Neuro-pharmacological Properties of Repurposed Posaconazole in Glioblastoma: A Phase 0 Clinical Trial

重新利用泊沙康唑治疗胶质母细胞瘤的神经药理学特性：0 期临床试验

基本信息

批准号：
10610937
负责人：
Alireza Mansouri
金额：
$ 7.04万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610937
关键词：
Adult Affect Antifungal Agents Apoptosis Astrocytes Biological Biological Assay Blood Blood - brain barrier anatomy Blood specimen Brain Neoplasms Catheters Cell Proliferation Central Nervous System Agents Clinical Trials Clinical Trials Design Collection Correlative Study Dose Down-Regulation Drug Delivery Systems Drug Industry Drug Kinetics Economic Burden Eligibility Determination Enrollment Enzymes Evaluable Disease Excision FDA approved Future Genes Glioblastoma Glioma Glycolysis Glycolysis Inhibition Government Growth Hexokinase 2 Hour Human Implant In Situ Nick-End Labeling In Vitro Individual Indwelling Catheter Investigation Laboratories Liquid substance Mass Spectrum Analysis Measurement Measures Mediating Methods Microdialysis Mus Mycoses Oncologist Operative Surgical Procedures Oral Participant Pathway interactions Patient-Focused Outcomes Patients Penetrance Penetration Pharmaceutical Preparations Pharmacodynamics Phase Phase 0 Clinical Trial Phase 0 Study Phase 0 Trial Plasma Pre-Clinical Model Production Property Pyruvate Research Design Research Personnel Resected Role Safety Sampling Schedule Secondary to Signal Transduction Stains Surgically-Created Resection Cavity Testing Therapeutic Time Tumor Tissue Work angiogenesis antitumor effect blood-brain barrier disruption cell growth contrast enhanced cost design drug development drug discovery drug repurposing efficacy evaluation enzyme activity high-throughput drug screening improved in vivo indexing neoplastic cell neurosurgery novel novel therapeutics open label patient subsets pharmacokinetics and pharmacodynamics phase II trial posaconazole pre-clinical response success tumor tumor metabolism

项目摘要

Project Summary Background: We have used high-throughput drug screening to identify posaconazole (PCZ) as a repurposed drug that can inhibit high grade glioma tumor cell growth, attributable to inhibition of hexokinase 2 enzyme (HK2)-mediated pathways. HK2 is typically up-regulated in high-grade gliomas (HGGs) but not normal human astrocytes. In further pre-clinical in vitro and in vivo studies, we have shown that PCZ can down-regulate glycolysis, reduce angiogenesis, and induce HGG tumor cell apoptosis. Objectives: Our primary objective is to establish tumor tissue penetrance by PCZ, following preoperative steady-state oral dosing. Our secondary objectives are to establish its neuro- pharmacokinetics and pharmacodynamic profile. Methods: This will be a single-center, Phase 0, proof-of-concept study. Five eligible and evaluable participants, suspected of having HGGs and requiring surgical resection on a non-emergent basis, will be enrolled for preoperative PCZ administration. Five control subjects will also be enrolled. To achieve steady-state dosing, at least 5 half-lives of drug are needed. PCZ dosing will be 300mg PO BID on the first day, followed by 300mg PO daily, beginning 168-240 hours before scheduled surgery. Control subjects will receive no drug. Surgical samples, along with blood samples, will be taken for analysis from both contrast-enhancing and non-enhancing regions. 1-2 microdialysis catheters will then be inserted into the tumor resection boundary. After administering the last dose of drug the morning after surgery, collection of dialysate fluid and arterial blood will immediately begin (Time 0). Additional samples will be collected at 15 and 30 minutes, along with 1, 2, 4, 6, 8, 18, and 24 hours after ‘Time 0’. Control subjects will also have catheters implanted for measurement of lactate and pyruvate. Mass spectrometry will be used to assess for concentration of drug, lactate, and pyruvate in tumor tissue, dialysate fluid, and blood. HK2 activity assay, TUNEL staining, and Ki67 index will be used to study pharmacodynamics. Long-term objectives and potential impact: Demonstration of PCZ accumulation of ≥500ng/g of tumor tissue in ≥2 of 5 participants would warrant further investigation into its role in HGGs. Evidence of associated anti-tumor effect would warrant a Phase II trial to assess tumor response and survival, while signal for biological effect in a sub-set of patients but lower than expected intra-tumoral drug concentrations would warrant a Phase I dose-escalation trial. Establishment of the neuro-pharmacokinetic parameters of PCZ in individuals with HGGs would provide valuable information toward the design of either a Phase I or Phase II trial.

项目概要背景：我们使用高通量药物筛选将泊沙康唑 (PCZ) 鉴定为一种重新利用的药物，可以抑制高级神经胶质瘤肿瘤细胞的生长，归因于抑制己糖激酶 2 酶 (HK2) 介导的途径 HK2 通常在高级中上调。神经胶质瘤（HGG），但不是正常人星形胶质细胞在进一步的临床前体外和体内研究中。研究表明，PCZ 可以下调糖酵解、减少血管生成，并且诱导HGG肿瘤细胞凋亡。目标：我们的主要目标是通过 PCZ 确定肿瘤组织外显率，如下我们的次要目标是确定其术前稳态口服剂量。药代动力学和药效学特征：这将是一个单中心阶段。 0，概念验证研究，五名合格且可评估的参与者，怀疑患有 HGG。并需要非紧急手术切除，将参加术前 PCZ 还将招募五名对照受试者以实现稳态给药。第一天至少需要 5 个药物半衰期的 PCZ 剂量为 300mg PO BID，随后每天口服 300 毫克，在预定手术前 168-240 小时开始。受试者不会接受任何手术样本以及血液样本。来自对比度增强和非增强区域的分析 1-2 个微透析导管。然后将在施用最后一剂药物后插入肿瘤切除边界。手术后第二天早上，将立即开始收集透析液和动脉血（时间 0）将在 15 和 30 分钟以及 1、2、4、6、8、18、 “时间 0”后 24 小时，对照受试者也将植入导管。乳酸和丙酮酸的测量将用于评估。肿瘤组织、透析液和血液中药物、乳酸和丙酮酸的浓度。活性测定、TUNEL染色和Ki67指数将用于研究药效学。长期目标和潜在影响：证明 PCZ 累积量≥500ng/g 5 名参与者中≥2 名的肿瘤组织有必要进一步研究其在 HGG 中的作用。相关抗肿瘤作用的证据需要进行 II 期试验来评估肿瘤反应和生存，而一部分患者的生物效应信号但低于预期的肿瘤内药物浓度需要进行一期剂量递增试验。在患有 HGG 的个体中建立 PCZ 的神经药代动力学参数将为第一阶段或第二阶段试验的设计提供有价值的信息。