HSV G207 With a Single Radiation Dose in Children With Recurrent High-Grade Glioma
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|ClinicalTrials.gov Identifier: NCT04482933|
Recruitment Status : Not yet recruiting
First Posted : July 23, 2020
Last Update Posted : July 8, 2021
|Condition or disease||Intervention/treatment||Phase|
|Neoplasms High Grade Glioma Glioblastoma Multiforme Malignant Glioma of Brain Anaplastic Astrocytoma of Brain High-grade Glioma Anaplastic Glioma Giant Cell Glioblastoma||Drug: Biological G207||Phase 2|
Outcomes for children with recurrent or progressive high-grade glioma (brain tumor) are very poor, and there are a lack of effective salvage therapies once a patient fails standard treatments. Novel innovative treatments are greatly needed.
G207 is an oncolytic herpes simplex virus-1 (HSV) that has been successfully engineered to introduce mutations in the virus that enable it to selectively replicate in and kill cancer cells, but not normal cells. Replication of G207 in the tumor not only kills the infected tumor cells, but causes the tumor cell to act as a factory to produce new virus. These virus particles are released as the tumor cell dies, and can then proceed to infect other tumor cells in the vicinity, and continue the process of tumor kill. In addition to this direct oncolytic activity, the virus engenders an anti-tumor immune response; the virus is immunogenic and produces a debris field which exposes cancer cell antigens to immune cells, which can target other cancer cells. Thus, the oncolytic effect of the virus and the immune response that the virus stimulates provide a dual attack against cancer cells. In preclinical studies, a single 5 Gy dose of radiation within 24 hours of virus inoculation to the tumor increased virus replication and tumor cell killing. Radiation may also enhance the immune response against the tumor.
The University of Alabama at Birmingham has conducted three phase I trials of G207 injected into the recurrent tumor alone or combined with a single dose of radiation in adults with recurrent high-grade gliomas. In these trials, high doses (up to 3 x 10^9 plaque-forming units) of virus were safely injected directly into the tumor or surrounding brain tissue without serious toxicities. Radiographic and neuropathologic evidence of an antitumor response was seen in some patients. Preclinical laboratory studies have demonstrated that a variety of aggressive pediatric brain tumor types are sensitive to G207.
A Phase I study of intratumoral G207 alone or combined with a 5 Gy dose of radiation in children ages 3-18 with biopsy-confirmed recurrent/progressive supratentorial brain tumors recently completed the highest planned dose level (UAB1472; NCT02457845). The study used a 3 + 3 design with 4 dose cohorts.12 Patients underwent stereotactic placement of up to 4 intratumoral catheters. The following day they received a single controlled-rate infusion of G207 (1 x 10^7 or 1 x 10^8 pfu) over 6 hours. Cohorts 3 and 4 received a 5 Gy radiation fraction to the gross tumor volume within 24 hours of G207. Twelve subjects with progressive high-grade glioma received G207. Twenty adverse events, all grade 1, were attributed to G207. G207 was determined to be safe and tolerable in children and a recommended Phase 2 was established (1 x10^8 followed by 5 Gy radiation to the tumor).
This study is a phase II, open-label, single arm clinical trial of G207 alone or combined with a single low dose of radiation in children with recurrent or progressive high grade glioma. The primary objective is to assess the efficacy. The secondary objective is to confirm the safety and tolerability of G207 and to survey for virologic shedding following G207.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Phase II Clinical Trial of HSV G207 with a Single 5 Gy Radiation Dose in Children with Recurrent High-Grade Glioma|
|Masking:||None (Open Label)|
|Official Title:||Phase II Clinical Trial of HSV G207 With a Single 5 Gy Radiation Dose in Children With Recurrent High-Grade Glioma|
|Estimated Study Start Date :||December 1, 2021|
|Estimated Primary Completion Date :||October 1, 2024|
|Estimated Study Completion Date :||October 1, 2025|
Experimental: Experimental: HSV G207
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.
Drug: Biological G207
Single dose of HSV-1 (G207) infused through catheters into region(s) of tumor defined by MRI
Other Name: Experimental: HSV G207
- Efficacy (overall survival) [ Time Frame: Baseline to 24 months ]The overall survival for each patient receiving G207 will be calculated by estimating the 1-year and 2-year overall survival.
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Baseline to 15 years ]All events with a Grade 3 or above toxicity (defined by the CTCAE v5.0) will be tabulated by event and by relationship to G207.
- Virologic Shedding [ Time Frame: Baseline to 15 years ]Virologic shedding will be assessed from saliva, conjunctiva and blood by polymerase chain reaction (PCR)
- Immunologic Response: HSV-1 Antibody Titers [ Time Frame: Baseline to 12 months ]HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment
- Immunologic Response: Expression Levels of Peripheral Blood Immune Cells, Cytokines, and Chemokines [ Time Frame: Baseline to 12 months ]Expression levels will be determined prior to the administration of G207 and at regular intervals after treatment
- Correlate Radiographic Changes to G207 + 5 Gy Radiation [ Time Frame: Baseline to 24 months ]MRI of the brain will be checked and radiographic changes assessed in relation to baseline mitotic index, cerebral blood volume and fractional tumor burden
- Change in Performance (Ability to Perform Normal Activities) [ Time Frame: Baseline to 12 months ]A modified Lansky score (for children under 16 years of age) or Karnofsky score (for children 16 and older) will be recorded and measured serially. The score is a standard performance score that measures overall function of the child with a scale range from 0 (lowest, poorest performance score) to 100 (highest, best performance).
- Child Physical, Emotional, Social and School Functioning (optional) [ Time Frame: Baseline to 12 months ]Pediatric Quality of Life Inventory 4.0 Generic Core Scales questionnaires will be filled out by primary caregivers, and when appropriate, the child. Lower score indicates better outcome.
- Child Physical, Emotional, Social and School Functioning (optional) [ Time Frame: Baseline to 12 months ]Pediatric Quality of Life Brain Tumor Module questionnaires will be filled out by primary caregivers, and when appropriate, the child. Lower score indicates better outcome.
- Family Physical, Emotional, Social, and Cognitive Functioning, Worry, Daily Activities and Relationships (optional) [ Time Frame: Baseline to 12 months ]Pediatric Quality of Life Family Impact Scale questionnaires will be filled out by primary caregivers. Lower score indicates better outcome.
- Sibling Physical, Emotional, Social and School Functioning (optional) [ Time Frame: Baseline to 12 months ]Strengths and Difficulties Questionnaire will be filled out by primary caregivers. Lower score indicates better outcome.
- Number or Presence of Immune and Neuroinflammatory Cell Populations, Checkpoint Proteins, Stem Cell Markers, and/or HSV Entry Molecules in Tumor Tissue [ Time Frame: Baseline to 12 months ]The microenvironment of tumor tissue will be surveyed.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04482933
|Contact: Kara Kachurak, CRNPfirstname.lastname@example.org|
|Contact: Gregory Friedman, M.D.||email@example.com|
|United States, Alabama|
|Children's of Alabama|
|Birmingham, Alabama, United States, 35233|
|Contact: Kara Kachurak, CRNP 205-638-9285 firstname.lastname@example.org|
|Contact: Gregory Friedman, M.D. 205-638-9285 email@example.com|
|Principal Investigator: Gregory Friedman, M.D.|
|Principal Investigator:||Gregory Friedman||University of Alabama at Birmingham|