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-异柠檬酸脱氢酶1(MIDH1)基因突变的鉴定导致了显著的 低级别胶质瘤的认识进展。较低级别的胶质瘤，世卫组织II-III级，可以有更长的 中位总存活率低于世卫组织IV级，但他们仍出现显著的神经并发症，并最终 死亡率，因为标准的护理疗法是不能治愈的。需要新的治疗方法来针对较低的年级 以改善这些患者的生活质量、结果和生存。MIDH1突变存在于Over 70%的胶质瘤亚型，是低级别胶质瘤的致癌驱动因素 肿瘤代谢物R-2-羟基戊二酸(2HG)产量过高。因为这种突变是针对肿瘤的， 它为以下方面的发展提供了重要的目标：1)靶向治疗，如mIDH1/2抑制剂和 免疫治疗性疫苗(例如，分别为vorasidenib和PEPIDH1M)和2)非侵入性肿瘤诊断 以及通过磁共振波谱(MRS)进行监测的方法。最近，有报道称， 除了促进低级别胶质瘤的肿瘤形成外，2HG还具有免疫抑制作用。它的角色是 2HG是胶质瘤形成的驱动因素，现在又诱导了抗肿瘤T细胞的免疫抑制。 治疗低级别胶质瘤的关键靶点。因此，我们建议进行一项联合治疗的临床试验。 Vorasidenib和PEPIDH1M。我们推测，伏拉西尼对2HG的早期抑制将允许 随后或同时接种PEPIDH1M疫苗以产生更强大的T细胞反应和 导致免疫介导的肿瘤细胞杀伤增加(特定目标1)。在这一阶段的单部位临床试验中，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标准将被用来评估基于常规的放射学无进展生存 核磁共振成像。作为一个探索性的目标，我们将利用现有的高速技术纵向绘制大脑中的2HG图 磁共振波谱成像(MRSI)和离线处理技术监测伏拉西尼的疗效 (具体目标2)。最后，在临床试验的同时，我们将把经过验证的2HG标测工具转换为 通用电气和西门子扫描仪上用于报告2HG水平的标准化正在进行的工作(WIP)包 DICOM工作流程(具体目标3)。这个项目建立在1)我们以前参与早期项目的经验基础上 PEPIDHM1和vorasidenib的临床试验，我们还研究了纵向2HG水平，以及2)我们的 在自动化MRS方法并将其转换为制造商支持的WIP方面拥有数十年的经验 包裹。