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

• 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
• 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

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 在所有被诊断为结直肠癌的患者中，大约有一半会发生肝转移(4期疾病)。 预后也很差。手术切除仍然是10%-30%的患者的标准护理 结直肠癌肝转移，但复发率高(60-80%)。溶瘤病毒 免疫疗法代表了一种新的肝转移治疗方法，结合了肿瘤溶解对细胞的杀伤作用 以及对反应持久性至关重要的免疫介导性效应。DNX-2440是一种肿瘤选择性药物， 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在单一试剂中结合了溶瘤活性和抗肿瘤免疫活性 DNX-2401(TasAdoturev)谓词腺病毒，已完成第二期复发性 胶质母细胞瘤，由OX40途径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细胞存活并抑制其分化和活性 调节性T细胞。临床前研究表明，DNX-2440导致OX40L的高表达， 注射和未注射肿瘤中的肿瘤特异性抗肿瘤免疫记忆和有效的细胞杀伤。 在这项应用中，一期开放标签的机会窗研究被提出以评估临床安全性 以及新佐剂DNX-2440在可切除肝转移患者中的抗肿瘤免疫反应。这个 研究干预包括两次连续的肿瘤内注射DNX-2440，相隔两周， 出现两个或两个以上肝转移灶的患者的肝转移灶(靶病变) 计划进行手术切除所有病变。这项研究将评估安全和最大限度的 DNX-2440肿瘤内给药的耐受量，并将提供有关 DNX-2440在研究人群中的生物学和免疫治疗作用。相关分析 将对从目标病变和治疗后组织收集的治疗前肿瘤活检进行 (注射病变、非注射病变、正常组织)。