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.

项目概要/摘要大约一半被诊断患有结直肠癌的患者会出现肝转移（第 4 期疾病）并且预后较差。手术切除仍然是 10-30% 患者的标准治疗方法结直肠肝转移，但此类患者的复发率很高（60-80%）。溶瘤病毒免疫疗法代表了一种新的肝转移治疗方法，结合了溶瘤细胞杀伤作用以及对于反应持久性至关重要的免疫介导效应。 DNX-2440 是一种肿瘤选择性、编码人 OX40 配体 (OX40L) 的条件复制溶瘤腺病毒，开发用于治疗癌症。 DNX-2440 将溶瘤活性和抗肿瘤免疫活性结合在单一药物中谓语腺病毒 DNX-2401 (tasadeturev) 已完成复发性 2 期测试胶质母细胞瘤，具有 OX40 通路参与介导的额外免疫调节。 OX40L基因 DNX-2440 的修饰增强了肿瘤内的免疫激活，因为 OX40 的参与 OX40L 受体增强记忆 T 细胞的存活并抑制 T 细胞的分化和活性调节性T细胞。临床前研究表明 DNX-2440 导致 OX40L 高表达水平，肿瘤特异性抗肿瘤免疫记忆，以及对注射和非注射肿瘤的有效细胞杀伤。在本申请中，提出了一项第一阶段开放标签、机会之窗研究来评估临床安全性可切除肝转移患者对新辅助 DNX-2440 的抗肿瘤免疫反应。这研究干预包括两次连续瘤内注射 DNX-2440，间隔两周，单个注射肝转移病灶（目标病灶）存在两个或多个肝转移病灶的患者，并且计划进行手术切除所有病变。这项研究将评估安全性和最大 DNX-2440 瘤内给药的耐受剂量，并将提供有关 DNX-2440 的广泛信息 DNX-2440 在研究的患者群体中的生物学和免疫治疗作用。相关分析将在治疗前从目标病变和治疗后组织收集的肿瘤活检中进行（注射病变、非注射病变、正常组织）在手术切除过程中收集。