A Phase I/II Trial for Intravitreous Treatment of Severe Ocular Von Hippel-Lindau Disease Using a Combination of the PDGF Antagonist E10030 and the VEGF Antagonist Ranibizumab

• Participant Eligibility Criteria

The participant must meet all of the eligibility criteria and none of the exclusion criteria below.

INCLUSION CRITERIA

• Participant must understand and sign the informed consent.
• Participant must be 18 years of age or older.
• Participant must have a diagnosis of VHL disease. In accordance with established criteria for diagnosis, any one of the following will be considered sufficient evidence that VHL disease is present:
• A family history of VHL disease plus one or more of the following lesions: RCH, spinal or cerebellar hemangioblastoma, pheochromocytoma, multiple pancreatic cysts, epididymal or broad ligament cystadenomas, multiple renal cysts or renal cell carcinoma before age 60 years.
• Presence of two or more hemangioblastomas of the retina or brain or a single hemangioblastoma in association with a visceral manifestation such as kidney or pancreatic cysts; renal cell carcinoma; adrenal or extra-adrenal pheochromocytomas; endolymphatic sac tumors; papillary cystadenomas of the epididymis or broad ligament; or neuroendocrine tumors of the pancreas.
• Presence of a known disease-causing germline mutation in the VHL gene.
• Any female participant of childbearing potential must not be pregnant or breast-feeding, must have a negative pregnancy test at screening and must be willing to undergo pregnancy testing immediately prior to each treatment.
• Any female participant of childbearing potential and any male participant able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two effective methods of contraception throughout the course of the study and for at least two months following the last administration of combination investigational treatment. Acceptable methods of contraception include:
• hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring),
• intrauterine device,
• barrier methods (diaphragm or condom) with spermicide, or
• surgical sterilization (hysterectomy, tubal ligation or vasectomy).

EXCLUSION CRITERIA

• Participant has a history or evidence of significant cardiac disease (for example, use of cardiac medications aside from agents to control blood pressure, past acute coronary syndrome, past myocardial infarction, past revascularization procedure or arrhythmias requiring past or present treatment).
• Participant has a history of stroke or transient ischemic attack.

Note: cerebrovascular manifestations and/or complications of central nervous system hemangioblastomas are not exclusionary, in the absence of past stroke or transient ischemic attack.

• Participant has used systemic medication with significant anti-VEGF or anti-PDGF activity within 30 days of study entry or expects use of such a medication within 12 months of study entry.
• Participant is medically unable to comply with study procedures or follow-up in the judgment of the investigator.
• Participant has a diagnosis of diabetic mellitus (type 1 or type 2). Any one of the following will be considered sufficient evidence that diabetes is present:
• Current regular use of insulin for the treatment of diabetes,
• Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes,
• Hemoglobin A1C of greater than or equal to 6.5%, or
• Documented diabetes by the American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria.

Study Eye Eligibility Criteria

The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.

INCLUSION CRITERIA

• Participant has at least one RCH secondary to VHL disease in the study eye that fulfills the following criteria:
• The RCH must exhibit growth potential with consequent threat to vision. Growth potential with consequent threat to vision is defined by AT LEAST ONE of the following:
• Associated intra- or sub-re