Molecular Evaluation of Targeted Therapies in Lymphoid Malignancies

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是成人白血病中最常见的形式，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，虽然基于氟达拉滨的化学免疫治疗是年轻患者的标准初始治疗，但老年患者的最佳治疗尚不清楚。一项随机III期研究和一项癌症和白血病B组试验的回顾性分析均显示，在老年人群中，氟达拉滨与苯丁酸氮芥相比无获益，而利妥昔单抗则与年龄无关。虽然最近的数据表明，烷化剂chloramubucil或benadmustine与利妥昔单抗一起给药在这一人群中是可行的，但对于代表最大CLL患者人群的结果仍然是次优的。此外，尚未在老年患者中探索新生物标志物和微小残留疾病状态预测年轻患者缓解持续时间和生存期的相关性和影响。因此，在年轻患者中发现的新疗法和生物标志物的验证是该人群研究的高度优先事项。伊布替尼是一种口服生物可利用的布鲁恩酪氨酸激酶（BTK）抑制剂，BTK是一种参与B细胞发育和通过B细胞受体（BCR）信号传导的关键激酶。在我们小组共同领导的一项Ib/II期试验中，与该药物相关的临床活性非常显著，复发性和难治性CLL患者的26个月PFS为76%，既往未经治疗的老年患者为96%。这种药物在延长的连续给药下也具有良好的耐受性。在我们以前的工作的基础上，在本申请中，我们提出了一项III期临床试验，研究在患有先前未经治疗的CLL的老年患者中，与苯达莫司汀加利妥昔单抗（BR）的标准治疗相比，单独的伊曲替尼或伊曲替尼加利妥昔单抗。建立和新的预后标志物的相关分析，提出了在试图确定与响应和结果相关的生物标志物。该提案的具体目的是：1：在≥ 65岁的症状性CLL患者中进行III期临床试验，比较a）伊鲁替尼、B）伊鲁替尼+利妥昔单抗和c）BR，以确定具有最高缓解、PFS和OS的治疗。2：在本III期研究中进行药效学（PD）研究，以确定传统基因组特征、选择基线BCR活化标志物，1个月内miR标志物表达的变化可预测最佳缓解、临床缓解时间、PFS和OS。3：评价伊布替尼治疗后的纵向样本，以评价持续淋巴细胞的特征，并确定编码或非编码RNA的变化、BTK或PLCγ2突变的获得，或在9个月或24个月时存在微小残留疾病将预测基于伊匹替尼的治疗后的晚期复发和PFS。预计这项试验的临床和实验室结果将改变老年CLL的治疗方式，并对这些患者未来临床试验的设计做出重大贡献。

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