title: Phase I and pharmacokinetic studies of PNU-159548, a novel alkycycline, administered intravenously to patients with advanced solid tumours.
abstract: PNU-159548 (4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin) is the lead compound of a novel class of cytotoxic agents (alkycyclines) with a unique mechanism of action combining DNA intercalation with alkylation of guanines in the DNA major groove. The objectives of two phase I studies were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics (PKs) of PNU-159548 and its active metabolite PNU-169884 when administered intravenously (i.v.) over 10 or 60 min to patients with advanced solid tumours. Patients were treated with escalating doses of PNU-159548, courses repeated every 21 days at doses ranging from 1.0 to 16 mg/m(2). For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. 69 patients received a total of 161 courses. The MTD was reached at 14 and 16 mg/m(2) in heavily (HP) and minimally pretreated/non-pretreated (MP) patients, respectively, with thrombocytopenia as the DLT. A hypersensitivity reaction was observed in 8 patients across all dose levels, characterised by fever with chills, erythema, facial oedema and dyspnoea. The PKs of PNU-159548 and PNU-169884 were linear over the dose range studied. A significant correlation was observed between the percentage decrease in platelet count and the AUC of PNU-159548. In these studies, the DLT of PNU-159548 was thrombocytopenia. The recommended dose for phase II studies of PNU-159548 is 12 and 14 mg/m(2) administered i.v. over 10 min, once every 21 days, in HP and MP patients, respectively.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, 3075 EA Rotterdam, The Netherlands. jonge@onch.azr.nl
authors.forename: M J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: A
authors.initials: A
authors.lastname: van der Gaast
authors.forename: O
authors.initials: O
authors.lastname: Valota
authors.forename: O
authors.initials: O
authors.lastname: Mora
authors.forename: A S Th
authors.initials: AS
authors.lastname: Planting
authors.forename: M A
authors.initials: MA
authors.lastname: Mantel
authors.forename: S Van Den
authors.initials: SV
authors.lastname: Bosch
authors.forename: M J
authors.initials: MJ
authors.lastname: Lechuga
authors.forename: F
authors.initials: F
authors.lastname: Fiorentini
authors.forename: D
authors.initials: D
authors.lastname: Hess
authors.forename: C
authors.initials: C
authors.lastname: Sessa
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003630:Daunorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000209:etiology; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014839:Vomiting / Q000139:chemically induced
chemical_list: C402179:4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulfonyldaunorubicin; D000903:Antibiotics, Antineoplastic; D003630:Daunorubicin