Sunitinib Malate to Treat Advanced Eye Disease in Patients With Von Hippel-Lindau Syndrome

Von Hippel-Lindau Syndrome Clinical Trial

— VHL3  

Official title:

Pilot Study of Sunitinib Malate for Advanced Ocular Disease of Von Hippel-Lindau Syndrome

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00673816
• Other study ID #: 080129
• Secondary ID: 08-EI-0129
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: May 2008
• Est. completion date: February 2011

Study information

• Verified date: November 2011
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 nine months of sunitinib malate therapy (six cycles total - one cycle consists of 50 mg oral dose once daily for four weeks followed by a two week rest period). The primary outcome will be a change in the best-corrected visual acuity of more than or equal to 15 letters from baseline to the Week 36 visit. The secondary ocular outcomes will focus on retinal thickness and leakage of the retinal angioma at the Week 36 visit. Optical coherence tomography will document changes in retinal thickening and fluorescein angiography will be used to determine leakage of the retinal angioma.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: February 2011
• Est. primary completion date: February 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

1. Participant must understand and sign the informed consent.

2. Participant must be at least 18 years of age.

3. Participant must have genetically confirmed VHL disease.

4. Participant must have an optic nerve angioma secondary to VHL in one or both eyes.

5. 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.

6. Participant must have clear ocular media and adequate pupillary dilation to permit good quality stereoscopic fundus photography.

7. 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).

8. 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.

9. Participants must have normal organ and marrow function as defined below: WBC count = 3,000/µL, absolute neutrophil count = 1,500/µL, platelet count = 100,000/µL, HGB> 10g/dl, serum creatinine = 2.0 or measured 24 hr. creatinine clearance > 50 ml/min, AST and ALT < 2.5 x ULN, total bilirubin = ULN (< 3 x NL in participants with Gilbert's disease).

10. Participant must have a negative HbsAg and nonreactive HCV.

11. 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.

12. Participant must be at least four weeks from completion of any investigational therapy for VHL.

13. Participant must have an ECOG performance score of 0-2. (See Appendix 3 - ECOG Performance Criteria).

14. Participant has recovered from the acute toxicities of prior treatment for VHL.

Exclusion Criteria

1. Participant has a history (within past five 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.

2. Participant has a history of serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation, = three beats in a row) or left ventricular ejection fraction = 40%.

3. Participant has a history of serious intercurrent medical illness.

4. Participant had transient ischemic attacks or cerebrovascular accident within 12 months of study entry.

5. Participant has hypertension that cannot be controlled with medications (persistent elevation of systolic BP > 150 or diastolic BP > 100 mmHg despite optimal medical therapy).

6. Participant is on therapeutic anticoagulation, including aspirin.

7. 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.

8. Participant has received any major surgical procedures within one month of study entry or has surgical scars that have not healed.

9. Participant has a known serious allergy to fluorescein dye.

10. 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).

11. 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.

12. Participant has had chemotherapy or radiotherapy within four weeks (six 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 four weeks earlier.

13. Participant is receiving other investigational agents.

14. Participants with known brain metastases (except when adequately controlled, i.e., have not grown in size, for = 6 months before enrollment), not including hemangioblastoma, a known VHL complication of the brain.

15. Participant has a known bleeding disorder.

16. Participant is currently taking sunitinib malate or has taken sunitinib malate in the past.

Related Conditions & MeSH terms

• Syndrome
• Von Hippel-Lindau Disease
• Von Hippel-Lindau Syndrome

Intervention

Drug:
• Sunitinib Malate
Participants were expected to receive 9 months of sunitinib malate therapy administered in 6 cycles. Each cycle consisted of a daily oral dose of 50 mg sunitinib malate for 4 weeks followed by a 2-week rest period).

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Eye Institute (NEI)

Country where clinical trial is conducted

United States, 

References & Publications (45)

Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003 May;2(5):471-8. — View Citation

Abrams TJ, Murray LJ, Pesenti E, Holway VW, Colombo T, Lee LB, Cherrington JM, Pryer NK. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. Mol Cancer Ther. 2003 Oct;2(10):1011-21. — View Citation

Aiello LP, George DJ, Cahill MT, Wong JS, Cavallerano J, Hannah AL, Kaelin WG Jr. Rapid and durable recovery of visual function in a patient with von hippel-lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor su5416. Ophthalmology. 2002 Sep;109(9):1745-51. doi: 10.1016/s0161-6420(02)01159-4. — View Citation

Alvarez RH, Kantarjian HM, Cortes JE. Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin Proc. 2006 Sep;81(9):1241-57. doi: 10.4065/81.9.1241. — View Citation

Bello CL, Sherman L, Zhou J, Verkh L, Smeraglia J, Mount J, Klamerus KJ. Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs. 2006 Mar;17(3):353-8. doi: 10.1097/00001813-200603000-00015. — View Citation

Blanke CD, Corless CL. State-of-the art therapy for gastrointestinal stromal tumors. Cancer Invest. 2005;23(3):274-80. doi: 10.1081/cnv-200055972. — View Citation

Corless CL, McGreevey L, Town A, Schroeder A, Bainbridge T, Harrell P, Fletcher JA, Heinrich MC. KIT gene deletions at the intron 10-exon 11 boundary in GI stromal tumors. J Mol Diagn. 2004 Nov;6(4):366-70. doi: 10.1016/S1525-1578(10)60533-8. — View Citation

Dahr SS, Cusick M, Rodriguez-Coleman H, Srivastava SK, Thompson DJ, Linehan WM, Ferris FL 3rd, Chew EY. Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina. 2007 Feb;27(2):150-8. doi: 10.1097/IAE.0b013e318030a290. — View Citation

Escudier B, Chevreau C, Lasset C, Douillard JY, Ravaud A, Fabbro M, Caty A, Rossi JF, Viens P, Bergerat JP, Savary J, Negrier S. Cytokines in metastatic renal cell carcinoma: is it useful to switch to interleukin-2 or interferon after failure of a first treatment? Groupe Francais d'Immunotherape. J Clin Oncol. 1999 Jul;17(7):2039-43. doi: 10.1200/JCO.1999.17.7.2039. — View Citation

Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla P, Raymond E. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006 Jan 1;24(1):25-35. doi: 10.1200/JCO.2005.02.2194. Epub 2005 Nov 28. — View Citation

Girmens JF, Erginay A, Massin P, Scigalla P, Gaudric A, Richard S. Treatment of von Hippel-Lindau retinal hemangioblastoma by the vascular endothelial growth factor receptor inhibitor SU5416 is more effective for associated macular edema than for hemangioblastomas. Am J Ophthalmol. 2003 Jul;136(1):194-6. doi: 10.1016/s0002-9394(03)00101-6. — View Citation

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. doi: 10.1073/pnas.93.20.10589. — View Citation

Green JS, Bowmer MI, Johnson GJ. Von Hippel-Lindau disease in a Newfoundland kindred. CMAJ. 1986 Jan 15;134(2):133-8, 146. — View Citation

Guo P, Hu B, Gu W, Xu L, Wang D, Huang HJ, Cavenee WK, Cheng SY. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol. 2003 Apr;162(4):1083-93. doi: 10.1016/S0002-9440(10)63905-3. — View Citation

Hardwig P, Robertson DM. von Hippel-Lindau disease: a familial, often lethal, multi-system phakomatosis. Ophthalmology. 1984 Mar;91(3):263-70. doi: 10.1016/s0161-6420(84)34304-4. — View Citation

Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9. doi: 10.1200/JCO.2003.04.190. — View Citation

Horton WA, Wong V, Eldridge R. Von Hippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med. 1976 Jul;136(7):769-77. doi: 10.1001/archinte.136.7.769. — View Citation

http://ctep.cancer.gov/forms/CTCAEv3.pdf

http://ctep.cancer.gov/guidelines/recist.html

http://www.pfizer/download/uspi_sutent.pdf

http://www.rxlist.com/cgi/generic/sutent

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. doi: 10.1073/pnas.93.20.10595. — View Citation

Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep;2(9):673-82. doi: 10.1038/nrc885. — View Citation

Kurban G, Hudon V, Duplan E, Ohh M, Pause A. Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res. 2006 Feb 1;66(3):1313-9. doi: 10.1158/0008-5472.CAN-05-2560. — View Citation

Lamiell JM, Salazar FG, Hsia YE. von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore). 1989 Jan;68(1):1-29. doi: 10.1097/00005792-198901000-00001. — View Citation

Maher ER, Bentley E, Yates JR, Latif F, Lerman M, Zbar B, Affara NA, Ferguson-Smith MA. Mapping of the von Hippel-Lindau disease locus to a small region of chromosome 3p by genetic linkage analysis. Genomics. 1991 Aug;10(4):957-60. doi: 10.1016/0888-7543(91)90185-h. — View Citation

Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990 Nov;77(283):1151-63. doi: 10.1093/qjmed/77.2.1151. — View Citation

McDonald HR, Schatz H, Johnson RN, Abrams GW, Brown GC, Brucker AJ, Han DP, Lewis H, Mieler WF, Meyers S. Vitrectomy in eyes with peripheral retinal angioma associated with traction macular detachment. Ophthalmology. 1996 Feb;103(2):329-35 ; discussion 334-5. doi: 10.1016/s0161-6420(96)30696-9. — View Citation

MELMON KL, ROSEN SW. LINDAU'S DISEASE. REVIEW OF THE LITERATURE AND STUDY OF A LARGE KINDRED. Am J Med. 1964 Apr;36:595-617. doi: 10.1016/0002-9343(64)90107-x. No abstract available. — View Citation

Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003 Jan;9(1):327-37. — View Citation

Morabito A, De Maio E, Di Maio M, Normanno N, Perrone F. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist. 2006 Jul-Aug;11(7):753-64. doi: 10.1634/theoncologist.11-7-753. — View Citation

Motzer RJ, Hoosen S, Bello CL, Christensen JG. Sunitinib malate for the treatment of solid tumours: a review of current clinical data. Expert Opin Investig Drugs. 2006 May;15(5):553-61. doi: 10.1517/13543784.15.5.553. — View Citation

Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. doi: 10.1056/NEJMoa065044. — View Citation

Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. doi: 10.1200/JCO.2005.02.2574. Epub 2005 Dec 5. — View Citation

Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006 Jun 7;295(21):2516-24. doi: 10.1001/jama.295.21.2516. — View Citation

Murray LJ, Abrams TJ, Long KR, Ngai TJ, Olson LM, Hong W, Keast PK, Brassard JA, O'Farrell AM, Cherrington JM, Pryer NK. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis. 2003;20(8):757-66. doi: 10.1023/b:clin.0000006873.65590.68. — View Citation

O'Farrell AM, Foran JM, Fiedler W, Serve H, Paquette RL, Cooper MA, Yuen HA, Louie SG, Kim H, Nicholas S, Heinrich MC, Berdel WE, Bello C, Jacobs M, Scigalla P, Manning WC, Kelsey S, Cherrington JM. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res. 2003 Nov 15;9(15):5465-76. — View Citation

Patyna S, Peng G. Distribution of sunitinib and its active metabolite in brain and spinal cord tissue following oral or intravenous administration in rodents and monkeys. European Journal of Cancer Suppl 4(12):21(Abstract 56), 2006.

Ridley M, Green J, Johnson G. Retinal angiomatosis: the ocular manifestations of von Hippel-Lindau disease. Can J Ophthalmol. 1986 Dec;21(7):276-83. — View Citation

Rosenblatt MI, Azar DT. Anti-angiogenic therapy: Prospects for treatment of ocular tumors. Semin Ophthalmol. 2006 Jul-Sep;21(3):151-60. doi: 10.1080/08820530500350787. — View Citation

Sakamoto KM. Su-11248 Sugen. Curr Opin Investig Drugs. 2004 Dec;5(12):1329-39. — View Citation

Schueneman AJ, Himmelfarb E, Geng L, Tan J, Donnelly E, Mendel D, McMahon G, Hallahan DE. SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res. 2003 Jul 15;63(14):4009-16. — View Citation

Seizinger BR, Rouleau GA, Ozelius LJ, Lane AH, Farmer GE, Lamiell JM, Haines J, Yuen JW, Collins D, Majoor-Krakauer D, et al. Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature. 1988 Mar 17;332(6161):268-9. doi: 10.1038/332268a0. — View Citation

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. — View Citation

Van Glabbeke M, Verweij J, Casali PG, Le Cesne A, Hohenberger P, Ray-Coquard I, Schlemmer M, van Oosterom AT, Goldstein D, Sciot R, Hogendoorn PC, Brown M, Bertulli R, Judson IR. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol. 2005 Aug 20;23(24):5795-804. doi: 10.1200/JCO.2005.11.601. — View Citation

* Note: There are 45 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Best Corrected Visual Acuity (BCVA) From Baseline to Week 36	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.	Baseline and 36 Weeks
Secondary	Change in Retinal Thickness From Baseline to Week 36	Retinal thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue.	Baseline and 36 Weeks
Secondary	Reduction in Leakage Intensity as Measured by Fluorescein Angiography From Baseline to Week 36	Number of participants with improvement in leakage intensity.	Baseline and 36 Weeks
Secondary	Visual Field Changes as Documented by Microperimetry From Baseline to Week 36		Baseline and 36 Weeks
Secondary	Changes in Non-ocular VHL Lesion Status	Count of participants with new non-ocular lesions present since baseline at any follow-up visit.	Duration of study
Secondary	Reduction in Leakage Area as Measured by Fluorescein Angiography at the Week 36 Visit	Number of participants with improvement in leakage area.	Baseline and 36 Weeks