Phase I Clinical Investigation of Episcleral Topotecan in Retinoblastoma

巩膜外拓扑替康治疗视网膜母细胞瘤的 I 期临床研究

• 批准号: 10459222
• 负责人: Ricardo A Carvalho
• 金额: $ 22万
• 依托单位: TARGETED THERAPY TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459222
• 关键词: Phase; Clinical; Investigation; Episcleral; Topotecan

Abstract Retinoblastoma (RB) is a rare (micro-orphan disease) intraocular cancer in infants and children (typically diagnosed between birth and 5 years of age). See FDA OOPD orphan drug letter designation for RB in Appendix documents. Approximately, 250 new cases are diagnosed annually in the United States. Current standard treatment of affected children consists of either removing the one affected eye (in the case of unilateral disease), or by giving systemic chemotherapy for a period of 6-9 months, or by giving multiple regional (intra-arterial) chemotherapy (IAC) infusions. Systemic chemotherapy is associated with bone-marrow toxicity and relatively high costs. External beam radiotherapy is no longer standard primary therapy. There has never been an FDA approved intervention for Rb. Episcleral Topotecan (IND #112785) is a novel system for making possible the sustained local delivery of Topotecan directly to the interior of the eye without breaching the eye wall (by injection or incision) while sequestering Topotecan from washout to peripheral circulation. Local Episcleral Topotecan may reduce or eliminate the need for systemic chemotherapy. Inside the impermeable silicone episcleral device, the contents of the drug reservoir are maintained in direct contact with a broad expanse of the outer surface of the eye wall (the episclera), greatly facilitating the net passive unidirectional transscleral diffusion of the drug to the intraocular tumor inside the eye. Episcleral Topotecan enables sustained- release delivery of Topotecan with continuous-high-dose Topotecan retinal delivery while eliminating detectable system exposure and systemic toxicity. This FDA Orphan Drug Grant application requests funding to support Phase I clinical trials in patients with advanced unilateral group D retinoblastoma at presentation. In developing countries as many as half of all children diagnosed with retinoblastoma care are abandoned by the family for cultural or social reasons (Kumar, A., et al. (2013). "Causes, outcome and prevention of abandonment in retinoblastoma in India—Pediatr Blood Cancer 60(5): 771-775). Current options for the primary treatment of RB children include, enucleation, systemic chemotherapy, and IAC. These therapeutic options are invasive, costly and associated with significant side effects. Episcleral Topotecan offers a potential therapeutic avenue that is less invasive and less costly with far fewer side effects. It also could be the first FDA-approved therapy for this micro-orphan childhood disease. Under Emergency Use protocol, we've treated our first RB patient. This child had failed multiple cycles of systemic chemo and IAC. The child had >10 refractory tumors and vitreous seeds in his remaining eye. Post Episcleral Topotecan placement, all tumors and vitreous seeds were resolved by day 28 and all but two tumors were resolved by day 12. As of day 98 EUA, there was no recurrence. There was no systemic toxicity and there was no ocular toxicity other than grade 1 vitreous hemorrhage (consider normal response to tumor response/regression). See letter and retcam images from Brenda Gallie, MD in Appendix Documents.

摘要 视网膜母细胞瘤(RB)是一种罕见的(微小孤儿病)婴幼儿眼内癌(典型的 在出生到5岁之间确诊)。参见FDA OOPD孤儿药物字母名称中的RB 附录文件。在美国，每年大约有250例新确诊病例。 目前对受影响儿童的标准治疗包括摘除受影响的一只眼睛(在 单侧疾病)，或给予6-9个月的全身化疗，或通过给予 多次区域(动脉内)化疗(IAC)。全身化疗与 具有骨髓毒性和相对较高的成本。外照射不再是标准放射治疗 初级治疗。从来没有FDA批准过对RB的干预。 巩膜外拓扑替康(IND#112785)是一种能够实现持续局部给药的新系统 在不破坏眼壁的情况下(通过注射或切开)直接将拓扑替康注射到眼内 同时将拓扑替康从洗涤中隔离到外周循环中。当地主教拓朴特肯可能会 减少或消除全身化疗的需要。在不透气的硅胶上巩膜内 装置，药物储存库的内容物保持与大范围的 眼壁的外表面(上巩膜)，极大地促进了网状被动单向巩膜穿透 药物扩散到眼内的眼内肿瘤。主教巩膜拓扑特肯使持续的- 拓扑替康连续大剂量视网膜给药的缓释作用 可检测到的系统暴露和系统毒性。 这项FDA孤儿药物拨款申请申请资金用于支持患者的I期临床试验 表现为单侧晚期视网膜母细胞瘤D组。在发展中国家，多达一半的人 在所有被诊断为视网膜母细胞瘤的儿童中，家庭出于文化或社会原因抛弃了照顾 原因(Kumar，A.，et al.(2013年)。视网膜母细胞瘤患者放弃治疗的原因、结果和预防 印度--儿童血癌60(5)：771-775)。RB儿童初级治疗的当前选择 包括眼球摘除、全身化疗和IAC。这些治疗方案具有侵入性，成本高昂。 并伴随着显著的副作用。外巩膜拓扑替康提供一种潜在的治疗途径 这种方法侵入性更小，成本更低，副作用要少得多。这也可能是FDA批准的第一个 治疗这种微小孤儿儿童疾病的方法。 根据紧急使用方案，我们已经治疗了我们的第一位RB患者。这个孩子已经多次失败了 全身化疗和IAC。这名儿童有10个难治性肿瘤和玻璃体种子。 眼睛。外巩膜拓扑替康植入后，所有肿瘤和玻璃体种子在第28天全部消退。 但两个肿瘤在第12天消失。截至第98天EUA，没有复发。根本没有 全身毒性，除了1级玻璃体出血外，没有眼部毒性(考虑 肿瘤反应正常/消退)。查看来自马里兰州布伦达·加利的信件和反摄像图像 附录文件。