Optimizing novel agent combination therapy for previously untreated, high risk chronic lymphocytic leukemia

优化针对先前未治疗的高风险慢性淋巴细胞白血病的新药联合疗法

• 批准号: 10522611
• 负责人: MATTHEW S DAVIDS
• 金额: $ 42.14万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522611
• 关键词: Achievement; Agammaglobulinaemia tyrosine kinase; Apoptotic; B lymphoid malignancy; B-Cell Leukemia; BCL2L1 gene; Biological Assay; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dependence; Disease; Elderly; Elements; Family member; Flow Cytometry; Future; Generations; Genes; Genomics; Genotype; Goals; Grant; Head; Heme; In complete remission; Karyotype; Laboratories; Laboratory Study; MCL1 gene; Mitochondria; Monoclonal Antibody CD20; Multi-Institutional Clinical Trial; Mutation; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Phosphorylation; Phosphotransferases; Population; Principal Investigator; Progression-Free Survivals; Protein Family; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Regimen; Research Personnel; Residual Neoplasm; Resistance; Resistance development; Rest; Risk; Safety; Sampling; Sampling Studies; Somatic Mutation; Subgroup; TP53 gene; Technology; Testing; Therapeutic; Therapy trial; Time; Toxic effect; Triplet Multiple Birth; Tyrosine Kinase Inhibitor; anti-CD20; base; chronic lymphocytic leukemia cell; clinical predictors; comorbidity; design; experience; genomic predictors; high risk; individualized medicine; inhibitor; innovation; leukemia/lymphoma; next generation sequencing; novel; optimal treatments; personalized decision; predicting response; protein B; resistance mechanism; response; response biomarker; standard of care; survival prediction; targeted agent; therapy duration; tositumomab; treatment duration; treatment response

SUMMARY/ABSTRACT Patients with high-risk TP53 aberrant chronic lymphocytic leukemia (CLL) have a shorter survival than other CLL patients. We previously found that the BTK inhibitor acalabrutinib (A) and the BCL-2 inhibitor venetoclax (V) are highly effective at killing CLL cells ex vivo. We developed AVO, a new time-limited triplet combination regimen combining AV with an anti-CD20 antibody obinutuzumab (O). The AVO clinical trial and correlative laboratory studies on primary samples from this trial comprise the key elements of this project. The first aim of the project is to determine the efficacy of the AVO combination regimen in patients with previously untreated TP53 aberrant CLL. We hypothesize that AVO will be a highly efficacious and well- tolerated novel agent triplet regimen, with individualized therapy duration guided by achievement of undetectable minimal residual disease (uMRD). This hypothesis will be tested through determining the proportion of patients who achieve complete response (CR) with uMRD, as well as characterizing the safety of the regimen, in an investigator-initiated, phase 2, multicenter clinical trial of AVO in patients with previously untreated CLL. The second aim of the project is to assess whether MRD clonal dynamics, pre-treatment mitochondrial priming, or genomic complexity predict clinical response to AVO. We will utilize a next-generation sequencing (NGS) based technology, Adaptive ClonoSEQ, to assess whether MRD clonal dynamics with this assay can more accurately predict survival and guide treatment duration decisions compared with conventional flow cytometry- based MRD. Through functional interrogation of CLL cell mitochondria by BH3 profiling, we hypothesize that patients with higher levels of mitochondrial priming at baseline and/or early on treatment will achieve a higher rate of CR with uMRD on AVO. Genomic predictors of response will also be assessed through stimulated karyotype and mutational profiling with a 95-gene NGS ‘rapid heme panel’ (RHP). The third aim of the project is to elucidate mechanisms of resistance to AVO, including acquired somatic mutations, modulation in mitochondrial priming, alterations in phosphorylation, and kinase activity. We will use RHP to evaluate the pattern of somatic mutations as they develop. We will also evaluate whether CLL cells that are typically dependent on BCL-2 at baseline will develop alternative survival dependencies on other anti- apoptotic proteins at progression. In addition, we will assess whether BCL-2 family protein phosphorylation may represent a functional resistance mechanism, and whether PP2A activators can help reverse this and thereby restore sensitivity. And we will use high-throughput kinase activity mapping (HT-KAM) to identify which kinases are activated in resistant patients to identify new, potentially therapeutically actionable targets. Elucidating resistance mechanisms will inform the design of future novel agent combination therapy trials, with the goal of decreasing the risk of acquired therapy resistance in CLL and eventually other B cell malignancies.

总结/摘要 高危TP 53异常慢性淋巴细胞白血病（CLL）患者的生存期比其他患者短。 CLL患者。我们以前发现BTK抑制剂acalabrutinib（A）和BCL-2抑制剂venetoclax（A） (V)在体外杀死CLL细胞方面非常有效。我们开发了一种新的限时三重组合AVO AV与抗-CD 20抗体obinutuzumab（0）组合的方案。AVO临床试验及相关研究 这项计划的主要部分是对试验所得的主要样本进行实验室研究。 该项目的第一个目的是确定AVO联合方案在以下患者中的疗效： 先前未经治疗的TP 53异常CLL。我们假设AVO将是一种非常有效的- 耐受的新型药物三联方案，个体化治疗持续时间根据 不可检测的微小残留病（uMRD）。这一假设将通过确定 使用uMRD达到完全缓解（CR）的患者比例，以及表征 该方案在一项针对既往患有AVO的患者的、由药物启动的、2期、多中心临床试验中， 未治疗的CLL。 该项目的第二个目的是评估MRD克隆动力学，治疗前线粒体启动， 或基因组复杂性预测对AVO的临床反应。我们将利用下一代测序（NGS） 的技术，自适应克隆SEQ，以评估是否MRD克隆动力学与此测定可以更多 与传统流式细胞术相比，准确预测生存率并指导治疗持续时间决策- 基于MRD通过BH 3谱对CLL细胞线粒体的功能性询问，我们假设， 在基线和/或治疗早期具有较高水平的线粒体启动的患者将实现较高的 AVO上uMRD的CR率。反应的基因组预测因子也将通过刺激 用95个基因的NGS“快速血红素板”（RHP）进行核型和突变分析。 该项目的第三个目的是阐明对AVO的抗性机制，包括获得性体细胞抗性。 突变、线粒体启动的调节、磷酸化的改变和激酶活性。我们将使用 RHP评估体细胞突变的模式，因为他们发展。我们还将评估CLL细胞是否 在基线时通常依赖于BCL-2的患者将发展对其他抗- 细胞凋亡蛋白。此外，我们将评估BCL-2家族蛋白磷酸化是否 可能代表一种功能性耐药机制，以及PP 2A激活剂是否可以帮助逆转这种机制， 从而恢复灵敏度。我们将使用高通量激酶活性图谱（HT-KAM）来确定 激酶在耐药患者中被激活，以鉴定新的、潜在的治疗上可行的靶点。 阐明耐药机制将为未来新型药物联合治疗试验的设计提供信息， 目的是降低CLL和最终其他B细胞恶性肿瘤中获得性治疗耐药性的风险。