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慢性阻塞性肺疾病的重要治疗手段