Phase I and Pharmacokinetic Study of the Dolastatin 10 Analogue TZT-1027, Given on Days 1 and 8 of a 3-Week Cycle in Patients with Advanced Solid Tumors

• Published in: Clinical cancer research 2005-05, Vol.11 (10), p.3806-3813
• Main Authors: de Jonge, Maja J A, van der Gaast, Ate, Planting, André S T, van Doorn, Leny, Lems, Aletta, Boot, Inge, Wanders, Jantien, Satomi, Masahiko, Verweij, Jaap
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Chromatography, High Pressure Liquid; Dolastatin 10 analog; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Oligopeptides - pharmacokinetics; Phase I; Solid tumors; TZT-1027
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-1937

Purpose: TZT-1027 { N 2 -( N,N -dimethyl- l -valyl)- N -[(1 S ,2 R )-2-methoxy-4-[(2 S )-2-[(1 R ,2 R )-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)]amino]propyl]-1-pyrrolidinyl]-1-[( S )-1-methylpropyl]-4-oxobutyl]- N -methyl- l -valinamide} is a cytotoxic dolastatin 10 derivative inhibiting microtubule assembly through the binding to tubulins. The objectives of this phase I study was to assess the dose-limiting toxicities (DLT), to determine the maximum tolerated dose, and to study the pharmacokinetics of TZT-1027 when given i.v. over 60 minutes on days 1 and 8 every 3 weeks to patients with advanced solid tumors. Experimental Design: Patients were treated with escalating doses of TZT-1027 at doses ranging from 1.35 to 2.7 mg/m 2 . For pharmacokinetic analysis, plasma sampling was done during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. Results: Seventeen patients received a total of >70 courses. The stopping dose was reached at 2.7 mg/m 2 , with neutropenia and infusion arm pain as DLT. Neutropenia was not complicated by fever. Over all dose levels, eight patients experienced pain in the infusion arm 1 to 2 days after administration of the drug, which seemed ameliorated by adding additional flushing after drug administration. Other side effects included nausea, vomiting, diarrhea, and fatigue. One partial response lasting >54 weeks was observed in an extensively pretreated patient with metastatic liposarcoma. The pharmacokinetics of TZT-1027 suggested linearity over the dose ranges. No correlation between body surface area and absolute CL of TZT-1027 was established, vindicating that a flat dosing regimen might be used in the future. A correlation was observed between the percentage decrease in neutrophil count and the AUC of TZT-1027. Conclusions: In this study, the DLT of TZT-1027 was neutropenia and infusion arm pain. The recommended dose for phase II studies of TZT-1027 is 2.4 mg/m 2 given i.v. over 60 minutes, on days 1 and 8 every 21 days. Phase II studies have recently started.