SBIR-STTR Award

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.

Public Health Relevance Statement:
Treovir LLC is requesting Direct-to-Phase II SBIR support to conduct a Phase I/II clinical trial in 32 children with recurrent high-grade malignant brain tumors to evaluate the safety and efficacy of a single intratumoral infusion of an oncolytic Herpes Simplex Virus, G207 followed within 24 hrs with a single 5 Gy dose of radiation to the tumor. Based on a remarkable increase in survival of 10 children with recurrent gliomas coupled with a striking immune cell-related infiltration of their tumors after G207 therapy, we believe that this combination virotherapy (G207 plus 5Gy radiation) will be proven to have improved efficacy leading to long-term survival responses, with little to no serious toxicities. We have obtained Orphan Drug Designation for G207 for several types of pediatric brain tumors and will seek Breakthrough Status Designation to accelerate the approval of G207 with radiation as a safe and effective therapy for children harboring these fatal malignant brain tumors.

Project Terms:
Adult; 21+ years old; Adult Human; adulthood; Aftercare; After Care; After-Treatment; post treatment; Age; ages; Alabama; Archives; Biopsy; Brain Neoplasms; Brain Neoplasia; Brain Tumors; tumors in the brain; Cells; Cell Body; Child; 0-11 years old; Child Youth; Children (0-21); children; childrens'; youngster; Clinical Research; Clinical Study; Clinical Trials; Diagnosis; Orphan Drugs; Engineering; Ependymoma; WHO Grade II Ependymal Neoplasm; WHO Grade II Ependymal Tumor; Foundations; Future; Glioblastoma; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Grade IV Astrocytoma; glioblastoma multiforme; spongioblastoma multiforme; Glioma; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Neuroglial Neoplasm; Neuroglial Tumor; glial-derived tumor; neuroglia neoplasm; neuroglia tumor; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Pediatric Hospitals; Children's Hospital; Immunohistochemistry; Immunohistochemistry Cell/Tissue; Immunohistochemistry Staining Method; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Infection; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; medulloblastoma; Transgenic Mice; Nervous System Physiology; Neurologic function; Neurological function; nervous system function; Oncogenic Viruses; Tumor Viruses; Patients; Publishing; Quality of life; QOL; Radiation therapy; Radiotherapeutics; Radiotherapy; radiation treatment; radio-therapy; treatment with radiation; Recurrence; Recurrent; Research Support; Safety; Supratentorial Neoplasms; Supratentorial Brain Neoplasms; Supratentorial Tumors; Testing; Genetic Transduction; Universities; Virus; Diagnostic radiologic examination; Conventional X-Ray; Diagnostic Radiology; Diagnostic X-Ray; Diagnostic X-Ray Radiology; Radiography; Roentgenography; X-Ray Imaging; X-Ray Medical Imaging; Xray imaging; Xray medical imaging; conventional Xray; diagnostic Xray; diagnostic Xray radiology; Measures; Caregivers; Care Givers; Developmental Delay; Specific Child Development Disorders; Developmental Delay Disorders; Brain Cancer; Malignant Tumor of the Brain; Malignant neoplasm of brain; base; improved; Site; Clinical; Phase; Biological; longterm survivors; Long-Term Survivors; Survivors; HSV; Herpes Simplex Virus; Herpes labialis Virus; Simplexvirus; CNS PNET; CNS Primitive Neuroectodermal Neoplasm; CNS Primitive Neuroectodermal Tumor; Central Nervous System PNET; Central Nervous System Primitive Neuroectodermal Neoplasm; Central Nervous System Primitive Neuroectodermal Tumor; Central Primitive Neuroectodermal Neoplasm; Central Primitive Neuroectodermal Tumor; Primitive Neuroepithelial Neoplasms; Primitive Neuroepithelial Tumors; primitive neuroectoderm tumor; Primitive Neuroectodermal Tumor; HSV-1; HSV1; Herpes Simplex Virus 1; Herpes Simplex Virus Type 1; herpes simplex i; Herpesvirus 1; Childhood Brain Tumor; pediatric brain neoplasm; pediatric brain tumor; Childhood Brain Neoplasm; Training; mental; Psyche structure; pediatric; Childhood; Progression-Free Survivals; Relapsed Disease; Recurrent disease; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Immunological response; host response; immunoresponse; Immune response; Therapeutic; Infiltration; Inflammatory; Nature; Research Specimen; Specimen; Knowledge; programs; Investigation; Immunes; Immune; brain tissue; Heterograft; Heterologous Transplantation; Xenograft; Xenotransplantation; xeno-transplant; xeno-transplantation; Xenograft procedure; Radiation Dose; Radiation Dose Unit; Infusion; Infusion procedures; experience; Tumor Cell; neoplastic cell; Toxicities; Toxic effect; Modality; Reporting; Radiation; Sampling; response; Meta-Analysis; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; Phase I Clinical Trials; G207; Normal Cell; Cellular Immune Function; immune function; Institution; irradiation; CNS Embryonal Tumor; Central Nervous System Embryonal Neoplasm; Central Nervous System Embryonal Tumor; Embryonal Neoplasm of the CNS; Dose; Data; Dose-Limiting; in vivo; Cancer Cause; Cancer Etiology; Exclusion Criteria; Newly Diagnosed; Oncolytic; SBIR; Small Business Innovation Research; Small Business Innovation Research Grant; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Immunologics; Process; Adjuvant; developmental; Development; preclinical; pre-clinical; pre-clinical study; preclinical study; Pediatric Glioma; Pediatric high-grade glioma; Childhood Glioma; efficacy trial; Outcome; Coupled; 19 years of age; age 19 years; nineteen year old; nineteen years old; 19 year old; therapeutic effectiveness; neuron toxicity; neuronal toxicity; neurotoxicity; chemotherapy; murine model; mouse model; commercialization; tumor; patient population; standard of care; effective treatment; effective therapy; Immune Cell Activation; immune activation; arm; Virotherapeutics; Virotherapy; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; phase 2 trial; phase II trial; phase 1 trial; phase I trial; anti-tumor effect; antitumor effect; improved outcome; cancer virotherapy; oncolytic viral therapy; oncolytic virus therapy; oncolytic virotherapy; cancer death in children; cancer mortality in children; cancer related death in children; childhood cancer death; childhood cancer mortality; DIPG; Diffuse intrinsic pontine glioma; Checkpoint inhibitor; immune check point inhibitor; Immune checkpoint inhibitor; antitumor immune response; anti-tumor immune response; oHSV; oncolytic herpes simplex virus; Immune infiltrates; T cell infiltration; T cell tumor trafficking; immune cell infiltrate; immune infiltration; intratumoral immune cell; tumor immune cell; Tumor-infiltrating immune cells; Phase 2/3 Clinical Trial; Phase II/III Clinical Trial; Phase 1/2 Clinical Trial; Phase I/II Clinical Trial

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.

Public Health Relevance Statement:
Treovir LLC is requesting Direct-to-Phase II SBIR support to conduct a Phase I/II clinical trial in 32 children with recurrent high-grade malignant brain tumors to evaluate the safety and efficacy of a single intratumoral infusion of an oncolytic Herpes Simplex Virus, G207 followed within 24 hrs with a single 5 Gy dose of radiation to the tumor. Based on a remarkable increase in survival of 10 children with recurrent gliomas coupled with a striking immune cell-related infiltration of their tumors after G207 therapy, we believe that this combination virotherapy (G207 plus 5Gy radiation) will be proven to have improved efficacy leading to long-term survival responses, with little to no serious toxicities. We have obtained Orphan Drug Designation for G207 for several types of pediatric brain tumors and will seek Breakthrough Status Designation to accelerate the approval of G207 with radiation as a safe and effective therapy for children harboring these fatal malignant brain tumors.

Project Terms: