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

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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.