NSC-630176 is a bicyclic peptide (CP) that was isolated from a strain of Chromobacterium violaceum in the course of a program by the Fujisawa Pharmaceutical Co. to isolate inhibitors of oncogene function. CP decreased mRNA expression of the c-myc oncogene in RAS 1 cells, but had no effect on Ha-ras mRNA expression. Cultured cells were arrested in G0/G1. CP has demonstrated potent cytotoxic activity against human tumor cell lines and in vivo efficacy against both human tumor xenografts and murine tumors. The in vitro and in vivo antitumor effects were observed originally by the Fujisawa Co., and then confirmed by the NCI. Development of CP was stopped by Fujisawa due to cardiotoxic effects observed in dogs following daily iv treatment for two weeks, or twice weekly treatment for four weeks. The Decision Network Committee of the National Cancer Institute approved selection of CP for further evaluation in March 1991 in order to determine if the cardiotoxicity could be overcome through modification of the administration schedule. Based on the results of the efficacy and toxicity studies in mice, it appears that efficacy can be maintained (10/10 CR in LOX) with no evidence of cardiotoxicity. Efficacy and toxicity were schedule dependent. Dose-limiting toxicity (DLT) in dogs is site of infusion and gastrointestinal. Dose-limiting toxicity in rats is bone marrow. The maximally tolerated dose (MTD) in dogs was 20mg/m2/day and in rats was 6mg/m2/day. The toxic dose low in rats was 3mg/m2/day (1/2 MTD). Depsipeptide will be administered on a weekly schedule as a 4 hour infusion. The proposed clinical starting dose was calculated two ways. One based on the 1/10 MTD in the most sensitive specie (rats) would yield a clinical starting dose of 0.6mg/m2/day. If 1/3 toxic dose low (TDL) is used the proposed clinical starting dose would be 1.0mg/m2/day. Based on the preclinical toxicology data, it was decided that 1mg/m2/day would be safe dose to initiate the Phase I clinical trials. The recommended clinical starting dose will be 1mg/m2 (1/3 TDL) given as a 4 hour infusion on study days 1, 8 and 15 repeated q 28. Depsipeptide (DP), NSC 630176, was selected for clinical study based on its high pre-clinical activity in a broad range of solid tumors and its possible unique, but unknown, mechanism of action based on analysis in the COMPARE program. Animal studies proved the severe cardiac, GI and skin toxicity could be avoided if the agent was infused over 4 hours (hr). Pre-clinical activity was dose and schedule dependent. We are performing the first trial of DP in humans infusing DP over 4 hr weekly x 3 q28 days. To date, 14 patients with advanced cancer meeting standard phase I eligibility plus normal cardiac function have been treated with DP at dose levels from 1 to 7.5 mg/m2 treating at least 3 patients at each dose level. No toxicity as been observed which can be attributed to DP and escalation continues. 1 minor response was seen in a patient with an ACTH producing islet cell tumor. A high-performance liquid chromatographic assay was developed and validated for the determination of DP levels in plasma. After extraction from plasma, DP was chromatograhed on 2 serial octadecyl stationary phases using mobile phase consisting of acetonitrile:potassium phosphate [0.03M, pH 3.0] (27:73, v/v), at a flow rate of 2,0 ml/min and at ambient temperature. The method was linear over a 0.05 to 2 &g/ml range with the intra- and inter-day coefficients of variations less than 8%. The full PK analysis will be presented. To date we have shown that steady state concentration in the &g/ml range has been achieved by the end of infusion and drug is undetectable 1 to 2 hr after the infusion ends suggesting rapid clearance.
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