Phase one clinical trial of a novel small molecule EBNA1 inhibitor, VK-2019, in patients with Epstein- Barr positive nasopharyngeal cancer, with pharmacokinetic and pharmacodynamic correlative studies

标题：新型小分子EBNA 1抑制剂VK-2019在爱泼斯坦-巴尔氏阳性患者中的一期临床试验 鼻咽癌的药代动力学和药效学相关研究。 7.项目摘要 与EB病毒（EBV）相关的癌症需要新的治疗方法。EB病毒在病因学上 与多种恶性肿瘤相关，包括鼻咽癌（NPC）。只有一个病毒编码的 EBNA1蛋白在所有已知的EBV相关恶性肿瘤中一致表达，是有效的抑制靶点 EB病毒依赖的转化和致癌作用。 Wistar研究所的研究人员已经开发出VK-2019，这是一种一流的EBNA1抑制剂作为治疗剂， 在先导化合物和先导化合物优化阶段，从超过2000种候选抑制剂化合物中进行选择。VK-2019 符合或超过行业公认的效价、选择性、代谢稳定性、药物适用性、药物安全性标准， 毒理学和生物利用度。VK-2019在具有纳摩尔效力的生化测定中抑制EBNA1并破坏EBNA1 在几种基于细胞的测定中的体内结合。VK-2019在4种不同的异种移植物中引起显著的肿瘤生长保护 EBV驱动的肿瘤进展模型，包括2个来源于NPC患者的肿瘤细胞系。VK-2019的体内靶点 已经对接合和临床前药代动力学概况进行了稳健的评估。测距（RF）和 在大鼠和犬中进行的最大耐受剂量（MTD）研究表明， 治疗指数> 87：1。所有IND使能研究，包括GLP 28天毒理学和安全药理学 研究已经完成。1.9 kg cGMP级VK-2019可用，并正在配制成胶囊供使用 本研究Wistar工作人员与FDA成功举行了IND前会议，并正在准备IND提交 2018年4月，该公司将进行I期首次人体临床试验。 这笔赠款的目的是资助VK-2019在NPC患者中的1期临床试验。 I期研究将招募转移性或复发性鼻咽癌（NPC）患者， 原因：1.几乎所有的NPC都是EBV阳性的; 2.由于目前的治疗既有毒性， 有限的功效。3.可获得与预测机制相关的NPC临床相关生物标志物 VK-2019的行动。4.鼻咽癌患者血浆EBV DNA水平与预后和疾病进展相关， 用作EBNA1抑制剂的有效生物标志物。 该试验旨在研究VK-2019的安全性和耐受性。Simon 4b加速滴定设计 计划在斯坦福大学癌症研究所（SCI）进行多达40名患者的每日口服VK-2019治疗，这是一个NCI综合性癌症研究所。 癌症中心和NPC转诊中心。主要结局将是确定药代动力学和 VK-2019的药效学、剂量限制性毒性（DLT）和推荐的II期剂量（RP2D） 高级NPC重要的其他终点包括生物标志物和肿瘤EBNA 1抑制作用研究。临床试验 进行这项研究所需的基础设施，已在SCI。这项临床试验将提供关键的 关于VK-2019的安全性、耐受性和初步疗效的信息，以询问是否开发了 作为癌症治疗的药物应该继续。

Title: Phase one clinical trial of a novel small molecule EBNA1 inhibitor, VK-2019, in patients with Epstein- Barr positive nasopharyngeal cancer, with pharmacokinetic and pharmacodynamic correlative studies. 7. PROJECT SUMMARY New therapeutic approaches are needed for cancers associated with Epstein-Barr Virus (EBV). EBV is etiologically associated with a diverse collection of malignancies, including nasopharyngeal carcinoma (NPC). Only one viral-encoded protein, EBNA1, is consistently expressed in all known EBV-associated malignancies and is a validated target for inhibition of EBV-dependent transformation and carcinogenesis. Investigators at the Wistar Institute have developed VK- 2019, a first-in-class EBNA1 inhibitor as a therapeutic agent, selecting it from over 2000 candidate inhibitor compounds during the hit-to-lead and lead optimization phases. VK-2019 meets or exceeds industry-accepted criteria for potency, selectivity, metabolic stability, drug suitability, drug safety, toxicology and bioavailability. VK-2019 inhibits EBNA1 in biochemical assays with nanomolar potency and disrupts EBNA1 binding in vivo in several cell-based assays. VK-2019 causes significant tumor growth protection in 4 different xenograft models of EBV-driven tumor progression, including 2 tumor lines derived from NPC patients. VK-2019’s in vivo target engagement and preclinical pharmacokinetic profiles have both been robustly evaluated. Range Finding (RF) and Maximum Tolerated Dose (MTD) studies in rat and dog have demonstrated an exceptionally favorable safety profile with a therapeutic index of >87:1. All of the IND-enabling studies including GLP 28-day toxicology and safety pharmacology studies have been completed. 1.9 kg of cGMP grade VK- 2019 is available and is being formulated into capsules for use in this study. Wistar staff have held a successful pre-IND meeting with the FDA and are preparing for an IND submission in April 2018 to facilitate a Phase I first-in-human clinical trial. The purpose of this grant is to fund the phase 1 clinical trial of VK- 2019 in patients with NPC. The phase I study will enroll patients with metastatic or recurrent nasopharyngeal carcinoma (NPC) for the following reasons: 1. Almost all NPC is EBV positive; 2.There is an unmet medical need as current treatments are both toxic and of limited efficacy. 3. Clinically relevant biomarkers for NPC are available that have relevance for the predicted mechanism of action of VK-2019. 4. Plasma EBV DNA levels of NPC patients correlate with prognosis and disease progression so can be used as efficacy biomarkers EBNA1 inhibitors. The proposed trial is designed to look at the safety and tolerability of VK-2019. A Simon 4b accelerated titration design of up to 40 patients treated with daily oral VK- 2019 is planned at the Stanford Cancer Institute (SCI), a NCI comprehensive cancer center and NPC referral center. The primary outcomes will be determination of the pharmacokinetics and pharmacodynamics of VK-2019, Dose Limiting Toxicity (DLT) and Recommended Phase 2 Dose (RP2D) in patients with advanced NPC. Important additional endpoints include biomarker and tumor EBNA 1 inhibition effect studies. Clinical trial infrastructure necessary for the conduct of this study is already in place at the SCI. This clinical trial will provide critical information on the safety, tolerability and preliminary efficacy of VK-2019 in order to ask whether development of the agent as a cancer treatment should continue.