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 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 > or = 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.

• Authors: Chooi P Lee, Maja J A de Jonge, Anne E O'Donnell, Kristel L Schothorst, Janet Hanwell, Jon B Chick, Rik A Brooimans, Laurel M Adams, Daniel W Drolet, Johann S de Bono, Stan B Kaye, Ian R Judson, Jaap Verweij
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 9 Pg. 2841-8 (May 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16675579 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• Arabinonucleosides
• 4'-thio-arabinofuranosylcytosine

Topics

• 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)