title: A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer.
abstract: BACKGROUND
  Everolimus (mammalian target of rapmaycin (mTOR) inhibitor) and dovitinib (vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. The combination is explored in this phase Ib study.
  
  
  METHODS
  Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalating doses of everolimus and dovitinib. Dose-limiting toxicities (DLTs) were assessed to determine the maximum tolerated dose (MTD). An expansion cohort (n=15) was investigated to obtain additional efficacy information. Sequential fluorodeoxyglucose positron emission tomography (FDG-PET) was used as a surrogate marker of response.
  
  
  RESULTS
  Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5mg orally (PO) once daily (OD) and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (Common Toxicity Criteria (CTC) grade 1-4) of patients, respectively. Frequent biochemical abnormalities occurred (such as hypertriglyceridaemia in 67%). Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% confidence interval (CI) 2.2-11 months). Pharmacokinetic data at the MTD showed stable kinetics with time.
  
  
  CONCLUSIONS
  Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK. Electronic address: thomas.powles@bartshealth.nhs.uk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Shah-Jalal Sarker
authors.initials: SJ
authors.lastname: Foreshew
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shamash
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sarwar
authors.affiliation: Department of Medical Oncology, Southampton Hospital, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Crabb
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Anju
authors.initials: A
authors.lastname: Sahdev
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Jude
authors.initials: J
authors.lastname: Nixon
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Lim
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Ashish
authors.initials: A
authors.lastname: Pungaliya
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Abigail
authors.initials: A
authors.lastname: Foreshaw
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Davies
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Greenwood
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Wilson
authors.affiliation: Department of Oncology, Cambridge University, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Pacey
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London, UK.
authors.forename: Myra
authors.initials: M
authors.lastname: Galazi
authors.affiliation: Department of Medical Oncology, The Beatson Cancer Centre, Glasgow, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Jones
authors.affiliation: Department of Uro-oncology, Guys and St Thomas's Hospital, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Chowdhury
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D015331:Cohort Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D015363:Quinolones; D000068338:Everolimus; D020123:Sirolimus
keywords: Combination; Dovitinib; Everolimus; FGF; Renal cancer; VEFG; mTOR