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：新型分子EBNA1抑制剂VK-2019的第一阶段临床试验，Epstein- Barr阳性患者 鼻咽癌，具有药代动力学和药效学相关性研究。 7。项目摘要 与爱泼斯坦 - 巴尔病毒（EBV）相关的癌症需要新的治疗方法。 与鼻腔癌（NPC）相关的各种恶性肿瘤相关 蛋白质EBNA1在所有已知的EBV相关的恶性肿瘤中都始终表达，并且是抑制的验证靶标。 debv的转化和致癌作用。 Wistar Institute的研究人员已开发了VK-2019，这是一种阶级的EBNA1抑制剂作为治疗剂， 从2000多个候选抑制剂化合物中选择铅铅铅优化phiss 达到或超过行业所接受的势力，选择性，代谢稳定性，药物适用性，药物安全性的标准 毒理学和生物利用度。 在基于细胞的细胞测定中的体内结合。 EBV驱动的肿瘤进展模型，包括来自NPC患者的2种肿瘤线。 参与和临床前药代动力学特征对范围发现（RF）和 大鼠和狗的最大耐受剂量（MTD）研究已证明了具有特征的异常有利的安全性。 > 87：1的治疗指数。 研究已完成。 在这项研究中。 2018年4月，促进了第一阶段的人类临床试验。 这是为VK-2019在NPC患者中的第一阶段临床试验提供资金的目的。 第一阶段研究将招募转移性或复发性鼻腔癌（NPC）的患者 原因：1。几乎所有的NPC都是EBV阳性的； 有限的功效。3。具有预测机制的NPC的临床相关生物标志物 VK-2019的作用。 用作功效生物标志物EBNA1抑制剂。 该试验旨在研究VK-2019的安全性和耐受性。 在NCI综合的斯坦福癌症研究所（SCI）计划，最多有40名接受了每日口服VK-2019治疗的患者。 癌症中心和NPC转介中心。 VK-2019的药效学，剂量限制毒性（DLT）和建议的2期剂量（RP2D）患者 高级NPC 接触此接触所需的基础架构是SCI的alredy。 有关VK-2019的安全性，耐受性和预后功效的信息，以询问是否发展 代理作为癌症治疗应继续。