Medpedia

• von Hippel-Lindau Syndrome

-  INCLUSION CRITERIA:
-  Participant must understand and sign the informed consent.
-  Participant must be at least 18 years of age.
-  Participant must have genetically confirmed VHL disease.
-  Participant must have an optic nerve angioma secondary to VHL in one or both eyes.
-  Participant must have an optic nerve tumor that has caused any visual field
depression on microperimetry-1 that correlates with the retinal angioma OR the
participant clinically may have hard exudates correlating with the retinal angioma OR
has best-corrected visual acuity of 20/40 or worse in the study eye.
-  Participant must have clear ocular media and adequate pupillary dilation to permit
good quality stereoscopic fundus photography.
-  All women of childbearing potential must have a negative urine pregnancy test at
baseline, and have regular negative pregnancy testing while taking sunitinib malate.
(Sunitinib malate has the potential for teratogenic or abortifacient effects, and no
data regarding its safety in pregnant women are available).
-  All women of childbearing potential who are sexually active and all men who are
sexually active are required to use two forms of birth control during the course of
the study.
-  Participants must have normal organ and marrow function as defined below: WBC count
greater than or equal to 3,000/microL, absolute neutrophil count greater than or
equal to 1,500/microL, platelet count greater than or equal to 100,000/microL, HGB
greater than 10g/dl, serum creatinine less than or equal to 2.0 or measured 24 hr.
creatinine clearance greater than 50 ml/min, AST and ALT less than 2.5 x ULN, total
bilirubin less than or equal to ULN (less than 3 x NL in participants with Gilbert's
disease).
-  Participant must have a negative HbsAg, HIV-1 and nonreactive HCV.
-  Participant must have a negative HIV-1, as potential pharmacokinetic interactions of
drugs used to treat HIV, such as anti-retroviral drugs, with sunitinib malate are
unknown.
-  Participant must be at least four weeks from completion of any investigational
therapy for VHL.
-  Participant must have an ECOG performance score of 0-2. (See Appendix 3 - ECOG
Performance Criteria).
-  Participant has recovered from the acute toxicities of prior treatment for VHL.
EXCLUSION CRITERIA:
-  Participant has a history (within past 5 years) or evidence of severe cardiac disease
including heart failure that meets New York Heart Association (NYHA) class III and IV
definitions, uncontrolled dysrhythmias, dysrhythmias requiring anti-arhythmic drugs,
or has active ischemic heart disease including myocardial infarction and poorly
controlled angina within 12 months of study entry.
-  Participant has a history of serious ventricular arrhythmia (ventricular tachycardia
or ventricular fibrillation, greater than or equal to 3 beats in a row) or left
ventricular ejection fraction less than or equal to 40%.
-  Participant has a history of serious intercurrent medical illness.
-  Participants had transient ischemic attacks or cerebrovascular accident within 12
months of study entry.
-  Participant has hypertension that cannot be controlled with medications (persistent
elevation of systolic BP greater than 150 or diastolic BP greater than 100 mmHg
despite optimal medical therapy).
-  Participant is on therapeutic anticoagulation, including aspirin.
-  Participant who is breast-feeding, as there is an unknown but potential risk for
adverse events in nursing infants secondary to treatment of the mother with sunitinib
malate.
-  Participant has received any major surgical procedure within one month of study entry
or has surgical scars that have not healed.
-  Participant has a known serious allergy to fluorescein dye.
-  Participant is currently taking drugs or ingesting food that affect sunitinib malate
plasma concentrations: strong inhibitors of the CYP3A4 family (e.g., ketoconazole,
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice) and/or inducers
of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin,
rifabutin, rifapentin, phenobarbital, St. John's Wort).
-  Participant has had a prior or concomitant non-VHL-associated malignancy with the
exception of adequately treated basal or squamous cell carcinoma of the skin or any
other malignancy from which the patient has remained disease free for more than five
years.
-  Participant has had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (to grade 1 or less toxicity according to CTCAE 3.0)
due to agents administered more than 4 weeks earlier.
-  Participant is receiving other investigational agents.
-  Participants with known brain metastases (except when adequately controlled, i.e.,
have not grown in size, for greater than or equal to 6 months before enrollment), not
including hemangioblastoma, a known VHL complication of the brain.
-  Participant has a known bleeding disorder.
-  Participant is currently taking sunitinib malate or has taken sunitinb malate in the
past.

This open-label study will pilot the use of systemic sunitinib malate, a dual inhibitor of
vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), in five
participants with Von Hippel-Lindau (VHL) to investigate its potential efficacy as a
treatment for retinal angiomas.  Participants will have visual dysfunction with either
visual acuity loss or visual field loss from retinal angiomas secondary to genetically
confirmed VHL. This open-label study will pilot the use of systemic sunitinib malate in five
participants to investigate its potential efficacy as a treatment for retinal angiomas
associated with VHL.  Participants will receive 9 months of sunitinib malate therapy (six
cycles total - one cycle consists of 50 mg oral dose once daily for 4 weeks followed by a
2-week rest period).  The primary outcome will be a change in the best-corrected visual
acuity of greater than or equal to 15 letters at 9 months from baseline. The secondary
ocular outcomes will focus on lesion size, fluorescein leakage and visual field changes at 9
months from baseline. Fluorescein angiography and optical coherence tomography will document
changes in retinal thickening and leakage of the retinal angioma, while microperimetry
(MP-1) will record changes in visual field function. Other secondary outcomes will include
any changes in non-ocular VHL lesion status, adverse events and toxicities.

• Drug: Sunitinib Malate
  N/A

• Change in best corrected visual acuity of 15 letters or more three months after completion of drug therapy (at 1-year follow-up)
  One year
  Safety Issue: No
• Reduction in lesion size as recorded by OCT
  One year
  Safety Issue: No

• National Institutes of Health Clinical Center, 9000 Rockville Pike
  Bethesda, Maryland, 20892, United States
  Recruiting

• National Eye Institute (NEI)
  Lead Sponsor
• United States: Federal Government

• Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G, Marme D. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res. 1996 May 15;56(10):2299-301.
• Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10595-9.
• Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A, Papavassiliou E, Oldfield EH, Klausner RD, Linehan WM. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10589-94.

• NIH Clinical Center Detailed Web Page
  http://clinicalstudies.info.nih.gov/detail/A_2008-EI-0129.html