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

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.
项目摘要 背景:我们使用高通量药物筛选来鉴定泊沙康唑(PCZ)作为 一种重新利用的药物,可以抑制高级别胶质瘤肿瘤细胞的生长,归因于抑制 己糖激酶2酶(HK 2)介导的途径。HK 2通常在高等级中上调 神经胶质瘤(HGG),而不是正常的人星形胶质细胞。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, 诱导HGG肿瘤细胞凋亡。 目的:我们的主要目的是通过PCZ建立肿瘤组织转移率, 术前稳态口服给药。我们的次要目标是建立它的神经系统- 药代动力学和药效学特征。方法:这将是一项单中心、阶段 0,概念验证研究。5名合格且可评价的受试者,疑似患有HGG 并且需要在非紧急情况下进行手术切除的患者,将入组进行术前PCZ 局还将入组5例对照受试者。为了达到稳态给药, 需要至少5个药物半衰期。第一天PCZ给药为300 mg PO BID, 随后每天口服300 mg,在预定手术前168-240小时开始。控制 受试者将不接受药物。将采集手术样本,沿着血液样本, 从对比度增强和非增强区域进行分析。1-2微透析导管 然后将其插入肿瘤切除边界。最后一剂药物给药后 手术后的早晨,透析液和动脉血的收集将立即开始 (Time 0)。将在15和30分钟时采集额外样本,沿着采集1、2、4、6、8、18、 在“时间0”之后24小时。对照受试者也将植入导管, 乳酸和丙酮酸的测量。质谱法将用于评估 肿瘤组织、透析液和血液中药物、乳酸盐和丙酮酸盐的浓度。HK2 活性测定、TUNEL染色和Ki 67指数将用于研究药效学。 长期目标和潜在影响:证明PCZ蓄积≥ 500 ng/g 5例受试者中≥2例的肿瘤组织中的肿瘤细胞数量将需要进一步研究其在HGG中的作用。 相关抗肿瘤作用的证据将需要进行II期试验来评估肿瘤 反应和生存,而信号的生物效应在一个子集的患者,但低于 预期的肿瘤内药物浓度将保证I期剂量递增试验。 在HGG患者中建立PCZ的神经药代动力学参数, 为I期或II期试验的设计提供有价值的信息。

项目成果

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Alireza Mansouri其他文献

Alireza Mansouri的其他文献

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{{ truncateString('Alireza Mansouri', 18)}}的其他基金

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
  • 批准号:
    10610937
  • 财政年份:
    2022
  • 资助金额:
    $ 7.04万
  • 项目类别:

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