Phase II Clinical Trial of G207 HSV To Treat Children with High Grade Gliomas

G207 HSV治疗儿童高级别胶质瘤的II期临床试验

• 批准号: 10595804
• 负责人: George Yancey Gillespie
• 金额: $ 61.19万
• 依托单位: TREOVIR, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595804
• 关键词: Phase; II; Clinical; Trial; G207

Treovir, LLC is requesting Small Business Innovation Research (SBIR) support to conduct a single arm Phase II clinical trial in children (age 3-18 years) who have been diagnosed with recurrent or progressive high grade glioma (HGG). We propose to determine efficacy of a cGMP-produced (clinical grade) G207 Herpes Simplex Virus (HSV) in children with recurrent HGG. Our rationale is based on a Phase I clinical trial of G207 in children with recurrent HGG that has (1) established safety of intratumoral infusion of G207 HSV, alone or with a 5Gy fraction of radiotherapy and (2) resulted in an apparent significant increase in overall survival. We have orphan drug designations for G207 HSV for treatment of HGG (glioblastoma multiforme, Ependymomas), Medulloblastoma, and Primitive Neuroectodermal Tumors (PNETs). G207 has been used safely in 3 clinical trials in 35 adults with recurrent HGG with 17 obvious radiographic responses and at least 2 long term survivors (>5.5 years) in a patient population with an expected median survival of 5.5–6.5 months. We have published compelling preclinical data using in vitro cultures and mouse models of pediatric brain tumors that demonstrated an increased sensitivity to G207 compared with adult brain tumors. In children with HGG, we have observed radiographic, neuropathologic and/or clinical responses in 9 of 10 patients and a median survival of 12.2 months (95% CI=5.05–19.4) with 3 patients surviving long-term (18.3, 20+ and 32+ months). A recent meta-analysis (Kline et al., 2018) reported an average median survival of 5.6 months (95% CI=3.9-7.3) for 129 children with recurrent HGG in 17 clinical trials. G207 is not just producing an oncolytic effect but is obviously eliciting a potent immune inflammatory cell-based response. Immunohistochemical examination of 4 paired samples (pre- vs. post-virus tumor) revealed extensive infiltration of immune-related inflammatory cells in all 4 post-treatment tumor even 5 months post-G207. We propose that G207 infection of tumor cells converts an immunologically “cold” tumor to a “hot” one. We propose to conduct a Phase II trial to determine efficacy of a single intratumoral G207 infusion plus a single 5Gy fraction of radiation. The lead institution will be Children's of Alabama, University of Alabama at Birmingham together with other Pediatric Hospitals with experience in immunotherapy/virotherapy for brain tumors. This Phase II trial will involve a total of 32 subjects accrued according to the same inclusion/exclusion criteria as in the current Phase I trial (NCT02457845). The Recommended Phase II Dose (RP2D) will be 1 x 108 plaque-forming units (pfu) infused into multiple sites of the enhancing portions of the brain tumor in a total volume of 2.4cc. The overall clinical PI will be Gregory K. Friedman, MD, who has conducted the Phase I trial with G207 provided by Treovir, LLC. We hypothesize that 38 (both Phase I and II) subjects will provide >85% power to detect a significant difference (p<0.05) in overall survival over standard of care therapies for recurrent HGG patients with few associated serious toxicities of G207. This trial will lay the foundations for single/multiple dosing clinical trials leading to eventual registration of G207 for commercialization.

Treovir，LLC正在请求小型企业创新研究(SBIR)支持，以实施单一ARM第二阶段 对被诊断为复发或进展性高级别疾病的儿童(3-18岁)的临床试验 胶质瘤(HGG)。我们建议确定cGMP产生的(临床级)G207单纯疱疹病毒的疗效 复发HGG患儿中的单纯疱疹病毒感染。我们的理论基础是G207在儿童中的I期临床试验 复发的HGG患者：(1)单独或联合5Gy瘤内注射G207 HSV是安全的 放射治疗的分割和(2)导致总体生存率明显增加。我们有个孤儿 G207单纯疱疹病毒治疗HGG(多形性胶质母细胞瘤、室管膜瘤)的药物名称 髓母细胞瘤和原始神经外胚层肿瘤(PNET)。G207已在3个临床应用中安全使用 35例复发的成人HGG的试验，17例有明显的放射学反应，至少2例长期存活 (&gt；5.5年)，预期中位生存期为5.5-6.5个月。我们已经出版了 使用体外培养和儿童脑肿瘤小鼠模型的令人信服的临床前数据表明 与成人脑肿瘤相比，对G207的敏感性增加。在患有HGG的儿童中，我们观察到 10例患者中有9例出现放射学、神经病理和/或临床反应，中位生存期为12.2个月 (95%CI=5.05~19.4)，3例长期存活(18.3个月、20个月以上和32个月以上)。最近的一项荟萃分析 (Kline等人，2018年)报告了129名儿童的平均中位生存期为5.6个月(95%CI=3.9-7.3)。 17项临床试验中复发的HGG。G207不仅产生了溶瘤作用，而且显然引发了一种强有力的 以免疫炎症细胞为主的反应。4个配对样本的免疫组织化学检查(前和 病毒后肿瘤)显示免疫相关炎症细胞在所有4个治疗后广泛渗透 肿瘤甚至在G207术后5个月。我们认为，肿瘤细胞的G207感染可以在免疫学上转化为 从“冷”瘤到“热”瘤。我们建议进行第二阶段试验，以确定单个肿瘤内注射的疗效。 G207输注加单次5Gy射线照射。牵头机构将是阿拉巴马州儿童大学 阿拉巴马大学伯明翰分校与其他在免疫治疗/病毒治疗方面有经验的儿科医院 治疗脑瘤。本次第二阶段试验共涉及32名受试者，根据同一 纳入/排除标准与当前第一阶段试验相同(NCT02457845)。推荐的第二阶段剂量 (RP2D)将1×108个斑块形成单位(PFU)注入大脑增强部分的多个部位 肿瘤总体积2.4cc。总体临床PI将由格雷戈里·K·弗里德曼医学博士担任，他领导了 G207由Treovir，LLC提供的第一阶段试验。我们假设38名受试者(包括第一阶段和第二阶段)将 提供85%的能力来检测总体存活率与标准护理疗法之间的显著差异(p&lt；0.05) 对于复发的HGG患者，很少与G207相关的严重毒性。这场审判将为 单剂量/多剂量临床试验导致G207最终注册用于商业化。