title: A phase I study of a new nucleoside analogue, OSI-7836, using two administration schedules in patients with advanced solid malignancies.
abstract: OBJECTIVE
  To investigate the safety, tolerability, and pharmacokinetic profile of the novel nucleoside analogue OSI-7836 in patients with advanced solid malignancies.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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: Royal Marsden Hospital, Sutton, United Kingdom. chooil@barwonhealth.org.au
authors: Chooi P
authors: CP
authors: Lee
authors: Maja J A
authors: MJ
authors: de Jonge
authors: Anne E
authors: AE
authors: O'Donnell
authors: Kristel L
authors: KL
authors: Schothorst
authors: Janet
authors: J
authors: Hanwell
authors: Jon B
authors: JB
authors: Chick
authors: Rik A
authors: RA
authors: Brooimans
authors: Laurel M
authors: LM
authors: Adams
authors: Daniel W
authors: DW
authors: Drolet
authors: Johann S
authors: JS
authors: de Bono
authors: Stan B
authors: SB
authors: Kaye
authors: Ian R
authors: IR
authors: Judson
authors: Jaap
authors: J
authors: Verweij