Dose-finding and Safety Study of PVSRIPO Against Recurrent Glioblastoma

Inclusion Criteria:

1. Disease Status. Patients must have a resectable, recurrent supratentorial GBM based
on imaging studies with measurable disease (≥ 1 cm or ≤ 5 cm of contrast-enhancing
tumor). Prior histopathology consistent with a World Health Organization (WHO) Grade
IV GBM confirmed by the study pathologist, Roger McLendon, or his designate.

2. Age. Due to the potential implications of the treatment on the developing CNS, all
patients must be ≥ 18 years of age at the time of entry into the study.

3. Prior Therapy. Patients may be included in the study independent of the regimen of
previous surgical, radiation, or chemotherapy treatments administered. However, the
exclusions listed in #5 of the Exclusions below must be followed.

4. Performance Status. The patient must have a Karnofsky Performance Score (KPS) of ≥
70% at the time of entry.

5. Laboratory Studies

- Platelet count ≥ 100,000/ml

- Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal

- Positive serum anti-poliovirus titer

- Creatinine ≤ 1.2 x normal

- Total bilirubin, SGOT, SGPT, alkaline phosphatase ≤ 2.5 x normal

- Neutrophil count ≥ 1000

- Hemoglobin ≥ 9

6. Poliovirus Immunization Booster. The subject must have received a boost immunization
with monovalent inactivated (Salk) poliovirus vaccine type 1 at least 2 weeks prior
to administration of the study agent.

7. Disease Confirmation. At the time of biopsy, prior to administration of virus, the
presence of recurrent tumor must be confirmed by histopathological analysis of frozen
sections.

8. Informed Consent. A signed informed consent form approved by the Duke University
Institutional Review Board (IRB) will be required for patient enrollment into the
study. Patients must be able to read and understand the informed consent document and
must sign the informed consent indicating that they are aware of the investigational
nature of this study.

Exclusion Criteria:

1. Pregnancy. Because of the unknown risk of virus administration potentially affecting
a developing fetus or growing infant, females who are pregnant or breast-feeding
during the study period will be excluded. Adults of reproductive potential not
employing an effective method of birth control will be excluded. Barrier
contraceptives must be used throughout the trial in both sexes.

2. Disease Status. Because patients will receive drug intracerebrally, patients with an
impending, life-threatening cerebral herniation syndrome, based on the assessment of
the study neurosurgeons, Allan Friedman or John Sampson, or their designate, will be
excluded.

3. Medical Conditions. Because the potential toxicities from the agent being studied in
this protocol may be similar to some known diseases or may be more dangerous in the
context of certain known diseases, the following patients will be excluded to avoid
confounding the study results:

- Patients with an active infection requiring treatment or having an unexplained
febrile illness (Tmax > 99.5 F).

- Patients with known immunosuppressive disease or known human immunodeficiency
virus infection.

- Unstable or severe intercurrent medical conditions such as severe heart (New
York Heart Association Class 3 or 4) or lung (FEV1 < 50%) disease, uncontrolled
diabetes mellitus.

- Albumin allergy. Albumin is added to the agent as a stabilizer. Patients with a
known allergy will be excluded.

- Gadolinium allergy. Gadolinium is used as contrast for the MRI.

4. Previous Poliomyelitis. A history of neurological complications due to poliovirus
infection would imply previous virus replication in the CNS. Based on animal studies,
previous exposure to poliovirus administered intracerebrally can reduce subsequent
virus replication in the CNS.

5. Prior Therapy. Patients who have not recovered from the toxic effects of prior
chemotherapy and/or radiation therapy will be excluded. Guidelines for this recovery
period are dependent upon the specific therapeutic agent being used.

- Patients may not have received chemotherapy ≤ 4 weeks [except for nitrosourea (6
weeks) or metronomic dosed chemotherapy such as daily etoposide or
cyclophosphamide (1 week)] prior to starting the study drug or patients have
recovered from side effects of such therapy.

- Patients may not have received immunotherapy ≤ 4 weeks prior to starting the
study drug or patients have recovered from side effects of such therapy.

- Patients may not have received investigational drugs ≤ 4 weeks prior to starting
the study drug or must have recovered from side effects of such therapy.

Patients must have completed all standard of care treatments including resection and
concurrent chemo-radiation prior to participating in this trial.

6. Location and Extent of Tumor. Because of the potential toxicities from the agent,
patients with neoplastic lesions in the brainstem, cerebellum or spinal cord,
radiological evidence of multifocal disease, or leptomeningeal disease. Patients with
evidence of diffuse subependymal disease or tumor in the brainstem, cerebellum,
spinal cord, or CSF will be excluded.

- Since the study agent is a local treatment, patients with radiological evidence
of multifocal disease, tumors extending into or crossing the corpus callosum or
leptomeningeal disease, will be excluded.

- Patients with contrast-enhancing tumors of < 1 cm or > 5 cm diameter in any
plane will be excluded.

- Patients with tumor ≤ 1 cm in proximity to the ventricle.

7. Subjects must not have diagnosis of agammaglobulinemia. Patients with the following
will be excluded:

- IgG levels < 400 mg/dL [4 g/L]

- Undetectable anti-tetanus toxoid IgG

- Known history of agammaglobulinemia