title: A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies.
abstract: OBJECTIVE
  UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.
  
  
  METHODS
  Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained.
  
  
  RESULTS
  Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks).
  
  
  CONCLUSIONS
  UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.
authors.affiliation: Department of Internal Medicine, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St Louis, MO, USA. fracasso@virginia.edu
authors.forename: Paula M
authors.initials: PM
authors.lastname: Fracasso
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Williams
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Chen
authors.forename: Joel
authors.initials: J
authors.lastname: Picus
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Tan
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Pluard
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Adkins
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Naughton
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Arquette
authors.forename: James W
authors.initials: JW
authors.lastname: Fleshman
authors.forename: Allison N
authors.initials: AN
authors.lastname: Creekmore
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Goodner
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Wright
authors.forename: Zhanfang
authors.initials: Z
authors.lastname: Guo
authors.forename: Christine E
authors.initials: CE
authors.lastname: Ryan
authors.forename: Yu
authors.initials: Y
authors.lastname: Tao
authors.forename: Eliane M
authors.initials: EM
authors.lastname: Soares
authors.forename: Shi-Rong
authors.initials: SR
authors.lastname: Cai
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Janet
authors.initials: J
authors.lastname: Dancey
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Helen
authors.initials: H
authors.lastname: Piwnica-Worms
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000077146:Irinotecan; C054852:7-hydroxystaurosporine; D019311:Staurosporine; D002166:Camptothecin