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)

目的：von Hippel-Lindau病(VHL)是一种常染色体显性遗传性疾病，可在肾脏、肾上腺、胰腺、脑、脊髓、眼、内耳、附睾部和宽韧带等部位发生多种良、恶性肿瘤和特定组织病理学的囊性病变。在美国，这种疾病影响了大约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，RCH的不可阻挡的进展仍会导致失明和眼球肺结核。血管内皮生长因子(VEGF)是血管生成和血管通透性的强大中介，已被证明在VHL蛋白(PVHL)缺乏的多种细胞类型中水平升高。血小板衍生生长因子(PDGF)在pVHL缺陷细胞系中表达上调，在pVHL缺陷肿瘤中表达，在新生血管生成过程中起着稳定未成熟新生血管的重要作用。在之前的两项1期研究中，单纯的抗血管内皮生长因子治疗对眼部VHL疾病没有有利的效果。本研究的目的是探讨PDGF-B拮抗剂E10030和血管内皮生长因子A拮抗剂雷尼比单抗联合玻璃体内注射治疗严重眼部VHL疾病的安全性和可能的疗效。 研究人群：5名患有严重眼部VHL疾病的参与者将在一只眼睛接受联合研究治疗，并将被跟踪104周。最多可以再招募两名参与者，以取代在第52周访问之前退出研究的参与者。 设计：在这一I/II期、单中心、前瞻性、开放标签、非随机、非对照、单组试验中，符合条件的参与者的一只眼将接受研究产品、PDGF-B拮抗剂E10030和血管内皮生长因子-A拮抗剂雷尼比珠单抗的治疗。参与者将接受联合研究治疗，包括从基线到第16周每4周玻璃体内注射E10030(1.5 mg/0.05毫升)和雷尼比珠单抗(0.5 mg/0.05毫升/0.05毫升)(总共5个治疗)，然后每8周到48周(从基线开始总共9个治疗)。从第52周开始，符合充分应答标准的参与者将有资格在治疗延长阶段每4周至第92周继续根据需要接受注射。所有参与者将被跟踪104周。 结果指标：该研究的主要结果将是联合研究治疗的安全性，通过52周报告的不良事件列表进行评估。次要结果将包括第104周的不良事件列表，以及研究眼在第52周和第104周的以下指标：在没有进行其他消融治疗的情况下，参与者经历至少一个RCH大小缩小的比例(通过眼底照相和荧光素血管造影FA进行评估)；经历中度视力丧失的参与者的比例(通过电子视力EVA测试，定义为较基线丢失15个字母)；视力的平均变化；RCH的大小变化(通过眼底照相和FA测量)；渗出的变化(通过眼底照相、光学相干断层扫描和FA测量)；通过OCT和眼底照相评估视网膜前增生、纤维化或视网膜牵引力的变化；接受RCH或眼科手术消融治疗的参与者的比例；RCH消融治疗成功的参与者的比例；以及出现一种或多种新的RCH的参与者的比例。 三名参与者在2017财年登记，并继续学习跟踪。

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 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). Starting at Week 52, participants meeting criteria for a sufficient response will be eligible to continue to receive injections as needed as frequently as every 4 weeks through Week 92 in the treatment extension phase. 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 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. Three participants were enrolled in fiscal year 2017 and continue study follow up.