A Correlative Biomarker Analysis for A Phase I Trial of the Combination of Lenalidomide and Blinatumomab in Patients with Relapsed or Refractory NHL

来那度胺和博纳吐单抗联合治疗复发或难治性 NHL 患者的 I 期试验的相关生物标志物分析

• 批准号: 10192396
• 负责人: PRIMO N. LARA
• 金额: $ 20.74万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-28 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192396
• 关键词: Adverse event; Age; Ancillary Study; Antibodies; Antineoplastic Agents; Archives; Autologous Transplantation; B-Cell Lymphomas; B-Lymphocytes; Biological Assay; Biological Markers; Bite; Blood; CAR T cell therapy; CD19 Antigens; CD19 gene; CD3 Antigens; CLIA certified; Cities; Clinical; Clinical Trials; Companions; Complex; Comprehensive Cancer Center; Correlative Study; Cryopreservation; Cytotoxic Chemotherapy; Cytotoxic T-Lymphocytes; Data; Data Analyses; Data Set; Diagnosis; Diagnostic tests; Dose; Funding; Goals; Grant; Homologous Transplantation; Immune; Immune response; Immune system; Immunologic Monitoring; Indolent; Life; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Medical; Modeling; Morbidity - disease rate; Myelosuppression; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Pathway interactions; Patient Care; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Physicians; Production; Proteomics; Protocols documentation; Publishing; Refractory; Regimen; Relapse; Research; Research Design; Research Personnel; Resistance; Resource Sharing; Response Elements; Risk; Sampling; Serum; Specimen; Study models; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Time; Translations; Treatment Cost; United States National Institutes of Health; Work; biomarker discovery; clinical diagnostics; clinically relevant; comorbidity; computerized tools; cost; cytokine; cytotoxicity; disorder control; exhaust; exhaustion; experience; insight; investigator-initiated trial; large cell Diffuse non-Hodgkin' s lymphoma; lenalidomide; mortality; novel; patient response; phase 1 study; phase I trial; predictive marker; predictive modeling; prevent; ranpirnase; recruit; responders and non-responders; response; rituximab; tool; treatment response

Project Summary Of the 70,000 new cases of non-Hodgkin’s lymphoma (NHL) diagnosed in 2014, the most common subtype is diffuse large B-cell lymphoma (DLBCL), of these approximately 40% will relapse after standard induction with CHOP-R. Of these patients, the only opportunity for long-term disease control is with CAR T cell therapy, autologous or allogeneic transplant. Many patients are not candidates due to age or co-morbidities, cannot achieve required disease control, or do not have a suitable donor. Additionally, many relapsed indolent and mantle cell lymphoma (MCL) patients eventually exhaust all treatment options are not candidates for aggressive cytotoxic chemotherapy due to co-morbidities or the potential for substantial myelosuppression. Patients with relapsed/refractory (R/R) NHL clearly represent an unmet medical need. Both lenalidomide and blinatumomab have proven, but limited, efficacy in R/R NHL. Lenalidomide has been shown to modulate different components of the immune system by altering cytokine production, regulating T cell co-stimulation and augmenting the NK cell cytotoxicity. Blinatumomab specifically targets the CD19 antigen present on B cells. The inability of blinatumomab to mediate responses or durable responses is likely due to the inability to recruit competent cytotoxic T cells or eventual T cell exhaustion. The current approach will mediate redirection of lenalidomide-mediated, activated, competent, cytotoxic T cells to the malignant CD19+ B cells. UC Davis protocol # PHI-79 (NCI protocol # 9924, Clinicaltrials.gov identifier NCT02568553) examines the relationship between blinatumomab-, or lenalidomide + blinatumomab-mediated T cell activation and response. The phase I portion of the study has been completed and demonstrated the combination was well tolerated with an encouraging ORR of 90% (Poh et al ASH 2019). We are seeking supplemental funds to conduct the ancillary studies associated with this trial, studies which are directly in line with the goals of the City of Hope and UC Davis Comprehensive Cancer Center UM1 grant. Using biospecimens collected from PHI-79, we aim to identify biomarkers for therapeutic response. Our team has extensive experience integrating omic data sets to develop multi-analyte classifiers (biomarkers) for clinical diagnostic tests and have developed computational tools to streamline these efforts. Our specific hypothesis is that composite biomarkers comprised of easily quantifiable immune response elements will be able to predict a patient’s ultimate responsiveness to therapy.

项目摘要 在2014年确诊的7万例新的非霍奇金淋巴瘤（NHL）病例中， 亚型是弥漫性大B细胞淋巴瘤（DLBCL），其中约40%在标准治疗后会复发。 用CHOP-R诱导。在这些患者中，长期疾病控制的唯一机会是使用CAR T细胞。 治疗、自体或异体移植。许多患者由于年龄或合并症而不是候选人， 不能达到所需的疾病控制，或没有合适的供体。此外，许多复发性惰性 和套细胞淋巴瘤（MCL）患者最终用尽所有的治疗方案， 由于合并症或潜在的严重骨髓抑制而进行的侵袭性细胞毒性化疗。 复发性/难治性（R/R）NHL患者明显代表未满足的医疗需求。 来那度胺和blinatumomab在R/R NHL中的疗效均已得到证实，但有限。来那度胺具有 已经显示通过改变细胞因子的产生来调节免疫系统的不同组分， 调节T细胞共刺激和增强NK细胞的细胞毒性。Blinatumomab专门针对 存在于B细胞上的CD 19抗原。Blinatumomab不能介导缓解或持久缓解， 这可能是由于不能募集有能力的细胞毒性T细胞或最终的T细胞耗竭。当前 这种方法将介导来那度胺介导的、活化的、感受态的细胞毒性T细胞重定向至 恶性CD 19 + B细胞。UC Davis方案# PHI-79（NCI方案# 9924，Clinicaltrials.gov标识符 NCT 02568553）检查了Blinatumomab或来那度胺+Blinatumomab介导的 T细胞活化和反应。研究的第一阶段已经完成，并证明了 联合治疗耐受性良好，ORR为90%（Poh et al ASH 2019）。 我们正在寻求补充资金，以进行与本试验相关的辅助研究， 这与希望之城和加州大学戴维斯分校综合癌症中心UM 1的目标直接一致 格兰特.使用从PHI-79收集的生物标本，我们的目标是确定治疗反应的生物标志物。我们 团队拥有整合组学数据集以开发多分析物分类器（生物标志物）的丰富经验 临床诊断测试，并开发了计算工具，以简化这些工作。我们的具体 假设由容易定量的免疫应答元件组成的复合生物标志物将 能够预测病人对治疗的最终反应。