title: Time to disease progression to evaluate a novel protein kinase C inhibitor, UCN-01, in renal cell carcinoma.
abstract: BACKGROUND
  Renal cell carcinoma (RCC) is characterized by von Hippel-Lindau gene inactivation and vascular endothelial growth factor (VEGF) overproduction. The mechanism of VEGF overproduction may involve protein kinase C (PKC) delta and zeta isoforms. UCN-01 (7-hydroxystaurosporine) is a selective inhibitor of PKC. Given the historically low objective response rate in RCC, time to disease progression (TTP) as an alternative endpoint was employed to evaluate the antitumor activity of UCN-01 in RCC.
  
  
  METHODS
  Patients with progressive, metastatic RCC received UCN-01 intravenously on Day 1 of each 21-day cycle. The initial dose was 90 mg/m(2) and all subsequent doses were 45 mg/m(2) unless modified for toxicity. TTP was the primary endpoint, defined as the period from the first day of treatment until disease progression. Detection of circulating EpCAM-positive renal carcinoma cells was undertaken for predictive or prognostic potential.
  
  
  RESULTS
  Twenty-one patients were enrolled in this Phase II study. Accrual was halted after failure to reach a predetermined efficacy requirement with 7 patients remaining disease progression free after 4 months (6 cycles). The median TTP for all patients was 2.67 months (range, 0.4-7.6 months). There were no objective responses. Therapy was generally well tolerated. Thirteen patients had < 0.6 EpCAM-positive cells/mL (considered negative) at all time points measured. Two patients had detectable EpCAM-positive cells at a single time point with other measurements being negative.
  
  
  CONCLUSIONS
  TTP is a novel endpoint for the evaluation of agents in RCC. UCN-01 did not demonstrate significant antitumor activity. No evidence for significant circulating EpCAM-positive cells was found in this study cohort.
authors.affiliation: UCSF Comprehensive Cancer Center, The University of California-San Francisco, 1600 Divisadero, Rm. A717, San Francisco, CA 94115, USA. brini@medicine.ucsf.edu
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Vivian
authors.initials: V
authors.lastname: Weinberg
authors.forename: Vanessa
authors.initials: V
authors.lastname: Shaw
authors.forename: Janet
authors.initials: J
authors.lastname: Scott
authors.forename: Robert
authors.initials: R
authors.lastname: Bok
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018450:Disease Progression; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D019311:Staurosporine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; C054852:7-hydroxystaurosporine; D019311:Staurosporine