A combination strategy to target pathophysiology of chronic lymphocytic leukemia

针对慢性淋巴细胞白血病病理生理学的组合策略

• 批准号: 10577652
• 负责人: VARSHA GANDHI
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577652
• 关键词: Achievement; Adverse event; Agammaglobulinaemia tyrosine kinase; Age; Alkylating Agents; Apoptotic; B-Cell Antigen Receptor; B-Lymphocytes; BCL-2 Protein; BCL1 Oncogene; Binding; Biochemical; Biological Markers; Biology; Blood; Blood Cells; Blood specimen; Bone Marrow; Cells; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Data; Clinical Protocols; Clinical Trials; Clonal Evolution; Combined Modality Therapy; Cyclophosphamide; Cytogenetics; Data; Dependence; Disease; Disease remission; Dose; Drug Combinations; Drug Kinetics; Drug usage; Event; Functional disorder; Generations; Genes; Goals; Immuno-Chemotherapy; In complete remission; Incidence; Investigation; Laboratories; Link; MCL1 gene; Maintenance; Measurable; Measures; Messenger RNA; Molecular; Molecular Profiling; Moon; Mutation; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase III Clinical Trials; Phosphotransferases; Plasma; Prognosis; Prognostic Factor; Progression-Free Survivals; Proliferating; Protein Family; Proteins; Proteome; Proteomics; Ramp; Randomized; Receptor Signaling; Recurrent disease; Refractory; Relapse; Research Personnel; Residual Neoplasm; Residual state; Resistance; Role; Sampling; Second Primary Cancers; Signal Transduction; TP53 gene; Testing; Time; Translational Research; Tumor Debulking; Tumor Lysis Syndrome; Tyrosine Kinase Inhibitor; antagonist; arm; biomarker identification; chemokine; chemotherapy; chromosome 17p loss; chronic lymphocytic leukemia cell; cohort; del(11q); design; disorder risk; driver mutation; effective therapy; efficacy evaluation; fludarabine; genome sequencing; genomic profiles; genotoxicity; high risk; improved; inhibitor; lymph nodes; migration; nucleoside analog; patient subsets; phase I trial; pre-clinical; response; response biomarker; rituximab; selective expression; standard of care; success; targeted agent; targeted treatment; therapeutic target; tositumomab; transcriptome; transcriptome sequencing; treatment response; trial comparing; whole genome

PROJECT SUMMARY Survival of chronic lymphocytic leukemia (CLL) cells is largely due to B-cell receptor (BCR) signaling and to the anti-apoptotic function of BCL-2 family proteins. The BCR pathway is critical for the proliferation, maintenance, and survival of B-cells. Bruton’s tyrosine kinase (BTK) is pivotal in the BCR axis and is activated when BCR is stimulated. Due to its critical role in BCR axis signaling and importance of the BCR pathway in B-cells, BTK is an attractive therapeutic target and ibrutinib (IBR) was approved for CLL. The dependency of CLL cells on BCL- 2 protein for survival makes BCL-2 antagonists such as venetoclax (VEN) optimal combination partners for BTK inhibitors. Acalabrutinib (ACA) is a second-generation more selective BTK inhibitor that irreversibly binds to Cys-481 in the BTK kinase domain and potently blocks its enzymatic activity. ACA demonstrated compelling activity in the clinic and during Phase I trials, and it became clear that this oral drug is highly effective with greater selectivity than first-generation inhibitor IBR. However, clinically, patients rarely achieve complete remissions (CR) or cures, and continuous use of the drug or combination strategies are needed. Similar to BCR targeting, BCL-2 inhibitor, VEN, was effective in the clinic but with limited CRs. Based on our preclinical investigations and three distinct rationales, we designed and initiated a clinical trial combining IBR and VEN in CLL. Rationales included decline in MCL-1 survival protein in CLL cells following IBR treatment, mobilization of CLL cells from lymph nodes to circulating blood after IBR, and potential decreased incidence of VEN-induced tumor lysis syndrome due to debulking of tumor by IBR. Data demonstrated a dramatic increase in CR rates compared with IBR or VEN monotherapy as well as achievement of undetectable measurable residual disease in 2/3 of previously untreated patients. Based on this data we hypothesized that more selective BTK inhibitor ACA combined with VEN may be more effective strategy for CLL with greater response rates. A clinical protocol (NCT04169737) has been established and initiated to evaluate the efficacy of the combination treatment with or without obinutuzumab treatment-naïve and previously treated cohorts. In this proposal, we will focus only on the ACA+VEN combination (i.e. without obinutuzumab). Through this trial, we will obtain samples during treatment to evaluate the components that contribute to response to therapy. In Aim 1, we will conduct pharmacodynamic analyses during therapy to determine the impact of VEN addition to ACA. Plasma pharmacokinetics of each drug will be measured, and molecular endpoints will be compared using RNAseq and proteomics analyses. For Aim 2, we will compare the combination of ACA/VEN combination against IBR/VEN for non-inferiority. These analyses will include pharmacodynamic analysis, -omics and biomarker comparisons using retrospective data from IBR/VEN combination with the ongoing ACA/VEN clinical trial. We have prior data from untreated (n=120) and previously treated (n=80) CLL patients on IBR/VEN trial. Ultimately, the goals of this proposal are to identify hallmarks and biomarkers of response and resistance that may lead to more effective treatment of CLL.

项目摘要 慢性淋巴细胞性白血病（CLL）细胞的存活主要是由于B细胞受体（BCR）信号传导和细胞内的免疫应答。 BCL-2家族蛋白的抗凋亡功能。BCR途径对于细胞的增殖、维持 和B细胞的存活。布鲁顿酪氨酸激酶（BTK）在BCR轴中是关键的，并且当BCR被激活时被激活。 受刺激由于BTK在BCR轴信号传导中的关键作用和BCR途径在B细胞中的重要性，BTK是 作为一个有吸引力的治疗靶点，伊曲替尼（IBR）被批准用于CLL。CLL细胞对BCL的依赖性- 2蛋白使BCL-2拮抗剂如维奈托克（VEN）成为BTK的最佳组合伴侣 抑制剂的Acalabrutinib（ACA）是第二代更有选择性的BTK抑制剂，其不可逆地结合至 Cys-481在BTK激酶结构域中，并有效地阻断其酶活性。ACA显示出令人信服的 在临床和I期试验期间，很明显这种口服药物非常有效， 选择性高于第一代抑制剂IBR。然而，临床上，患者很少达到完全缓解 (CR)或治愈，并且需要持续使用药物或组合策略。与BCR靶向类似， BCL-2抑制剂VEN在临床上是有效的，但CR有限。根据我们的临床前研究， 三个不同的理由，我们设计并启动了一项临床试验结合IBR和VEN在CLL。理由 包括IBR治疗后CLL细胞中MCL-1存活蛋白的下降， IBR后淋巴结与循环血液的接触，并可能降低VEN诱导的肿瘤溶解的发生率 IBR减瘤综合征。数据显示，与对照组相比， IBR或VEN单药治疗以及在2/3的患者中实现不可检测的可测量残留病变 以前未治疗的患者。基于这些数据，我们假设选择性更高的BTK抑制剂ACA 联合VEN可能是治疗CLL更有效的策略，有效率更高。临床方案 （NCT 04169737）已经建立并启动，以评价与或 无obinutuzumab初治和既往治疗的队列。在本提案中，我们将只关注 ACA+VEN组合（即不含obinutuzumab）。通过这项试验，我们将在治疗期间获得样本， 评估对治疗反应有贡献的成分。在目标1中，我们将进行药效学研究 在治疗期间分析，以确定VEN除了ACA的影响。每种药物的血浆药代动力学 将测量药物，并使用RNAseq和蛋白质组学分析比较分子终点。为 目的2，我们将比较ACA/VEN联合与IBR/VEN联合的非劣效性。这些 分析将包括使用回顾性数据的药效学分析、组学和生物标志物比较 从IBR/VEN组合与正在进行的ACA/VEN临床试验。我们有未经治疗的既往数据（n=120） 和IBR/VEN试验中既往接受过治疗（n=80）的CLL患者。最终，本提案的目标是确定 标志物和生物标志物的反应和耐药性，可能导致更有效的治疗CLL。