Clinical evaluation and non-invasive monitoring of Vorasidenib in combination with tumor specific peptide PEP-IDH1M vaccine therapy in patients with recurrent mutant IDH1 glioma

沃拉西尼联合肿瘤特异性肽 PEP-IDH1M 疫苗治疗复发性突变 IDH1 胶质瘤患者的临床评价和无创监测

• 批准号: 10419216
• 负责人: KATHERINE B PETERS
• 金额: $ 39.27万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419216
• 关键词: Address; Adult; Automation; Automobile Driving; Blood; Brain; Brain Neoplasms; Cancer Therapy Evaluation Program; Clinical; Clinical Trials; Common Terminology Criteria for Adverse Events; Development; Digital Imaging and Communications in Medicine; Effectiveness; Enzymes; Evaluation; Event; Future; Genes; Glioma; Gliomagenesis; Goals; Image; Immune; Immunologics; Immunosuppression; Immunotherapeutic agent; Impairment; Infrastructure; Isocitrate Dehydrogenase; Lead; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manufacturer Name; Maps; Measurement; Measures; Mediating; Methods; Mission; Monitor; Morbidity - disease rate; Mutation; Neurologic; Oncogenic; Outcome; Patients; Peptide Vaccines; Phase; Progression-Free Survivals; Proteins; Protocols documentation; Quality of life; Recurrence; Reporting; Research; Role; Safety; Serum; Serum Markers; Signal Transduction; Speed; Standardization; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Therapeutic; Toxic effect; Translating; Translations; Tumor Specific Peptide; Vaccine Therapy; Vaccines; Validation; Work; base; cell killing; cell mediated immune response; clinical decision-making; clinical research site; combinatorial; computerized data processing; design; diagnostic biomarker; diagnostic technologies; early phase clinical trial; experience; fighting; first-in-human; human study; image guided intervention; immunogenic; improved; inhibitor; inhibitor therapy; magnetic resonance spectroscopic imaging; mortality; mutant; neoplastic cell; new therapeutic target; non-invasive monitor; novel; novel anticancer drug; novel diagnostics; novel therapeutics; patient tolerability; phase I trial; public health relevance; radiological imaging; research clinical testing; response; standard of care; support tools; targeted treatment; tool; treatment strategy; tumor; tumor diagnosis; tumorigenesis; vaccine development

Abstract – The identification of mutations in the isocitrate dehydrogenase 1 (mIDH1) gene has led to significant advances in understanding lower grade gliomas. Lower grade gliomas, WHO grade II-III, can have a longer median overall survival than WHO grade IV, yet they still develop significant neurological morbidity and ultimately mortality, as standard of care therapies are not curative. New therapeutics are needed to target lower grade gliomas to improve quality of life outcomes and survival for these patients. The mIDH1 mutation exists in over 70% of glioma subtypes and is the oncogenic driver in lower grade gliomas by leading to the extreme overproduction of the oncometabolite R-2-hydroxyglutarate (2HG). Because the mutation is specific to the tumor, it provides significant targets for the development of: 1) targeted therapeutics, such as mIDH1/2 inhibitors and immunotherapeutic vaccines (e.g., vorasidenib and PEPIDH1M, respectively) and 2) non-invasive tumor diagnosis and monitoring methods, via magnetic resonance spectroscopy (MRS). More recently, it has been reported that in addition to driving the oncogenesis of lower grade gliomas, 2HG has immunosuppressive actions. Its role as a driver of gliomagenesis and now induction of immunosuppression of tumor-fighting T-cells places 2HG as a critical target in fighting lower grade gliomas. Thus, we propose a clinical trial for a combined therapy of vorasidenib and PEPIDH1M. We hypothesize that early suppression of 2HG by vorasidenib would allow subsequent or concurrent administration of PEPIDH1M vaccine to generate a more robust T-cell response and lead to increased immune-mediated tumor cell kill (Specific Aim 1). In this phase I, single-site clinical trial, we will determine the safety of this combinatorial approach. Toxicity events will be evaluated and graded by CTCAE 5.0 criteria. The RANO criteria will be used to assess radiographic progression-free survival based on routine MRI imaging. As an exploratory goal, we will map 2HG across the brain longitudinally using existing high-speed magnetic resonance spectroscopic imaging (MRSI) and offline processing to monitor the effects of vorasidenib (Specific Aim 2). Finally, in parallel with the clinical trial, we will convert the validated 2HG mapping tool into a standardized works-in-progress (WIP) package for reporting 2HG levels on both GE and Siemens scanner DICOM workflow (Specific Aim 3). This project builds on 1) our previous experiences participating in the early clinical trials for PEPIDHM1 and vorasidenib, where we also characterized longitudinal 2HG levels, and 2) our decades-long experience with automating MRS methods and translating them into manufacturer supported WIP packages.

摘要 – 异柠檬酸脱氢酶 1 (mIDH1) 基因突变的鉴定已导致显着的 在了解低级别神经胶质瘤方面取得了进展。较低级别的神经胶质瘤，即 WHO II-III 级，可以有更长的时间 中位总生存率高于 WHO IV 级，但他们仍然出现显着的神经系统发病率，最终 死亡率，因为标准护理疗法无法治愈。需要新的治疗方法来针对较低级别 神经胶质瘤，以改善这些患者的生活质量和生存率。 mIDH1 突变存在于超过 70% 的神经胶质瘤亚型，是低级别神经胶质瘤的致癌驱动因素，通过导致极端 致癌代谢物 R-2-羟基戊二酸 (2HG) 的过量产生。因为突变是肿瘤特有的， 它为以下方面的开发提供了重要的目标：1) 靶向治疗，例如 mIDH1/2 抑制剂和 免疫治疗疫苗（例如，分别为 vorasidenib 和 PEPIDH1M）和 2) 非侵入性肿瘤诊断 和监测方法，通过磁共振波谱（MRS）。近日，有报道称 除了促进低级别神经胶质瘤的肿瘤发生外，2HG 还具有免疫抑制作用。其作用为 神经胶质瘤发生的驱动因素，现在诱导抗肿瘤 T 细胞的免疫抑制，使 2HG 成为一种 对抗低级别神经胶质瘤的关键目标。因此，我们建议进行一项联合治疗的临床试验 沃拉西尼和 PEPIDH1M。我们假设 vorasidenib 早期抑制 2HG 将允许 随后或同时施用 PEPIDH1M 疫苗以产生更强大的 T 细胞反应，并且 导致免疫介导的肿瘤细胞杀伤增加（具体目标 1）。在这个 I 期单中心临床试验中，我们 将决定这种组合方法的安全性。毒性事件将由CTCAE进行评估和分级 5.0标准。 RANO 标准将用于根据常规评估影像学无进展生存期 核磁共振成像。作为探索性目标，我们将利用现有的高速在大脑中纵向绘制 2HG 磁共振波谱成像 (MRSI) 和离线处理来监测沃拉西尼的效果 （具体目标 2）。最后，在临床试验的同时，我们会将经过验证的 2HG 绘图工具转换为 标准化在制品 (WIP) 包，用于报告 GE 和西门子扫描仪上的 2HG 水平 DICOM 工作流程（具体目标 3）。该项目建立在 1) 我们之前参与早期项目的经验基础上 PEPIDHM1 和 vorasidenib 的临床试验，其中我们还表征了纵向 2HG 水平，以及 2) 我们的 在自动化 MRS 方法并将其转化为制造商支持的 WIP 方面拥有数十年的经验 包。