Pilot study of dovitinib in patients with VHL disease.

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587 Background: Von Hippel-Lindau (VHL) is an autosomal dominant inherited disease occurring in 1 in 35,000 births. Individuals with germline mutations in the VHL gene may phenotypically express a variety of lesions including hemangioblastomas (HBs), pancreatic cysts, renal cysts, and renal cell carcinomas (RCC). Previous studies have shown differentially increased FGFR3 levels in HBs compared to RCC. In this pilot trial, we investigated the safety and efficacy profile of TKI 258 (dovitinib), a tyrosine kinase inhibitor of VEGF and FGF receptors, in VHL related lesions, focusing on HBs. Methods: A MDACC IRB-approved protocol planned to enroll 25 subjects who had genetically confirmed VHL disease or clinical diagnosis of VHL, and measurable HBs with no immediate risk of needing intervention. Dovitinib 500mg/day was given in a 4 week cycle on 5 day on/2 day off schedule. In the absence of adverse events (AE), treatment lasted 6 cycles or until disease progression. Evaluation of response to treatment was done every 8 weeks including imaging, laboratory, and clinical evaluation. The trial design used a continuous Bayesian stopping rule based on toxicities that resulted in discontinuation of dovitinib and another for lack of efficacy. Signed informed consent completed on all patients enrolled. Results: Trial stopped after six patients enrolled due to toxicity stopping rule. Patients’ ages ranged 18-61 with 5/6 being male. With regards to safety, 6/6 subjects had at least one AE with the most common AEs being rash, diarrhea, and fatigue including a grade 3 AE (severe rash) in one patient. 1/6 was stopped due to noncompliance, 1/6 stopped due to progression, 3/6 stopped due to side effects despite dose reduction, and 1/6 completed full six cycles at full dose. Best response in 6/6 subjects was stable disease (SD) in HBs. Conclusions: This pilot study of dovitinib in patients with VHL disease with measureable HBs did not show a favorable safety or efficacy profile for this dose and schedule. Half of the patients discontinued the drug due to AEs before study completion, and the best achieved response was SD. Further investigation into alternative scheduling and other FGFR inhibitors in the treatment of HBs is warranted given the strong pre-clinical data. Clinical trial information: NCT01266070.