Clinical Trial: 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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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:

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: Five participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks. Up to an additional two participants may be enrolled to replace participants withdrawing from the study prior to their Week 52 visit.

Design: In this phase I/II, single-center, prospective, open label, non-randomized, uncontrolled, single group trial, one eye o

Detailed Summary:

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: Five participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks. Up to an additional two participants may be enrolled to replace participants withdrawing from the study prior to their Week 52 visit.

Design: In this phase I/II, single-center, prospective, open label, non-randomized, uncontrolled, single group trial, one eye o
Sponsor: National Eye Institute (NEI)

Current Primary Outcome: Tabulation of adverse events [ Time Frame: Through Week 52 ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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]) [ Time Frame: Through Week 104 ]
  • Proportion of participants undergoing ablative treatment of RCH or ocular surgery [ Time Frame: Through Week 104 ]
  • Proportion of participants with successful ablative treatment of RCH [ Time Frame: Through Week 104 ]
  • Mean change in visual acuity [ Time Frame: Through Week 104 ]
  • Tabulation of adverse events [ Time Frame: Through Week 104 ]
  • 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) [ Time Frame: Through Week 104 ]
  • Change in size of RCH (measured by fundus photography and FA) [ Time Frame: Through Week 104 ]
  • Change in exudation (measured by fundus photography, optical coherence tomography [OCT] and FA) [ Time Frame: Through Week 104 ]
  • Change in epiretinal proliferation, fibrosis or retinal traction (assessed by OCT and fundus photography) [ Time Frame: Through Week 104 ]
  • Proportion of participants with appearance of one or more new RCH [ Time Frame: Through Week 104 ]


Original Secondary Outcome: Same as current

Information By: National Institutes of Health Clinical Center (CC)

Dates:
Date Received: August 6, 2016
Date Started: August 1, 2016
Date Completion: August 31, 2018
Last Updated: May 12, 2017
Last Verified: March 22, 2017