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：用于Epstein-Barr阳性患者的新型小分子EBNA1抑制剂VK-2019的第一阶段临床试验 鼻咽癌的药代动力学和药效学相关研究。 7.项目总结 与EB病毒(EBV)相关的癌症需要新的治疗方法。EB病毒在病原学上是 与多种恶性肿瘤有关，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相关恶性肿瘤中持续表达，是有效的抑制靶点 EB病毒依赖的转化和致癌的关系。 维斯塔尔研究所的研究人员已经开发出一种一流的EBNA1抑制剂VK-2019作为治疗剂， 在点击到领先和领先优化阶段，从2000多种候选抑制剂化合物中选择它。VK-2019 在效力、选择性、代谢稳定性、药物适宜性、药物安全性、 毒理学和生物利用度。VK-2019在纳摩尔效力的生化分析中抑制EBNA1并干扰EBNA1 在几种基于细胞的分析中进行体内结合。VK-2019对4种不同的异种移植瘤具有显著的肿瘤生长保护作用 EBV驱动的肿瘤进展模型，包括来自鼻咽癌患者的2个肿瘤株。VK-2019年S体内靶点 参与度和临床前药代动力学特征都得到了强有力的评估。测距(RF)和 在大鼠和狗身上进行的最大耐受量(MTD)研究表明， 治疗指数：87：1。包括GLP 28天毒理学和安全药理学在内的所有IND使能研究 研究已经完成。1.9公斤cGMP级VK-2019现已上市，正在配制成胶囊供使用 在这项研究中。Wistar的工作人员已经成功地与FDA举行了IND前会议，并正在准备IND提交 2018年4月，为第一阶段人类临床试验提供便利。 这笔赠款的目的是为VK-2019在鼻咽癌患者中的第一阶段临床试验提供资金。 I期研究将招募转移性或复发性鼻咽癌(NPC)患者参加以下项目 原因：1.几乎所有的鼻咽癌都是EBV阳性；2.目前的治疗方法既有毒性，又有严重的毒性，因此有一种未得到满足的医疗需求 疗效有限。3.鼻咽癌的临床相关生物标记物与预测的机制相关 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 可作为疗效生物标记物EBNA1抑制剂。 拟议的试验旨在观察VK-2019的安全性和耐受性。西蒙4b加速滴定设计 计划在斯坦福癌症研究所(SCI)进行每日口服VK-2019治疗的多达40名患者，这是一家NCI综合医院 癌症中心和全国人大转诊中心。主要结果将是确定药物动力学和 VK-2019的药效学、剂量限制毒性(DLT)和推荐第二阶段剂量(RP2D) 先进的全国人大。重要的附加终点包括生物标记物和肿瘤EBNA 1抑制效应研究。临床试验 进行这项研究所需的基础设施已经在SCI就位。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 试剂作为一种癌症治疗应该继续下去。

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.