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

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. 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.

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

- 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)

- Monoclonal antibodies: At least 3 half-lives must have elapsed prior to study entry

- 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
> 4 weeks 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

- Prior participant in experimental viral therapy (e.g., adenovirus, retrovirus or
herpes virus protocol)

- 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).