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.
CONCLUSION: Dovitinib and everolimus had modest activity, but did not meet all 
of the planned efficacy end-points. Fatigue was the dose limiting toxicity.