title: Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours.
abstract: Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: Gerrits
authors.forename: H
authors.initials: H
authors.lastname: Burris
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: A S
authors.initials: AS
authors.lastname: Planting
authors.forename: M E
authors.initials: ME
authors.lastname: van den Burg
authors.forename: G I
authors.initials: GI
authors.lastname: Rodriguez
authors.forename: V
authors.initials: V
authors.lastname: van Beurden
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: I
authors.initials: I
authors.lastname: Hudson
authors.forename: S
authors.initials: S
authors.lastname: Fields
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: D D
authors.initials: DD
authors.lastname: von Hoff
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan