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: 9989088
• 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/9989088
• 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（微孤儿疾病）眼内癌症，在婴儿和儿童（通常 在出生到5岁之间诊断）。参见FDA关于RB的OOPD孤儿药指定函， 附录文件。在美国，每年大约有250例新病例被诊断出来。 受影响儿童的当前标准治疗包括移除一只受影响的眼睛（在 单侧疾病的情况下），或给予全身化疗6-9个月，或给予 多次区域（动脉内）化疗（IAC）输注。全身化疗与 具有骨髓毒性和相对较高的成本。体外放射治疗不再是标准 主要治疗FDA从未批准过Rb的干预措施。 巩膜外托泊替康（IND #112785）是一种新的系统，可持续局部给药 将托泊替康直接注射到眼内，而不破坏眼壁（通过注射或切开） 同时将托泊替康从洗脱液隔离到外周循环。局部巩膜外托泊替康可能 减少或消除对全身化疗的需要。在不渗透的硅胶巩膜外层 在该装置中，药物储存器的内容物保持与药物储存器的广阔区域直接接触。 眼壁的外表面（巩膜外层），极大地促进了网状被动单向经巩膜 药物扩散到眼内的眼内肿瘤。巩膜外托泊替康能够持续- 持续高剂量托泊替康视网膜给药，同时消除 可检测的系统暴露和全身毒性。 FDA孤儿药补助金申请要求提供资金支持患者的I期临床试验 患有晚期单侧D组视网膜母细胞瘤在发展中国家， 所有被诊断患有视网膜母细胞瘤的儿童中， 原因（Kumar，A.，等（2013年）。“视网膜母细胞瘤中遗弃的原因、结果和预防” India-Pediatr Blood Cancer 60（5）：771-775）。RB儿童主要治疗的当前选择 包括眼球摘除术、全身化疗和IAC。这些治疗方案是侵入性的，昂贵的 并伴有明显的副作用。上巩膜拓扑替康提供了一种潜在的治疗途径 它的侵入性更小，成本更低，副作用也更少。它也可能是第一个FDA批准的 治疗这种微型孤儿儿童疾病。 根据紧急使用协议，我们已经治疗了第一位RB患者。这个孩子多次失败 全身化疗和IAC。该儿童有>10个难治性肿瘤和玻璃体种子在他的剩余 眼睛巩膜外托泊替康植入后，所有肿瘤和玻璃体种子在第28天消退，所有肿瘤和玻璃体种子在第28天消退。 但两个肿瘤在第12天消退。截至第98天EUA，未复发。没有 全身毒性，除1级玻璃体出血外无眼毒性（考虑 对肿瘤反应/消退的正常反应）。见信和retcam图像从布伦达加利，医学博士在 附录文件。