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

基本信息

批准号：
10244948
负责人：
George Yancey Gillespie
金额：
$ 89.08万
依托单位：
TREOVIR, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10244948
关键词：
19 year old Acceleration Adjuvant Adult Aftercare Age Alabama Archives Biological Biopsy Brain Neoplasms Cancer Etiology Caregivers Cells Child Childhood Childhood Brain Neoplasm Childhood Glioma Clinical Clinical Research Clinical Trials Coupled Cyclic GMP Cytolysis Data Development Developmental Delay Disorders Diagnosis Diffuse intrinsic pontine glioma Dose Dose Limiting Embryonal Neoplasm of the CNS Engineering Ependymoma Exclusion Criteria Foundations Future G207 Genetic Transduction Glioblastoma Glioma Immune Immune checkpoint inhibitor Immune response Immunohistochemistry Immunologics Immunotherapy In Vitro Infection Infiltration Inflammatory Infusion procedures Investigation Knowledge Laboratories Long-Term Survivors Malignant neoplasm of brain Measures Meta-Analysis Modality Nature Nervous System Physiology Newly Diagnosed Normal Cell Oncogenic Viruses Oncolytic Orphan Drugs Outcome Patients Pediatric Hospitals Phase Phase I Clinical Trials Phase I/II Clinical Trial Phase II Clinical Trials Phase II/III Clinical Trial Primitive Neuroectodermal Tumor Process Progression-Free Survivals Psyche structure Publishing Quality of life Radiation Radiation Dose Unit Radiation therapy Recommendation Recurrence Recurrent disease Reporting Research Support Safety Sampling Simplexvirus Site Small Business Innovation Research Grant Specimen Supratentorial Survivors Testing Therapeutic Toxic effect Training Transgenic Mice Universities Virotherapy Virus anti-tumor immune response antitumor effect arm brain tissue chemotherapy childhood cancer mortality commercialization effective therapy efficacy evaluation efficacy trial experience immune activation immune cell infiltrate immune function improved improved outcome in vivo irradiation medulloblastoma mouse model neoplastic cell neuropathology neurotoxicity oncolytic herpes simplex virus oncolytic virotherapy patient derived xenograft model patient population phase I trial phase II trial pre-clinical preclinical study programs radiological imaging response standard of care targeted treatment therapeutic effectiveness tumor

项目摘要

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) 支持以开展单臂 II 期研究针对被诊断患有复发性或进行性高级别疾病的儿童（3-18 岁）进行的临床试验我们建议确定 cGMP 生产的（临床级）G207 单纯疱疹病毒的功效。患有复发性 HGG 的儿童中的病毒 (HSV) 我们的基本原理基于 G207 在儿童中的 I 期临床试验。复发性 HGG 已 (1) 确定单独或与 5Gy 瘤内输注 G207 HSV 的安全性放射治疗的一部分和（2）导致总体生存率明显显着增加。 G207 HSV 用于治疗 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) 已在 3 个临床中安全使用。在 35 名患有复发性 HGG 的成年人中进行的试验，其中 17 名患者有明显的放射学反应，并且至少有 2 名长期幸存者我们已经发表了预期中位生存期为 5.5-6.5 个月的患者群体（>5.5 年）。使用儿科脑肿瘤的体外培养物和小鼠模型得出令人信服的临床前数据，证明我们观察到，与成人脑肿瘤相比，患有 HGG 的儿童对 G207 的敏感性更高。 10 名患者中有 9 名出现放射学、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 名患者长期存活（18.3、20+ 和 32+ 个月）。（Kline 等人，2018）报告称，129 名患有此病的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，G207 反复出现的 HGG 不仅产生溶瘤作用，而且明显引发了强大的作用。基于免疫炎症细胞的反应对 4 个配对样本（之前与之后）进行免疫组织化学检查。病毒后肿瘤）显示在所有 4 种治疗后均存在免疫相关炎症细胞的广泛浸润甚至在 G207 后 5 个月，我们认为肿瘤细胞的 G207 感染会转化为免疫学。我们建议进行一项 II 期试验，以确定单个瘤内肿瘤的疗效。 G207 输注加上单次 5Gy 部分辐射牵头机构将是阿拉巴马州儿童大学。阿拉巴马州伯明翰分校与其他具有免疫治疗/病毒治疗经验的儿科医院合作这项 II 期试验将涉及根据相同的方法收集的总共 32 名受试者。纳入/排除标准与当前 I 期试验 (NCT02457845) 推荐的 II 期剂量相同。 (RP2D) 将 1 x 108 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为 2.4cc。由 Treovir, LLC 提供的 G207 的 I 期试验我们发现 38 名（I 期和 II 期）受试者将。提供 >85% 的功效来检测总体生存率与标准护理疗法的显着差异 (p<0.05) 对于很少有 G207 严重毒性的复发性 HGG 患者，该试验将为 G207 奠定基础。单/多剂量临床试验导致 G207 最终注册商业化。