HSV G207 With a Single Radiation Dose in Children With Recurrent High-Grade Glioma

Sponsor

University of Alabama at Birmingham (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04482933

Collaborator

Treovir, LLC (Other)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is a clinical trial to assess the efficacy and confirm the safety of intratumoral inoculation of G207 (an experimental virus therapy) combined with a single 5 Gy dose of radiation in recurrent/progressive pediatric high-grade gliomas

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

Detailed Description

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 Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

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 GliomaPhase II Clinical Trial of HSV G207 with a Single 5 Gy Radiation Dose in Children with Recurrent High-Grade Glioma

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Clinical Trial of HSV G207 With a Single 5 Gy Radiation Dose in Children With Recurrent High-Grade Glioma

Anticipated Study Start Date :

Dec 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Experimental: HSV G207

Arm

Intervention/Treatment

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 Names:

Experimental: HSV G207

Outcome Measures

Primary Outcome Measures

Efficacy (overall survival) [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.

Secondary Outcome Measures

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [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 [Baseline to 15 years]
Virologic shedding will be assessed from saliva, conjunctiva and blood by polymerase chain reaction (PCR)

Other Outcome Measures

Immunologic Response: HSV-1 Antibody Titers [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 [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 [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) [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) [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) [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) [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) [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 [Baseline to 12 months]
The microenvironment of tumor tissue will be surveyed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients meeting the following inclusion criteria will be eligible for the study:

Age ≥ 3 years of age and ≤ 21 years of age at the time of study enrollment
Patients must have a pathologically proven malignant high-grade glioma (including glioblastoma multiforme, giant cell glioblastoma, anaplastic astrocytoma, midline diffuse glioma) which is progressive or recurrent despite standard care including surgery, radiotherapy, and/or chemotherapy
Lesion must be ≥ 1.0 cm and ≤ 4.0 cm in longest dimension and surgically accessible as determined by MRI. Larger tumors may be surgically debulked and treated if ≤ 4.0 cm after debulking
Multifocal disease on the unilateral side is eligible if at least one catheter can be placed in all multifocal areas
Performance score ≥ 60% (Karnofsky for children ≥16 years old; modified Lansky for children < 16 years old)
Patients with neurological deficits should have deficits that are stable for ≥ 1 week prior to enrollment. A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study
Prior therapy: patients must have recovered from acute treatment related toxicities of all prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy, biologic therapy, or virotherapy prior to entering this study
Myelosuppressive chemotherapy: patients must have received their last dose at least 3 weeks prior and demonstrated count recovery as defined below
Investigational/Biologic agents: patients must have recovered from any acute toxicities potentially related to the agent and received the last dose ≥ 7 days prior to entering this study (this period must be extended beyond the time during which adverse events are known to occur for agents with known adverse events ≥ 7 days). For viral therapy or cellular therapy, patients must have received therapy ≥ 3 months prior to study entry and have recovered from all acute toxicities potentially related to the agent.
Monoclonal antibodies: patient must have received last dose ≥ 28 days prior
Radiation: Patients must have received their last fraction of radiation (≥ 54 Gy) ≥ 3 months prior to study entry. Patients must have received local palliative radiation ≥ 28 days prior to study entry
Patient must have adequate organ and marrow function as defined by the following: Hemoglobin ≥8 g/dL (may receive blood transfusions); absolute neutrophil count ≥ 1.0 x 10^{9 cells/L; platelet count ≥ 100 x 10}9 cells/L (transfusion independent defined as not receiving platelets transfusions ≥ 7 days prior to enrollment); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the institutional upper limit of normal for age; creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Written informed consent in accordance with institutional and FDA guidelines must be obtained from patient or legal guardian

Exclusion Criteria:

Patients with the following conditions will be excluded from participation in the study:

Primary cerebellar, brainstem or spinal tumors
Metastatic disease or gliomatosis cerebri
Acute infection or medical condition precluding surgery
Pregnant or lactating
Diagnosis of encephalitis or central nervous system (CNS) infection < 3 months prior, or receiving ongoing treatment for encephalitis, CNS infection or multiple sclerosis
Tumor involvement which would require ventricular, cerebellar or brainstem inoculation or would require access through a ventricle in order to deliver treatment
Required steroid increase within 1 week prior to G207 inoculation or patients requiring >4 mg of dexamethasone daily
Known HIV seropositivity
Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir) or any immunosuppressive drug therapy (except dexamethasone or prednisone).
Other current malignancy
Concurrent anticancer or investigational drug