Overview

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

Status:
Completed
Trial end date:
2019-07-09
Target enrollment:
0
Participant gender:
All
Summary
Background: People with Von-Hippel-Lindau (VHL) disease may experience significant vision loss as a result of retinal capillary hemangiomas (RCH), the most common and often earliest manifestation of VHL. Objective: To investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease. Design: Three participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks. Primary Outcome: The safety of the combination investigational treatment, assessed by tabulation of adverse events reported through Week 52.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
National Eye Institute (NEI)
Treatments:
Ranibizumab
Criteria
- Participant Eligibility Criteria

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

INCLUSION CRITERIA:

1. Participant must understand and sign the informed consent.

2. Participant must be 18 years of age or older.

3. 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.

4. 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.

5. 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:

1. 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).

2. 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.

3. 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.

4. Participant is medically unable to comply with study procedures or follow-up in the
judgment of the investigator.

5. 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:

1. Participant has at least one RCH secondary to VHL disease in the study eye that
fulfills the following criteria:

1. 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-retinal exudation or lipid deposition that, in the
judgment of the investigator, reflects ongoing vascular incompetence and is
not solely reflective of residual changes following previous treatment or
solely secondary to coexistent retinal traction.

- Increased size of the tumor compared to a previous time point as assessed by
fundus photography or FA.

- Associated intra-, sub- or pre-retinal hemorrhage not secondary to previous
treatment, as assessed by fundus photography or FA.

- The presence of dilated and/or tortuous feeder vessels.

- Vitreous cell or haze indicative of vitreous exudation, in the absence of
other ocular features potentially responsible for such findings.

2. The RCH, in the judgment of the investigator, is NOT readily treatable using
thermal laser because of its size, posterior location, poor previous response to
conventional therapy, association with significant exudation, epiretinal
proliferation, associated vascular abnormalities such as vascular proliferation
or diffusely incompetent retinal vessels, or other factors predictive of a poor
response to standard of care approaches.

2. The study eye must have clarity of ocular media and degree of pupil dilation
sufficient to permit adequate fundus photography.

EXCLUSION CRITERIA:

1. The study eye has present or chronic ocular or periocular infection (including any
history of ocular herpes zoster).

2. The study eye has chronic glaucoma; OR has received anti-glaucoma medication at any
time within 90 days of study entry; OR has significant ocular hypertension, defined as
documented intraocular pressure of greater than or equal to 28 mmHg on any occasion in
the absence of self-limited acute glaucoma, OR greater than or equal to 24 mmHg on at
least two occasions in the absence of self-limited acute glaucoma.

Note: History of self-limited acute glaucoma in a study eye, if now resolved and not
expected to recur, is not exclusionary. History of glaucoma or ocular hypertension in
the fellow eye, if not felt to significantly impact risk of glaucoma in the study eye,
is not exclusionary.

3. The study eye has undergone any surgical procedure within 60 days prior to study entry
(inclusive of cryotherapy or thermal laser).

4. The study eye has a history of intravitreal injection of an anti-VEGF agent (such as
bevacizumab, ranibizumab or aflibercept) within 42 days prior to study entry.

5. The study eye has a history of intravitreal or periocular injection of long-acting
corticosteroids (such as triamcinolone acetonide) within 90 days of study entry or
history of any sustained-release ocular drug delivery device with reasonable
expectation of residual activity in the study eye.

Choice of Study Eye in Cases of Bilateral Eligibility

If both eyes of a participant meet the criteria described above, the investigator will
choose to enroll one eye in consultation with the participant.