Molecular Evaluation of Targeted Therapies in Lymphoid Malignancies

描述(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一种，目前是无法治愈的。三分之二被诊断为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疗法是年轻患者的标准初始治疗，但对老年患者的最佳治疗尚不清楚。一项随机的III期研究和一项对癌症和白血病B组试验的回顾分析都表明，在老年人口中，氟达拉滨与氯氨丁苯相比没有好处，而利妥昔单抗则无论年龄大小都有好处。虽然最近的数据表明烷化剂氯氨丁苯或苯那丁胺与利妥昔单抗联合应用在这一人群中是可行的，但对于CLL患者中最大的人群来说，结果仍然不是最理想的。此外，新的生物标志物和最小残留疾病状态预测年轻患者的反应持续时间和生存时间的相关性和影响尚未在老年人中进行探索。因此，在年轻患者中确定的新疗法和生物标记物的验证是这一人群研究的高度优先事项。伊布鲁替尼是一种口服生物可用的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)传递信号的关键激酶。在我们团队共同领导的一项Ib/II期试验中，与该药相关的临床活动一直很不寻常，复发和难治性CLL患者26个月的PFS为76%，而患有先前未治疗疾病的老年患者的PFS为96%。该制剂耐受性良好，可延长连续给药时间。在我们以前工作的基础上，在本申请中，我们提议进行一项第三阶段临床试验，研究ibrutinib Alne或ibrutinib加利妥昔单抗与标准疗法苯达莫司汀加利妥昔单抗(BR)治疗老年未经治疗的CLL的比较。对已建立的和新的预后标记物的相关分析被提出，试图确定与反应和结果相关的生物标记物。这项建议的具体目标是：1：进行一项III期临床试验，比较a)ibrutinib、b)ibrutinib加利妥昔单抗和c)BR在有症状的慢性淋巴细胞性白血病患者≥65年的疗效，以确定最有效的治疗方案、有效率和有效率。2：在这项第三阶段研究中进行药效学(PD)研究，以确定传统基因组特征、选择基线BCR激活标记和miR标记表达在1个月内的变化是否可以预测最佳反应、临床反应时间、PFS和OS。3：评估伊布鲁替尼治疗后的纵向样本，以评估持久性淋巴细胞的特征，并确定编码或非编码RNA的变化、btk或plcγ2突变的获得，或者9个月或24个月时存在微小残留疾病是否将预测基于ibrutinib的治疗后的晚期复发和pFS。预计从这项试验中得出的临床和实验室结果将改变老年慢性淋巴细胞性白血病的治疗方式，并对这些患者的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