Clinical and pharmacologic study of the novel prodrug delimotecan (MEN 4901/T-0128) in patients with solid tumors.
OBJECTIVE
To investigate i.v. administration of delimotecan (MEN 4901/T-0128), a carboxymethyldextran polymer prodrug of the active camptothecin derivative T-2513, and to assess the maximum tolerated dose, safety profile, clinical pharmacology, and antitumor activity of delimotecan and metabolites.


METHODS
Patients with solid tumors refractory to standard therapy received i.v. delimotecan as 3-hour infusion once every 6 weeks. The starting dose was 150 mg/m2, followed by an accelerated dose escalation with at least one patient per dose level. The pharmacokinetics of delimotecan, T-2513, and its metabolites, SN-38, SN-38G, T-1335, T-0055, and T-3921, were assessed in plasma and urine, and their pharmacodynamics were determined by measuring the effect of the treatment on hematologic and nonhematologic toxicity.


RESULTS
Twenty-two patients received 35 courses. Dose-limiting toxicities were observed at 5,400 mg/m2 (n = 1), 3,600 mg/m2 (n = 1), and 2,400 mg/m2 (n = 2). The dose level of 1,800 mg/m2 was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m2) and head and neck cancer (2400 mg/m2). Delimotecan had a long terminal half-life of 109 h, and relatively high exposures to T-2513 and SN-38 were obtained. The percentage decrease in WBC and absolute neutrophil count significantly correlated with the dose of delimotecan.


CONCLUSIONS
Based on its preliminary antitumor activity, safety profile, and pharmacokinetic profile, we recommend to evaluate delimotecan given as 3-hour infusion once every 6 weeks at a dose level of 1,800 mg/m2 in a phase II study.
Veltkamp
Stephan A
SA
Division of Experimental Therapy, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, The Netherlands. veltkamp@nl.astellas.com
Witteveen
Els O
EO
Capriati
Angela
A
Crea
Attilio
A
Animati
Fabio
F
Voogel-Fuchs
Marja
M
van den Heuvel
Ingeborg J G M
IJ
Beijnen
Jos H
JH
Voest
Emile E
EE
Schellens
Jan H M
JH
D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003911:Dextrans / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019772:Topotecan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D003911:Dextrans; D011355:Prodrugs; D019772:Topotecan; C410031:T 0128