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

新型小分子 EBNA1 抑制剂 VK-2019 在 Epstein-Barr 阳性鼻咽癌患者中的一期临床试验，并进行药代动力学和药效学相关研究

• 批准号: 10608154
• 负责人: A. Dimitrios Colevas
• 金额: $ 58.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608154
• 关键词: Acceleration; Address; Aftercare; Animal Model; Binding; Biochemical; Biological Assay; Biological Availability; Biological Markers; Biopsy; Burkitt Lymphoma; CLIA certified; Canis familiaris; Cells; Characteristics; Clinical; Clinical Protocols; Clinical Trials; Collection; Comprehensive Cancer Center; Correlative Study; Cyclic GMP; DNA; DNA Binding; DNA-Binding Proteins; Detection; Development; Disease Progression; Dose; Dose Limiting; Drug Kinetics; EBV-associated disease; EBV-encoded nuclear antigen 1; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Malignant Neoplasm; Etiology; Funding; Gene Expression; Genetic Transcription; Genomic DNA; Goals; Grant; HIV/AIDS; Hodgkin Disease; Human; Human Genome; Human Herpesvirus 4; Human Resources; Industry; Infrastructure; Laboratories; Lead; Lymphoma; Lymphoproliferative Disorders; Maintenance; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Maximum Tolerated Dose; Measurement; Mediating; Medical; Metabolic; Nasopharynx Carcinoma; Newly Diagnosed; Oral; Oral Administration; Orthologous Gene; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology Study; Phase; Phase I Clinical Trials; Plasma; Prognosis; Proteins; Proteome; Rattus; Recommendation; Recurrence; Research Personnel; Resistance; Safety; Scheme; Standardization; Stomach Carcinoma; Systemic Therapy; Technology; The Wistar Institute; Therapeutic Agents; Therapeutic Index; Titrations; Toxic effect; Toxicology; Treatment outcome; Viral; Viral Genes; Viral Genome; Virus Latency; Virus Replication; Xenograft Model; anti-cancer; anticancer activity; biomedical referral center; cancer therapy; capsule; carcinogenesis; clinical application; clinical candidate; clinical development; clinical practice; clinically relevant; cohort; design; drug candidate; early detection biomarkers; effective therapy; experimental study; first-in-human; genetic regulatory protein; human study; immunosuppressed; in vivo; inhibitor; lead optimization; medication safety; nano-string; nanomolar; novel; novel therapeutic intervention; novel therapeutics; open label; participant enrollment; patient population; pharmacokinetics and pharmacodynamics; pharmacologic; phase 1 study; pre-Investigational New Drug meeting; pre-clinical; primary outcome; progression marker; response; small molecule; small molecule inhibitor; success; tumor; tumor growth; tumor progression; viral DNA; virtual

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.

标题：新型小分子 EBNA1 抑制剂 VK-2019 在 Epstein-Barr 阳性患者中的一期临床试验 鼻咽癌，具有药代动力学和药效学相关研究。 7. 项目概要 与 Epstein-Barr 病毒 (EBV) 相关的癌症需要新的治疗方法。 EBV 的病因学 与多种恶性肿瘤相关，包括鼻咽癌（NPC）。只有一种病毒编码 蛋白质 EBNA1 在所有已知的 EBV 相关恶性肿瘤中一致表达，是经过验证的抑制靶点 EBV 依赖性转化和致癌作用。 Wistar 研究所的研究人员开发了 VK-2019，这是一种一流的 EBNA1 抑制剂作为治疗剂， 在从命中到先导化合物和先导化合物优化阶段从 2000 多种候选抑制剂化合物中进行选择。 VK-2019 达到或超过行业公认的效力、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 在生化测定中以纳摩尔效力抑制 EBNA1 并破坏 EBNA1 在几种基于细胞的测定中进行体内结合。 VK-2019 在 4 种不同的异种移植物中产生显着的肿瘤生长保护作用 EBV 驱动的肿瘤进展模型，包括来自 NPC 患者的 2 个肿瘤系。 VK-2019的体内目标 参与度和临床前药代动力学特征均已得到严格评估。测距 (RF) 和 对大鼠和狗进行的最大耐受剂量 (MTD) 研究表明，具有极其良好的安全性 治疗指数>87:1。所有支持 IND 的研究，包括 GLP 28 天毒理学和安全药理学 研究已经完成。 1.9公斤cGMP级VK-2019可供使用，正在配制成胶囊使用 在这项研究中。 Wistar 工作人员已与 FDA 成功举行了 IND 前会议，并正在准备 IND 提交 2018 年 4 月，以促进 I 期首次人体临床试验。 这笔赠款的目的是资助 VK-2019 在鼻咽癌患者中进行的 1 期临床试验。 I 期研究将招募患有转移性或复发性鼻咽癌 (NPC) 的患者进行以下治疗 原因： 1.几乎所有鼻咽癌都是EBV阳性； 2.由于目前的治疗方法有毒且效果不佳，因此医疗需求未得到满足 功效有限。 3. 可以获得与预测机制相关的鼻咽癌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，因此可以 被用作EBNA1抑制剂的功效生物标志物。 拟议的试验旨在考察 VK-2019 的安全性和耐受性。 Simon 4b 加速滴定设计 斯坦福癌症研究所 (SCI) 计划对多达 40 名患者进行每日口服 VK-2019 治疗，该研究所是 NCI 综合性研究机构 癌症中心和全国人大转诊中心。主要结果将是确定药代动力学和 VK-2019、剂量限制毒性 (DLT) 和推荐 2 期剂量 (RP2D) 在患者中的药效学 高级NPC。重要的额外终点包括生物标志物和肿瘤 EBNA 1 抑制效应研究。临床试验 SCI 已经具备了进行这项研究所需的基础设施。该临床试验将提供关键的 有关 VK-2019 的安全性、耐受性和初步疗效的信息，以便询问是否可以开发该药物 作为癌症治疗剂应该继续下去。