title: 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.affiliation: 1TZT-1027 Cooperative Study Group, and Division of Thoracic Oncology, Shizuoka Cancer Center, Shimonagakubo 1007 Shunto-gun, Shizuoka, Japan. n.yamamoto@scchr.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Andoh
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kawahara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Niitani
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047630:Depsipeptides / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use*; D058105:Polymerization; D015996:Survival Rate; D016896:Treatment Outcome; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; D014404:Tubulin; D050257:Tubulin Modulators; C105791:soblidotin; C064570:dolastatin 10