Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT).
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 mg m(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mg m(-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 mg m(-2). The half-lives of both MAG-CPT and released CPT were prolonged (>6 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.
Bissett
D
D
Department of Medical Oncology, University of Aberdeen, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, UK. d.bissett@arh.grampian.scot.nhs.uk
Cassidy
J
J
de Bono
J S
JS
Muirhead
F
F
Main
M
M
Robson
L
L
Fraier
D
D
Magnè
M L
ML
Pellizzoni
C
C
Porro
M G
MG
Spinelli
R
R
Speed
W
W
Twelves
C
C
D000178:Acrylamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D002166:Camptothecin / Q000031:analogs & derivatives*; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D018805:Sepsis / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
D000178:Acrylamides; D000972:Antineoplastic Agents, Phytogenic; C411473:poly(1-methacryloylamido-2-hydroxypropane-co-20-O-(methacryloylglycyl-6-aminohexanoylglycyl)); D002166:Camptothecin