Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT)

Bissett, D. et al. (2004) Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT). British Journal of Cancer, 91(1), pp. 50-55. (doi:10.1038/sj.bjc.6601922)

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Abstract

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide ( average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mgm(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mgm(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mgm(-2). The half-lives of both MAG-CPT and released CPT were prolonged (46 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cassidy, Professor James
Authors: Bissett, D., Cassidy, J., de Bono, J., Muirhead, F., Main, M., Robson, L., Fraier, D., Magne, M., Pellizzoni, C., Porro, M., Spinelli, R., Speed, W., and Twelves, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:British Journal of Cancer
ISSN:0007-0920

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