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：检查点阻断免疫疗法已成为重要的治疗手段 治疗晚期肺癌患者。然而，改善治疗方法仍是一个未满足的临床需求。 考虑到只有一小部分患者从免疫治疗中受益这一事实。据我们了解 有关反应和耐药机制的更多信息，目前正在进行大量临床试验来测试 联合治疗以改善反应。 EZH2，Polycomb Repressive 的酶成分 复合物 (PRC) 2 成为肺癌患者的一个可行靶点，因为研究显示其效果不佳 在联合治疗的小鼠模型中，其过度表达和改善的肿瘤控制改善了预后， 特别是检查点阻断免疫疗法。此外，第一种口服 EZH2 抑制剂他泽美司他 (tazemetostat) 已上市 FDA 于 2020 年初批准用于治疗晚期上皮样肉瘤患者。因此，我们建议测试 他泽美司他和派姆单抗联合治疗晚期非小细胞肺癌退伍军人患者 细胞肺癌（NSCLC）。 假设：EZH2 抑制剂 tazemetostat 能够使癌细胞对检查点做出反应重新变得敏感 封锁免疫疗法。 目标：主要目标：他泽司他和派姆单抗组合的安全性和有效性 对从一线或二线治疗中进展的晚期 NSCLC 患者的治疗 客观缓解率由 RECIST v1.1 评估。次要目标：疾病控制率、进展 自由生存率、一年生存率和反应持续时间。 具体目标： 目标 1. 对 EZH2 的安全性和有效性进行开放标签单臂 Ib/II 期研究 抑制剂他泽美司他和 PD-1 阻断剂派姆单抗用于治疗晚期 NSCLC 患者。 目标 2. 进行探索性分析，以确定相关的临床或分子标志物（生物标志物） 对这种联合疗法的反应和抵抗。 研究设计：目标1.利用3+3标准剂量递增策略确定推荐的II期剂量 3 个剂量水平，400、600 和 800 mg 每日两次的他泽美司他与固定剂量 200 mg 的 静脉注射派姆单抗。对于 II 期临床试验，我们的目标是总共招募 54 名使用 Simon Optimum 的患者 两阶段设计来测试功效。 目标 2.生物标志物和相关研究。使用肿瘤测试主要生物标志物 H3K27me3 和 PD-L1 活检。将使用肿瘤来测试肿瘤突变负荷、新抗原和无细胞 DNA (ctDNA) 动态 活检和连续抽血以及免疫监测（通过流/CyTOF、NanoString 进行免疫表型 和多重免疫荧光）。 与军事健康相关：改善多种晚期癌症的治疗对于军事健康至关重要 退伍军人的健康。许多退伍军人在被诊断患有癌症时患有严重的疾病 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，并且具有巨大的潜力 然而，持久的反应，其益处仅限于一小部分患者（和退伍军人）。因此，它是 使用合理的组合策略来提高免疫疗法的疗效势在必行。新兴 有证据表明 EZH2 在肺癌生物学和治疗耐药性中发挥重要作用。此外， 第一个口服 EZH2 抑制剂已在临床上市。因此，拟议的试验具有巨大的发展潜力 为患有晚期肺癌的退伍军人患者提供有效治疗且副作用可控 从第一线或第二线治疗开始进展。