• Thomas Powles, Shah-Jalal Sarker Foreshew, Jonathan Shamash, Naveed Sarwar, Simon Crabb, Anju Sahdev, Jude Nixon, Louise Lim, Ashish Pungaliya, Abigail Foreshaw, Rachel Davies, Michelle Greenwood, Peter Wilson, Simon Pacey, Myra Galazi, Robert Jones, and Simon Chowdhury.
• 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.
• Eur. J. Cancer. 2014 Aug 1;50(12):2057-64.

BackgroundEverolimus (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.MethodsPatients 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.ResultsOverall 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.ConclusionDovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

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