title: Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with Fluorouracil in patients with advanced solid tumors.
abstract: OBJECTIVE
  Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01.
  
  
  METHODS
  FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m(2) over 72 hours in cycle 1 and 67.5 mg/m(2) over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction.
  
  
  RESULTS
  We escalated the weekly FU dose to 2,600 mg/m(2) in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 micromol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines.
  
  
  CONCLUSIONS
  The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m(2).
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. schwartg@mskcc.org
authors.forename: Jeremy
authors.initials: J
authors.lastname: Kortmansky
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.forename: Andreas
authors.initials: A
authors.lastname: Kaubisch
authors.forename: Amanda
authors.initials: A
authors.lastname: Weyerbacher
authors.forename: Sandy
authors.initials: S
authors.lastname: Yi
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sowers
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.forename: Eileen
authors.initials: E
authors.lastname: O'reilly
authors.forename: Nancy
authors.initials: N
authors.lastname: Kemeny
authors.forename: David I
authors.initials: DI
authors.lastname: Ilson
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsen
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; C054852:7-hydroxystaurosporine; D019311:Staurosporine; D005472:Fluorouracil