Incorporating FLT3 Inhibitors into Acute Myeloid Leukemia(AML)Treatment Regimens

将 FLT3 抑制剂纳入急性髓系白血病 (AML) 治疗方案

• 批准号: 8499749
• 负责人: MARK J LEVIS
• 金额: $ 29.76万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499749
• 关键词: Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Address; Age; Allogenic; Azacitidine; Blast Cell; Bone Marrow; Caring; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Clinical Trials Design; Consolidation Therapy; Correlative Study; DNA Methyltransferase Inhibitor; Data; Development; Diagnosis; Disease remission; Dose; Drug Kinetics; Drug usage; Elderly; FLT3 gene; FLT3 inhibition; FLT3 inhibitor; FLT3 ligand; Goals; Hematopoietic; In Vitro; Instruction; Laboratories; Maintenance Therapy; Marrow; Modeling; Molecular Cytogenetics; Mutation; Newly Diagnosed; Outcome; Patients; Phase; Phase II Clinical Trials; Phosphotransferases; Plasma; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Recovery; Regimen; Relapse; Relative (related person); Research Personnel; Risk; Sampling; Schedule; Sequential Treatment; Series; Staging; Transplantation; Treatment Protocols; Tretinoin; Tyrosine Kinase Inhibitor; University of Texas M D Anderson Cancer Center; Work; base; chemotherapy; cytotoxicity; improved; in vivo; leukemia; older patient; outcome forecast; programs; resistance mutation; small molecule; therapeutic target

Activating mutations of the rejceptor tyrosine kinase FLT3 are one of the most common mutations found in acute myeloid leukemia (AML) and are clearly associated with a poor prognosis. FLT3 therefore represents a logical therapeutic target. During the first five years of this project, we used in vitro studies to identify and characterize a series of small molecule FLT3 inhibitors for use as monotherapy and in combination with chemotherapy, and carried out early phase single agent trials of the most promising compounds. Over the past five years we carried out correlative studies using samples collected from a large number of trials of FLT3 inhibitors used as single agents and in combination with chemotherapy. We have determined that potent FLT3 inhibition in vivo results in significant clinical benefit, inducing clearance of circulating leukemia cells and terminal differentiation of marrow blasts. We hypothesize that survival for patients with FLT3/ITD AML can be significantly improved with the use of FLT3 inhibitors. For younger patients, we predict that FLT3 inhibition combined with induction chemotherapy will increase the remission rate, and that combination with consolidation therapy, as well as maintenance therapy, will minimize the relapse risk. For older patients, the combination of FLT3 inhibition with hypomethylating agents offers the potential for synergistic anti-leukemic effect as well as better tolerability. However, the data from our correlative studies indicates that a number of clinical variables influence the efficacy of FLT3 inhibition, depending on the context in which the TKIs are used. Monotherapy with FLT3 TKIs leads to the development of resistance mutations, while the combination of FLT3 TKIs with chemotherapy is complicated by the effects of c-KlT inhibition, the competing effects of FLT3 ligand, and less predictable pharmacokinetics. In order to address these issues, we propose to optimize the use of two FLT3 TKIs, AC220 and crenolanib, with a combination of in vitro studies and clinical trials with correlative studies. Our approach is organized into 3 specific aims. First, we will establish the optimal dose and schedule for AC220 both as monotherapy and in combination with standard chemotherapy using correlative studies from clinical trial samples. Second, we will investigate combinations of FLT3 inhibitors with DNA methyltransferase inhibitors (DNMTi), both in vitro and in the context of a proposed clinical trial. Third, we will use in vitro cell line models and primary AML samples cultured with bone marrow stroma, as well as correlative data from a proposed phase 2 clinical trial, to establish the efficacy of crenolanib as a FLT3 inhibitor with activity against FLT3 kinase domain mutations. RELEVANCE (See instructions): The translational impact of the proposed work will be to synthesize the laboratory correlative data obtained from several previous monotherapy and combination FLT3 inhibitor trials into a series of focused trials designed to improve outcomes for specific subsets of patients with FLT3/ITD AML. The clinical impact of this proposed work will be to provide exact treatment regimens, derived from an integration of FLT3 inhibitors into standard-of-care practice, that will improve the overall survival for these patients.

受体酪氨酸激酶FLT 3的激活突变是在人乳腺癌中发现的最常见的突变之一。 急性髓性白血病（AML），并且与不良预后明显相关。因此，FLT 3代表 合理的治疗目标在这个项目的前五年，我们使用体外研究来识别和 表征一系列小分子FLT 3抑制剂，用作单一疗法和与 化疗，并进行了早期阶段的单一药物试验的最有前途的化合物。来 在过去的五年里，我们使用从大量试验中收集的样本进行了相关研究， FLT 3抑制剂用作单药和与化疗联合使用。我们已经确定 有效的体内FLT 3抑制导致显著的临床获益，诱导循环白血病的清除 细胞和骨髓母细胞的终末分化。我们假设FLT 3/ITD患者的生存率 使用FLT 3抑制剂可以显著改善AML。对于年轻患者，我们预测， FLT 3抑制联合诱导化疗将增加缓解率， 巩固治疗和维持治疗将使复发风险最小化。老年 在患者中，FLT 3抑制剂与低甲基化剂的组合提供了协同治疗的潜力。 抗白血病作用以及更好的耐受性。然而，我们相关研究的数据表明， 许多临床变量影响FLT 3抑制的疗效，这取决于 使用TKI。FLT 3 TKI单药治疗导致耐药突变的发生，而 FLT 3 TKI与化疗的组合由于c-KlT抑制作用、竞争性KKI抑制作用和FLT 3 TKI与化疗的联合作用而变得复杂。 FLT 3配体的作用，以及较难预测的药代动力学。为了解决这些问题，我们建议 优化两种FLT 3 TKI（AC 220和crenolanib）的使用，结合体外研究和 临床试验和相关研究。我们的方法分为三个具体目标。首先，我们将建立 AC 220作为单药治疗和与标准药物联合治疗最佳剂量和时间表 使用来自临床试验样本的相关研究进行化疗。其次，我们将研究组合 FLT 3抑制剂与DNA甲基转移酶抑制剂（DNMTi），无论是在体外还是在一个 拟进行临床试验。第三，我们将使用体外细胞系模型和原代AML样品， 骨髓基质，以及拟议的2期临床试验的相关数据，以确定 crenolanib作为具有抗FLT 3激酶结构域突变活性的FLT 3抑制剂的功效。 相关性（参见说明）： 拟议工作的转化影响将是综合实验室获得的相关数据 从之前的几项FLT 3抑制剂单药治疗和联合治疗试验， 旨在改善FLT 3/ITD AML患者特定亚群的结局。的临床影响 这项拟议的工作将提供确切的治疗方案，从FLT 3抑制剂的整合中衍生出来， 纳入标准治疗实践，这将提高这些患者的总体生存率。