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 {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.

Angiogenesis: An update and potential drug approaches (Review)

“…Data has shown that 33% of patients treated with TZT-1027 had stable disease as defined by RECIST criteria. Another phase I trial of TZT-1027 in 17 patients treated on days 1 and 8 of a 3-week course was reported (134). A partial response within 50 weeks of treatment in a patient with metastatic liposarcoma was observed.…”

Antimycobacterial Activity from Cyanobacterial Extracts and Phytochemical Screening of Methanol Extract ofHapalosiphon.

“…Many compounds isolated from cyanobacteria such as dolastatins, curacins, and cryptophycins have shown antitumor activity (Simmons et al, 2005). Among these, dolastatin 10 and cryptiphycin 52 have entered into clinical trials for solid tumors (Jonge et al, 2005) and lung cancer, respectively (Edelman et al, 2005). Kreitlow and Sabine (1999) evaluated the antibiotic activities of hydrophilic and lipophilic extracts of 12 strains of cyanobacteria collected from fresh and brackish water.…”

Novel Agents on the Horizon for Cancer Therapy

“…The dose-limiting toxicities during phase 1 trials included fatigue, neutropenia, peripheral neuropathy, constipation, hyponatremia, and pain at the infusion site. 97,98 The agent was tested in sarcoma and nonsmall cell lung cancer during phase 2 development. Flavanoids 5,6-dimethylxanthenone-4acetic acid (DMXAA, AS-1404) is a flavanoid derivative that damages DNA and induces apoptosis in endothelial cells in preclinical models.…”