Molecular Evaluation of Targeted Therapies in Lymphoid Malignancies

淋巴恶性肿瘤靶向治疗的分子评价

• 批准号: 8653237
• 负责人: JOHN C. BYRD
• 金额: $ 50.05万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653237
• 关键词: Agammaglobulinaemia tyrosine kinase; Age; Alkylating Agents; Apoptosis; B-Cell Development; Bioavailable; Biological Markers; Bone Marrow; Cancer and Leukemia Group B; Cells; Characteristics; Chlorambucil; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Clinical; Clinical Trials; Code; Communities; Consensus; Correlative Study; Cyclophosphamide; Cytogenetics; Data; Dependence; Diagnosis; Disease; Disease remission; Dose; Effectiveness; Elderly; Evaluation; Functional RNA; Future; Genes; Genomics; Health; Interphase; Laboratory Finding; Lymphocyte; Malignant lymphoid neoplasm; Methylation; Molecular; Mutation; NOTCH1 gene; Non-Hodgkin' s Lymphoma; Older Population; Oral; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase III Clinical Trials; Phosphotransferases; Population; Prognostic Factor; Prognostic Marker; Progression-Free Survivals; Protein Kinase; Protein Tyrosine Kinase; Randomized; Reaction Time; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Refractory; Regimen; Relapse; Research Priority; Residual Neoplasm; Residual state; Resistance; Risk; Sampling; Signal Pathway; Signal Transduction; Survival Rate; Therapeutic; Time; Ursidae Family; Validation; Work; ZAP-70 Gene; adult leukemia; base; design; fludarabine; high risk; human old age (65+); inhibitor/antagonist; kinase inhibitor; leukemia; lymph nodes; novel; novel strategies; older patient; patient population; phase 1 study; phase 3 study; response; rituximab; standard care; treatment strategy; trial comparing

Project Summary/Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia and is currently incurable. Two thirds of patients diagnosed with CLL are age 65 or older, and while fludarabine-based chemoimmunotherapy is standard initial therapy for younger patients, the optimal therapy for older patients is less clear. Both a randomized phase III study and a retrospective analysis of Cancer and Leukemia Group B trials showed no benefit to fludarabine over chlorambucil in the elderly population, while rituximab offers benefit irrespective of age. While recent data suggest that administration of the alkylator agent chloramubucil or benadmustine together with rituximab is feasible in this population, outcome is still suboptimal for what represents the largest population of CLL patients. Additionally, the relevance and impact of new biologic markers and minimal residual disease status predictive of response duration and survival in younger patients has not explored in the elderly. New therapies and validation of biomarkers identified in younger patients is therefore a high priority for research in this population. Ibrutinib is an orally bioavailable inhibitor of Bruton's Tyrosine Kinase (BTK), a critical kinase involved in B cell development and signaling through the B cell receptor (BCR). In a Phase Ib/II trial co-led by our group, the clinical activity associated with this agent has been extraordinary, with a 26 month PFS of 76% for patients with relapsed and refractory CLL, and 96% for elderly patients with previously untreated disease. This agent has been well tolerated as well with extended continuous dosing. Building upon our previous work, in this application we propose a Phase III clinical trial investigating ibrutinib alone or ibrutinib plus rituximab compared with standard therapy of bendamustine plus rituximab (BR) in older patients with previously untreated CLL. Correlative analyses of established and novel prognostic markers are proposed in an attempt to identify biomarkers associated with response and outcomes. The specific aims of this proposal are: 1: To perform a phase III clinical trial comparing a) ibrutinib, b) ibrutinib plus rituximab and c) BR in symptomatic CLL patients > 65 years to determine the therapy with highest response, PFS and OS. 2: To perform pharmacodynamic (PD) studies in this phase III study to determine whether traditional genomic features, select baseline BCR activation markers, and changes in miR marker expression over 1 month are predictive for best response, time to clinical response, PFS, and OS. 3: To evaluate longitudinal samples after ibrutinib therapy to evaluate the characteristics of persistent lymphocytes and determine whether changes in coding or non-coding RNAs, acquisition of mutations in BTK or PLC¿2, or presence of minimal residual disease at 9 or 24 months will be predictive of late relapse and PFS after ibrutinib-based therapies. It is anticipated that the clinical and laboratory findings derived from this trial will be transformative in how elderly CLL are treated and contribute significantly to the design of future clinical trials for these patients.

项目概要/摘要 慢性淋巴细胞白血病（CLL）是成人白血病最常见的形式，目前无法治愈。 三分之二被诊断患有 CLL 的患者年龄在 65 岁或以上，而以氟达拉滨为基础的药物 化学免疫治疗是年轻患者的标准初始治疗，老年患者的最佳治疗是 一项随机 III 期研究和 B 组癌症和白血病的回顾性分析均不太明确。 试验表明，在老年人群中，氟达拉滨相对于苯丁酸氮芥并无益处，而利妥昔单抗则有益处 尽管最近的数据表明，服用烷化剂苯丁酸氮芥或 贝那莫司汀联合利妥昔单抗在该人群中是可行的，但结果仍不理想 代表了最大的 CLL 患者群体此外，新生物制剂的相关性和影响。 标志物和微小残留病状态可预测年轻患者的缓解持续时间和生存率 尚未在老年人中探索新的疗法和在年轻患者中鉴定的生物标志物的验证。 因此，针对这一人群的研究具有高度优先性。 依鲁替尼是一种口服生物可利用的布鲁顿酪氨酸激酶 (BTK) 抑制剂，BTK 是 B 细胞中参与的关键激酶。 在我们小组共同领导的 Ib/II 期试验中， 与该药物相关的临床活性非常出色，患有以下疾病的患者的 26 个月 PFS 为 76% 复发性和难治性 CLL，以及 96% 患有先前未治疗疾病的老年患者。 长期连续给药也具有良好的耐受性。 根据我们之前的工作，在本申请中，我们提出了一项研究 ibrutinib（依鲁替尼）的 III 期临床试验 单独或依鲁替尼加利妥昔单抗与老年患者苯达莫司汀加利妥昔单抗 (BR) 标准治疗的比较 既往未接受治疗的 CLL 患者对已建立的和新的预后标志物进行了相关分析。 提出的目的是试图识别与反应和结果相关的生物标志物。 该提案是： 1：进行 III 期临床试验，比较 a) 依鲁替尼、b) 依鲁替尼加利妥昔单抗和 c) 对 > 65 岁有症状的 CLL 患者进行 BR 以确定具有最高反应、PFS 和 OS 的治疗方法 2： 在这项 III 期研究中进行药效学 (PD) 研究，以确定传统基因组学是否有效 特征，选择基线 BCR 激活标记，以及 1 个月内 miR 标记表达的变化 预测最佳反应、临床反应时间、PFS 和 OS 3：纵向评估样本。 依鲁替尼治疗可评估持久性淋巴细胞的特征并确定淋巴细胞是否发生变化 编码或非编码 RNA、BTK 或 PLC 突变的获得¿ 2、或存在微量残留 9 或 24 个月时的疾病可预测基于依鲁替尼的治疗后的晚期复发和 PFS。 预计该试验的临床和实验室结果将彻底改变老年人的生活方式 CLL 得到治疗，并对这些患者未来临床试验的设计做出了重大贡献。