Phase I Study of HSV1716 in Pediatric Non-CNS Solid Tumors,IND 13196 12/04/2006

描述（由申请人提供）： 儿童、青少年和年轻人的癌症是一种罕见疾病。 非CNS实体瘤在该年龄组中的患病率约为90，000;目前治疗未治愈的患病率约为27，000。 多次复发或转移性非中枢神经系统实体瘤（特别是肉瘤）患者的治愈率仍<30%，尽管进行了积极的多模式治疗，包括手术、放疗和化疗。 申请人的初步数据表明，在人类异种移植模型中，儿童、青少年和年轻人中常见的高度恶性类型的癌症易被减毒单纯疱疹病毒突变体杀死。 HSV 1716是由Crusade Laboratories，Ltd.开发的ICP34.5突变体。这些“溶瘤”突变病毒对许多类型的癌细胞具有裂解作用，但在正常细胞中复制的能力减弱。 这些药物诱导的细胞毒性机制绕过了传统的癌症耐药机制。 HSV 1716已在Crusade先前的几项临床试验中通过肿瘤内注射在患有脑肿瘤、头颈部鳞状细胞癌和黑色素瘤的成年人中显示出安全性，但尚未在年轻患者或注射到非CNS深层肿瘤中进行安全性测试。 申请人假设瘤内注射HSV 1716在浅表区域（四肢、头部和颈部）以及腹膜后和肺部位置肿瘤的年轻患者中是安全的，病毒脱落最少。 基于他们的临床前疗效研究，申请人提出了一项I期临床试验，以测试在患有复发性或难治性非CNS实体瘤的青少年和年轻人中直接瘤内注射HSV 1716的安全性。 他们将在两个具体目标中检验他们的假设：（1）评估单次和重复瘤内注射HSV 1716在复发性癌症青少年和年轻人中的安全性和可行性，以及（2）确定瘤内注射病毒后HSV 1716病毒传播的发生率。 这项研究将是开发HSV 1716作为非CNS实体瘤局部控制的新方法的第一个临床步骤，用于手术和放疗不可选或不再有效的情况。 该项目是最终获得FDA批准HSV 1716用于这些患者的第一步。 由于非临床数据表明，病毒的全身递送也可能对转移有治疗益处，因此这项研究也可能使未来的系统性HSV 1716试验成为可能。

DESCRIPTION (provided by applicant): Cancer in children, adolescents, and young adults is an orphan disease. The prevalence of non-CNS solid tumors in this age group is ~90,000; the prevalence of those who are not cured by current therapies is ~27,000. Cure rates for patients with multiply relapsed or metastatic non-CNS solid tumors, particularly sarcomas, remain <30% despite aggressive multimodal therapy including surgery, radiation, and chemotherapy. The applicant's preliminary data suggest the highly malignant types of cancers commonly found in children, adolescents, and young adults in human xenograft models are susceptible to killing by attenuated herpes simplex virus mutants. HSV1716 is an ICP34.5 mutant under development by Crusade Laboratories, Ltd. These "oncolytic" mutant viruses are lytic for many types of cancer cells, but are attenuated in their ability to replicate in normal cells. The mechanisms of cytotoxicity induced by these agents circumvent traditional cancer-resistance mechanisms. HSV1716 has been shown to be safe in several previous clinical trials by Crusade via intratumoral injection in adults with brain tumors, head/neck squamous cell carcinomas, and melanomas, but has not been tested for safety in young patients or for injection into non-CNS, deep-seated tumors. The applicant hypothesizes that intratumoral injection of HSV1716 is safe in young patients with tumors in superficial regions (extremities, head and neck) as well as retroperitoneal and lung locations, with minimal shedding of virus. Based on their preclinical efficacy studies, the applicant proposes a Phase 1 clinical trial to test the safety of direct intratumoral injections of HSV1716 in adolescents and young adults with relapsed or refractory non-CNS solid tumors. They will test their hypothesis in two specific aims: (1) Assess the safety and feasibility of single and repeated intratumoral HSV1716 administration in adolescents and young adults with relapsed cancer, and (2) Determine the incidence of HSV1716 virus spread following intratumoral virus injection. This study will be the first clinical step in developing HSV1716 as a new method of local control for non-CNS solid tumors, to be used when surgery and radiotherapy are not options or no longer effective. The project is the first step in ultimately gaining FDA approval for HSV1716 for these patients. Because nonclinical data suggest systemic delivery of the virus may also have therapeutic benefit for metastases, this study may also enable future trials of systemic HSV1716.