• Tubulin (metabolism)
• Tubulin Modulators (chemistry, therapeutic use)