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、Ad/PNP和基因导向进行基因转移 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，一种嘌呤碱基，显著破坏包括肿瘤在内的非周期肿瘤细胞隔间 祖细胞。我们认为，以这种方式对肿瘤实质进行强有力的破坏也可能是有利的 影响检查点封锁和免疫肿瘤细胞清除。该战略的基本工作包括 之前由大约1000万美元的NCI支持提供资金。临床前的安全性和有效性已经被 世界各地的许多实验室证实了这一点，该战略得到了广泛的临床前数据库的支持。 我们小组已经获得了IND，并在终末期头颈部进行了该入路的第一次临床试验 鳞状细胞癌(HNSCC)，通过瘤内直接接种携带Ad/PNP。这项研究 专注于没有其他治疗选择的个人，并获得FDA的孤儿药物指定 (批准编号14-4438)。我们的1期试验于2015年末完成并发表，包括12名患者，以及 表现出极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 在未满足临床需求的终末期头颈癌患者中，对常规治疗反应差 治疗，以及使用Ad/PNP强大的抗肿瘤活性的证据。我们被告知FDA将会 如果我们能够表现出显著的改善，愿意根据总体响应率的终点来讨论BLA 护理标准过高。我们的第一阶段数据显示，与所有标准治疗相比，我们的情况有了显著改善 在此背景下的医疗模式。目前申请的目的是在斯坦福大学进行1/2阶段试验 重复给药的大学使用Ad/PNP，然后是全身氟达拉滨，作为获得更多 在扩大到更大规模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 整合了许多新的机械和生物识别终端，由经验丰富的实验室在 埃默里大学。该方法的IND批准和孤儿药物状态已经到位，GMP级 腺病毒可以用于这项研究。这项工作将提供一种手段，推动一种新颖而有力的 具有持久肿瘤消退作用的抗癌剂(氟化腺嘌呤)。

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.