Penclomedine (NSC-338720; 3,5-dichloro-2,4dimethoxy-trichloromethylpyridine) is a synthetic alpha-picoline derivative and was first identified by the National Cancer Institute as a potential antitumor agent in the P388 Leukemia prescreen. It was selected for preclinical development by the NCI after demonstrating activity against two in vivo breast tumor models, human MX-1 mammary adenocarcinoma and murine CD8F1 adenocarcinoma. The mechanism of action is undetermined although cross-sensitivity studies suggest it may act as an alkylating agent. This is a phase I study using the drug penclomedine in patients for whom no effective anticancer therapy exists. As part of this study an oral bioavailability study will be conducted. Penclomedine will be given as an oral dose each day for five consecutive days, repeating the cycle every four weeks. Study endpoints are: determination of the maximum tolerated dose (MTD) and phase II dose of penclomedine; description and quantitation of toxicities of penclomedine; and description of the pharmacokinetic behavior of penclomedine. Patients will also be observed for anticancer effect. Accrual to this study will be determined by the MTD and phase II dose. Studies such as this usually have accrual of approximately thirty patients. The bioavailability portion of this study will be given to the first six patients. These patients will receive one dose of penclomedine at 400 mg/m2 intravenously over one hour. This will be followed by a three-week washout period. At the end of three weeks, these patients will receive oral penclomedine at a dose of 400 mg/m2 daily x five days orally every 28 days. The primary objectives of this study are: (1) to determine the MTD and phase II dose of oral penclomedine on a daily x 5 every four weeks schedule; (2) describe the toxicity profile of penclomedine; (3) describe the pharmacokinetic behavior of oral penclomedine; and (4) determine the bioavailability of oral penclomedine.
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