Development of a Phenotype-based Predictive Analytic for Acute Myeloid Leukemia

开发基于表型的急性髓系白血病预测分析

• 批准号: 10276293
• 负责人: Tomer M Mark
• 金额: $ 59.7万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276293
• 关键词: Academic Medical Centers; Acute Myelocytic Leukemia; Address; BCL2 gene; Biological Assay; Caring; Cell Line; Cell Nucleus; Cells; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; Cytoplasm; Data; Data Set; Dependence; Development; Disease; Disease-Free Survival; Dose; Effectiveness; Evaluation; Excision; Exhibits; Exportins; FLT3 gene; Family; Flow Cytometry; Gene Mutation; Genetic Markers; Genomics; Genotype; Immunophenotyping; Industry; Investigation; Laboratories; Lead; Leukemic Cell; Link; MCL1 gene; Measurement; Medicine; Methods; Minority; Modeling; Mutate; Mutation; Neoadjuvant Therapy; Nuclear; Nuclear Export; Outcome; Patient Education; Patient-Focused Outcomes; Patients; Pattern; Phase; Phase II Clinical Trials; Phenotype; Phosphotransferases; Play; Population; Predictive Analytics; Proteins; RAS Family Gene; Refractory; Regimen; Relapse; Reproducibility; Research; Research Personnel; Resistance; Role; Safety; Sampling; Selection for Treatments; Sensitivity and Specificity; Site; Specificity; TP53 gene; Testing; Therapeutic; Time; Training; Translations; Tumor Suppressor Proteins; Validation; Work; acute myeloid leukemia cell; alternative treatment; analytical tool; antitumor effect; base; clinical practice; cohort; companion diagnostics; drug sensitivity; effective therapy; efficacy trial; exportin 1 protein; genetic resistance; high risk; industry partner; inhibitor/antagonist; leukemia; leukemia initiating cell; monocyte; new combination therapies; novel; novel therapeutics; older patient; phase 1 study; phase 2 study; phase I trial; phase II trial; precision medicine; preclinical efficacy; preclinical study; predicting response; pressure; protein transport; relapse patients; resistance mechanism; responders and non-responders; response; single cell technology; standard of care; targeted sequencing; targeted treatment; tool; translational study

Project Summary The 5-year overall survival from acute myeloid leukemia (AML) is less than 30%. While some patients are cured with initial induction therapy, most patients relapse, and the expected outcomes in patients with relapsed and refractory (R/R) AML are dismal. For this reason, developing methods to identify therapies likely to benefit R/R AML patients is a top priority. This proposal aims to address critical unmet needs with a unique Academic- Industry Partnership (AIP) between investigators at Vanderbilt University Medical Center, Karyopharm Therapeutics, and Notable Labs. The BCL2 inhibitor, venetoclax (VEN), is transforming clinical practice for AML, but activity in R/R AML is less pronounced, and resistance occurs in most patients. AIP investigators currenty lead a multi-site investigator-sponsored study, testing VEN in combination with the selective inhibitor of nuclear export (SINE) selinexor (SEL) in a Phase I trial for R/R AML (NCT03955783). This SEL/VEN trial grew from the discovery that SEL synergizes with VEN and overcomes resistance mechanisms in some VEN-insensitive patient samples. Given this, our AIP team has worked together to develop a precision medicine functional platform for this novel combination in R/R AML. Notable Labs utilizes an automated high-throughput, immunophenotype-based flow cytometry method to provide real time drug sensitivity data on multiple, specific cell populations simultaneously within a given patient sample. Building from the only annotated cohort of patient samples treated with SEL/VEN in the world, we propose to develop a precision medicine functional assay to identify R/R AML patients most likely to benefit from SINE/VEN combination therapy. We will build, refine and optimize the functional platform for SEL/VEN with samples from our current Phase I study and train the platform on samples from the Phase 2 SEL/VEN clinical trial proposed by the AIP. Aim 1 will focus on determining assay parameters specifically for SEL/VEN in R/R AML. Aim 2 will train the model with the phase II clinical trial of SEL/VEN in R/R AML, and Aim 3 will contextualize the predictive analytic model on heterogenous genotypes found in R/R AML. At the conclusion of this study, the functional medicine platform will be a companion diagnostic ready for external validation which we will lead in a phase III efficacy trial of SEL/VEN in R/ R AML, and serve as proof-of-principle for development of similar therapy-specifc precision medicine tools.

项目摘要 急性髓样白血病（AML）的5年总生存率小于30％。虽然有些患者被治愈 通过初始诱导疗法，大多数患者复发以及复发患者的预期结果 难治（R/R）AML令人沮丧。因此，开发方法来识别可能受益R/R的疗法 AML患者是重中之重。该建议旨在通过独特的学术 - Karyopharm范德比尔特大学医学中心调查员之间的行业合作伙伴关系（AIP） 治疗和著名实验室。 Bcl2抑制剂Venetoclax（VEN）正在转变AML的临床实践， 但是R/R AML的活动不太明显，大多数患者的耐药性发生。 AIP调查人员当前 领导多站点研究者赞助的研究，与核的选择性抑制剂结合测试VEN 在R/R AML（NCT0395578​​3）的I期试验中出口（SINE）SELINEXOR（SEL）。这项SEL/VEN试验从 SEL与VEN协同并克服某些不敏感的电阻机制的发现 病人样本。鉴于此，我们的AIP团队共同努力开发精确的医学功能 R/R AML的这种新颖组合的平台。著名的实验室使用自动高通量， 基于免疫表型的流式细胞术方法，可在多个特定的，特定的方面提供实时药物敏感性数据 在给定患者样本中同时同时进行细胞群体。从唯一注释的患者队列中建造 在世界范围内用SEL/VEN处理的样本，我们建议开发一种精密医学功能测定法 确定最有可能受益于正弦/VEN组合疗法的R/R AML患者。我们将建造，完善和 通过我们当前I阶段研究的样品来优化SEL/VEN的功能平台，并训练平台 在AIP提出的第2阶段SEL/VEN临床试验的样品上。 AIM 1将专注于确定测定 专为R/R AML中的SEL/VEN参数。 AIM 2将通过II期临床试验训练模型 R/R AML中的SEL/VEN，AIM 3将在异质基因型上的预测分析模型背景下 在R/R AML中发现。在这项研究的结尾，功能医学平台将成为伴侣 诊断准备外部验证，我们将在R/ R AML中SEL/ VEN的III期疗效试验中领导， 并作为开发类似疗法精确药物工具的原则证明。