title: Dose escalation and pharmacokinetics study of enzastaurin and sunitinib versus placebo and sunitinib in patients with metastatic renal cell carcinoma.
abstract: OBJECTIVE
  To assess antiangiogenic effects of enzastaurin in combination with sunitinib in patients with renal cell carcinoma (RCC).
  
  
  METHODS
  This was a multicenter, phase 2 study of enzastaurin and sunitinib versus placebo and sunitinib for adult patients with metastatic clear cell RCC. Part 1 was a 6-week, open-label, safety lead-in phase with 2 cohorts (sunitinib, both cohorts: 50 mg/d for 4 weeks; enzastaurin, cohort 1: a loading dose of 500 mg, followed by 250 mg daily; cohort 2: a loading dose of 1125 mg, followed by 500 mg daily). Part 2 was to be a randomized, double-blinded phase, with efficacy as the primary objective. Secondary objectives included the assessment of treatment-emergent adverse events (TEAEs) and pharmacokinetics.
  
  
  RESULTS
  Seventeen patients received ≥1 dose of study medication. Six patients (54.5%) in cohort 1 and 2 patients (33.3%) in cohort 2 received ≥6 cycles of treatment. All patients experienced ≥1 TEAE possibly related to study drug. Dose reductions were required as follows: cohort 1--enzastaurin, n=4 (36.4%), sunitinib, n=6 (54.5%); cohort 2--enzastaurin, n=3 (50.0%), sunitinib, n=2 (33.3%).
  
  
  CONCLUSIONS
  Whereas the hypothesis that combining sunitinib and enzastaurin may result in greater antiangiogenic effects in RCC is based on solid scientific evidence, part 2 of the study was not activated due to the high number of TEAE-related dose reductions at the expected efficacious dose and overall decision by the sponsor not to pursue further development of enzastaurin for solid tumors.
authors.affiliation: Department of Medicine I and Cancer Center, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria. manuela.schmidinger@meduniwien.ac.at
authors.forename: Manuela
authors.initials: M
authors.lastname: Schmidinger
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.forename: Marek
authors.initials: M
authors.lastname: Kania
authors.forename: Claudia Sue
authors.initials: CS
authors.lastname: Kelly
authors.forename: Rodney
authors.initials: R
authors.lastname: Decker
authors.forename: Oday
authors.initials: O
authors.lastname: Hamid
authors.forename: Taron
authors.initials: T
authors.lastname: Faelker
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007390:International Agencies; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D011758:Pyrroles; C504878:enzastaurin; D000077210:Sunitinib