PVSRIPO in Recurrent Malignant Glioma

This is a phase 2 study of oncolytic polio/rhinovirus recombinant (PVSRIPO) in adult patients
with recurrent World Health Organization (WHO) grade IV malignant glioma. The primary
objective of this study is to assess the efficacy of a single dose of PVSRIPO among adults
with WHO grade IV malignant glioma at first or second recurrence relative to the survival
observed in a historical control group. The secondary objective is to determine the safety of
PVSRIPO treatment in recurrent WHO grade IV malignant glioma patients. The proportion of
patients who experience grade 3, 4, or 5 AEs that are possibly, probably, and definitely
related to protocol treatment will be estimated. Subjects will be receive PVSRIPO alone to
evaluate the impact of the treatment regimens on 24-month survival relative to historical
controls. PVSRIPO will be delivered intratumorally by convection-enhanced delivery (CED)
using an intracerebral catheter placed within the enhancing portion of the tumor. Based on
experience with a Phase 1 study at Duke, previously published reports, and institutional
review board (IRB)- and FDA-approved trials using similar infusion techniques, patients will
be infused at a rate of 0.5 mL/hr. A Medfusion™ 3500 infusion pump (Smiths Medical,
Minneapolis, MN) or any other comparable FDA-cleared syringe infusion pump approved by the
sponsor or their designee, will be pre-programmed to a delivery rate of 0.5 mL/hr. The target
accrual for the study is 102 patients. All patients who are randomized and receive PVSRIPO
treatment will be included in efficacy and safety analyses.

Inclusion Criteria

1. Patients must have a recurrent (first or second recurrence only, including this
recurrence; transformation from a lower grade tumor to a WHO grade IV malignant glioma
will be considered a first recurrence) supratentorial WHO grade IV malignant glioma
based on imaging studies with measurable disease (a minimum measurement of 1 cm and
maximum of 5.5 cm of contrast-enhancing tumor). Tumor size and location requirements
will need to be confirmed by the reviewer designated by the Sponsor. Prior
histopathology consistent with a WHO grade IV malignant glioma confirmed by the site's
neuropathologist or the neuropathologist's designate

1. Assuming patient meets all other criteria, site neurosurgeon must confirm
placement of infusion catheter tip can occur ≥ 1cm from ventricles and at a safe
distance relative to eloquent brain function.

2. Tumor size and location requirements per protocol must be confirmed as qualifying
and safe to proceed by the reviewer(s) designated by the Sponsor.

2. If the subject is male and sexually active, he is eligible to enter and participate in
this study if his partner(s) meets the criteria outlined in 2a or if he or his
partner(s) is using one of the methods of birth control outlined in 2b. If the subject
is female, she is eligible to enter and participate in this study if she meets the
following criteria:

1. Non-childbearing potential (i.e. physiologically incapable of becoming pregnant,
including any female who is postmenopausal or surgically sterile). Surgically
sterile females are defined as those with a documented hysterectomy and/or
bilateral oophorectomy or tubal ligation. Postmenopausal for purposes of this
study, is defined as 1 year without menses); or

2. Childbearing potential, has a negative serum pregnancy test at screening, and
agrees to use one of the following methods of birth control: approved hormonal
contraceptives (e.g. birth control pills, patches, implants, or infusions), an
intrauterine device, or a barrier method of contraception (e.g. a condom or
diaphragm) used with spermicide.

3. If the male has had a vasectomy or is using a condom with spermicide, the female
partner does not need to use additional birth control noted in 2a and 2b.

3. Age ≥ 18 years of age at the time of entry into the study

4. Karnofsky Performance Status (KPS) Score ≥ 70%

5. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy

6. Total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic
pyruvic transaminase (SGPT), alkaline phosphatase ≤ 2.5 x normal prior to biopsy

7. Neutrophil count ≥ 1000 prior to biopsy

8. Hemoglobin ≥ 9 prior to biopsy

9. Platelet count ≥ 100,000/µL unsupported is necessary for eligibility on study;
however, because of risks of intracranial hemorrhage with catheter placement, platelet
count ≥ 125,000/µL is required for the patient to undergo biopsy and catheter
insertion, which can be attained with the help of platelet transfusion

10. Creatinine ≤ 1.2 x normal range prior to biopsy

11. Positive serum anti-PV titer prior to biopsy

12. The patient must have received a boost immunization with trivalent inactivated IPOL™
(Sanofi-Pasteur) at least 1 week, but less than 6 weeks, prior to administration of
the study agent

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

14. A signed informed consent form (ICF) approved by the IRB will be required for patient
enrollment into the study. Patients or their legally authorized representative (LAR)
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

15. Able to undergo brain MRI with and without contrast

Exclusion Criteria

1. Females who are pregnant or breast-feeding.

2. Patients with an impending, life-threatening cerebral herniation syndrome, based on
the assessment of the study neurosurgeons, their designate, and the reviewer
designated by the sponsor

3. Patients with severe, active co-morbidity, defined as follow:

1. Patients with an active infection requiring intravenous treatment or having an
unexplained febrile illness (Tmax > 99.5°F/37.5°C)

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

3. Patients with unstable or severe intercurrent medical conditions such as severe
heart disease (New York Heart Association Class 3 or 4)

4. Patients with known lung (forced expiratory volume in the first second of
expiration [FEV1] < 50%) disease or uncontrolled diabetes mellitus

5. Patients with albumin allergy

6. Patients with gadolinium allergy

4. Patients with a previous history of neurological complications due to PV infection

5. 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.

6. Patients may not have received tumor treating fields (≤ 1 week), chemotherapy or
bevacizumab ≤ 4 weeks [except for nitrosourea and lomustine (≤ 6 weeks); metronomic
dosed chemotherapy, such as daily temozolomide, etoposide or cyclophosphamide (≤ 1
week)] prior to starting the study drug.

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

8. Patients may not be less than 12 weeks from radiation therapy, unless progressive
disease outside of the radiation field or 2 progressive scans at least 4 weeks apart
or histopathologic confirmation

9. Patients who have not completed all standard of care treatments, including surgical
procedure and radiation therapy (at least 59Gy)

1. If the MGMT promoter in their tumor is known to be unmethylated, patients are not
mandated to have received chemotherapy prior to participating in this trial

2. If the MGMT promoter in their tumor is known to be methylated or the MGMT
promoter methylation status is unknown at time of screening, patients must have
received at least one chemotherapy regimen prior to participating in this trial

10. Patients with neoplastic lesions in the brainstem, cerebellum, or spinal cord;
radiological evidence of multiple areas of active (growing) disease (active multifocal
disease); tumors with contrast-enhancing tumor component crossing the midline
(crossing the corpus callosum); extensive subependymal disease (tumor touching
subependymal space is allowed); or extensive leptomeningeal disease (tumor touching
leptomeninges is allowed)

11. Patients with undetectable anti-tetanus toxoid immunoglobulin G (IgG)

12. Patients with known history of agammaglobulinemia

13. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to
admission for PVSRIPO infusion

14. Patients with worsening steroid myopathy (history of gradual progression of bilateral
proximal muscle weakness, and atrophy of proximal muscle groups)

15. 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

16. Patients with active autoimmune disease requiring systemic immunomodulatory treatment
within the past 3 months