title: Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma.
abstract: BACKGROUND
  Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC.
  
  
  METHODS
  Sequential cohorts of 3 to 6 patients with advanced RCC received dose-escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained.
  
  
  RESULTS
  Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed.
  
  
  CONCLUSIONS
  The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC.
authors: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. molinaa@mskcc.org
authors: Ana M
authors: AM
authors: Molina
authors: Darren R
authors: DR
authors: Feldman
authors: Martin H
authors: MH
authors: Voss
authors: Michelle S
authors: MS
authors: Ginsberg
authors: Michael S
authors: MS
authors: Baum
authors: Dion R
authors: DR
authors: Brocks
authors: Patricia M
authors: PM
authors: Fischer
authors: Michael J
authors: MJ
authors: Trinos
authors: Sujata
authors: S
authors: Patil
authors: Robert J
authors: RJ
authors: Motzer
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D000068338:Everolimus; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077210:Sunitinib
chemical_list: D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000077210:Sunitinib; D020123:Sirolimus