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Clinical and Pharmacologic Study of the Novel Prodrug Delimotecan (MEN 4901/T-0128) in Patients with Solid Tumors

Authors' Affiliations: ¹ Division of Experimental Therapy and ² Department of Medical Oncology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital; ³ Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute-Slotervaart Hospital, Amsterdam, the Netherlands; ⁴ Faculty of Science, Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht University; ⁵ Department of Medical Oncology, University Medical Center, Utrecht, the Netherlands; ⁶ Menarini Ricerche S.p.A., Clinical Research Department, Florence, Italy; and ⁷ Menarini Ricerche S.p.A., Department of Pharmacokinetics and Drug Metabolism; ⁸ Menarini Ricerche S.p.A., Preclinical Development, Pomezia, Italy

Requests for reprints: Sander Veltkamp, NKI-AvL, Postbus 90203, 1006 BE, Amsterdam, the Netherlands. Phone: 31-71-545-5067; Fax: 31-71-545-5276; E-mail: sander.veltkamp{at}nl.astellas.com.

Purpose: 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.

Experimental Design: 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.