Overseen ByGregory Friedman
Age: < 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Pediatric Brain Tumor Consortium
No Placebo Group
Prior Safety Data
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?This trial tests a new treatment for children with aggressive brain tumors that haven't responded to other treatments. The treatment uses a special virus injected into the tumor, followed by a small dose of radiation. The virus kills cancer cells and helps the immune system fight the tumor.
Will I have to stop taking my current medications?
The trial requires that you stop taking any other anti-cancer or investigational drug therapy, and you cannot be on certain medications like high doses of dexamethasone or drugs active against HSV (a type of virus). If you're on immunosuppressive therapy, you may need to stop, unless it's a low dose of certain steroids.
What data supports the effectiveness of the treatment G207 + Radiation for Pediatric Brain Tumor?
Research shows that G207, a genetically engineered herpes simplex virus, has been effective in targeting and killing cancer cells in both adult and pediatric brain tumor models. In adult trials, about half of the patients showed a positive response, and preclinical studies in children indicate high sensitivity of various pediatric tumors to G207.
12345Is the G207 treatment safe for use in humans?
G207, a genetically engineered herpes simplex virus, has been tested in several studies and shown to be safe in humans, including children and adults with brain tumors. No serious side effects directly linked to G207 were reported, and no patients developed herpes encephalitis (brain inflammation caused by the virus).
12367What makes the treatment G207 unique for pediatric brain tumors?
G207 is a genetically engineered herpes simplex virus designed to specifically target and kill tumor cells without harming normal brain cells, making it a novel approach compared to traditional treatments like surgery, radiation, and chemotherapy. It is administered directly into the tumor through catheters, allowing for targeted delivery and potentially reducing side effects.
16789Eligibility Criteria
This trial is for children and young adults aged 3 to less than 22 with recurrent high-grade gliomas, who've had prior surgery and radiotherapy. They must have stable neurological deficits, if any, and adequate organ/marrow function. Those on a steady or decreasing dose of dexamethasone are eligible. Patients cannot join if they have HIV, cerebellum/brainstem/spinal cord tumors requiring ventricular access, widespread brain involvement, recent CNS infections or encephalitis, ongoing anti-cancer treatments other than the study's protocol.Inclusion Criteria
My tumor is at least 1.0 cm big and can be removed by surgery.
I can care for myself and do most daily activities.
My condition worsened for the first time after surgery and radiation.
I've had surgery and radiotherapy for my condition and have recovered from major side effects.
I was diagnosed after turning 3 and am currently younger than 22.
My high-grade brain tumor is confirmed by a biopsy and is getting worse.
I haven't taken any growth factor medications for at least 1 week.
My surgeon believes my tumor can be reduced to 4.0 cm or less.
Exclusion Criteria
I am not taking any medication for herpes.
My primary tumor is in my cerebellum, brainstem, spinal cord, or needs surgery through a ventricle.
I do not have HIV, confirmed by tests.
I am not currently taking any cancer treatment or experimental drugs.
I am HIV positive.
My cancer has spread to other parts of my body or affects 3 or more lobes of my brain.
I have not had radiation therapy to my brain and spine.
I am taking more than 1.5 mg of dexamethasone or 10 mg of prednisone daily.
My tumor is causing significant brain pressure or blockage.
I do not have a high-grade secondary brain tumor.
I was diagnosed with or am being treated for encephalitis, a CNS infection, or multiple sclerosis recently.
Participant Groups
The trial tests G207 (an experimental virus therapy) combined with a single radiation dose in pediatric patients with recurring brain tumors called high-grade gliomas. The aim is to see how effective this combination is at treating these tumors and confirm its safety.
1Treatment groups
Experimental Treatment
Group I: Experimental: HSV G207Experimental Treatment1 Intervention
All subjects will receive G207 at 1 x 10\^8 plaque-forming units (pfu), intratumorally via controlled rate infusion through up to 4 silastic catheters over a 6 hour period. The subject will then receive a single 5 Gy dose of radiation to the tumor within 24 hours of virus inoculation.
G207 is already approved in United States for the following indications:
🇺🇸 Approved in United States as G207 for:
- Recurrent/progressive pediatric high-grade gliomas
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Memorial Sloan KetteringNew York, NY
UPMC Children's Hospital of PittsburghPittsburgh, PA
Holly Lindsay MDAurora, CO
Children's of AlabamaBirmingham, AL
More Trial Locations
Loading ...
Who is running the clinical trial?
Pediatric Brain Tumor ConsortiumLead Sponsor
University of Alabama at BirminghamLead Sponsor
American Lebanese Syrian Associated Charities (ALSAC)Collaborator
National Cancer Institute (NCI)Collaborator
Treovir, LLCCollaborator
American Lebanese Syrian Associated CharitiesCollaborator
References
Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors. [2021]Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.
Design and Rationale for First-in-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic HSV G207 to Treat Malignant Pediatric Cerebellar Brain Tumors. [2021]Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.
Safety and efficacy of oncolytic HSV-1 G207 inoculated into the cerebellum of mice. [2021]Primary malignant central nervous system (CNS) tumors are the leading cause of childhood cancer-related death and morbidity. While advances in surgery, radiation, and chemotherapy have improved the survival rates in children with malignant brain tumors, mortality persists in certain subpopulations and current therapies are associated with extreme morbidity. This is especially true for children with malignant infratentorial tumors. Accordingly, G207, a genetically engineered herpes simplex virus (HSV-1) capable of selectively targeting cancer cells has emerged as a promising therapeutic option for this patient population. Herein, we demonstrate that cerebellar inoculation of G207 was systemically non-toxic in an immunocompetent, HSV-1 sensitive mouse strain (CBA/J). Mice had neither abnormal brain/organ pathology nor evidence of G207 replication by immunohistochemistry at days 7 and 30 after cerebellar G207 inoculation. While a minute amount viral DNA was recovered in the cerebellum and brainstem of mice at day 7, no viral DNA persisted at day 30. Critically, G207 delivered to the cerebellum was able to target/treat the highly aggressive MYC-overexpressed group 3 murine medulloblastoma increasing survival vs controls. These results provide critical safety and efficacy data to support the translation of G207 for pediatric clinical trials in intractable cerebellar malignancies.
Oncolytic virotherapy: Potentially a game-changing tumor treatment. [2021]A two-center phase I trial published in the New England Journal of Medicine shows safety and feasibility of locally administered oncolytic herpes simplex virus-1 virus plus 5 Gy radiation for progressive pediatric high-grade gliomas. Patients seemed to have an unusually good clinical course and showed immune activation in post-treatment tissues.
The application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors. [2022]Due to lack of effective therapy, primary brain tumors are the focus of intense investigation of novel experimental approaches that use vectors and recombinant viruses. Therapeutic approaches have been both indirect, whereby vectors are used, or direct to allow for direct cell killing by the introduced virus. Genetically engineered herpes simplex viruses are currently being evaluated as an experimental approach to eradicate malignant human gliomas. Initial studies with gamma (1)34.5 mutants, R3616 (from which both copies of the gamma (1)34.5 gene have been deleted) and R4009 (a construct with two stop codons inserted into the gamma (1)34.5 gene), have been assessed. In a syngeneic scid mouse intracranial tumor model, recombinant herpes simplex virus can be experimentally used for the treatment of brain tumors. These viruses and additional engineered viruses were subsequently tested in human glioma cells both in vitro and in vivo. Using a xenogeneic scid mouse intracranial glioma model, R4009 therapy of established tumors significantly prolonged survival. Most importantly, long-term survival was achieved, with histologic evidence that R4009 eradicated intracranial tumors in this model. Furthermore, the opportunity to evaluate gamma (1)34.5 mutants that have enhanced oncolytic activity, e.g., R8309 where the carboxyl terminus of the gamma (1)34.5 gene has been replaced by the murine homologue, MyD116, are considered.
Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. [2023]G207 is a conditionally replicating derivative of herpes simplex virus (HSV) type-1 strain F engineered with deletions of both gamma(1)34.5 loci and a lacZ insertion disabling the UL39 gene. We have demonstrated the efficacy of G207 in treating malignant glial tumors in athymic mice, as well as the safety of intracerebral G207 inoculation in mice and in Aotus nancymai. We sought to determine the safety of G207 inoculation into cerebral malignant glial tumors in humans. Criteria for inclusion into this dose-escalation study were the diagnosis of histologically proven malignant glioma, Karnofsky score > or = 70, recurrence despite surgery and radiation therapy, and an enhancing lesion greater than 1 cm in diameter. Serial magnetic resonance images were obtained for volumetric analysis. The trial commenced at a dose of 10(6) plaque forming units (p.f.u.) inoculated at a single enhancing site and was completed when the 21st patient was inoculated with 3x10(9) p.f.u. at five sites. While adverse events were noted in some patients, no toxicity or serious adverse events could unequivocally be ascribed to G207. No patient developed HSV encephalitis. We found radiographic and neuropathologic evidence suggestive of anti-tumor activity and long-term presence of viral DNA in some cases.
A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. [2021]G207, a mutant herpes simplex virus (HSV) type 1, is safe when inoculated into recurrent malignant glioma. We conducted a phase 1 trial of G207 to demonstrate the safety of stereotactic intratumoral administration when given 24 hours prior to a single 5 Gy radiation dose in patients with recurrent malignant glioma. Nine patients with progressive, recurrent malignant glioma despite standard therapy were included. Patients received one dose of G207 stereotactically inoculated into the multiple sites of the enhancing tumor margin and were then treated focally with 5 Gy radiation. Treatment was well tolerated, and no patient developed HSV encephalitis. The median interval between initial diagnosis and G207 inoculation was 18 months (mean: 23 months; range: 11-51 months). Six of the nine patients had stable disease or partial response for at least one time point. Three instances of marked radiographic response to treatment occurred. The median survival time from G207 inoculation until death was 7.5 months (95% confidence interval: 3.0-12.7). In conclusion, this study showed the safety and the potential for clinical response of single-dose oncolytic HSV therapy augmented with radiation in the treatment of malignant glioma patients. Additional studies with oncolytic HSV such as G207 in the treatment of human glioma are recommended.
Stereotactic Placement of Intratumoral Catheters for Continuous Infusion Delivery of Herpes Simplex Virus -1 G207 in Pediatric Malignant Supratentorial Brain Tumors. [2019]The engineered herpes simplex virus-1 G207, is a promising therapeutic option for central nervous system tumors. The first-ever pediatric phase 1 trial of continuous-infusion delivery of G207 via intratumoral catheters for recurrent or progressive malignant brain tumors is ongoing. In this article, we describe surgical techniques for the accurate placement of catheters in multiple supratentorial locations and perioperative complications associated with such procedures.
Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. [2023]We have created a double mutant of the herpes simplex virus (HSV) type 1 (termed G207) with favourable properties for treating human malignant brain tumours: replication-competence in glioblastoma cells (and other dividing cells), attenuated neurovirulence, temperature sensitivity, ganciclovir hypersensitivity, and the presence of an easily detectable histochemical marker. G207 has deletions at both gamma 34.5 (RL1) loci and a lacZ gene insertion inactivating the ICP6 gene (UL39). G207 kills human glioma cells in monolayer cultures. In nude mice harbouring subcutaneous or intracerebral U-87MG gliomas, intraneoplastic inoculation with G207 causes decreased tumour growth and/or prolonged survival. G207 is avirulent upon intracerebral inoculation of mice and HSV-sensitive non-human primates. These results suggest that G207 should be considered for clinical evaluation in the treatment of glioblastomas.