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 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. x 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. x 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.
Van Ummersen
Lynn
L
Department of Medicine, University of Wisconsin, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, USA. lvanummersen@facstaff.wisc.edu
Binger
Kim
K
Volkman
Jennifer
J
Marnocha
Rebecca
R
Tutsch
Kendra
K
Kolesar
Jill
J
Arzoomanian
Rhoda
R
Alberti
Dona
D
Wilding
George
G
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy; D008139:Loperamide / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D058831:Serotonin 5-HT3 Receptor Antagonists; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D058831:Serotonin 5-HT3 Receptor Antagonists; D010767:Phosphorylcholine; C105905:perifosine; D008139:Loperamide; D003907:Dexamethasone