Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies
| Autor: | Mark D, Minden, Donna E, Hogge, Scott J, Weir, Jim, Kasper, Debra A, Webster, Lavonne, Patton, Yulia, Jitkova, Rose, Hurren, Marcela, Gronda, Carolyn A, Goard, Lian G, Rajewski, John L, Haslam, Kathleen E, Heppert, Kevin, Schorno, Hong, Chang, Joseph M, Brandwein, Vikas, Gupta, Andre C, Schuh, Suzanne, Trudel, Karen W L, Yee, Gregory A, Reed, Aaron D, Schimmer |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Adult
Aged 80 and over Male Salvage Therapy Gastrointestinal Diseases Pyridones Survivin Administration Oral Antineoplastic Agents Ciclopirox Middle Aged Iron Chelating Agents Inhibitor of Apoptosis Proteins Neoplasm Proteins Gene Expression Regulation Neoplastic Treatment Outcome Hematologic Neoplasms Inactivation Metabolic Humans Female RNA Messenger RNA Neoplasm Aged Half-Life |
| Zdroj: | American journal of hematology. 89(4) |
| ISSN: | 1096-8652 |
| Popis: | The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m² oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m² ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m², demonstrating biological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m² four times daily, and no dose limiting toxicity was observed at 40 mg/m² once daily. Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text