A Phase I Trial of Perifosine (NSC 639966) on a Loading Dose/Maintenance Dose Schedule in Patients with Advanced Cancer

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 i...

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Bibliographic Details
Published in:Clinical cancer research 2004-11, Vol.10 (22), p.7450-7456
Main Authors: VAN UMMERSEN, Lynn, BINGER, Kim, VOLKMAN, Jennifer, MARNOCHA, Rebecca, TUTSCH, Kendra, KOLESAR, Jill, ARZOOMANIAN, Rhoda, ALBERTI, Dona, WILDING, George
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Dexamethasone - therapeutic use
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Leiomyosarcoma - drug therapy
Loperamide - therapeutic use
Male
Maximum Tolerated Dose
Medical sciences
Middle Aged
Models, Chemical
Neoplasms - drug therapy
Pharmacology. Drug treatments
Phosphorylcholine - analogs & derivatives
Phosphorylcholine - therapeutic use
Serotonin 5-HT3 Receptor Antagonists
Signal Transduction
Time Factors
Treatment Outcome
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Summary: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-HT 3 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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-03-0406