Milly E. de Jonge, Alwin D. R. Huitema, Annemarie C. Tukker
2005
Citations
0
Influential Citations
67
Citations
Journal
Clinical Cancer Research
Abstract
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.