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.

Abstract

PURPOSE:

TZT-1027 [N(2)-(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/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.

• Authors: Maja J A de Jonge, Ate van der Gaast, André S T Planting, Leny van Doorn, Aletta Lems, Inge Boot, Jantien Wanders, Masahiko Satomi, Jaap Verweij
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 10 Pg. 3806-13 (May 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15897580 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Oligopeptides
• soblidotin

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Chromatography, High Pressure Liquid
• Drug Administration Schedule
• Female
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Oligopeptides (administration & dosage, adverse effects, pharmacokinetics)