A Phase II proof-of-concept trial to study kinase inhibition in relapsed/refracto

描述（由申请人提供）：复发或难治性急性白血病患者和既往未治疗的老年急性白血病患者，不适合标准诱导，常规化疗预后不佳。开发更有效、毒性更小的治疗方法将需要确定导致白血病发生的分子异常，并确定特异性阻断这些病变活动的药物。我们假设异常激活的酪氨酸激酶信号通路在急性白血病的发病机制中起着关键作用，我们的初步数据表明，导致异常激酶激活的分子异常在相当数量的患者中是独特的。因此，急性白血病的有效治疗方法需要根据患者的个体情况来确定。为了满足这一需求，我们开发了一种小分子激酶抑制剂检测方法，可以识别原发性急性白血病样本中酪氨酸激酶信号通路的治疗靶点，并在临床相关的时间框架内提供个性化的治疗选择。该项目的主要目标是验证我们的临床前激酶抑制剂筛选在预测有效的个体化治疗中的作用，并探索药物敏感性的分子异常。因此，第一个目标是在一项纳入24例患者的单臂II期试点试验中，评估体外抑制剂敏感性试验的有效性，以预测急性白血病患者的临床有效个体化/靶向治疗。纳入标准将仅限于复发/难治性急性白血病患者以及在抑制剂试验中对一种或多种药物体外敏感性不适合常规化疗的老年患者。主要目的是确定临床活性，定义为在治疗开始后28天骨髓母细胞计数下降> 25%。第二个目标是快速确定个体患者白血病样本中异常激活的酪氨酸激酶途径的遗传病因。小分子激酶抑制剂检测将用于识别对个体样本中恶性细胞活力至关重要的活化激酶途径，并将使用高通量序列和表达谱来探索活化机制。通过利用我们的临床前分析来选择个体化的白血病治疗方法，我们希望创建一个平台，在这个平台上我们可以快速测试个体化激酶治疗的有效性，并应用这些信息来加强白血病患者新药和新药物组合的开发。我们也希望建立一种模式，为所有癌症患者提供量身定制的治疗方法。

DESCRIPTION (provided by applicant): Patients with relapsed or refractory acute leukemias and elderly patients with previously untreated acute leukemia who are unfit for standard induction have a dismal prognosis with conventional chemotherapy. The development of more effective and less toxic therapies will require the identification of the molecular abnormalities contributing to leukemogenesis and the identification of drugs that specifically block the activity of these lesions. We hypothesize that aberrantly activated tyrosine kinase signaling pathways play a critical role in the pathogenesis of acute leukemia, and our preliminary data suggest that the molecular abnormalities causing aberrant kinase activation are unique in a significant number of patients. Thus, effective therapies for acute leukemia will need to be determined on an individual patient basis. To address this need, we have developed a small-molecule kinase inhibitor assay that can identify therapeutic targets in tyrosine kinase signaling pathways in primary acute leukemia samples and provide individualized therapeutic options in a clinically relevant time frame. The primary goals of the proposed project will be to validate the role of our pre- clinical kinase inhibitor screen in predicting effective individualized therapies and to explore the molecular abnormalities underlying drug sensitivity. Accordingly, the first aim is to evaluate the efficacy of an in-vitro inhibitor sensitivity assay for prediction of clinically effective individualized/targeted therapies for acute leukemia patients in a single-arm phase II pilot trial enrolling 24 patients. Inclusion criteria will be limited to relapsed/refractory acute leukemia patients as well as elderly patients not eligible for conventional chemotherapy with in vitro sensitivity to one or more drugs in the inhibitor assay. The primary objective is to determine the clinical activity, defined as > 25% decrease in bone marrow blast counts at 28 days after initiation of therapy. The second aim is to rapidly identify the genetic etiology underlying aberrantly activated tyrosine kinase pathways in leukemia samples from individual patients. The small molecule kinase inhibitor assay will be used to identify activated kinase pathways that are crucial for malignant cell viability in individual samples, and the mechanism of activation will be explored using high-throughput sequence and expression profiling. By utilizing our pre-clinical assay to select individualized leukemia therapies, we hope to create a platform upon which we can rapidly test the effectiveness of individualized kinase therapy and apply this information to enhance development of new drugs and new drug combinations in leukemia patients. It is also our hope to establish a paradigm in which patient-tailored therapies can be offered to all patients with cancer. PUBLIC HEALTH RELEVANCE: The development of more effective and less toxic therapies for acute leukemia will require identification of the causative molecular abnormalities and identification of drugs that specifically block the activity of these abnormalities. We hypothesize that these abnormalities are unique in many leukemia patients and that these patients will require individualized therapies to target their unique lesions. Our proposed clinical trial that integrates molecular target identification with individualized treatment will help to establish a paradigm where cancers are defined by molecular targets and patients are matched with specific targeted therapies to yield improved therapeutic outcomes.