A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer

Powles, T. et al. (2014) A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. European Journal of Cancer, 50(12), pp. 2057-64. (doi: 10.1016/j.ejca.2014.04.021)

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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.<p></p> 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.<p></p> Results: Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5 mg orally (PO) once daily (OD) and dovitinib 200 mg 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.<p></p> Conclusion: Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jones, Professor Robert
Authors: Powles, T., Foreshew, S.-J. S., Shamash, J., Sarwar, N., Crabb, S., Sahdev, A., Nixon, J., Lim, L., Pungaliya, A., Foreshaw, A., Davies, R., Greenwood, M., Wilson, P., Pacey, S., Galazi, M., Jones, R., and Chowdhury, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:European Journal of Cancer
Publisher:Elsevier Ltd.
ISSN:0959-8049
ISSN (Online):1879-0852
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