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

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Brief Title

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

Official Title

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

Brief 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.
    

Detailed Description

      Objective: Von Hippel-Lindau (VHL) disease is an autosomal dominant heritable disorder in
      which multiple benign and malignant neoplasms and cysts of specific histopathologies develop
      in the kidney, adrenal gland, pancreas, brain, spinal cord, eye, inner ear, epididymis and
      broad ligament. The disease affects about 7,000 individuals in the United States. Retinal
      capillary hemangiomas (RCH) are the most common and often the earliest manifestation of VHL
      disease and may lead to significant vision loss. In some such eyes, inexorable progression of
      RCH leads to blindness and phthisis bulbi despite aggressive treatment. Levels of vascular
      endothelial growth factor (VEGF), a potent mediator of angiogenesis and vascular
      permeability, have been shown to be elevated in multiple cell types deficient in the VHL
      protein (pVHL). Platelet-derived growth factor (PDGF), which has an important role in
      stabilization of immature new vessels during angiogenesis, is upregulated in pVHL-defective
      cell lines and expressed in other pVHL-defective tumors. Anti-VEGF therapy alone had no
      beneficial effect on ocular VHL disease in two previous phase 1 studies. The objective of
      this study is 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.

      Study Population: Three participants with severe ocular VHL disease will receive the
      combination investigational treatment in one eye and will be followed for 104 weeks.

      Design: In this phase I/II, single-center, prospective, open label, non-randomized,
      uncontrolled, single group trial, one eye of eligible participants will be treated with
      investigational products, E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist.
      Participants will receive combination investigational treatment consisting of intravitreal
      injections of E10030 (1.5 mg in 0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) every four weeks
      from baseline through Week 16 (totaling five treatments) and then every eight weeks through
      Week 48 (totaling nine treatments from baseline). All participants will be followed for 104
      weeks.

      Outcome Measures: The primary outcome for the study will be safety of the combination
      investigational treatment, assessed by tabulation of adverse events reported through Week 52.
      Secondary outcomes will include tabulation of adverse events at Week 104, and the following
      measures in the study eye at Week 52 and 104: the proportion of participants experiencing
      reduction in size of at least one RCH in the absence of other ablative treatment (assessed by
      fundus photography and fluorescein angiography (FA)); the proportion of participants
      experiencing moderate vision loss (defined as a loss of greater than or equal to 15 letters
      from baseline on Electronic Visual Acuity (EVA) testing); mean change in visual acuity;
      change in size of RCH (measured by fundus photography and FA); change in exudation (measured
      by fundus photography, optical coherence tomography (OCT) and FA); change in epiretinal
      proliferation, fibrosis or retinal traction (assessed by OCT and fundus photography);
      proportion of participants undergoing ablative treatment of RCH or ocular surgery; proportion
      of participants with successful ablative treatment of RCH; and the proportion of participants
      with appearance of one or more new RCH.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Tabulation of Adverse Events

Secondary Outcome

 Tabulation of Adverse Events

Condition

Von Hippel-Lindau Syndrome

Intervention

Ranibizumab

Study Arms / Comparison Groups

 E10030 and Ranibizumab
Description:  Intravitreal injections of E10030 and Ranibizumab

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

3

Start Date

January 23, 2017

Completion Date

July 9, 2019

Primary Completion Date

July 9, 2019

Eligibility 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Henry E Wiley, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02859441

Organization ID

160159

Secondary IDs

16-EI-0159

Responsible Party

Sponsor

Study Sponsor

National Eye Institute (NEI)


Study Sponsor

Henry E Wiley, M.D., Principal Investigator, National Eye Institute (NEI)


Verification Date

July 2019