Purpose of the Study:
To determine the maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) of PVSRIPO
when delivered intracerebrally by convection-enhanced delivery. To estimate progression-free
and overall survival in supratentorial resectable, recurrent WHO grade IV malignant glioma
patients. To evaluate immunologic, virologic and histopathologic parameters of the effect of
virus infection on WHO Grade IV malignant gliomas.
Agent: PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus (PV) vaccine
containing a heterologous internal ribosomal entry site (IRES) from human rhinovirus type 2
(HRV2). PVSRIPO recognizes Necl-5, an oncofetal cell adhesion molecule and tumor antigen
widely expressed ectopically in malignancy, e.g. glioblastoma multiforme (GBM), as host cell
receptor. PVSRIPO has been manufactured at NCI-Frederick, NCI, NIH.
Catheter Implantation: PVS-RIPO will be delivered directly into the tumor. A stereotactic
biopsy will be performed prior to virus administration for frozen section confirmation of
viable tumor and further analysis. The biopsy needle will be placed with stereotactic
guidance by an MRI-compatible, stereotactic head frame. Immediately following the
stereotactically-guided tumor biopsy, a catheter will be implanted in the OR at a site
different from that used for the biopsy. A CT or MRI scan may be used to confirm catheter
Agent infusion: The entire volume of the agent to be delivered will be pre-loaded into a
syringe by the investigational pharmacist and connected to the catheter under sterile
conditions in the OR at the time of the biopsy procedure. Drug infusion will occur in the
NICU so that all other emergency facilities will be available. Patients will be infused
through a Medfusion 3500 infusion pump pre-programmed to a delivery rate of 0.5 l/hr. The
total amount of the inoculum delivered to the patient will be 3 ml. The virus injection
procedure will be completed within 6.5 hrs. The catheter will be removed immediately
following the delivery of PVSRIPO.
Biopsy sampling and analyses: Biopsy material will be obtained from tumor tissue prior to
virus administration. This tissue material will be subjected to routine histology to confirm
tumor recurrence by the study neuropathologist, Dr. R. McLendon or his designate.
1. Disease Status. Patients must have a recurrent supratentorial WHO Grade IV malignant
glioma based on imaging studies with measurable disease (≥ 1 cm or ≤ 5.5 cm of
contrast-enhancing tumor). Prior histopathology consistent with a World Health
Organization (WHO) Grade IV malignant glioma 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 ≥ 125,000/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
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.
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. Sexually active
women of child bearing potential, whose partner is male, must use medically approved
birth control. Sexually active men, whose partner is a female of child bearing
potential, must use a medically acceptable method of contraception.
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
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
- Unstable or severe intercurrent medical conditions such as severe heart (New
York Heart Association Class 3 or 4) or lung (FEV1 < 50%) disease, uncontrolled
- 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 unless patients have
recovered from side effects of such therapy.
- Patients may not have received immunotherapy ≤ 4 weeks prior to starting the
study drug unless patients have recovered from side effects of such therapy.
- Patients may not have received investigational drugs ≤ 4 weeks prior to starting
the study drug unless patient has 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
active (growing) multifocal disease, tumors extending into or crossing the corpus
callosum or leptomeningeal disease, will be excluded.
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
8. Patient is on greater than 4mg per day of dexamethasone within the 2 weeks prior to
9. Patient has worsening steroid myopathy (history of gradual progression of bilateral
proximal muscle weakness, and atrophy of proximal muscle groups).