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

Treovir，LLC正在请求小企业创新研究（SBIR）支持，以进行单臂II期 在已被诊断为复发性或进行性高分级的儿童（3-18岁）中进行的临床试验 胶质瘤（HGG）。我们建议确定cGMP生产的（临床级）G207单纯疱疹的疗效 病毒（HSV）在儿童复发HGG。我们的理由是基于G207在儿童中的I期临床试验 复发性HGG患者，（1）单独或联合5Gy G207 HSV瘤内输注已确定安全性 放疗的分数和（2）导致总生存率明显显着增加。我们有孤儿 用于治疗HGG（多形性胶质母细胞瘤，室管膜瘤）的G207 HSV药物名称， 髓母细胞瘤和原始神经外胚层肿瘤（PNDT）。G207已安全用于3例临床 在35例复发性HGG成人中进行的试验，其中17例有明显的放射学缓解，至少2例长期存活 （>5.5年），预期中位生存期为5.5-6.5个月。我们已经发表 令人信服的临床前数据使用体外培养和小鼠模型的小儿脑肿瘤，证明 与成人脑肿瘤相比，对G207的敏感性增加。在HGG儿童中，我们观察到 10例患者中有9例放射学、神经病理学和/或临床反应，中位生存期为12.2个月 (95% CI=5.05-19.4），3例患者长期存活（18.3、20+和32+个月）。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）， 在17项临床试验中复发HGG。G207不仅产生溶瘤作用，而且明显地引发了一种有效的 免疫炎症细胞为基础的反应。对4对样本进行免疫组织化学检查（术前与术后）。 病毒后肿瘤）显示，在所有4个治疗后 肿瘤甚至在G207后5个月。我们认为，G207感染肿瘤细胞， “冷”肿瘤转变为“热”肿瘤我们建议进行一项II期试验，以确定单次瘤内注射的疗效。 G207输注加单次5Gy分次放疗。牵头机构将是亚拉巴马大学儿童基金会 位于伯明翰的亚拉巴马的儿科医院以及其他具有免疫治疗/病毒治疗经验的儿科医院 治疗脑瘤这项II期试验将涉及根据相同的标准累积的总共32名受试者。 入选/排除标准与当前I期试验（NCT 02457845）相同。推荐的II期剂量 （RP 2D）将是1 × 108空斑形成单位（pfu）注入大脑增强部分的多个部位 肿瘤总体积为2.4cc。总体临床PI为Gregory K。弗里德曼，医学博士，谁进行了 Treovir，LLC提供的G207 I期试验。我们假设38名（I期和II期）受试者将 提供>85%的把握度来检测总生存期与标准治疗相比的显著差异（p<0.05） 对于复发性HGG患者，G207几乎没有相关的严重毒性。这次审判将为 单次/多次给药临床试验导致G207最终注册用于商业化。

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.