This study is a clinical trial to determine the safety of inoculating G207 (an experimental
virus therapy) into a recurrent or refractory cerebellar brain tumor. The safety of combining
G207 with a single low dose of radiation, designed to enhance virus replication, tumor cell
killing, and an anti-tumor immune response, will also be tested.
Outcomes for children with recurrent or progressive cerebellar 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 safety of G207 has been demonstrated in 3 phase I clinical trials involving adults with
supratentorial high-grade gliomas adults at the University of Alabama (UAB) and in an ongoing
phase I clinical trial involving children with recurrent supratentorial brain tumors at
Children's of Alabama. In the adult 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 anti-tumor responses have
been seen. 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
cerebellar 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 cohort will
receive G207 alone, and the next cohorts will receive G207 at one of three doses followed by
a 5 Gy dose of radiation to active areas of tumor.
- Age ≥ 36 months and < 19 years
- Pathologically proven malignant cerebellar brain tumor (including medulloblastoma,
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 cerebellar tumor without curative treatment options is
- Lesion must be ≥ 1.0 cm ≤ 3.0 cm in diameter and surgically accessible as determined
by MRI. Larger tumors may be surgically debulked and treated if ≤ 3.0 cm after
- 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: For bevacizumab, the patient must have received last dose ≥ 28
days prior. At least 3 half-lives must have elapsed prior to study entry for other
- 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 creatinine clearance
>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
- Patients < 16 years, Modified Lansky performance score ≥ 60; patients ≥ 16 years,
Karnofsky performance 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
- Any treatment outside the allowable guidelines outlined in section 5.1.
- Acute infection, granulocytopenia or medical condition precluding surgery
- Pregnant or lactating females
- Prior history of encephalitis, multiple sclerosis, or other central nervous system
- Tumor involvement which would require ventricular 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, valacyclovir,
penciclovir, famciclovir, gancyclovir, foscarnet, cidofovir) or any immunosuppressive
drug therapy (except dexamethasone or prednisone).