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 (16-EI-0159)

使用 PDGF 拮抗剂 E10030 和 VEGF 拮抗剂 Ranibizumab 组合进行玻璃体内治疗严重眼部 von Hippel-Lindau 病的 I/II 期试验 (16-EI-0159)

• 批准号: 10930533
• 负责人: EMILY Y CHEW
• 金额: $ 3.85万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10930533
• 关键词: Adrenal Glands; Adverse event; Affect; Appearance; Benign; Blindness; Brain; Broad Ligament; Cell Line; Cyst; Disease; Electronics; Epididymis; Exudate; Eye; Fibrosis; Fluorescein Angiography; Fundus photography; Hereditary Disease; Histopathology; Individual; Investigational Therapies; Kidney; Labyrinth; Letters; Malignant Neoplasms; Manuscripts; Measures; Mediator; Operative Surgical Procedures; Optical Coherence Tomography; Outcome Measure; Outcome Study; PDGFA gene; Pancreas; Paper; Participant; Phase; Phase I/II Trial; Platelet-Derived Growth Factor; Proliferating; Publications; Publishing; Reporting; Retina; Role; Safety; Spider nevus; Spinal Cord; Testing; Traction; United States; VEGFA gene; VHL protein; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; Visual Acuity; Von Hippel-Lindau Syndrome; aggressive therapy; angiogenesis; antagonist; autosome; cell type; design; eligible participant; experience; intravitreal injection; open label; phase 1 study; primary outcome; prospective; ranibizumab; secondary outcome; standard care; study population; tumor

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 (AE) reported through Week 52. Secondary outcomes will include tabulation of AEs 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 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. In fiscal year 2021, the trial remains in analysis status. The analysis of primary results has been completed, and a manuscript has been submitted and provisionally accepted for publication. This paper was published.

目的：Von Hippel-Lindau （VHL）病是一种常染色体显性遗传病，在肾脏、肾上腺、胰腺、脑、脊髓、眼、内耳、附睾和宽韧带发生多发性良恶性肿瘤和囊肿。这种疾病在美国影响了大约7000人。视网膜毛细血管瘤（RCH）是VHL疾病最常见和最早期的表现，可能导致严重的视力丧失。在一些这样的眼睛中，尽管进行了积极的治疗，但RCH的不可阻挡的进展导致失明和球性肺结核。血管内皮生长因子（VEGF）是一种有效的血管生成和血管通透性介质，在多种缺乏VHL蛋白（pVHL）的细胞类型中，其水平被证明是升高的。

项目成果

Retrobulbar Hemangioblastomas in von Hippel-Lindau Disease: Clinical Course and Management.

希佩尔-林道病中的球后血管母细胞瘤：临床过程和治疗。

• DOI: 10.1093/neuros/nyaa565
• 发表时间: 2021
• 期刊: Neurosurgery
• 影响因子: 4.8
• 作者: Alvarez,Reinier;Mastorakos,Panagiotis;Hogan,Elizabeth;Scott,Gretchen;Lonser,RussellR;Wiley,HenryE;Chew,EmilyY;Chittiboina,Prashant
• 通讯作者: Chittiboina,Prashant