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: 10703636
• 负责人: George Yancey Gillespie
• 金额: $ 0.16万
• 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/10703636
• 关键词: 19 year old; 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; 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; Herpesvirus 1; Immune; Immune checkpoint inhibitor; Immune response; Immunohistochemistry; Immunologics; Immunotherapy; In Vitro; Infection; Infiltration; Inflammatory; Infusion procedures; Institution; Investigation; Knowledge; Laboratories; Lead; Long-Term Survivors; Magnetic Resonance Imaging; 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; Recurrence; Recurrent disease; Reporting; Research Support; Safety; Sampling; Simplexvirus; Site; Small Business Innovation Research Grant; Specimen; Supratentorial Neoplasms; Survivors; Testing; Therapeutic; Toxic effect; Training; Transgenic Mice; Tumor-infiltrating immune cells; Universities; Virotherapy; Virus; anti-tumor immune response; antitumor effect; arm; base; brain tissue; chemotherapy; childhood cancer mortality; commercialization; effective therapy; efficacy trial; experience; immune activation; immune function; improved; improved outcome; in vivo; irradiation; medulloblastoma; mouse model; neoplastic cell; 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公司正在申请小企业创新研究（SBIR）支持，以进行单臂II期研究