A phase I study of a new nucleoside analogue, OSI-7836, using two administration schedules in patients with advanced solid malignancies
Abstract Purpose: To investigate the safety, tolerability, and pharmacokinetic profile of the novel nucleo-side 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 61treatment 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 z200 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.
|Keywords||Adult, Aged, Antimetabolites, Antineoplastic/administration & dosage/toxicity, Arabinonucleosides/administration & dosage/*pharmacokinetics/*toxicity, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Male, Metabolic Clearance Rate, Middle Aged, Neoplasms/blood/*drug therapy|
|Persistent URL||dx.doi.org/10.1158/1078-0432.CCR-05-1932, hdl.handle.net/1765/21768|
Lee, C.P., de Jonge, M.J.A., O'Donnell, A.E., Schothorst, K.L., Hanwell, J., Chick, J.B., … Verweij, J.. (2006). A phase I study of a new nucleoside analogue, OSI-7836, using two administration schedules in patients with advanced solid malignancies. Clinical Cancer Research, 12(9), 2841–2848. doi:10.1158/1078-0432.CCR-05-1932