Background: Everolimus (mTOR inhibitor) and dovitinib (VEGF and FGF-2 inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. In this study we establish the tolerability and an early activity signal of this combination. 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 escalated doses of daily oral everolimus (5-10 mg PO OD) and dovitinib (200-500mg 5/7 days PO) Dose-limiting toxicities (DLTs) were assessed determine the MTD. An expansion cohort (n=15) was treated to obtain additional efficacy and safety information. Results: Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5 mg PO 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% (CTC grade 1-4) of patients respectively. Frequent biochemical abnormalities occurred such as hypertrygliceridaemia 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% CI 2.2-11 months). Conclusions: Dovitinib and everolimus had modest activity, but did not meet all of the the planned efficacy endpoints. Fatigue was the dose limiting toxicity. Clinical trial information: NCT01714765.