Phase I clinical trial of viral oncolysis of liver tumo*

肝肿瘤病毒溶瘤I期临床试验*

• 批准号: 7056439
• 负责人: KENNETH K TANABE
• 金额: $ 31.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056439
• 关键词: clinical research; clinical trial phase I; liver; neoplasm /cancer; neoplasm /cancer remission /regression

DESCRIPTION (provided by applicant): The long-term objectives of this research program are to examine effectiveness and toxicity of replicating Herpes simplex virus 1 (HSV-1) mutants for treatment of malignancies. Patients with primary and secondary liver tumors that are unresectable have a poor prognosis, and current treatment options are inadequate. Thus, there is strong rationale for development of new and effective therapies. Viral replication in tumor cells leads to their destruction, with liberation of progeny virion that infect and destroy adjacent cancer cells in a process referred to as viral oncolysis. We have conducted research demonstrating effectiveness of HSV-1 mutants for oncolysis of liver tumors in preclinical models. One specific mutant, rRp450, replicates preferentially in liver tumors rather than normal liver following intravascular delivery. This selective viral replication dramatically reduces liver tumor burden and enhances animal survival. On the basis of these and several other preclinical studies, the National Cancer Institute Rapid Access to Intervention Development (RAID) program has taken responsibility of translating this lead discovery into a phase I clinical trial. Specifically, RAID is responsible for cGMP rRp450 production, IND-directed preclinical toxicology, and release of cGMP rRp450 to the Principal Investigator via the Cancer Therapy Evaluation Program. The proposed clinical trial is a phase I study of 4 weekly administrations of rRp450 into the hepatic artery of study subjects with unresectable primary or secondary liver tumors. Study objectives are to [i] determine maximum tolerated dose and dose-limiting toxicity; [ii] perform rRp450 pharmacokinetics and biodistribution; [iii] assess immunologic responses to rRp450; and [iv] perform pathologic and radiographic assessments of rRp450 effect on liver tumors and normal liver. This phase I trial uses a standard algorithm for dose escalation. Data from this trial are a necessary first step to determine whether further clinical study of this novel and promising therapy is warranted. These data will also provide insight into rRp450 mechanism of action.

描述（由申请人提供）：该研究计划的长期目标是检查复制型单纯疱疹病毒 1 (HSV-1) 突变体治疗恶性肿瘤的有效性和毒性。无法切除的原发性和继发性肝脏肿瘤患者预后较差，目前的治疗方案不足。因此，开发新的有效疗法有充分的理由。肿瘤细胞中的病毒复制导致其被破坏，并释放子代病毒粒子，在称为病毒溶瘤的过程中感染并破坏邻近的癌细胞。我们进行的研究证明了 HSV-1 突变体在临床前模型中对肝肿瘤溶瘤的有效性。一种特定的突变体 rRp450 在血管内递送后优先在肝肿瘤而不是正常肝脏中复制。这种选择性的病毒复制极大地减少了肝脏肿瘤负担并提高了动物的存活率。在这些研究和其他几项临床前研究的基础上，国家癌症研究所快速干预开发 (RAID) 计划负责将这一先导发现转化为 I 期临床试验。具体来说，RAID 负责 cGMP rRp450 生产、IND 指导的临床前毒理学，并通过癌症治疗评估计划向首席研究员发布 cGMP rRp450。拟议的临床试验是一项 I 期研究，每周 4 次将 rRp450 注射到患有不可切除的原发性或继发性肝脏肿瘤的研究对象的肝动脉中。研究目标是[i]确定最大耐受剂量和剂量限制毒性； [ii] 进行 rRp450 药代动力学和生物分布； [iii]评估对rRp450的免疫反应； [iv]对rRp450对肝脏肿瘤和正常肝脏的影响进行病理学和放射学评估。该一期试验使用剂量递增的标准算法。该试验的数据是确定是否有必要对这种新颖且有前途的疗法进行进一步临床研究的必要的第一步。这些数据还将提供对 rRp450 作用机制的深入了解。