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）是最常见的成人白血病，目前无法治愈。三分之二被诊断为CLL的患者年龄在65岁或以上，虽然以氟达拉滨为基础的化学免疫疗法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期研究和对癌症和白血病B组试验的回顾性分析显示，氟达拉滨在老年人群中没有比氯霉素更好的疗效，而利妥昔单抗无论年龄如何都有疗效。虽然最近的数据表明，烷基化剂氯脲或苯那莫司定联合利妥昔单抗在这一人群中是可行的，但对于最大的CLL患者群体来说，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时间和生存的相关性和影响尚未在老年患者中探索。因此，在年轻患者中发现的新疗法和生物标志物的验证是这一人群研究的重中之重。Ibrutinib是布鲁氏酪氨酸激酶（bron’s Tyrosine Kinase， BTK）的口服生物有效抑制剂，布鲁氏酪氨酸激酶是一种通过B细胞受体（BCR）参与B细胞发育和信号传导的关键激酶。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，对于复发和难治性CLL患者，26个月的PFS为76%，对于以前未治疗疾病的老年患者，PFS为96%。该药在延长连续给药的情况下也具有良好的耐受性。基于我们之前的工作，在本申请中，我们提出了一项III期临床试验，研究依鲁替尼单宁或依鲁替尼加利妥昔单抗与苯达莫司汀加利妥昔单抗（BR）的标准治疗对先前未经治疗的老年CLL患者的影响。提出了对已建立的和新的预后标志物的相关分析，试图确定与反应和结果相关的生物标志物。该提案的具体目的是：1：进行一项III期临床试验，比较a)依鲁替尼、b)依鲁替尼联合利妥昔单抗和c) BR在≥65岁的症状性CLL患者中的疗效、PFS和OS最高的治疗方法。2：在这项III期研究中进行药效学（PD）研究，以确定传统的基因组特征、选择基线BCR激活标志物和miR标志物在1个月内的表达变化是否可以预测最佳反应、临床反应时间、PFS和OS。3：对依鲁替尼治疗后的纵向样本进行评估，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9或24个月时微小残留疾病的存在是否可预测依鲁替尼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改变老年CLL的治疗方式，并为这些患者的未来临床试验设计做出重大贡献

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