HSV G207 Alone or With a Single Radiation Dose in Children With Progressive or Recurrent Supratentorial Brain Tumors

Study Overview
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Brief Summary
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This study is a clinical trial to determine the safety of injecting G207 (a new experimental virus therapy) into a recurrent or progressive brain tumor. The safety of combining G207 with a single low dose of radiation, designed to enhance virus replication and tumor cell killing, will also be tested.

Detailed Description
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Outcomes for children with recurrent or progressive supratentorial malignant brain tumors are very poor, and there are a lack of effective salvage therapies once a patient fails standard treatments. 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 one-two punch at attacking 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. 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. A maximum tolerated dose was not reached in all 3 trials. 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. This study is a phase I, open-label, single institution clinical trial of G207 alone or combined with a single low dose of radiation in children with recurrent or progressive supratentorial brain tumors. The primary goal is to determine safety. The secondary aims are to obtain preliminary information on the effectiveness of and immune response to G207. A traditional 3 + 3 design will be used with four patient cohorts. The first two cohorts will receive G207 at one of two doses, and the second two cohorts will receive G207 at one of two doses followed by a 5 Gy dose of radiation.

Official Title
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Phase I Clinical Trial of HSV G207 Alone or With a Single Radiation Dose in Children With Recurrent Supratentorial Brain Tumors

Conditions
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PNET, Supratentorial Neoplasms, Malignant, Malignant Glioma, Glioblastoma, Anaplastic Astrocytoma, Cerebral Primitive Neuroectodermal Tumor, Embryonal Tumor

Intervention / Treatment
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* Biological: G207


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 36 months and < 19 years Pathologically proven malignant supratentorial brain tumor (including glioblastoma multiforme, giant cell glioblastoma, anaplastic astrocytoma, primitive neuroectodermal tumor, ependymoma, atypical teratoid/rhabdoid tumor, germ cell tumor, or other high-grade malignant tumor) which is progressive or recurrent despite standard care including surgery, radiotherapy, and/or chemotherapy. A pathologically proven secondary malignant tumor without curative treatment options is eligible. Lesion must be > 1.0 cm in diameter and surgically accessible as determined by MRI Patients must have fully recovered from acute treatment related toxicities of all prior chemotherapy, immunotherapy or radiotherapy prior to entering this study. Myelosuppressive chemotherapy: patients must have received their last dose at least 3 weeks prior (or at least 6 weeks if nitrosurea) Investigational/Biologic agents: patients must have recovered from any acute toxicities potentially related to the agent and received 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, patients must have received viral 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 ≥ 21 days prior Radiation: Patients must have received their last fraction of craniospinal radiation (>24 Gy) or total body irradiation ≥ 3 months prior to study entry. Patients must have received focal radiation to symptomatic metastatic sites or local palliative radiation > 28 days prior to study entry. Autologous bone marrow transplant: Patients must be ≥ 3 months since transplant prior to study entry. Normal hematological, renal and liver function (Absolute neutrophil count > 1000/mm3, Platelets > 100,000/mm3, Prothrombin Time (PT) or Partial Thromboplastin Time (PTT) < 1.3 x control, Creatinine within normal institutional limits OR > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal, Total Bilirubin < 1.5 mg/dl, Transaminases < 3 times above the upper limits of the institutional norm) Patients < 10 years, Modified Lansky score ≥ 60; patients > 10 years, Karnofsky score ≥ 60 Patient life expectancy must be at least 8 weeks Written informed consent in accordance with institutional and FDA guidelines must be obtained from patient or legal guardian Exclusion Criteria: Acute infection, granulocytopenia or medical condition precluding surgery Pregnant or lactating females Prior history of encephalitis, multiple sclerosis, or other central nervous system (CNS) infection 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 injection Known HIV seropositivity Concurrent therapy with any drug active against HSV (acyclovir, valaciclovir, penciclovir, famciclovir, gancyclovir, foscarnet, cidofovir) or any immunosuppressive drug therapy (except dexamethasone or prednisone).

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HSV G207<br>Single dose of HSV-1 (G207) infused through catheters into region(s) of tumor defined by MRI. If G207 is safe in the first two cohorts of patients, subsequent patients will receive a single dose of G207 infused through catheters into region(s) of tumor defined by MRI followed by a 5 Gy dose of radiation to the tumor given with 24 hours of virus inoculation. Intervention: Biological: G207 | Biological: G207<br>* Single dose of HSV-1 (G207) infused through catheters into region(s) of tumor defined by MRI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Measured by Frequency of Grade 3 or Above Adverse Events | All events with a Grade 3 or above toxicity (defined by the CTCAE v4.0) will be tabulated by event and by relationship to G207. | Baseline to 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunologic Response | HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment. | Baseline to 12 months | 
| Virologic Shedding | Saliva, blood and conjunctival secretions will be checked by polymerase chain reaction (PCR) and culture at regular intervals for evidence of HSV shedding and/or viremia. | Baseline to 15 years | 
| Progression Free Survival | Time after G207 administration to clinical and radiographic disease progression will be evaluated. | Baseline to 24 months | 
| Overall Survival | The overall survival for each patient receiving G207 will be calculated. | Baseline to 24 months | 
| Change in Performance (Ability to Perform Normal Activities) | 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 with the pre-treatment score. | Baseline to 12 months | 
| Quality of Life (optional) | Quality of life will be measured with questionnaires taken at baseline (before administration of G207) and at specified times thereafter. | Baseline to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Tumor, Recurrent, Glioma, Glioblastoma, Gliosarcoma, Anaplastic Astrocytoma, Oligodendroglioma, Rhabdoid Tumor, Cerebral Primitive Neuroectodermal Tumor, PNET, Ependymoma, Germ Cell Tumor, Choroid Plexus Carcinoma, Oncolytic Virus Therapy, Virotherapy, Oncolytic, Immunotherapy, Central Nervous System Agents, Antineoplastic Agents, Neoplasms, Pediatric, Pediatrics, Embryonal Tumor, Oncolytic, Virus, HSV, Herpes Virus