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

• Published in: Cancer science 2009-02, Vol.100 (2), p.316-321
• Main Authors: Yamamoto, Nobuyuki, Andoh, Masahiro, Kawahara, Masaaki, Fukuoka, Masahiro, Niitani, Hisanobu
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Depsipeptides - chemistry; Female; Humans; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oligopeptides - chemistry; Oligopeptides - therapeutic use; Original; Polymerization; Survival Rate; Treatment Outcome; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - therapeutic use; Tumors
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/j.1349-7006.2008.01023.x

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. (Cancer Sci 2009; 100: 316–321)