title: A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma.
abstract: BACKGROUND
  Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), and sunitinib, an oral inhibitor of vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor tyrosine kinase signaling, have both been shown to provide clinical benefit in patients with advanced renal cell carcinoma (RCC). We sought to determine the safety and efficacy of combination therapy with these agents in patients with advanced RCC.
  
  
  METHODS
  We conducted a phase 1b dose escalation trial of sunitinib and everolimus in patients with advanced metastatic RCC. Prior nephrectomy was required, and prior radiation or chemotherapy other than VEGF/mTOR-based therapies was permitted. The primary end point was to determine the maximum tolerated dose/recommended phase 2 dose.
  
  
  RESULTS
  A total of 4 out of a planned 30 subjects were enrolled onto this study (M:F = 2:2; mean age 52 years, 50% with Karnofsky performance status < 80). The first 3 patients were enrolled onto a 4 + 2 dosing schedule of daily sunitinib 50 mg and weekly everolimus 30 mg. Mean time receiving drug was 99 days. One partial response was seen. Toxicities included mucositis, thrombocytopenia, anemia, fatigue, dehydration, and hypoglycemia. Because of multiple grade 3 to 4 toxicities, the protocol was amended to 2 + 1 dosing of sunitinib 37.5 mg and daily everolimus 5 mg. The first patient on this schedule died from multiorgan failure with septic shock after 1 cycle of treatment. Subsequently, the study was closed. Pharmacokinetic results inconclusively suggest that toxicities could be attributed to the drug exposure.
  
  
  CONCLUSIONS
  Combined use of everolimus and sunitinib in the treatment of metastatic RCC was not well tolerated in this small cohort.
authors.affiliation: Duke University Medical Center, Durham, NC.
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kanesvaran
authors.affiliation: Duke Clinical Research Institute, Durham, NC.
authors.forename: Kevin
authors.initials: K
authors.lastname: Watt
authors.affiliation: Duke University, Durham, NC.
authors.forename: James D
authors.initials: JD
authors.lastname: Turnbull
authors.affiliation: Duke University Medical Center, Durham, NC.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.affiliation: Duke Clinical Research Institute, Durham, NC.
authors.forename: Michael Cohen
authors.initials: MC
authors.lastname: Wolkowiez
authors.affiliation: Duke University Medical Center, Durham, NC. Electronic address: daniel.geoge@duke.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000077210:Sunitinib
keywords: Combination; Kidney cancer; Metastatic; VEGF TKI; mTOR inhibitor