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.

摘要/摘要 患有高危 TP53 异常慢性淋巴细胞白血病 (CLL) 的患者的生存期比其他患者短 慢性淋巴细胞白血病患者。我们之前发现 BTK 抑制剂 acalabrutinib (A) 和 BCL-2 抑制剂 Venetoclax (V) 在离体杀死 CLL 细胞方面非常有效。我们开发了 AVO，一种新的限时三重组合 AV 与抗 CD20 抗体 obinutuzumab (O) 相结合的方案。 AVO临床试验及相关 对本次试验的主要样本进行的实验室研究构成了该项目的关键要素。 该项目的首要目标是确定 AVO 联合方案对患有以下疾病的患者的疗效： 先前未经治疗的 TP53 异常 CLL。我们假设 AVO 将是一种非常有效且良好的 耐受的新药三联方案，个体化治疗持续时间以达到以下目标为指导 无法检测到的微小残留病 (uMRD)。该假设将通过确定 使用 uMRD 实现完全缓解 (CR) 的患者比例，以及表征其安全性 该方案是在一项由研究者发起的针对先前患有 AVO 的患者的 2 期多中心临床试验中进行的 未经治疗的慢性淋巴细胞白血病。 该项目的第二个目标是评估 MRD 克隆动力学、治疗前线粒体启动是否 或基因组复杂性预测 AVO 的临床反应。我们将利用下一代测序（NGS） 基于 Adaptive ClonoSEQ 的技术，评估使用该检测的 MRD 克隆动态是否可以更有效 与传统流式细胞术相比，可以准确预测生存并指导治疗持续时间决策- 基于MRD。通过 BH3 分析对 CLL 细胞线粒体进行功能询问，我们假设 在基线和/或治疗早期线粒体启动水平较高的患者将获得更高的 AVO 上 uMRD 的 CR 率。反应的基因组预测因子也将通过刺激进行评估 使用 95 基因 NGS“快速血红素组合”(RHP) 进行核型和突变分析。 该项目的第三个目标是阐明 AVO 的耐药机制，包括获得性躯体细胞耐药机制。 突变、线粒体引发的调节、磷酸化的改变和激酶活性。我们将使用 RHP 用于评估体细胞突变的发展模式。我们还将评估 CLL 细胞是否 基线时通常依赖于 BCL-2 的细胞将发展出对其他抗 BCL-2 的替代生存依赖 进展中的凋亡蛋白。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抵抗机制，PP2A 激活剂是否可以帮助逆转这种机制以及 从而恢复敏感性。我们将使用高通量激酶活性图谱 (HT-KAM) 来识别哪些 激酶在耐药患者中被激活，以识别新的、潜在的治疗可行的靶点。 阐明耐药机制将为未来新药联合治疗试验的设计提供信息，其中 目标是降低 CLL 以及最终其他 B 细胞恶性肿瘤获得性治疗耐药的风险。