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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

Authors' Affiliations: ¹ Erasmus University Medical Center/Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; ² Daiichi Pharmaceuticals UK, Ltd., London, United Kingdom; and ³ Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan

Requests for reprints: Maja J.A. de Jonge, Department of Medical Oncology,Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands. Phone: 31-10-4391760; Fax: 31-10-4391003; E-mail: m.dejonge{at}erasmusc.nl.

Purpose: TZT-1027 {N²-(N,N-dimethyl-L-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-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/m². 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/m², 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/m² given i.v. over 60 minutes, on days 1 and 8 every 21 days. Phase II studies have recently started.

Key Words: TZT-1027 • Dolastatin 10 analog • Phase I • Solid tumors

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