Phase 1 Study of DNX-2440 for Resectable Colorectal Liver Metastasis - IND 018569

DNX-2440 用于可切除结直肠肝转移的 1 期研究 - IND 018569

基本信息

批准号：
10475394
负责人：
Joan Marie Robbins
金额：
$ 85.26万
依托单位：
DNATRIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475394
关键词：
Abscopal effect Adenoviruses Adverse event Affinity Aftercare Antigens Applications Grants Biological Biopsy Cancer Center Cancer Model Cell Survival Cell surface Cells Clinical Clinical Data Clinical Research Colorectal Colorectal Cancer Common Terminology Criteria for Adverse Events Development Diagnosis Disease Dose Dose-Limiting Engineering Enrollment Ensure Environment Evaluation Event Excision Frequencies Funding Genetic Genome Glioblastoma Grant Human Immune Immunologic Memory Immunophenotyping Immunotherapeutic agent Immunotherapy Infection Injections Institutional Review Boards Integrin Binding Interferon Type II Intervention Studies Investigation Investigational Drugs Investigational New Drug Application Lesion Malignant Neoplasms Maximum Tolerated Dose Mediating Metastatic Neoplasm to the Liver Modeling Modification Monitor Mutation National Cancer Institute Neoadjuvant Therapy Neoplasm Metastasis Normal tissue morphology OX40 Oncolytic Oncolytic Immunotherapy Oncolytic viruses Operative Surgical Procedures Pathway interactions Patient Care Patients Phase Production Prognosis Protocols documentation Recurrence Regulatory T-Lymphocyte Resectable Rodent Safety Sampling Schedule Severities Signal Transduction T cell response T memory cell T-Lymphocyte T-cell receptor repertoire TNFSF4 gene Therapeutic Effect Tissues Toxic effect Toxicology Tumor Antigens United States Food and Drug Administration Virus Replication Work adaptive immune response anti-cancer anti-tumor immune response cell killing clinical research site design first-in-human immune activation immunoregulation institutional biosafety committee neoplastic cell next generation nonhuman primate novel novel therapeutic intervention oncolysis oncolytic adenovirus open label overexpression patient population peripheral blood phase 1 study phase 2 testing preclinical study response retinoblastoma pathway standard of care tumor tumor microenvironment tumor necrosis factor ligand superfamily member 4 tumor necrosis factor receptor superfamily member 4

项目摘要

PROJECT SUMMARY/ABSTRACT Approximately half of all patients diagnosed with colorectal cancer develop liver metastases (stage 4 disease) and have a poor prognosis. Surgical resection remains the standard of care for 10-30% of patients with colorectal liver metastasis, but the recurrence rate for these patients is high (60-80%). Oncolytic virus immunotherapy represents a novel therapeutic approach for liver metastasis, combining cell killing by oncolysis and immune-mediated effects that are crucial for response durability. DNX-2440 is a tumor-selective, conditionally-replicative oncolytic adenovirus encoding human OX40 ligand (OX40L), developed to treat cancer. DNX-2440 combines in a single agent the oncolytic activity and anti-tumor immune activity of the predicate adenovirus, DNX-2401 (tasadenoturev) which has completed Phase 2 testing in recurrent glioblastoma, with additional immune modulation mediated by OX40 pathway engagement. The OX40L genetic modification in DNX-2440 enhances immune activation within the tumors, as engagement of the OX40 receptor by OX40L enhances memory T-cell survival and suppresses the differentiation and activity of regulatory T-cells. Preclinical studies demonstrate that DNX-2440 leads to high expression levels of OX40L, tumor-specific anti-tumor immune memory, and effective cell killing in both injected and non-injected tumors. In this application, a Phase 1 open-label, window-of-opportunity study is proposed to assess the clinical safety and anti-tumor immune response to neoadjuvant DNX-2440 in patients with resectable liver metastasis. The study intervention includes two sequential intratumoral injections of DNX-2440, two weeks apart, to a single lesion of liver metastasis (target lesion) in patients presenting with two or more lesions of liver metastasis and scheduled to have surgery for resection of all lesions. This study will evaluate the safety and maximum tolerated dose of intratumoral administration of DNX-2440 and will provide extensive information about the biological and immunotherapeutic effects of DNX-2440 in the studied patient population. Correlative analyses will be performed on collected pre-treatment tumor biopsies from the target lesion and post-treatment tissue (injected lesion, non-injected lesions, normal tissue) collected during the surgical resection.

项目摘要/摘要大约一半被诊断为结直肠癌的患者会发展出肝转移（第4期疾病）并且预后不佳。手术切除仍然是10-30％的患者的护理标准结直肠肝转移，但这些患者的复发率很高（60-80％）。溶瘤病毒免疫疗法代表了肝转移的一种新型治疗方法，结合了细胞杀死免疫介导的作用对于响应耐用性至关重要。 DNX-2440是一种肿瘤选择性，有条件地编码人OX40配体（OX40L）的有条件复制性癌性腺病毒，开发用于治疗癌症。 DNX-2440结合了单个药物的结合了溶瘤活性和抗肿瘤的免疫活性谓词腺病毒，DNX-2401（tasadenoturev），已完成了第2阶段测试胶质母细胞瘤，由OX40途径参与介导的其他免疫调节。 OX40L遗传随着OX40的参与，DNX-2440中的修饰会增强肿瘤内的免疫激活 OX40L受体可增强记忆T细胞存活，并抑制监管T细胞。临床前研究表明，DNX-2440导致OX40L的高表达水平，肿瘤特异性的抗肿瘤免疫记忆和注射和未注射肿瘤的有效细胞杀死。在此应用中，提出了1阶段开放标签的开放式研究窗口研究以评估临床安全性可切除肝转移患者的新辅助DNX-2440对新辅助DNX-2440的抗肿瘤免疫反应。这研究干预措施包括两周相隔两个星期的DNX-2440的两次顺序肿瘤内注射肝转移病变（靶病变），患有两个或更多病变的肝转移和计划进行手术以切除所有病变。这项研究将评估安全性和最高安全性 DNX-2440的肿瘤内给药剂量的剂量，将提供有关该剂量的广泛信息 DNX-2440在研究的患者人群中的生物和免疫治疗作用。相关分析将对靶病变和治疗后组织收集的治疗前肿瘤活检进行（注射病变，未注射病变，正常组织）在手术切除过程中收集。