A Phase 1 Trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in Advanced NSCLC Patients

MLN0128 (sapanisertib) 和 CB-839 HCl (telaglenastat) 在晚期 NSCLC 患者中的 1 期试验

• 批准号: 10297989
• 负责人: Paul K Paik
• 金额: $ 62.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-31 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297989
• 关键词: Affect; Age; Binding Sites; Biology; Biopsy; Blood; Cancer Patient; Cells; Citric Acid Cycle; Clinical Data; Contracts; Data; Dependence; Disease; Dose; Drug Kinetics; Exhibits; Eye; FRAP1 gene; Generations; Genotype; Glucose; Glutaminase; Glutamine; Glycolysis; Glycolysis Inhibition; Histologic; Histology; Image; Immune checkpoint inhibitor; Institution; Intervention; KRAS2 gene; Knowledge; Lead; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Metabolism; Metastatic Squamous Cell Carcinoma; Methods; Modeling; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Plasma; Platinum; Population Control; Positron-Emission Tomography; Prognosis; Proteins; Publishing; Recurrence; Resistance; Safety; Schedule; Signal Transduction; Squamous Cell Lung Carcinoma; Stress; Testing; Therapeutic; Time; Treatment Efficacy; Tumor Suppressor Genes; United States; Up-Regulation; Ursidae Family; Work; Xenobiotics; base; checkpoint inhibition; chemotherapy; cohort; combinatorial; druggable target; effective therapy; efficacy testing; fluorodeoxyglucose; glucose metabolism; inhibitor/antagonist; molecular subtypes; mutant; new therapeutic target; novel; novel strategies; partial response; pharmacodynamic biomarker; phase I trial; phase II trial; pre-clinical; resistance mechanism; response; targeted treatment; therapy resistant; transcription factor; tumor; tumor metabolism

Project Summary/Abstract Patients with metastatic squamous cell carcinomas of the lung (LUSC) and driver-negative non-small cell lung cancers (NSCLC) continue to have poor prognoses despite modest gains in survival in the age of immune checkpoint inhibitors. This is, in large part, due to the absence of targeted therapies for these patients, treatments which have had the biggest impact on patient prognoses in the past 15 years. The current proposal focuses on a novel interaction that occurs between a newly characterized NSCLC genotype and its effects on tumor metabolism. NFE2L2, which encodes for a transcription factor (NRF2) that protects cells from oxidative and xenobiotic stress and which upregulates TORC1 signaling, is recurrently mutated in 20% of LUSC tumors. These mutations occur in only a single hotspot domain (Neh2) that serves as the binding site for its negative regulator, KEAP1, which itself is mutated in 20% of LUSC cases. This pathway is also altered in 30% of KRAS- mutant lung cancer cases and is associated with poor prognosis and immune checkpoint inhibitor resistance. Our preliminary pre-clinical and clinical data show that inhibition of TORC1/2 by the orally available drug TAK228 has anti-tumor efficacy in these contexts, but that a metabolic switch away from glycolysis (blunted by TORC1/2 inhibition) to glutamine metabolism causes treatment resistance. We show that dual inhibition of glycolysis (TAK228) and glutaminolysis (CB-839) in mutation-specific LUSC and KRAS-mutant lung contexts yields synergistic anti-tumor activity. The proposed phase 1 clinical trial is based on the hypothesis that concurrent inhibition of these pathways with TAK228 and CB-839 will be an effective therapy for subsets of NSCLC patients who harbor these alterations or have activation of NRF2 signaling. Our phase 1 trial of TAK228 + CB-839 has three aims, including 1) determination of the recommended expansion dose of TAK228 + CB-839 in patients with advanced NSCLC; 2) establishing the preliminary efficacy of TAK228 + CB-839 in pre-selected genotype/histology cohorts; and 3) characterizing the metabolic pharmacodynamic markers in the blood, tumor, and through imaging. This trial is a first step in what we purport will be a new targeted therapy option for patients with NSCLC. The next step and longer term objective is to utilize these data as justification and hypothesis generation for formal phase 2 efficacy testing in a much larger cohort of patients, with an eye towards executing a study in larger cooperative groups such as LungMAP S1900, which would be uniquely suited to exploring this combination approach across institutions in the United States.

项目摘要/摘要 肺转移性鳞状细胞癌（LUSC）和驾驶员阴性非小细胞肺的患者 尽管免疫时代的生存率适度 检查点抑制剂。这在很大程度上是由于这些患者没有靶向疗法， 在过去15年中对患者预后产生最大影响的治疗方法。当前的建议 着重于新表征的NSCLC基因型及其对其对的影响之间发生的新型相互作用 肿瘤代谢。 NFE2L2，该NFE2L2编码转录因子（NRF2），可保护细胞免受氧化的影响 和异生元应力并上调TORC1信号传导，在20％的LUSC肿瘤中反复突变。 这些突变仅发生在单个热点域（NEH2）中，该结构域是其负面的结合位点 调节剂KEAP1本身在20％的LUSC病例中被突变。在30％的Kras-中，该途径也改变了 突变肺癌病例，与预后不良和免疫检查点抑制剂抗性有关。 我们的初步临床和临床数据表明，口服药物对TORC1/2抑制 TAK228在这些情况下具有抗肿瘤功效 TORC1/2抑制谷氨酰胺代谢会引起治疗抗性。我们证明了对双重抑制 突变特异性LUSC和KRAS突变肺部的糖酵解（TAK228）和谷氨酰胺溶解（CB-839） 产生协同的抗肿瘤活性。拟议的1期临床试验基于以下假设。 与TAK228和CB-839一起对这些途径的同时抑制作用将是针对子集的有效疗法 携带这些改变或激活NRF2信号传导的NSCLC患者。我们的第一阶段试验 TAK228 + CB-839具有三个目标，包括1）确定推荐的扩展剂量TAK228 晚期NSCLC患者的 + CB-839； 2）建立TAK228 + CB-839的初步疗效 预先选择的基因型/组织学队列； 3）表征代谢药效学标记 血液，肿瘤和通过成像。这项试验是我们声称将是一种新的目标疗法的第一步 NSCLC患者的选择。下一步和长期目标是利用这些数据作为理由 以及在更大的患者队列中进行正式2阶段疗效测试的假设生成 旨在在较大的合作团体（例如Lungmap S1900）中执行一项研究，这将是独特的 适合探索美国各机构的这种组合方法。