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）基因突变的鉴定导致了显著的