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: 10707909
• 负责人: KATHERINE B PETERS
• 金额: $ 46.23万
• 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/10707909
• 关键词: Address; Adult; Automation; Automobile Driving; Blood; Brain; Brain Neoplasms; Cancer Therapy Evaluation Program; Clinical; Clinical Trials; Combined Modality Therapy; 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; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manufacturer; Maps; Measurement; Measures; Mediating; Methods; Mission; Monitor; Morbidity - disease rate; Mutation; Neurologic; Oncogenic; Outcome; Patients; Peptide Vaccines; Phase; Production; 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; 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; safety assessment; standard of care; support tools; synergism; 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 - 在异位酸脱氢酶1（MIDH1）基因中突变的鉴定已导致显着 了解低年级神经胶质瘤的进步。 II-III级的低级神经膜瘤可以更长 比世卫组织IV级的总体生存中位数中位数，但他们仍然发展出明显的神经系统发病率 死亡率，作为护理疗法的标准无法治愈。需要新的疗法才能针对低年级 神经瘤可改善这些患者的生活质量和生存率。 MIDH1突变存在于 70％的神经胶质瘤亚型，是低级神经胶质瘤中的致癌驱动器 过度生产oncometabolite R-2-羟基戊二酸（2HG）。因为突变是特定于肿瘤的，所以 它为开发的重要目标提供了：1）靶向疗法，例如MIDH1/2抑制剂和 免疫治疗疫苗（例如，分别 通过磁共振光谱（MRS）进行监测方法。最近，据报道 除了驱动低级神经胶质瘤的肿瘤外，2HG还具有免疫抑制作用。它的作用 神经胶质作用的驱动器和诱导肿瘤抗衡T细胞免疫抑制的驱动 与低级神经胶质瘤作斗争的关键目标。这，我们提出了一项临床试验，以进行合并的疗法 伏拉地尼和pepidh1m。我们假设Vorasidenib对2HG的早期抑制允许 随后或同时服用PEPIDH1M疫苗以产生更强大的T细胞响应和 导致免疫介导的肿瘤细胞杀死增加（特定目标1）。在这阶段，单位临床试验，我们 将确定这种组合方法的安全性。毒性事件将通过CTCAE评估和分级 5.0标准。 RANO标准将用于根据常规评估无射线照相的生存 MRI成像。作为探索性目标，我们将使用现有的高速进行纵向绘制2HG 磁共振光谱成像（MRSI）和离线处理，以监测伏拉质的效应 （特定目标2）。最后，与临床试验并行，我们将将经过验证的2HG映射工具转换为 用于报告GE和Siemens扫描仪的2HG水平的标准化工作包（WIP）软件包 DICOM工作流程（特定目标3）。该项目建立在1）我们以前参与早期的经验 pepidhm1和vorasidenib的临床试验，我们还表征了纵向2HG水平，以及2） 数十年来自动化MRS方法并将其转化为制造商支持的WIP的经验 软件包。