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

D Bissett, J Cassidy, J S de Bono, F Muirhead, M Main, L Robson, D Fraier, M L Magne, C Pellizzoni, M G Porro, R Spinelli, W Speed, C Twelves

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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.

Original languageEnglish
Pages (from-to)50-55
Number of pages6
JournalBritish Journal of Cancer
Volume91
DOIs
Publication statusPublished - 2004

Keywords

  • MAG-CPT
  • polymeric
  • camptothecin
  • pharmacokinetics
  • POLYETHYLENE-GLYCOL
  • BOUND CAMPTOTHECIN
  • DELIVERY-SYSTEMS
  • ACCUMULATION
  • CONJUGATION
  • NSC-100880

Cite this

Bissett, D., Cassidy, J., de Bono, J. S., Muirhead, F., Main, M., Robson, L., Fraier, D., Magne, M. L., Pellizzoni, C., Porro, M. G., Spinelli, R., Speed, W., & Twelves, C. (2004). Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT). British Journal of Cancer, 91, 50-55. https://doi.org/10.1038/sj.bjc.6601922