Phase 2 Study of Vascular-Targeted Prodrug (G-202) for the Treatment of Recurrent Glioblastoma

血管靶向前药 (G-202) 治疗复发性胶质母细胞瘤的 2 期研究

• 批准号: 9261387
• 负责人: Santosh Kesari
• 金额: $ 29.62万
• 依托单位: SAINT JOHN'S CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-20 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261387
• 关键词: Phase; Study; Vascular; Targeted; Prodrug

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is an intractable disease with high mortality. In the U.S, the incidence of GBM is approximately 9,600 new cases/year. Even with current standard-of-care, surgical debulking followed by concurrent radiotherapy and chemotherapy with temozolomide, survival remains modest. There is a clear, major unmet medical need for novel approaches to treat patients with GBM. The goal of this four-year application is to evaluate the innovative approach of targeted prodrug therapy for GBM. In this investigator-initiated Phase 2 clinical study, the applicant will test a vascular-targeted prodrug, G-202 in patients with recurrent GBM. G-202 is a thapsigargin analog (12ADT) coupled with a masking/targeting peptide that renders the prodrug inactive and highly soluble (expected to cross blood-brain barrier). This peptide also targets the prodrug to a protein - prostate-specific membrane antigen (PSMA), expressed selectively on the tumor vasculature. On binding PSMA, the prodrug is cleaved and 12ADT is released, which in turn produces endoplasmic reticulum (ER) stress, apoptosis and cell death. The central hypothesis for this proposal is that G-202 will be clinically active against GBM. The preliminary data show that PSMA is selectively and highly expressed in GBM tumor vasculature. Further, patient-derived GBM cell lines are highly sensitive to thapsigargin in vitro. Studies on mouse xenograft models show renal, breast and prostate cancers to be highly sensitive to G-202. The objective of this study is to evaluate the clinical efficacy of G-202 against recurrent GBM and to investigate the effect of 12ADT on preclinical models of GBM. The applicant proposes three specific aims to test the hypothesis and achieve their objective. Aim 1 will determine the efficacy of G-202 in patients with recurrent GBM in a single-arm, open-label, Phase 2 clinical trial. Aim 2 will involve correlative studies - cerebrospinal (CSF) pharmacokinetics to confirm optimal dosing of G-202 and detailed blood/CSF and tissue biomarker analyses in GBM patients treated with G-202. These studies will attempt to identify markers predictive of response to G-202 and will provide guidelines to stratify patients for future trials. Aim 3, using patient-derive GBM cell lines, will seek to identify molecular predictors of responsiveness to 12ADT, the thapsigargin analog in G-202. In preliminary studies, the applicant found a differential sensitiviy of different GBM lines to thapsigargin that correlated with expression levels of GRP78, the master regulator of the ER stress response.

描述（由申请人提供）： 胶质母细胞瘤（GBM）是一种顽固的疾病，死亡率很高。在美国，GBM的发病率约为9,600个新病例。即使有当前的护理标准，手术延伸，然后进行同时放疗和替莫唑胺化疗，生存仍然适中。对于治疗GBM患者的新方法，有明确的未满足的医疗需求。 这项四年应用的目的是评估针对GBM的靶向前药疗法的创新方法。在这项研究者引发的2期临床研究中，申请人将对复发性GBM的患者进行血管靶向前药，G-202。 G-202是Thapsigargin类似物（12ADT），再加上掩盖/靶向肽，它使前药不活跃且高度溶于（预计将跨血脑屏障）。该肽还靶向前列腺特异性膜抗原（PSMA），在肿瘤脉管系统上有选择地表达。在结合PSMA上，该前药被切割并释放12ADT，进而产生内质网应激（ER）应激，凋亡和细胞死亡。该提议的中心假设是G-202将对GBM具有临床活性。初步数据表明，PSMA在GBM肿瘤脉管系统中有选择性和高度表达。此外，患者来源的GBM细胞系对Thapsigargin的体外高度敏感。小鼠异种移植模型的研究表明，肾脏，乳腺癌和前列腺癌对G-202高度敏感。 这项研究的目的是评估G-202对复发GBM的临床功效，并研究12ADT对GBM临床前模型的影响。申请人提出了三个特定旨在检验假设并实现其目标的特定旨在。 AIM 1将确定G-202在单臂，开放标签的2阶段临床试验中复发GBM患者的疗效。 AIM 2将涉及相关研究 - 脑脊液（CSF）药代动力学，以确认G-202的G-202和详细的血液/CSF的最佳剂量以及在接受G-202治疗的GBM患者中的组织生物标志物分析。这些研究将试图确定预测对G-202反应的标志物，并将提供对患者进行对以后试验进行分层的指南。 AIM 3使用患者源性GBM细胞系，将寻求识别G-202中Thapsigargin类似物的响应能力的分子预测指标。在初步研究中，申请人发现不同GBM线对Thapsigargin的差异敏感性与GRP78的表达水平相关，GRP78的表达水平是ER应力响应的主要调节剂。