Phase I - II Study of Ad/PNP(IND14271,1/19/10)for HNSCC(OrphanDrugDes,14-4438,6/8/15)

Ad/PNP(IND14271,1/19/10)用于 HNSCC 的 I - II 期研究(OrphanDrugDes,14-4438,6/8/15)

• 批准号: 10496780
• 负责人: EBEN L. ROSENTHAL
• 金额: $ 12.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10496780
• 关键词: Phase; II; Study; Ad; PNP

Abstract Over the past 15 years, our laboratories have pursued a mechanism for solid tumor sensitization using the E. coli PNP gene. The approach involves gene transfer with an adenoviral construct, Ad/PNP, and Gene Directed Enzyme Prodrug Treatment or GDEPT. Unique aspects of the strategy include intratumoral generation of fluoroadenine, a purine base that markedly disrupts the non-cycling tumor cell compartment, including tumor progenitor cells. We believe the robust destruction of tumor parenchyma in this manner may also favorably impact checkpoint blockade and immunologic tumor cell clearance. The basic work underlying the strategy has been funded previously by approximately $10 million in NCI support. Preclinical safety and efficacy have been confirmed by many laboratories worldwide, and the strategy is supported by an extensive preclinical database. Our group has obtained an IND and conducted the first clinical trial of the approach in end-stage head and neck squamous cell carcinoma (HNSCC), with directed intratumoral inoculation to deliver Ad/PNP. The study focused on individuals with no other therapeutic options, and received orphan drug designation from FDA (Approval #14-4438). Our Phase 1 trial was completed and published in late 2015, included 12 patients, and demonstrated excellent safety and efficacy. In our end-of-phase-1 meeting with FDA, we discussed the serious unmet clinical need in the setting of end-stage head and neck cancer, the poor response to conventional therapy, and evidence of strong anti-tumor activity using Ad/PNP. We were informed that the FDA would be willing to discuss BLA based on an endpoint of overall response rate, if we can show significant improvement over standard of care. Our Phase 1 data indicates significant improvement over all standard therapeutic modalities in this setting. The purpose of the current application is to conduct a Phase 1/2 trial at Stanford University of repeat administration using Ad/PNP followed by systemic fludarabine, as a way to gain additional information prior to expansion towards a larger patient trial. Through this RO1, we will treat 10 patients, and incorporate a number of new mechanistic and biometric endpoints carried out by experienced laboratories at Emory University. IND approval and orphan drug status for the approach are in place, and GMP-grade adenovirus is available for the study. The work will furnish a means to advance a novel and very potent anticancer agent (fluoroadenine) that confers durable tumor regression.

抽象的 在过去的 15 年里，我们的实验室一直在探索一种利用大肠杆菌进行实体瘤致敏的机制。 大肠杆菌 PNP 基因。该方法涉及利用腺病毒构建体、Ad/PNP 和基因定向进行基因转移 酶前药治疗或 GDEPT。该策略的独特之处包括瘤内生成 氟腺嘌呤，一种嘌呤碱基，可显着破坏非循环肿瘤细胞区室，包括肿瘤细胞 祖细胞。我们相信以这种方式强烈破坏肿瘤实质也可能有利 影响检查点封锁和免疫肿瘤细胞清除。该战略的基础工作是 此前已获得 NCI 约 1000 万美元的资助。临床前安全性和有效性已 该策略得到了世界各地许多实验室的证实，并且得到了广泛的临床前数据库的支持。 我们课题组已获得IND并开展了该方法在终末期头颈部的首次临床试验 鳞状细胞癌 (HNSCC)，通过瘤内定向接种来递送 Ad/PNP。研究 专注于没有其他治疗选择的个体，并获得 FDA 的孤儿药资格认定 （批准号#14-4438）。我们的 1 期试验于 2015 年底完成并发表，包括 12 名患者， 显示出优异的安全性和有效性。在我们与 FDA 的第一阶段结束会议中，我们讨论了严重的问题 终末期头颈癌的临床需求未得到满足，传统疗法反应不佳 疗法，以及使用 Ad/PNP 的强抗肿瘤活性的证据。我们获悉 FDA 将 如果我们能够显示出显着的改进，愿意根据总体响应率的终点来讨论 BLA 超过护理标准。我们的第一阶段数据表明比所有标准治疗都有显着改善 在此设置下的方式。当前申请的目的是在斯坦福大学进行1/2期试验 大学使用 Ad/PNP 重复给药，然后全身使用氟达拉滨，作为获得额外效果的一种方式 在扩展到更大的患者试验之前的信息。通过这个RO1，我们将治疗10名患者，并且 纳入了由经验丰富的实验室进行的许多新的机械和生物识别端点 埃默里大学。该方法的 IND 批准和孤儿药状态已到位，并且 GMP 级 腺病毒可用于该研究。这项工作将为推进一部小说提供一种非常有效的手段 抗癌剂（氟腺嘌呤）可实现肿瘤持久消退。