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.

项目概要 慢性淋巴细胞白血病 (CLL) 细胞的存活很大程度上取决于 B 细胞受体 (BCR) 信号转导和 BCL-2 家族蛋白的抗凋亡功能对于增殖、维持、 布鲁顿酪氨酸激酶 (BTK) 在 BCR 轴中至关重要，并且当 BCR 处于激活状态时被激活。 由于其在 BCR 轴信号传导中的关键作用以及 BCR 通路在 B 细胞中的重要性，BTK 受到刺激。 一个有吸引力的治疗靶点，伊布替尼（IBR）被批准用于治疗 CLL CLL 细胞对 BCL- 的依赖性。 2 生存蛋白使 BCL-2 拮抗剂（例如维奈托克 (VEN)）成为 BTK 的最佳组合伙伴 Acalabrutinib (ACA) 是第二代更具选择性的 BTK 抑制剂，可不可逆地结合。 BTK 激酶结构域中的 Cys-481 有效阻断其 ACA 酶活性。 在临床和 I 期试验期间的活动，很明显，这种口服药物变得非常有效，并且具有更大的效果 选择性优于第一代抑制剂 IBR，但临床上很少有患者达到完全缓解。 (CR) 或治愈，并且需要持续使用药物或联合策略，类似于 BCR 靶向。 BCL-2 抑制剂 VEN 在临床上有效，但根据我们的临床前研究，CR 有限。 出于三个不同的理由，我们设计并启动了一项将 IBR 和 VEN 结合用于 CLL 的临床试验。 包括 IBR 治疗后 CLL 细胞中 MCL-1 存活蛋白的下降、CLL 细胞从 IBR 后淋巴结进入循环血液，并可能降低 VEN 诱导的肿瘤溶解发生率 数据显示，与 IBR 相比，CR 率显着增加。 IBR 或 VEN 单一疗法以及 2/3 的患者达到不可检测的可测量残留疾病 根据这些数据，我们开发了更具选择性的 BTK 抑制剂 ACA。 联合 VEN 可能是治疗 CLL 的更有效策略，具有更高的缓解率。 (NCT04169737) 已建立并启动以评估联合治疗的疗效或 未接受 obinutuzumab 治疗和既往治疗的队列在本提案中，我们将仅关注 ACA+VEN 组合（即不含 obinutuzumab），我们将在治疗期间获得样本。 评估有助于治疗反应的成分 在目标 1 中，我们将进行药效学研究。 治疗期间进行分析，以确定 VEN 添加到 ACA 中的血浆药代动力学的影响。 将测量药物，并使用 RNAseq 和蛋白质组学分析比较分子终点。 目标 2，我们将比较 ACA/VEN 组合与 IBR/VEN 的非劣效性。 分析将包括药效学分析、组学和使用回顾性数据的生物标志物比较 来自 IBR/VEN 组合与正在进行的 ACA/VEN 临床试验 我们有未经治疗的先前数据 (n=120)。 和先前接受过 IBR/VEN 试验的 CLL 患者 (n=80)，该提案的最终目标是确定。 反应和耐药的标志和生物标志物可能会导致更有效的 CLL 治疗。