Molecular Evaluation of Targeted Therapies in Lymphoid Malignancies

淋巴恶性肿瘤靶向治疗的分子评价

基本信息

批准号：
8990463
负责人：
JOHN C. BYRD
金额：
$ 53.66万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8990463
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 Future Genes Genomics Health Interphase Laboratory Finding Lymphocyte Malignant lymphoid neoplasm Methylation Molecular Mutation NOTCH1 gene Non-Hodgkin&apos s Lymphoma Older Population Oral Outcome PLCgamma2 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 Untranslated RNA Ursidae Family Validation Work X-Linked Agammaglobulinemia ZAP-70 Gene adult leukemia base design fludarabine high risk human old age (65+)inhibitor/antagonist kinase inhibitor leukemia lymph nodes novel novel marker novel strategies novel therapeutics older patient overexpression patient population phase 1 study phase 3 study predicting response response rituximab standard care targeted treatment treatment strategy trial comparing

项目摘要

DESCRIPTION (provided by applicant): 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 Bruon'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 alne 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 PLCγ2, 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

描述（由申请人提供）：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。诊断为 CLL 的患者中有三分之二年龄在 65 岁或以上，而基于氟达拉滨的化学免疫疗法是标准的初始治疗。与年轻患者相比，老年患者的最佳治疗方案尚不明确，一项随机 III 期研究以及癌症和白血病 B 组试验的回顾性分析均显示氟达拉滨没有任何益处。尽管最近的数据表明烷化剂苯丁酸氮芥或贝那莫司汀与利妥昔单抗一起给药在老年人群中是可行的，但对于代表最大的 CLL 患者群体来说，结果仍然不理想。此外，新的生物标志物和微小残留病状态预测年轻患者的反应持续时间和生存的相关性和影响尚未在老年人中探索新的疗法和生物标志物的验证。因此，在年轻患者中发现的 Ibrutinib 是一种口服生物可利用的 Bruon 酪氨酸激酶 (BTK) 抑制剂，BTK 是一种参与 B 细胞发育和通过 B 细胞受体 (BCR) 发出信号的关键激酶。由我们团队共同领导的 Ib/II 期试验，与该药物相关的临床活性非常出色，复发难治性 CLL 患者的 26 个月 PFS 为 76%，并且对于先前未治疗的疾病的老年患者，该药物的耐受性良好，并且在长期连续给药的基础上，在本申请中，我们提出了一项 III 期临床试验，研究依鲁替尼 alne 或依鲁替尼加利妥昔单抗与标准疗法的比较。苯达莫司汀联合利妥昔单抗（BR）在先前未经治疗的慢性淋巴细胞白血病（CLL）老年患者中的应用对已建立的和新的预后标志物进行了相关分析，试图识别与反应和结果相关的生物标志物。该提案的具体目标是： 1：在≥ 65 岁的有症状 CLL 患者中进行 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) BR，以确定具有最高反应、PFS 和 OS 2 的治疗。：在这项 III 期研究中进行药效 (PD) 研究，以确定传统基因组特征、选择基线 BCR 激活标记物以及 1 个月内 miR 标记物表达的变化是否可以预测最佳反应、临床时间3：评估依鲁替尼治疗后的纵向样本，以评估持续性淋巴细胞的特征，并确定编码或非编码 RNA 的变化、BTK 或 PLCγ2 突变的获得或微小残留病的存在。 9 或 24 个月将预测基于依鲁替尼的治疗后的晚期复发和 PFS，预计该试验得出的临床和实验室结果将彻底改变老年 CLL 的治疗方式，并对老年 CLL 的治疗做出重大贡献。为这些患者设计未来的临床试验