title: Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma.
abstract: BACKGROUND
  Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Molecular profiling studies reveal that the PI3K/AKT/mTOR pathway is altered in a significant percentage of UCs.
  
  
  OBJECTIVE
  We conducted a phase I trial to evaluate the feasibility of combining the mTOR inhibitor everolimus with gemcitabine and split-dose cisplatin (GC) in advanced UC in the first-line setting.
  
  
  METHODS
  Patients received gemcitabine 800 mg/m2and cisplatin 35 mg/m2on days 1 and 8 of 21-day cycles for a total of 6 cycles in combination with everolimus at increasing dose levels (DL1:5 mg QOD, DL2:5 mg daily, DL3:10 mg daily) following a standard 3+3 design. Responses were assessed every 2 cycles. Patients with at least stable disease (SD) continued everolimus until progression. Goals were to establish dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for the combination.
  
  
  RESULTS
  12 patients were enrolled, 3 at DL1, 3 at DL2, and an additional 6 at DL1*(DL1 following de-escalation). 3/3 patients at DL2 had DLTs during cycle 1. 2/8 evaluable patients at DL1/DL1*had DLTs during cycle 1. DLTs were primarily hematologic. Further toxicities, also primarily hematologic, were observed during later treatment cycles, leading to 8 chemotherapy dose reductions overall. Partial responses were observed in 4/10 evaluable patients, and SD in 5/10. Median overall survival was 10.8 months (95% CI 6.9, not reached).
  
  
  CONCLUSIONS
  The maximum tolerated dose was reached at the lowest dose level, 5 mg QOD, for everolimus in combination with gemcitabine and split-dose cisplatin in advanced UC. The regimen was limited by hematologic toxicity.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: Abida
authors.affiliation: Division of Hematology and Oncology, UNC Lineberger Comprehensive Cancer Center , Chapel Hill, NC, USA.
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gerst
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Voss
authors.affiliation: National Cancer Institute , Bethesda, MD, USA.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Apolo
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Regazzi
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Asia S
authors.initials: AS
authors.lastname: McCoy
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Mariel E
authors.initials: ME
authors.lastname: Boyd
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
keywords: Everolimus; Urothelial carcinoma; cisplatin; gemcitabine; mTOR inhibitor