Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, which was administered to patients with advanced solid tumors on days 1 and 8 in 3-week courses

Purpose To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of TZT-1027 (soblidotin), a dolastatin 10 analogue, in Japanese patients with advanced solid tumors when administered on days 1 and 8 in 3-week courses. Methods Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and also met the following criteria: prior chemotherapy <= 2 regimens, Eastern Cooperative Oncology Group (ECOG) performance status <= 1, and acceptable organ function. The MTD was defined as the highest dose at which no more than one of six patients experienced a DLT during course 1. Pharmacokinetic samples were collected in courses 1 and 2. Results Eighteen patients were enrolled in the present study. Three doses (1.5, 1.65, and 1.8 mg/m(2)) were evaluated. Neutropenia was the principal DLT at doses of 1.65 and 1.8 mg/m(2). In addition, one patient also experienced grade 3 pneumonia with neutropenia, and another patient experienced grade 3 constipation, neuropathy, grade 4 neutropenia, and hyponatremia as DLTs at 1.65 mg/m(2). Phlebitis, the most frequent nonhematological toxicity, was improved by administration of additional saline after TZT-1027 administration. The MTD was 1.5 mg/m(2), at which DLT was not observed in a total of nine patients. The pharmacokinetic profile did not differ from that for the European population. One patient with metastatic esophageal cancer achieved partial response, and each of two patients with non-small cell lung cancer had a minor response. Conclusions When TZT-1027 was administered on days 1 and 8 in 3-week courses to Japanese patients, the MTD was 1.5 mg/m(2) and was lower than the value of 2.4 mg/m(2) in European patients. However, antitumor activity was observed at low doses. TZT-1027 was tolerated well at the MTD, without grade 3 nonhematological toxicities or neutropenia up to grade 2. TZT-1027 is a promising new tubulin polymerization inhibitor that requires further investigation in phase II studies.