A phase I dose-escalation study of edotecarin (J-107088) combined with infusional 5-fluorouracil and leucovorin in patients with advanced/metastatic solid tumors

• Published in: Anti-cancer drugs Vol. 21; no. 7; p. 716
• Main Authors: Saif, Muhammad Wasif, Sellers, Sandra, Diasio, Robert B, Douillard, Jean-Yves
• Format: Journal Article
• Language: English
• Published: England 01.08.2010
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carbazoles - administration & dosage; Carbazoles - adverse effects; Carbazoles - therapeutic use; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - therapeutic use; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - therapeutic use; Humans; Infusions, Intravenous; Leucovorin - administration & dosage; Leucovorin - adverse effects; Leucovorin - therapeutic use; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms - drug therapy; Neoplasms - pathology; Topoisomerase I Inhibitors
• ISSN: 1473-5741
• DOI: 10.1097/CAD.0b013e32833cb658

Edotecarin (J-107088), a novel inhibitor of topoisomerase I has an additive effect on colon cell lines (HCT-116) when combined with 5-fluorouracil (5-FU). We conducted a phase I study to determine the maximum tolerated dose and recommended a phase II dose of edotecarin in combination with infusional 5-FU/leucovorin (LV) in patients with advanced solid tumors. Patients and cohorts of three to six patients were sequentially enrolled at progressively higher dose levels of edotecarin administered as a 1-h intravenous (IV) infusion every 2 weeks. The edotecarin starting dose was 6 mg/m, followed by 200 mg/m LV IV infusion administered over 2 h, then 400 mg/m bolus dose of 5-FU before the start of 2400 mg/m 5-FU continuous infusion for a further 46 h. Patients were evaluated for safety, pharmacokinetics, and tumor response according to the Response Evaluation Criteria in Solid Tumors criteria. Fourteen patients (10 male; four female) received a total of 90 cycles (range 3-18). Dose-limiting toxicities were observed in five of the 14 patients treated in the study. All dose-limiting toxicities were related to neutropenia. Only the 6 and 8 mg/m edotecarin dose levels were explored; however, no maximum tolerated dose was declared. One confirmed complete response in a patient with hepatocellular carcinoma and seven stable disease responses were achieved in the 14 treated patients. Pharmacokinetic analysis showed that edotecarin achieved and maintained apparent steady-state plasma concentrations during the IV administration in both the cycles. The administration of edotecarin in combination with infusional 5-FU/LV once every 14 days, even without the 5-FU bolus, did not permit adequate time for recovery from neutropenia.