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

Authors' Affiliations: ¹ Royal Marsden Hospital, Sutton, United Kingdom; ² Erasmus University Medical Centre, Rotterdam, the Netherlands; ³ OSI Pharmaceuticals, Inc., Oxford, United Kingdom; ⁴ OSI Pharmaceuticals, Inc., Melville, New York; and ⁵ OSI Pharmaceuticals, Inc., Boulder, Colorado

Requests for reprints: Chooi P. Lee, Andrew Love Cancer Centre, Barwon Health, Swanston Street, Geelong, Victoria 3220, Australia. Phone: 61-3-5226-7851; Fax: 61-3-5260-3157; E-mail: chooil{at}barwonhealth.org.au.

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/m² in the 60-minute infusion, (three times per week) schedule; 400 mg/m² in the 5-minute bolus infusion, (three times per week) schedule; and 100 mg/m² 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/m² 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.