CLINICAL TRAILS IN MYELOID MALIGANANCIES WITH MOLECULARLY TARGETED THERAPIES

分子靶向治疗骨髓恶性肿瘤的临床试验

• 批准号: 8063511
• 负责人: Richard M Stone
• 金额: $ 28.71万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8063511
• 关键词: Age; Ancillary Study; Biological Products; Blast Cell; Bone Marrow Transplantation; Cell Line; Cell physiology; Clinical; Clinical Data; Clinical Trials; Collaborations; Critical Pathways; Cytogenetics; Dana-Farber Cancer Institute; Development; Diagnosis; FLT3 gene; FLT3 inhibitor; Frequencies; Functional disorder; Funding; Grant; Growth; Human; In Vitro; Laboratories; Laboratory Study; Lead; Leukemic Cell; Modeling; Mus; Mutation; Myelogenous; Neoplasms; Newly Diagnosed; Other Genetics; Outcome; PKC412; Pathway interactions; Patients; Pattern; Peripheral; Pharmacologic Substance; Phase III Clinical Trials; Protein Tyrosine Kinase; Relapse; Research Personnel; Resistance; Role; Signal Transduction; Subgroup; Syndrome; Testing; Transformed Cell Line; Work; adult leukemia; base; chemotherapeutic agent; chemotherapy; clinically relevant; design; effective therapy; experience; inhibitor/antagonist; killings; leukemia; mTOR Inhibitor; mutant; outcome forecast; phase 1 study; phase 3 study; pre-clinical; programs; research study

Activation mutations of FLT3 contribute to the pathophysiology of approximately 30% of AMI cases. Internal tandem duplication mutations are associated with an adverse prognosis especially in the subgroup with normal cytogenetics. Work from the prior funding period of this application showed that activating mutations of FLT3 confer factor-independent growth in leukemic cell lines and lead to a fatal myeloproliferative syndrome in a murine bone marrow transplant model. Pharmacological inhibitors of the FLT3 tyrosine kinase specifically kill such transformed cell lines and prolong the survival of mice with this model neoplasm. In partnership with pharmaceutical companies and in close collaboration with our laboratory-based colleagues, the adult leukemia program at the Dana-Farber Cancer Institute has taken the lead in developing FLT3 inhibitors for clinical use in AML. We established that PKC412 and MLN518 were tolerated as single agents in patients with AML and produced a reduction in peripheral leukemic blast count in most patients whose leukemia was documented to have a FLT3 mutation. However, the experience with all the FLT3 inhibitors to date suggests that their utility as single agents will be limited, due in part to pharmacological considerations but also due to the relevance of other genetic legions in AML. It will be necessary to combine FLT3 inhibitors with agents which either enhance target inhibition or interfere with critical pathways. We have led two studies in which a FLT3 inhibitor is combined with chemotherapy in patients with newly diagnosed AML. We propose to extend the studies with FLT3 inhibitors plus chemotherapy (specific Aim 1) by leading a definitive phase III study of standard chemotherapy +/- PKC412 and to perform ancillary studies to determine the potential mechanisms of FLT3 resistance. Ancillary studies associated with this U.S. Intergroup phase III trial will include (Specific Aim 1b) the impact of baseline FLT3 autophosphorylation and downstream signaling on outcome and (Specific Aim 1c) the frequency of changes in FLT3 mutational patterns at relapse compared with diagnosis. We will work closely with Dr. Griffin in Project 1 who will assess killing of human leukemic cells in vitro by combinations of FLT3 inhibitors and inhibitors of other pathways/cellular processes. We will then perform (Specific aim 2) clinical trials to test promising combinations in patients with mutant FLT3 AML. [The first such trial, based on preclinical experiments in Project 1, will be a phase I study of PKC412 and the mTOR inhibitor RAD001. Ancillary studies will determine if this combination of tyrosine kinase inhibition with downstream signaling inhibition is feasible and can inhibit the expected targets.] Based on pre-clinical development in this and the other projects in this grant we anticipate being able to devise new and potentially effective therapies for patients with this type of poor prognosis AML.

FLT3的激活突变有助于大约30％的AMI病例的病理生理学。内部的 串联重复突变与不良预后有关，尤其是在亚组中 正常的细胞遗传学。该应用程序的先前资金期间的工作表明激活突变 FLT3赋予因子非依赖性的白血病细胞系的生长，并导致致命的骨髓增生性 鼠骨髓移植模型中的综合征。 FLT3酪氨酸的药理抑制剂 激酶特异性地杀死了这种转化的细胞系，并使用该模型肿瘤延长小鼠的存活。 与制药公司合作，并与我们的基于实验室密切合作 同事，达纳 - 法伯癌症研究所的成人白血病计划领导着发展 用于AML临床用途的FLT3抑制剂。我们确定PKC412和MLN518被视为单个 大多数患者的AML患者的药物并导致外周白血病爆炸数量降低 其白血病被记录为FLT3突变。但是，所有FLT3的经验 迄今为止的抑制剂表明，它们作为单个药物的效用将受到限制，部分归因于药理 考虑因素，也是由于AML中其他遗传军团的相关性。有必要结合 具有增强靶标抑制或干扰关键途径的药物的FLT3抑制剂。我们有 LED两项研究，其中FLT3抑制剂与新诊断的患者的化学疗法结合 AML。我们建议通过领导FLT3抑制剂以及化学疗法（特定目标1）扩展研究 标准化疗+/- PKC412的确定性III期研究，并进行辅助研究 确定FLT3电阻的潜在机制。与该美国相关的辅助研究 组间III期试验将包括（特定目标1B）基线FLT3自磷酸化和 下游信号传导结果和（特定目标1C）FLT3突变变化的频率 与诊断相比，复发的模式。我们将在项目1中与格里芬博士紧密合作。 评估通过FLT3抑制剂和其他抑制剂的组合在体外杀死人类白血病细胞 途径/细胞过程。然后，我们将执行（特定目标2）临床试验以测试有希望的 突变FLT3 AML患者的组合。 [第一个此类试验，基于临床前实验 项目1将是对PKC412和MTOR抑制剂RAD001的I期研究。辅助研究将 确定这种酪氨酸激酶抑制与下游信号抑制的组合是否可行，并且 可以抑制预期的目标。 赠款我们预计能够为这种类型的患者设计新的和潜在的有效疗法 预后不良。