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This phase II study evaluated the antitumor activity of the tetracycline analog COL-3, a potent inhibitor of metalloproteinases (MMPs), particularly MMP-2 and MMP-9, on a continuous oral schedule at a dose of 50 mg/m2 daily in patients with advanced and/or metastatic soft tissue sarcoma (STS). The principal endpoints were the rate of objective tumor regression and the proportion of patients who did not experience disease progression during the first 8 weeks of treatment. Other study objectives included an assessment of pharmacology of COL-3, time to progression (TTP), and overall survival. A Simon two-stage design with multinomial stopping rule was employed, with 15 patients enrolled during the first stage of the study. Although COL-3 was generally well-tolerated, there were no objective responses and 5(33%) patients experienced disease progression during the first 8 weeks of treatment, which exceeded the criteria established a priori with regard to pursuing further evaluations of COL-3 in STS. The median values for TTP and survival were 109 and 279 days, respectively. Based on these results, further studies of COL-3 on this administration schedule in patients with STS are not warranted.

Purpose:The oral fluoropyrimidine S-1, which consists of a mixture of a 5-fluorouracil (5-FU) prodrug (tegafur), a dihydropyrimidine dehydrogenase inhibitor [5-chloro-2,4-dihydroxypyrimidine (CDHP)], and an inhibitor of orotate phosphoribosyltransferase [potassium oxonate (oxonic acid)], was developed to increase the feasibility and therapeutic index of 5-FU administered orally. The principal objective of this study was to assess the feasibility of administering S-1 on a once-daily-for-28-day schedule every 5 weeks, determine the maximum tolerated dose, characterize the pharmacokinetics of S-1, and seek evidence of anticancer activity.Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of S-1 on a once-daily oral schedule for 28 days every 5 weeks. The maximum tolerated dose was defined as the highest dose in which fewer than two of the first six new patients experienced dose-limiting toxicity. The pharmacokinetic profiles of the tegafur, CDHP, and oxonic acid constituents were characterized.Results: Twenty patients were treated with 72 courses of S-1 at three dose levels ranging from 50 to 70 mg/m 2 /day. Diarrhea, which was often associated with abdominal discomfort and cramping, was the principal dose-limiting toxicity of S-1 on this protracted schedule. Nausea, vomiting, mucositis, fatigue, and cutaneous effects were also observed but were rarely severe. Myelosuppression was modest and uncommon. A partial response and a 49% reduction in tumor size were observed in patients with fluoropyrimidineand irinotecan-resistant colorectal carcinoma. The pharmacokinetic data suggested potent inhibition of 5-FU clearance by CHDP, with resultant 5-FU exposure at least 10-fold higher than that reported from equitoxic doses of tegafur modulated by uracil in the oral fluoropyrimidine UFT.Conclusions: The recommended dose for Phase II studies of S-1 administered once daily for 28 consecutive days every 5 weeks is 50 mg/m 2 /day. The pharmacokinetic data indicate substantial modulation of 5-FU clearance by CDHP. Based on these pharmacokinetic data, the predictable toxicity profile of S-1, and the low incidence of severe adverse effects at the recommended Phase II dose, evaluations of S-1 on this schedule are warranted in malignancies that are sensitive to the fluoropyrimidines.

Purpose: This study was designed to determine the safety, tolerability, and pharmacokinetics, and to seek preliminary evidence of anticancer activity of trabectedin, a novel marine-derived DNA minor grove binder, when administered as a 1-hour or 3-hour i.v. infusion for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) levels of trabectedin on these schedules, as well as to recommend doses for disease-directed studies. Experimental Design: A total of 32 and 31 patients were treated in sequential cohorts with trabectedin on the 1-hour schedule (doses ranging from 0.46 to 0.80 mg/m 2 ) and on the 3-hour schedule (doses ranging from 0.30 to 0.65 mg/m 2 ). Results: Neutropenia, transient elevations in hepatic transaminases and creatine phosphokinase, and fatigue precluded dose escalation above 0.70 mg/m 2 (1-hour schedule) and 0.65 mg/m 2 (3-hour schedule), which were determined to be the MTD levels, respectively. The pharmacokinetics of trabectedin on both schedules were characterized by a high clearance rate, a long terminal half-life, and a large volume of distribution. A patient with soft tissue sarcoma had partial response, and several soft tissue sarcoma patients had prolonged (≥6 months) stable disease. Conclusions: The MTD levels of trabectedin given weekly for 3 weeks every 4 weeks is 0.61 mg/m 2 as a 1-hour infusion and 0.58 mg/m 2 as a 3-hour infusion. The manageable toxicities at the MTDs, preliminary evidence of antitumor activity, pharmacokinetic profile, and the unique mechanistic aspects of trabectedin warrant further disease-directed evaluations on weekly schedules.