A Phase I Study of a New Nucleoside Analogue, OSI-7836, Using Two Administration Schedules in Patients with Advanced Solid Malignancies

• Published in: Clinical cancer research 2006-05, Vol.12 (9), p.2841-2848
• Main Authors: LEE, Chooi P, DE JONGE, Maja J. A, KAYE, Stan B, JUDSON, Ian R, VERWEIJ, Jaap, O'DONNELL, Anne E, SCHOTHORST, Kristel L, HANWELL, Janet, CHICK, Jon B, BROOIMANS, Rik A, ADAMS, Laurel M, DROLET, Daniel W, DE BONO, Johann S
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - toxicity; Antineoplastic agents; Arabinonucleosides - administration & dosage; Arabinonucleosides - pharmacokinetics; Arabinonucleosides - toxicity; Biological and medical sciences; chemotherapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; nucleoside analogue; pharmacokinetics; Pharmacology. Drug treatments; Phase I study
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1932

Purpose: To investigate the safety, tolerability, and pharmacokinetic profile of the novel nucleoside analogue OSI-7836 in patients with advanced solid malignancies. Experimental Design: OSI-7836 was initially given as a 60-minute i.v. infusion on day 1 every 21 days. In view of its dose-limiting toxicities, the administration time was amended to a 5-minute bolus, and subsequently, the schedule was amended to weekly for 4 weeks followed by a 2-week rest. Blood and urine samples were collected for pharmacokinetic studies. Analyses of cytokines and lymphocyte subsets were added later in the study to elucidate a mechanism for the severe fatigue and lymphocyte depletion observed in earlier patients. Results: Thirty patients received a total of 61 treatment cycles. Fatigue was the main dose-limiting toxicity. Maximum-tolerated dose was defined as 300 mg/m 2 in the 60-minute infusion, (three times per week) schedule; 400 mg/m 2 in the 5-minute bolus infusion, (three times per week) schedule; and 100 mg/m 2 in the weekly schedule. Other common toxicities were nausea, vomiting, rash, fever, and a flu-like syndrome. There were no clinically significant hematologic toxicities. Following the initial dose, OSI-7836 was eliminated from plasma with a median (range) elimination half-life of 48.3 minutes (22.6-64.8 minutes). Lymphocyte subset analysis showed a significant drop in B cell counts, which persisted to day 14 and beyond. Cytokine analysis showed significant elevations of interleukin-6 and interleukin-10 in all patients who received ≥200 mg/m 2 OSI-7836. Best response was disease stabilization in seven patients. Conclusion: OSI-7836 was associated with excessive fatigue, and despite changes in its schedule and duration of administration, we did not observe an improvement in its tolerability. Its potentially selective effect on B lymphocytes could be exploited in further studies in specific hematologic malignancies.