Summary 3,5-Dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine (penclomedine, NSC 338720, CRC 88-04) is an a-picoline derivative with anti-tumour activity in preclinical models. Penclomedine administration by 1-h intravenous infusion on 5 consecutive days was repeated 3 weekly in the absence of dose-limiting toxicity (DLT) or disease progression. Five dose levels were investigated (22.5-340 mg m-2 day-'). Eight men and eight women were entered, median age 59 years (range 39-73 years), with good performance status (ECOG 0/1) in 11 patients. A total of 13 out of 16 patients had received previous chemotherapy. Common toxicity criteria grade (CTCg) II vomiting was recorded at all dose levels. Neurotoxicity (cerebellar ataxia and dizziness) was the DLT, CTCg IlIl toxicity occurring in three out of three patients treated at 340 mg m-2 day-'. CTCg IlIl dizziness was noted in one out of three patients at 250 mg m-2 day-1. Neurotoxicity developed during the 1-h infusion and persisted for a variable period (maximum 5 h) after infusion. Prophylactic antiemetic drugs appeared to reduce associated vomiting but did not prevent ataxia. No antiproliferative toxicities were noted and no anti-tumour responses were documented. Penclomedine pharmacokinetic studies confirmed preclinical evidence of extensive apparent distribution (931 m-2) and rapid clearance (41 1 h-1m-2). Purkinje cell loss has been identified in preclinical models after intraperitoneal administration (O'Reilly et al, 1 996a) and further clinical development of penclomedine will focus on oral administration.Keywords: phase l; penclomedine; neurotoxicity Penclomedine (3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl}-pyridine) was originally synthesized by Helen K Tobol, Dow Chemical, USA, as part of a programme to develop effective herbicides. It was identified as a potential anti-tumour agent by the NCI in vivo P388 leukaemia prescreen. After evidence of good activity against murine and human breast tumours, mouse CD8F, mammary carcinoma and human MX-1 mammary tumour xenograft (Plowman et al, 1989), penclomedine was selected for further studies and subsequent clinical development. The mechanism of action of penclomedine is unclear, although studies have been performed that suggest that it undergoes metabolism to yield reactive species that bind to DNA (Plowman et al, 1989; Reid et al, 1992;Benvenuto et al, 1995.) Penclomedine is poorly soluble in water but soluble in nonpolar solvents and lipids (Prankerd et al, 1989). Therefore, an experimental formulation of penclomedine as a 10% oil in water emulsion was developed for intravenous (i.v.) administration. Using this formulation, penclomedine was active against the advanced stage MX-1 mammary carcinoma: oral treatment with doses of 135 mg kg-' day-' for 5 days resulted in ten out of ten tumour-free survivors. The potency increased after intraperitoneal administration and the drug was most potent when administered i.v. (Harrison et al, 1991). No clear schedule dependency was been observed with the oral administratio...
