A Phase II Clinical Trial in Newly Diagnosed Glioblastoma Patients Treated with WP1066 and Radiation

新诊断的胶质母细胞瘤患者接受 WP1066 和放射治疗的 II 期临床试验

基本信息

批准号：
10658700
负责人：
Amy Beth Heimberger
金额：
$ 60.18万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-05 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658700
关键词：
Animal Model Animals Antigen Presentation Antigen-Presenting Cells Antitumor Response Blood - brain barrier anatomy Brain Brain Neoplasms Brain Stem Glioma CD11c Antigens CD3 Antigens Cell physiology Cells Cellular immunotherapy Childhood Clinical Clinical Trials Combined Modality Therapy Dendritic Cells Dendritic cell activation Dependence Dose Drug Kinetics Education Effectiveness Excision Flow Cytometry Glioblastoma Gliomagenesis Goals Heterogeneity High Pressure Liquid Chromatography Human Immune Immune response Immune system Immunocompromised Host Immunohistochemistry Immunologics Immunosuppression Immunotherapy Infiltration Inflammatory Response Lesion MGMT gene Magnetic Resonance Imaging Malignant Neoplasms Maps Memory Metastatic malignant neoplasm to brain Microglia Modeling Mus Myeloid Cells Natural Immunity Newly Diagnosed Operative Surgical Procedures Outcome Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Phase II Clinical Trials Phenotype Population Progression-Free Survivals Radiation Radiation therapy Recurrence Research Signal Induction Stat3 protein T cell infiltration T-Cell Activation T-Lymphocyte Testing Texture Tissues Universities Validation adaptive immunity cancer cell cohort first-in-human immune activation immune clearance immunogenicity improved nano-string neuro-oncology pharmacodynamic biomarker pharmacologic phase 3 study phase I trial phase II trial pre-clinical preclinical study radiological imaging response small molecule inhibitor standard of care tumor tumor microenvironment tumor-immune system interactions

项目摘要

SUMMARY The brain tumor microenvironment (TME) is dominated by myeloid cell infiltrates which are mostly brain resident microglia and infiltrating glioblastoma-associated myeloid cells (GAMs). Despite this fact, most clinical trials for glioblastoma have been directed to T cell-based immunotherapies, which have failed to impact outcome for most patients. Targeting glioblastoma based on re-education of GAMS to enable immunological clearance is the goal of this clinical trial. The signal transducer and activator of transcription 3 (STAT3) is a negative regulator of both innate and adaptive immunity and this pathway is markedly up regulated in the TME. We have previously developed and tested, in the context of Phase I clinical trials, a first-in-man blood-brain-barrier penetrant small molecule inhibitor of STAT3, designated WP1066. The Phase I trial results have shown that WP1066 is well tolerated and is inhibiting the STAT3 target in immune cells. As a monotherapy, WP1066 treatment has demonstrated the ability to stimulate robust anti-tumor response in multiple preclinical studies that is further enhanced with radiation therapy, which is standard of care for newly diagnosed glioblastoma and is known to increase tumor immunogenicity. Unbiased nanostring analysis of treated tumors revealed that activation of antigen presentation in the TME with the combination treatment. For the research proposed here we want to extend our preclinical findings to newly diagnosed glioblastoma patients. In this clinical trial, we will test the hypothesis that the administration of WP1066 with radiation will induce T cell-dendritic cell cluster interactions in the glioblastoma microenvironment, and this induction, in turn, will increase progression free survival (PFS) for glioblastoma patients. In specific Aim 1, we conduct a Phase II trial with an expansion cohort for the combination of WP1066 and radiation in newly diagnosed MGMT unmethylated glioblastoma patients. In cohort 1, newly diagnosed MGMT unmethylated, IDH1 wild-type glioblastoma patients will be treated with 8 mg/kg of WP1066 while undergoing standard-of-care radiation therapy at a daily dose of 2 Gy. PFS will be used to ascertain if there is indication of treatment benefit. In cohort 2, patients for whom gross total resection was not achieved will be treated with the combination of radiation and WP1066 with the intent of obtaining treated tumor, if a surgically amenable lesion is present. Such tissue would allow for analysis of TME immune activation and cluster interactions, drug concentrations and target engagement in Aim 2. Aim 2 will also use longitudinal textural MRI analysis to correlate inflammatory responses in the TME by using our STAT3-specific multiplex immune fluorescent panel and complementary ex vivo flow cytometry and nanostring profiling. STAT3 target inhibition, including within specific immune cell populations, will be ascertained through use of the multiplex panel, which will also inform regarding the induction of cluster interactions in the tumor. HPLC quantification of WP1066 concentrations in both enhancing and non-enhancing tumor will be used to determine drug pharmacokinetics. In Aim 3, we will clarify which human GAMs in the TME trigger T cell activation, and if such activation is altered by STAT3 inhibition.

概括脑肿瘤微环境（TME）以髓样细胞浸润为主，这些细胞大多驻留在大脑中小胶质细胞和浸润性胶质母细胞瘤相关骨髓细胞（GAM）。尽管如此，大多数临床试验胶质母细胞瘤已针对基于 T 细胞的免疫疗法，但未能影响大多数患者的结果患者。目标是基于 GAMS 的再教育来靶向胶质母细胞瘤，以实现免疫清除本次临床试验。信号转导子和转录激活子 3 (STAT3) 是两者的负调节因子先天免疫和适应性免疫，并且该途径在 TME 中显着上调。我们之前有过在 I 期临床试验的背景下开发和测试了一种首次用于人体的血脑屏障渗透剂小 STAT3 分子抑制剂，命名为 WP1066。 I期试验结果显示WP1066效果良好耐受并抑制免疫细胞中的 STAT3 靶标。作为单一疗法，WP1066 治疗具有在多项临床前研究中证明了其能够刺激强大的抗肿瘤反应，这一点值得进一步研究放射治疗是新诊断的胶质母细胞瘤的标准治疗方法，众所周知增加肿瘤免疫原性。对治疗肿瘤的无偏纳米线分析表明，联合治疗中 TME 中的抗原呈递。对于这里提出的研究，我们想要将我们的临床前研究结果扩展到新诊断的胶质母细胞瘤患者。在本次临床试验中，我们将测试假设 WP1066 与辐射一起给药会诱导 T 细胞-树突状细胞簇相互作用胶质母细胞瘤微环境，而这种诱导反过来将增加无进展生存期（PFS）胶质母细胞瘤患者。在具体目标 1 中，我们进行了一项 II 期试验，并扩大了该组合的队列新诊断的 MGMT 非甲基化胶质母细胞瘤患者的 WP1066 和放射治疗。在第 1 组中，新诊断为 MGMT 非甲基化、IDH1 野生型胶质母细胞瘤患者将接受 8 mg/kg 的 WP1066 治疗同时接受每日剂量 2 Gy 的标准护理放射治疗。 PFS 将用于确定是否存在是治疗益处的指标。在队列 2 中，未实现全切除的患者将被结合放疗和 WP1066 进行治疗，目的是获得治疗的肿瘤（如果通过手术）存在可调节的病变。这种组织将允许分析 TME 免疫激活和聚类目标 2 中的相互作用、药物浓度和目标参与度。目标 2 还将使用纵向纹理 MRI 通过使用我们的 STAT3 特异性多重免疫分析来关联 TME 中的炎症反应荧光面板和互补的离体流式细胞术和纳米线分析。 STAT3靶标抑制，包括在特定的免疫细胞群内，将通过使用多重面板来确定，这还将告知有关肿瘤中簇相互作用的诱导。 WP1066 的 HPLC 定量增强和非增强肿瘤中的浓度将用于确定药物药代动力学。在目标 3，我们将阐明 TME 中哪些人类 GAM 触发 T 细胞激活，以及这种激活是否会被以下因素改变： STAT3 抑制。