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

Abstract

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/m 2 , 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/m 2 (n = 1), 3,600 mg/m 2 (n = 1), and 2,400 mg/m 2 (n = 2). The dose level of 1,800 mg/m 2 was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m 2 ) and head and neck cancer (2400 mg/m 2 ). 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/m 2 in a phase II study.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…They are based on the traditional cytotoxic drugs (e.g. platinates [145,146], doxorubicin [147,148], camptothecin and analogues [149][150][151][152][153][154][155][156][157][158][159], paclitaxel/docetaxel [160][161][162][163][164], methotrexate [165], and irinotecan [166,167]). Xyotax (CT-2103 or OPAXIO), a PGA-paclitaxel conjugate, and NKTR-102, a polymer conjugate of irinotecan, are both currently in phase III clinical trials, being the conjugates closest to approval and market availability [164,[166][167][168].…”

Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study

“…[28][29][30][31] However, our findings in this trial illustrate the potential caveats of early pharmacological evaluation of investigational new drugs, stressing the need to systematically question the relevance of analytical data.…”

Nanoparticles containing insoluble drug for cancer therapy

“…To date, the most often-used hydrophilic polymers are HPMA (Duncan et al, 2001; Kopeček et al, 2000), Dextran (Kojima et al, 1980; Mitra et al, 2001) and poly-glutamic acid (Li, 2002; Singer et al, 2004). Several conjugates based on these copolymers are under clinical evaluation, such as PK1 (Seymour et al, 2009), Xyotax™ (Opaxio™ or CT-2103) (O'Brien et al, 2008), CT-2106 (Homsi et al, 2007), Delimotecan (MEN 4901/T-0128) (Veltkamp et al, 2008) and DOX-OXD (AD-70) (Danhauser-Riedl et al, 1993). Kopecek and colleagues first developed the HPMA–doxorubicin conjugate with a drug loading capacity of approximately 8wt.%(Duncan et al, 1987).…”