A randomized controlled phase 2 study of the ketogenic diet for patients with newly diagnosed glioblastoma in combination with standard-of-care treatment

一项针对新诊断胶质母细胞瘤患者的生酮饮食与标准护理治疗相结合的随机对照 2 期研究

• 批准号: 10568656
• 负责人: Stephen Jay Freedland
• 金额: $ 73.91万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568656
• 关键词: Address; Adherence; Adopted; Bioenergetics; Biological Markers; Blood specimen; Brain Neoplasms; Carbohydrates; Clinical; Cognition; Correlative Study; Counseling; Data; Diagnostic; Diet; Disease; Early identification; Environment; Fatigue; Fatty acid glycerol esters; Feces; Future; Glioblastoma; Glucose; Glycolysis; Goals; Growth; Human; Immune; Immune response; Inflammasome; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Interleukin-1 beta; Ketones; Knowledge; Leisures; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolism; Modeling; Monitor; Moods; Newly Diagnosed; Outcome; PIK3CG gene; Patient Care; Patient-Focused Outcomes; Patients; Peripheral; Personal Satisfaction; Persons; Persuasive Communication; Phase; Physical Function; Physical activity; Physiology; Production; Prognosis; Progression-Free Survivals; Quality of Life Assessment; Quality of life; Questionnaires; Randomized; Resistance; Seizures; Serum; Shapes; Signal Transduction; Stains; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Toxic effect; Trail Making Test; Translational Research; Tumor Immunity; Tumor Tissue; Tumor-Infiltrating Lymphocytes; Work; anti-cancer; anti-tumor immune response; arm; cancer therapy; clinical care; clinical efficacy; clinical practice; cognitive function; cognitive performance; cost; cytokine; diet and cancer; efficacy testing; experience; fitbit; genome sequencing; gut bacteria; gut microbiota; immunoregulation; improved; improved outcome; indexing; inflammatory marker; ketogenic diet; metabolomics; phase 1 study; phase 2 study; phase II trial; phase III trial; pre-clinical; predict responsiveness; predicting response; programmed cell death ligand 1; prospective; radiological imaging; response; safety and feasibility; secondary endpoint; single cell analysis; standard care; standard of care; stool sample; transcriptome sequencing; transcriptomics; translational study; treatment optimization; tumor; tumor metabolism; tumor-immune system interactions; tumorigenesis; whole genome

ABSTRACT Median glioblastoma (GBM) survival is ~15 months and is little changed the past 50 years. Better therapies are needed. Preclinical work from us and others has shown that a high-fat / low-carbohydrate ketogenic diet (KD) can slow cancer growth in multiple models including GBM. Like many cancers, GBM depends on glycolysis for the biosynthetic, bioenergetic, and signaling needs of oncogenesis. By limiting glycolytic flux and altering metabolism, KD may have anti-cancer effects, including abrogating dysregulated insulin-PI3K signaling, suppressing the pro-inflammatory tumor environment, and facilitating an anti-tumor immune response. Given the dismal prognosis, many GBM patients adopt a quasi-KD despite the lack of high-quality data supporting its use. To fill this gap, we conducted a pilot KD study for brain tumor patients, wherein we saw improvements in fatigue, mood, cognitive function, and seizure control, as well as radiographic responses. We recently completed a phase 1 KD trial for patients with newly diagnosed GBM. The primary objectives of the phase 1 study - safety and feasibility – were met. Importantly, we found an impressive median Overall Survival (OS) of 29.1 months, a 99% improvement vs. historic control from the phase 3 trial that established the current standard of care (SOC). We are now poised to conduct the first ever well-powered randomized controlled phase 2 study of KD + SOC vs. SOC for patients with newly diagnosed GBM. We propose a 170-person multicenter randomized controlled phase 2 study of KD plus SOC vs. SOC for patients newly diagnosed with GBM. Our primary objective is to test efficacy between KD + SOC vs. SOC as assessed by improved OS. We will assess quality of life (QoL), cognition, and physical function, as benefits in any of these would be impactful to patients’ lives. We will take full advantage of tumor, blood, and stool samples that we will be collecting to understand the effects of KD on tumor and host metabolism and immune response. Desperate patients are not waiting. We thus have an urgent responsibility to prospectively and comprehensively evaluate KD and understand its effects, good or bad. If negative, patients can be counseled accordingly, and spend their precious time and energy on other endeavors, though QoL benefits (if seen) may still persuade some to go on a KD. If positive, we have the potential to establish a new SOC that can be broadly applied without the cost or toxicity of most new cancer therapies. We will seize the opportunity to gain a greater mechanistic understanding of the effects of KD on GBM, which may shape future efforts to identify early markers/predictors of response and optimize therapeutic combinations. These data can also help manage GBM patients who choose to go on a KD either for OS or QoL benefits (if seen). Thus, regardless of outcome, this study will shape clinical practice.

抽象的 中位数胶质母细胞瘤（GBM）的生存率约为15个月，在过去的50年中几乎没有改变。更好的疗法是 需要。来自我们和其他人的临床前工作表明，高脂 /低碳水化合物生酮饮食（KD） 在包括GBM在内的多种模型中可以减缓癌症的生长。像许多癌症一样，GBM依赖于糖酵解 肿瘤发生的生物合成，生物能和信号传导需求。通过限制糖酵解通量并改变 代谢，KD可能具有抗癌作用，包括废除失调的胰岛素-PI3K信号传导， 抑制促炎性肿瘤环境，并支持抗肿瘤免疫反应。鉴于 令人沮丧的预后，许多GBM患者采用了准KD任务，缺乏支持其使用的高质量数据。 为了填补这一空白，我们为脑肿瘤患者进行了一项试验KD研究，其中我们看到了疲劳的改善， 情绪，认知功能和癫痫发作控制以及射线照相反应。我们最近完成了一个阶段 新诊断为GBM患者的1 kD试验。第一阶段研究的主要目标 - 安全性和 可行性 - 满足。重要的是，我们发现令人印象深刻的总生存期（OS）为29.1个月，99％ 改进与历史控制的第三阶段试验建立了当前的护理标准（SOC）。我们 现在被毒死了KD + SOC vs的首次有史以来第一个有力的随机控制阶段研究。 适用于新诊断为GBM的患者的SOC。 我们提出了170人的多中心随机控制阶段2研究KD Plus SOC与患者SOC的研究 新诊断为GBM。我们的主要目标是测试KD + SOC与SOC之间的效率 通过改进的操作系统。我们将评估生活质量（QOL），认知和身体机能，作为其中任何一个的好处 会对患者的生活产生影响。我们将充分利用肿瘤，血液和粪便样本 收集以了解KD对肿瘤和宿主代谢和免疫冲源的影响。 绝望的患者没有等待。因此，我们有迫切责任前瞻性，全面 评估KD并了解其效果，好坏。如果负面，可以相应地对抗患者，并且 将他们宝贵的时间和精力花在其他努力上，尽管QoL福利（如果看到）仍然可能说服一些 去KD。如果积极 大多数新癌症疗法的成本或毒性。我们将抓住机会获得更大的机制 了解KD对GBM的影响，这可能会影响未来的努力以识别早期标记/预测因子 反应并优化治疗组合。这些数据还可以帮助管理GBM患者 选择以操作系统或QOL福利（如果看到）进行KD。无论结果如何，这项研究都将成型 临床实践。