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: 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
• 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

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要求小型企业创新研究（SBIR）支持进行单臂II期 被诊断为复发或进行高级的儿童（3-18岁）的临床试验（3-18岁） 神经胶质瘤（HGG）。我们建议确定CGMP生产的（临床级）G207单纯疱疹的有效性 复发性HGG儿童的病毒（HSV）。我们的理由是基于儿童G207的I期临床试验 复发性HGG具有（1）单独或5GY的肿瘤内输注的确定安全性 放射疗法的部分和（2）导致总体存活率明显显着增加。我们有孤儿 G207 HSV治疗HGG的药物名称（胶质母细胞瘤多形，do症）， 髓母细胞瘤和原始神经外科肿瘤（PNET）。 G207已在3个临床中安全使用 在35名复发性HGG的35名成年人中的试验，具有17个明显的射线照相反应和至少2个长期存活率 （> 5。5年）在患者人群中中位生存期为5.5-6.5个月。我们已经出版了 使用体外培养物和小儿脑肿瘤的小鼠模型引人入胜的临床前数据，这些模型证明了 与成人脑肿瘤相比，对G207的敏感性提高。在患有HGG的孩子中，我们观察到 10例患者中有9例，射线照相，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）长期生存（18.3、20+和32+个月）。最近的荟萃分析 （Kline等，2018）报告的129名儿童的平均中位存活率为5.6个月（95％CI = 3.9-7.3） 在17次临床试验中经常性HGG。 G207不仅产生了溶瘤效应，而且显然正在引起有效的效果 免疫炎症细胞反应。 4个配对样品的免疫组织化学检查（PRE-VS。 病毒后肿瘤）显示，在所有4种治疗后，免疫相关炎症细胞广泛浸润 G207后5个月甚至肿瘤。我们提出，肿瘤细胞的G207感染在免疫学上转化 “冷”肿瘤为“热”。我们建议进行II期试验以确定单个肿瘤内的有效性 G207输注以及单个辐射的单个辐射。首席机构将是阿拉巴马州的儿童 阿拉巴马州的伯明翰和其他儿科医院的摄入率 用于脑肿瘤。这项II期试验将涉及总共32名受试者 包括当前I期试验（NCT02457845）中的包含/排除标准。推荐的II期剂量 （RP2D）将为1 x 108斑块形成单元（PFU），这些单元（PFU）注入了大脑增强部分的多个位置 肿瘤的总体积为2.4cc。总体临床PI将是医学博士Gregory K. Friedman，他进行了 由Treovir，LLC提供的G207的I期试验。我们假设38（I期和II期）受试者将 提供> 85％的功率，以检测护理疗法标准的总生存率显着差异（p <0.05） 对于复发性HGG患者，与G207相关的严重毒性很少。该试验将为 单个/多剂量临床试验，导致G207的事件注册进行商业化。