Phase Ib/II study of safety and efficacy of EZH2 inhibitor, tazemetostat, and PD-1 blockade for treatment of advanced non-small cell lung cancer

EZH2 抑制剂、他泽美司他和 PD-1 阻断治疗晚期非小细胞肺癌的安全性和有效性的 Ib/II 期研究

• 批准号: 10481965
• 负责人: Daniel SANGHOON Shin
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481965
• 关键词: Advanced Malignant Neoplasm; Animal Model; Animals; Biological Markers; Biopsy; Biopsy Specimen; Blood; CD8-Positive T-Lymphocytes; Cancer Biology; Cells; Chromatin; Clinic; Clinical; Clinical Markers; Clinical Research; Clinical Trials; Combined Modality Therapy; Complex; Correlative Study; Cytotoxic Chemotherapy; Data; Diagnosis; Dose; Enhancers; Enrollment; Epithelioid Sarcomas; FDA approved; Follicular Lymphoma; Futility; Genomics; Health; Homologous Gene; Immune; Immunofluorescence Immunologic; Immunohistochemistry; Immunologic Monitoring; Immunophenotyping; Immunotherapy; Impairment; Intravenous; Life; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Military Personnel; Modality; Morbidity - disease rate; Mutation; Non-Small-Cell Lung Carcinoma; Oral; Outcome; PD-1 blockade; PD-1 inhibitors; Patient Care; Patient Selection; Patients; Phase; Play; Polycomb; Prognosis; Prognostic Factor; Progression-Free Survivals; Recommendation; Refractory; Relapse; Research Design; Resistance; Role; Safety; Squamous cell carcinoma; Survival Rate; Testing; Therapeutic; Time; Treatment Efficacy; Tumor Biology; Tumor Immunity; Urothelium; Veterans; anti-PD1 antibodies; antitumor effect; arm; biomarker identification; cancer cell; cell free DNA; chemotherapy; combinatorial; comorbidity; design; disorder control; effective therapy; efficacy evaluation; efficacy testing; immune checkpoint blockade; improved; improved outcome; inhibitor; molecular marker; mouse model; nano-string; neoantigens; objective response rate; open label; overexpression; participant enrollment; patient subsets; pembrolizumab; pre-clinical; primary endpoint; programmed cell death ligand 1; response; response biomarker; safety assessment; safety study; secondary endpoint; side effect; standard of care; targeted treatment; therapy outcome; therapy resistant; transcriptomics; tumor

Background: Checkpoint blockade immunotherapy has become an essential therapeutic armamentarium for treating patients with advanced lung cancer. However, it is an unmet clinical need to improve the therapeutic outcome, given the fact that only a subset of patients are benefitting from immunotherapy. As we understand more about the mechanisms of response and resistance, numerous clinical trials are now underway to test combination therapy to improve the responses. EZH2, an enzymatic component of Polycomb Repressive Complex (PRC) 2 emerged as a viable target for patients with lung cancer based on the studies showing poor prognosis with its overexpression and improved tumor control in the mouse models in combination therapy, particularly with checkpoint blockade immunotherapy. In addition, a first oral EZH2 inhibitor, tazemetostat, was approved by FDA in early 2020 for patients with advanced epithelioid sarcoma. Therefore, we propose to test the combination treatment with tazemetostat and pembrolizumab for Veteran patients with advanced non-small cell lung cancer (NSCLC). Hypothesis: EZH2 inhibitor, tazemetostat, is able to re-sensitize cancer cells responding to checkpoint blockade immunotherapy. Objectives: Primary objectives: Safety and efficacy of the tazemtostat and pembrolizumab combination treatment for patients with advanced NSCLC who progressed from the front or 2nd line of therapy measured by Objective Response Rate assessed by RECIST v1.1. Secondary objectives: Disease control rate, progression free survival, one-year survival rate and duration of response. Specific aims: Aim 1. Perform an open label single arm phase Ib/II study of safety and efficacy of the EZH2 inhibitor, tazemetostat, and PD-1 blockade, pembrolizumab, for treatment of patients with advanced NSCLC. Aim 2. Perform exploratory analyses to identify correlative clinical or molecular markers (biomarkers) of response and resistance to this combination therapy. Study design: Aim 1. Utilize 3+3 standard dose escalation strategy to determine recommended phase II dose with 3 dose levels, 400, 600 and 800 mg twice daily of tazemetostat combined with flat dose, 200 mg of intravenous pembrolizumab. For phase II, we are aiming to enroll a total of 54 patients using Simon Optimum Two Stage design to test the efficacy. Aim 2. Biomarker and correlative studies. Primary biomarkers to be tested, H3K27me3 and PD-L1 using tumor biopsies. Tumor mutational burden, neoantigen and cell free DNA (ctDNA) dynamics will be tested using tumor biopsies and serial blood draw along with immune monitoring (immunophenotype via flow/CyTOF, NanoString and multiplex immunofluorescence). Relevant to Military health: Improving treatment of many types of advanced cancers is critically important to the health of Veterans. Many Veterans suffer from significant morbidity when they are diagnosed with cancer that limits their therapeutic options. Immunotherapy is generally well tolerated and has a significant potential for durable response, however, the benefit is limited to a subset of patients (and Veterans). Therefore, it is imperative to improve therapeutic efficacy of immunotherapy using rational combinatorial strategies. Emerging evidence indicates the important role of EZH2 in lung cancer biology and therapeutic resistance. Moreover, the first oral EZH2 inhibitor is available in clinics. Hence, the proposed trial has a great potential to develop effective treatment with manageable side effects for Veteran patients with advanced lung cancer who progressed from the first or 2nd line of therapy.

背景：检查点封锁免疫疗法已成为必不可少的治疗性手臂 治疗晚期肺癌患者。但是，这是改善治疗的未满足的临床需求 鉴于只有一部分患者从免疫疗法中受益的事实，结果。据我们了解 有关反应和抗性机制的更多信息，现在正在进行大量临床试验以进行测试 联合疗法改善反应。 EZH2，Polycomb抑制作用的酶促成分 基于研究表明较差的肺癌患者的复合物（PRC）2作为肺癌患者的可行靶 在组合疗法中的小鼠模型中的过表达和改善肿瘤控制的预后， 特别是检查点封锁免疫疗法。此外，第一个口服EZH2抑制剂TazeMetostat是 2020年初，FDA批准了上皮性肉瘤的患者。因此，我们建议测试 用tazemetostat和pembrolizumab的老退伍军人患者的联合治疗 细胞肺癌（NSCLC）。 假设：EZH2抑制剂TazeMetostat能够重新敏感癌细胞对检查点的响应 封锁免疫疗法。 目标：主要目标：Tazemtostat和Pembrolizumab组合的安全性和功效 从前或第二系的治疗患者的治疗 RECIST v1.1评估的客观响应率。次要目标：疾病控制率，进展 自由生存，一年生存率和响应持续时间。 具体目的：目标1。执行EZH2的安全性和功效的开放标签单臂IB/II研究 抑制剂，tazemetostat和PD-1阻滞，Pembrolizumab，用于治疗晚期NSCLC患者。 AIM 2。执行探索性分析以鉴定相关临床或分子标记物（生物标志物）（生物标志物） 对这种组合疗法的反应和抵抗力。 研究设计：目标1。利用3+3标准剂量升级策略来确定建议的II期剂量 每天两次两次tazemetostat与扁平剂量，200毫克，有3剂水平，400、600和800毫克 静脉注射pembrolizumab。对于第二阶段，我们的目标是使用Simon最佳选择总共54名患者 两个阶段设计以测试功效。 目标2。生物标志物和相关研究。要测试的主要生物标志物，使用肿瘤H3K27me3和PD-L1 活检。将使用肿瘤测试肿瘤突变负担，新抗原和无细胞DNA（CTDNA）动力学 活检和串行血液以及免疫监测（通过流量/细胞，纳米串的免疫表型 和多重免疫荧光）。 与军事健康相关：改善对许多类型的高级癌症的处理对于 退伍军人的健康。许多退伍军人被诊断出患有癌症时患有明显的发病率 这限制了他们的治疗选择。免疫疗法通常具有良好的耐受性，并且具有很大的潜力 但是，持久的反应，这种益处仅限于一部分患者（和退伍军人）。因此，是 必须使用合理组合策略提高免疫疗法的治疗功效。新兴 证据表明EZH2在肺癌生物学和治疗性抗性中的重要作用。而且， 诊所有第一口服EZH2抑制剂。因此，拟议的试验具有发展的巨大潜力 有效治疗具有可管理的副作用的晚期肺癌患者的副作用 从第一或第二线治疗发展。