Phase 1b Study PVSRIPO for Recurrent Malignant Glioma in Children

PVSRIPO will be delivered intratumorally by CED using an intracerebral catheter placed within
the enhancing portion of the tumor. The population group are patients with recurrent WHO
grade III or IV malignant glioma who are aged 12 through 21 years old. After a single dose of
PVSRIPO, subjects will return for periodic visits to monitor tumor status, adverse events,
and changes in blood immune profiles. A maximum of 12 pediatric patients will be treated with
PVSRIPO, and then carefully monitored for safety for at least a year after treatment.

Inclusion Criteria:

- Patients must have a recurrent supratentorial WHO Grade III malignant glioma
(anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma,
anaplastic pleomorphic xanthoastrocytoma, ependymoma) or WHO Grade IV malignant
glioma, medulloblastoma, or atypical teratoid/rhabdoid tumor (ATRT) based on imaging
studies with measurable disease (≥ 1 cm and ≤ 5.5 cm). The prior histopathology must
be consistent with a World Health Organization (WHO) Grade III or IV malignant tumor
confirmed by the study pathologist, Roger McLendon, or his designee.

- There is no standard of care treatment for children with Grade III/IV gliomas;
however, patients must have received some form of definitive treatment, i.e., standard
therapy with known clinical benefit, for their initial diagnosis prior to their
recurrence/progression. Definitive treatment includes maximal safe resection (if
possible) and radiation therapy with or without chemotherapy. (Please note that
patients who are unable to receive radiation therapy due to genetic disorders that put
them at significant risk for radiation-induced secondary malignancies (i.e., Gorlin's
syndrome or NF1 mutation) are still eligible to participate).

- Due to the potential implications of the treatment on the developing CNS, all patients
must be ≥ 12 years of age and ≤ 21 years of age at the time of entry into the study.

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

- Laboratory Studies:

1. Platelet count ≥ 125,000 per microliter prior to biopsy. Platelets ≥ 100,000 per
microliter prior to infusion;

2. Prothrombin and Activated Partial Thromboplastin Times ≤ 1.2 x upper limit of
normal (ULN) prior to biopsy;

3. Positive serum anti-poliovirus titer ≥ 1:8 prior to biopsy;

4. Creatinine ≤ 1.2 x ULN prior to biopsy;

5. Total bilirubin, AST, ALT, alkaline phosphatase ≤ 2.5 x ULN prior to biopsy;

6. Neutrophil count ≥ 1000 per microliter prior to biopsy;

7. Hemoglobin ≥ 9 gm/dl prior to biopsy (can be transfused).

- The patient must have received a boost immunization with trivalent inactivated IPOL™
(Sanofi-Pasteur) ≥ 1 week prior to administration of the study agent.

- At the time of biopsy, prior to administration of virus, the presence of recurrent
tumor must be confirmed by histopathological analysis.

- A signed informed consent form approved by the Duke University Institutional Review
Board (IRB) will be required for patient enrollment into the study. Patients (if 18
years old) or their parent(s) or guardian(s) 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. All children will have to provide
assent to the study.

- Able to undergo brain MRI with and without contrast without requiring general
anesthesia.

Exclusion Criteria:

- Pregnant or breast-feeding. Female patients of child-bearing potential or female
sexual partners (who are of child-bearing potential) of male patients must use at
least one of the following methods of medically acceptable contraceptives: approved
hormonal contraceptives (such as birth control pills, patches, implants or infusions),
an intrauterine device (IUD), or a barrier method of contraception (such as a condom
or diaphragm) used ith spermicide. Because all patients are required to have a boost
immunization of trivalent inactivated IPOL™, there should be no risk of transmission
of a mother to her fetus after receiving intracranial PVSRIPO. As such, patients who
become pregnant after receiving PVSRIPO will continue to be monitored in the same
manner, i.e. per protocol, unless the assessment is contra-indicated during pregnancy.
Partners who become pregnant will sign a Pregnant Partner Information Form and
information regarding the pregnancy and its outcome may be collected.

- Patients with an impending, life-threatening cerebral herniation syndrome, based on
the assessment of the study neurosurgeon.

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

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

- Patients with 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.

- Patients with allergy to human serum albumin.

- Gadolinium allergy.

- A history of neurological complications due to past PV 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.

- Patients who have not recovered from the toxic effects of prior chemo- and/or
radiation therapy. Guidelines for this recovery period are dependent upon the specific
therapeutic agent being used:

1. Patients who are less than 12 weeks from radiation therapy, unless progressive
disease outside of the radiation field or 2 consecutive scans with disease
progression or histopathologic confirmation of recurrent tumor.

2. Patients who have received chemotherapy or bevacizumab ≤ 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 unless patients have
recovered from side effects of such therapy.

3. Patients who have received immunotherapy ≤ 4 weeks prior to starting the study
drug unless patients have recovered from side effects of such therapy.

- Patients with neoplastic lesions in the brainstem, cerebellum, spinal cord,
intraventricular tumors, pituitary tumors, leptomeningeal disease, or other locations
at the discretion of the treating neurosurgeon.

- Patients with a diagnosis of agammaglobulinemia, that is:

1. Undetectable anti-tetanus toxoid IgG

2. Known history of agammaglobulinemia

- Patients who are on dexamethasone receiving > 4 mg/day in the two weeks prior to
admission for intra-cerebral delivery of PVSRIPO or who demonstrate worsening steroid
myopathy.

- Patients with prior, unrelated malignancy requiring current active treatment with the
exception of cervical carcinoma in situ and adequately treated basal cell or squamous
cell carcinoma of the skin.