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年中，我们的实验室采用了E.使用E的实体肿瘤致敏机制。 大肠杆菌PNP基因。该方法涉及使用腺病毒构建体，AD/PNP和定向的基因转移基因转移 酶前药治疗或GDEPT。该策略的独特方面包括肿瘤内产生 氟载氨酸是一种明显破坏非周期肿瘤细胞室的嘌呤碱基，包括肿瘤 祖细胞。我们相信以这种方式对肿瘤实质的强大破坏也可能有利 冲击检查点阻滞和免疫肿瘤细胞清除。该策略的基本工作 先前由大约1000万美元的NCI支持资助。临床前的安全性和功效已经 由全球许多实验室确认，该战略得到了广泛的临床前数据库的支持。 我们的小组获得了IND，并在末端颈部和颈部进行了第一次对方法的临床试验 鳞状细胞癌（HNSCC），带有肿瘤内接种以提供AD/PNP。研究 专注于没有其他治疗选择的人，并从FDA接收了孤儿药 （批准＃14-4438）。我们的第一阶段试验完成并于2015年底发布，包括12名患者， 表现出极好的安全性和功效。在与FDA的相结束1会议中，我们讨论了认真的 在终阶段头和颈癌的情况下，未满足的临床需求，对常规的反应不佳 治疗，以及使用AD/PNP强烈的抗肿瘤活性的证据。我们被告知FDA将是 愿意根据总体响应率的终点讨论BLA，如果我们能显示出重大改善 超过护理标准。我们的第1阶段数据表明对所有标准治疗方面的显着改善 在这种情况下的方式。当前申请的目的是在斯坦福进行1/2阶段试验 使用AD/PNP重复管理大学，然后是全身氟达拉滨 在扩展到更大的患者试验之前的信息。通过此RO1，我们将治疗10名患者，并 合并经验丰富的实验室在 埃默里大学。该方法的IND批准和孤儿药物状况已适用，GMP级 腺病毒可用于研究。这项工作将提供一种推动小说和非常有力的手段 抗癌剂（氟腺苷）赋予耐用的肿瘤消退。