ETCTN Biorepository Specimens to the University of Ottawa

NCI方案(S)：10075“AMG232联合地西他滨治疗急性髓系白血病的1B期研究”和10076“AMG232联合卡非佐米、来那度胺和地塞米松治疗复发和/或难治性骨髓瘤的第1期剂量递增和探索性剂量扩展研究” (10075)基因测序研究表明，平均而言，从头开始的急性髓细胞白血病病例包含10种以上重要的基因突变，其中许多可广泛归类为九类被认为影响白血病发生的基因：DNA甲基化、肿瘤抑制、转录因子融合、核磷蛋白、信号转导、染色质修饰、髓系转录因子、粘附素复合体和剪接体复合体。 该合同将提供一个全面的突变小组(ASXL1、TET2、PHF6、DNMT3A、IDH1/2、FLT3、NPM1、KIT、miR-29b、Flt3-ITD、CEBPA和MLL-PTD)，在所有患者接受试验登记资格筛选时，对他们收集的AML原始细胞进行检测。 (10076)mdm2抑制后，外周血中可检测到Mic-1，这是一种由激活的P53强烈诱导的分泌性蛋白。因此，MIC-1可作为AMG232的药效学生物标志物。MIC-1水平可以通过灵敏的ELISA试验来测定，如果与剂量或其他药效作用相关，则可以作为P53激活的血清生物标志物。我们预计，大多数接受AMG232治疗的受试者将有MIC-1的诱导，MIC-1的诱导水平将与AMG232的剂量和与KRD的组合相关。一种商用的ELISA试剂盒将被用来测量血清MIC-1水平。这是一种综合测试，旨在评估临床试验受试者的药物反应，并将用于确定血清MIC-1浓度，并最终确定药物反应。治疗后的MIC-1水平将恢复到该受试者的基线水平。在临床试验数据的初步分析中，血清MIC-1水平的变化与AMG232暴露(最大暴露(Cmax)和总暴露(AUC))之间存在暴露-反应相关性。

NCI Protocol(s): 10075 “A Phase 1B Study of AMG-232 in Combination with Decitabine in Acute Myeloid Leukemia” and 10076 “A Phase 1 Dose-Escalation and Exploratory Dose Expansion Study of AMG 232 in Combination with Carfilzomib, Lenalidomide, and Dexamethasone in Relapsed and/or Refractory Myeloma” (10075) Gene sequencing studies have shown that, on average, de novo AML cases contain more than 10 significant gene mutations, many of which can be broadly grouped into nine categories of genes thought to effect leukemogenesis: DNA-methylation, tumor suppression, transcription-factor fusions, nucleophosmin, signaling, chromatin-modification, myeloid transcription factor, the cohesin complex, and the spliceosome complex. This contract will provide for a comprehensive mutation panel (ASXL1, TET2, PHF6, DNMT3A, IDH1/2, FLT3, NPM1, KIT, miR-29b, FLT3-ITD, CEBPA, and MLL-PTD) to be performed on AML blasts collected from all patients when they undergo screening for enrollment eligibility in the trial. (10076) MIC-1, a secreted protein that is strongly induced by activated p53, can be detected in the peripheral blood following MDM2 inhibition. Therefore, MIC-1 could have utility as a pharmacodynamic biomarker for AMG 232. MIC-1 level can be determined by a sensitive ELISA test, and if correlated with dose or other pharmacodynamic effects, can serve as a serum biomarker for p53 activation. We anticipate that most subjects treated with AMG 232 will have an induction in MIC-1 and that the level of MIC-1 induction will be correlated with the dose of AMG 232 and the combination with KRd. A commercially available ELISA kit will be utilized to measure serum MIC-1 levels. This is for an integrated assay aimed at assessing drug response in subjects on the clinical trial and will be utilized to determine serum MIC-1 concentrations and ultimately the drug response. The post-treatment MIC-1 level will be normalized to the baseline level for that subject. In preliminary analyses of clinical trial data, there was an exposure-response correlation observed between changes in serum MIC-1 levels and AMG 232 exposure (both maximal (Cmax) and total exposure (AUC).