PHASE-I PHARMACOLOGICAL STUDY OF INTRAARTERIALLY INFUSED FOTEMUSTINE FOR COLORECTAL LIVER METASTASES

Fotemustine was investigated in 17 patients with progressive hepatic m etastases from colorectal carcinoma to define the maximally tolerated dose for a daily hepatic intra-arterial infusion (HAI) schedule. Haema totoxicity was delayed, dose-dependent and related to pretreatment, wi th thrombo- and leucocytopenia being dose-limiting. Local side-effects at the liver were mild. Infection (WHO grade III) occurred in 1 patie nt due to neutropenia. Other side-effects, particularly renal, pulmona l, neurological or cardiac toxicity, mucositis and diarrhoea, hair los s or allergic reactions did not occur. Pharmacokinetic analysis indica ted a short plasma half-life (t(1/2) = 25.8 +/- 11.5 min) and a high b ody clearance (C-L = 2193 +/- 870 ml/min) with large inter-and intra-i ndividual variations. Of 15 evaluable patients, one complete and three partial responses were observed (ORR = 27%; CI95% [4.5-49.5%]). All t umour remissions appeared at higher dose levels in previously untreate d patients. Considering the absence of mucosal side-effects, such as m ucositis/diarrhoea and of hepatic toxicity, this agent was well tolera ted. The recommended intra-arterial dose for consecutive phase II tria ls is 125 mg/m(2)/day(1-3). (C) 1998 Elsevier Science Ltd.