A Phase I Trial of Perifosine (NSC 639966) on a Loading Dose/Maintenance Dose Schedule in Patients with Advanced Cancer
| Autor: | Dona Alberti, Rebecca Marnocha, Kendra D. Tutsch, Lynn Van Ummersen, Rhoda Z. Arzoomanian, Jennifer Volkman, Kim Binger, Jill M. Kolesar, George Wilding |
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| Rok vydání: | 2004 |
| Předmět: |
Adult
Leiomyosarcoma Male Cancer Research Time Factors Maximum Tolerated Dose Phosphorylcholine Antineoplastic Agents Pharmacology Loperamide Loading dose Dexamethasone Drug Administration Schedule chemistry.chemical_compound Therapeutic index Pharmacokinetics Neoplasms Humans Serotonin 5-HT3 Receptor Antagonists Medicine Dosing Aged Dose-Response Relationship Drug business.industry Maintenance dose Middle Aged Perifosine Clinical trial Treatment Outcome Models Chemical Oncology chemistry Toxicity Female business Signal Transduction |
| Zdroj: | Clinical Cancer Research. 10:7450-7456 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-03-0406 |
| Popis: | Perifosine (NSC 639966) is a synthetic, substituted heterocyclic alkylphosphocholine that acts primarily at the cell membrane targeting signal transduction pathways. Early clinical trials were limited because of dose-limiting gastrointestinal toxicity, and parenteral dosing of this class of agents is not possible because of their hemolytic properties; therefore, related compounds with an improved therapeutic index were developed. Toxicity was minimized and efficacy improved by using a loading dose/maintenance dose schedule, and therefore, this schedule was carried into clinical trials. This phase I trial enrolled 42 patients with incurable solid malignancies. The starting doses were 100 mg p.o. × four doses (every 6 hours) load followed by a 50 mg p.o. once daily maintenance dose with escalation of either component in successive dose levels. No treatment related deaths occurred. The maximum-tolerated dose was determined to be 150 mg p.o. × four doses load and 100 mg p.o. once daily maintenance. Dose-limiting toxicities such as nausea, diarrhea, dehydration, and fatigue were seen early during the loading phase and were surmountable with the use of prophylactic 5-HT3 receptor antagonists, dexamethasone, and loperamide. Toxicities during the chronic phase were difficult to manage and, given that pharmacokinetic data showed biologically active serum concentrations (based on preclinical data), raised the question of less frequent maintenance dosing. Pharmacokinetic data confirmed the maintenance of stable drug levels with chronic dosing and the long half-life. One partial response was seen, as were multiple patients with stable disease beyond course 2. These results suggest perifosine activity in sarcoma and perhaps renal cell carcinoma (stable disease in two patients who continued for 6 and 14 courses), thus justifying additional investigation of this agent in a phase II sarcoma trial. |
| Databáze: | OpenAIRE |
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