title: A phase I and pharmacokinetic study of LAF389 administered to patients with advanced cancer.
abstract: LAF389 is a synthetic analogue of bengamide B, a natural product isolated from Jaspidae sponges. LAF389 has both antiproliferative and antiangiogenetic properties, and preclinical investigations showed a broad antitumour activity. This clinical trial aimed to determine the safety and pharmacokinetic profile of LAF389 administered as a slow intravenous injection for 3 consecutive days every 3 weeks in patients with advanced solid tumours. Eight dose levels were tested: 1, 2.5, 5, 10, 15, 30, 25 and 20 mg/day. A total of 33 patients, median age 52 years (range 33-72), with refractory solid tumours were enroled, 19 men and 14 women with a median World Health Organization performance status of 1 (0-4). Seventy-eight cycles of treatment have been administered (mean 2.5, range 1-10). Four cardiovascular dose-limiting toxicities were reported at 30 mg (2/2 patients) and 25 mg (2/9 patients), eight additional patients at various dose levels had (cardio)vascular toxicity, probably drug related, and one patient died owing to pulmonary embolism at the 5 mg dose. No objective responses were recorded. Pharmacokinetic parameters were variable, although linear and without obvious accumulation from cycle I to cycle II. LAF389 dose escalation was terminated owing to occurrence of unpredictable cardiovascular events. This, associated with the lack of clinical activity, did not warrant further investigation of this agent.
authors.affiliation: Department of General Medical Oncology, UZ Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. herlinde.dumez@uz.kuleuven.be
authors.forename: Herlinde
authors.initials: H
authors.lastname: Dumez
authors.forename: Helen
authors.initials: H
authors.lastname: Gall
authors.forename: Renaud
authors.initials: R
authors.lastname: Capdeville
authors.forename: Catherine
authors.initials: C
authors.lastname: Dutreix
authors.forename: Allan T
authors.initials: AT
authors.lastname: van Oosterom
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001381:Azepines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy
chemical_list: C438868:3,4,5-trihydroxy-2--methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl)non-6-enamide; D020533:Angiogenesis Inhibitors; D001381:Azepines