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: M J A de Jonge, J Verweij, A van der Gaast, O Valota, O Mora, A S Th Planting, M A Mantel, S Van Den Bosch, M J Lechuga, F Fiorentini, D Hess, C Sessa
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 38 Issue 18 Pg. 2407-15 (Dec 2002) ISSN: 0959-8049 [Print] England
• PMID: 12460785 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulfonyldaunorubicin
• Antibiotics, Antineoplastic
• Daunorubicin

Topics

• Adult
• Aged
• Antibiotics, Antineoplastic (adverse effects, pharmacokinetics, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Colorectal Neoplasms (drug therapy, metabolism)
• Daunorubicin (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Hypersensitivity (etiology)
• Female
• Hematologic Diseases (chemically induced)
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Male
• Middle Aged
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism)
• Vomiting (chemically induced)