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Phase I Trial and Clinical Pharmacology of 1-(2-Chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea¹

Department of Medicine, Division of Medical Oncology and Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, D. C. 20007.

1-(2-Chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (NSC 95466) is a lipid-soluble nitrosourea that is presently undergoing clinical evaluation. In this Phase I study, the toxicity of this drug was examined after administration of the drug to cancer patients on 3 successive days every 6 to 8 weeks. Clinical pharmacology was studied using 1-[chloroethyl-¹⁴C](2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea. The dose-limiting toxicity was myelosuppression. The maximal tolerated dose was 105 mg/sq m, which produced a median platelet nadir of 40,000/µl on Day 32 and a median white blood cell count nadir of 2200/µl on Day 42. Progressive anemia was also observed. There was no evidence of acute or chronic hepatic, renal, or pulmonary damage. One patient with a metastatic hypernephroma exhibited a partial clinical remission.

Plasma disappearance of the drug following bolus administration was biphasic, with an initial half-life of 18 to 25 min and a second half-life of 9 hr. Clearance of intact drug coincided largely with the initial disappearance phase of total radioactivity. Entry of radioactivity into the cerebrospinal fluid was observed. Approximately 35% of plasma radioactivity was protein bound, the major binder being albumin. Drug excretion was predominantly renal, and biliary elimination was only minor.

¹ Supported by National Cancer Institute Contract NO1-CM-97208, Division of Cancer Treatment, Investigational Drug Branch.

Received 1/14/81. Accepted 7/ 9/81.