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

摘要 在过去的15年里，我们的实验室一直在探索一种使用E。 coliPNP基因。该方法包括用腺病毒构建体Ad/PNP和基因导向的基因转移。 酶前药治疗或GDEPT。该策略的独特方面包括肿瘤内产生的 氟腺嘌呤是一种嘌呤碱基，可显著破坏非循环肿瘤细胞区室，包括肿瘤细胞， 祖细胞我们相信这种方式对肿瘤实质的强力破坏也可能有利于 影响检查点阻断和免疫肿瘤细胞清除。该战略的基础工作包括 此前，NCI资助了约1000万美元。临床前安全性和有效性已被 该策略得到了全球许多实验室的证实，并得到了广泛的临床前数据库的支持。 我们的团队已经获得了IND，并在终末期头颈部进行了第一次临床试验 鳞状细胞癌（HNSCC），通过直接瘤内接种来递送Ad/PNP。研究 专注于没有其他治疗选择的个体，并获得FDA的孤儿药认定 （批准编号14 -4438）。我们的1期试验于2015年底完成并发表，包括12名患者， 表现出良好的安全性和有效性。在我们与FDA的第一阶段结束会议上，我们讨论了严重的 在终末期头颈癌的情况下，未满足的临床需求，常规化疗的反应差， 治疗，以及使用Ad/PNP的强抗肿瘤活性的证据。我们被告知食品药品管理局 如果我们能够显示出显著改善，愿意基于总体缓解率终点讨论BLA 超过标准治疗我们的1期数据表明，与所有标准治疗相比， 在这种情况下的模式。当前申请的目的是在斯坦福大学进行1/2期试验 使用Ad/PNP重复给药，然后全身氟达拉滨，作为获得额外 在扩大到更大的患者试验之前，通过该RO 1，我们将治疗10名患者， 结合了一些新的机械和生物测定终点，由经验丰富的实验室进行， 埃默里大学。IND批准和孤儿药状态的方法已经到位，GMP级 腺病毒可用于研究。这项工作将提供一种手段，以推进一部小说， 抗癌剂（氟腺嘌呤），赋予持久的肿瘤消退。

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.