PVSRIPO for Recurrent Glioblastoma (GBM)

Inclusion Criteria:

1. Disease Status. Patients must have a recurrent supratentorial WHO Grade IV malignantglioma based on imaging studies with measurable disease (≥ 1 cm or ≤ 5.5 cm ofcontrast-enhancing tumor). Prior histopathology consistent with a World HealthOrganization (WHO) Grade IV malignant glioma confirmed by the study pathologist, RogerMcLendon, or his designate.
2. Age. Due to the potential implications of the treatment on the developing CNS, allpatients must be ≥ 18 years of age at the time of entry into the study.
3. Performance Status. The patient must have a Karnofsky Performance Score (KPS) of ≥ 70%at the time of entry.
4. Laboratory Studies

• Platelet count ≥ 125,000/microliter prior to biopsy. Platelets ≥ 100,000/microliter prior to infusion
• Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy
• Positive serum anti-poliovirus titer prior to biopsy (except for retreatment)
• Creatinine ≤ 1.2 x normal prior to biopsy
• Total bilirubin, SGOT, SGPT, alkaline phosphatase ≤ 2.5 x normal prior to biopsy
• Neutrophil count ≥ 1000 prior to biopsy
• Hemoglobin ≥ 9 prior to biopsy

5. Poliovirus Immunization Booster. The subject must have received a boost immunizationwith trivalent inactivated IPOL™ (Sanofi-Pasteur) at least 1 week prior toadministration of the study agent.
6. Disease Confirmation. At the time of biopsy, prior to administration of virus, thepresence of recurrent tumor must be confirmed by histopathological analysis.
7. Informed Consent. A signed informed consent form approved by the Duke UniversityInstitutional Review Board (IRB) will be required for patient enrollment into thestudy. Patients must be able to read and understand the informed consent document andmust sign the informed consent indicating that they are aware of the investigationalnature of this study.
8. Brain MRI. Able to undergo brain MRI with and without contrast

Exclusion Criteria:

1. Pregnancy. Because of the unknown risk of virus administration potentially affecting adeveloping fetus or growing infant, females who are pregnant or breast-feeding duringthe study period will be excluded. Adults of reproductive potential not employing aneffective method of birth control will be excluded. Sexually active women of childbearing potential, whose partner is male, must use medically accepted birth control.Sexually active men, whose partner is a female of child bearing potential, must use amedically accepted birth control.
2. Disease Status. Because patients will receive drug intracerebrally, patients with animpending, life-threatening cerebral herniation syndrome, based on the assessment ofthe study neurosurgeons, Allan Friedman, John Sampson, or Peter Fecci, or theirdesignate, will be excluded.
3. Medical Conditions. Because the potential toxicities from the agent being studied inthis protocol may be similar to some known diseases or may be more dangerous in thecontext of certain known diseases, the following patients will be excluded to avoidconfounding the study results:

• Patients with an active infection requiring intravenous treatment or having anunexplained febrile illness (Tmax > 99.5 F/37.5 C).
• Patients with known immunosuppressive disease or known human immunodeficiencyvirus infection.
• Unstable or severe intercurrent medical conditions such as severe heart (New YorkHeart Association Class 3 or 4) or known lung (FEV1 < 50%) disease, uncontrolleddiabetes mellitus.
• Albumin allergy. Albumin is added to the agent as a stabilizer. Patients with aknown allergy will be excluded.
• Current or history of anaphylactic reaction to gadolinium. Gadolinium is used ascontrast for the MRI.

4. Previous Poliomyelitis. A history of neurological complications due to poliovirusinfection would imply previous virus replication in the CNS. Based on animal studies,previous exposure to poliovirus administered intracerebrally can reduce subsequentvirus replication in the CNS.
5. Prior Therapy. Patients who have not recovered from the toxic effects of priorchemotherapy and/or radiation therapy will be excluded. Guidelines for this recoveryperiod are dependent upon the specific therapeutic agent being used:

• Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except fornitrosourea (6 weeks) or metronomic dosed chemotherapy such as daily etoposide orcyclophosphamide (1 week)] prior to starting the study drug unless patients haverecovered from side effects of such therapy.
• Patients may not have received immunotherapy ≤ 4 weeks prior to starting thestudy drug unless patients have recovered from side effects of such therapy.
• Patients may not be less than 12 weeks from radiation therapy, unless progressived disease outside of the radiation field or 2 progressive scans at least 4 weeksapart or histopathologic confirmation
• Patients must have completed all standard of care treatments including surgicalprocedure and radiation therapy (at least 59Gy):
• If the MGMT promoter in their tumor is known to be unmethylated, patientsare not mandated to have received chemotherapy prior to participating inthis trial.
• If the MGMT promoter in their tumor is known to be methylated or the MGMTpromoter status is unknown at the time of screening, patients must havereceived at least one chemotherapy regimen prior to participating in thistrial.

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 withevidence of diffuse subependymal disease or tumor in the brainstem, cerebellum, spinalcord, or CSF will be excluded. Since the study agent is a local treatment, patientswith radiological evidence of active (growing) multifocal disease, tumors extendinginto or crossing the corpus callosum or leptomeningeal disease, will be excluded.
7. Subjects must not have diagnosis of agammaglobulinemia. Patients with the followingwill be excluded:

• Undetectable anti-tetanus toxoid IgG (except for retreatment)
• Known history of agammaglobulinemia

8. Patient on greater than 4mg per day of dexamethasone within the 2 weeks prior toadmission for PVSRIPO infusion
9. Patient has worsening steroid myopathy (history of gradual progression of bilateralproximal muscle weakness, and atrophy of proximal muscle groups)
10. Patients with prior, unrelated malignancy requiring current active treatment with theexception of cervical carcinoma in situ and adequately treated basal cell or squamouscell carcinoma of the skin Eligibility Criteria for Retreatment: Subjects can be considered for PVSRIPO retreatment if they meet some of the pertinentinclusion and exclusion criteria above. In addition, the subject must also satisfy thefollowing criteria:

• Patient must have benefited from initial treatment with PVSRIPO (i.e. be at least 12months following their initial PVSRIPO infusion).
• Patient must have a recurrence of their supratentorial WHO grade IV malignant gliomabased on imaging studies with measurable disease (≥ 1 cm of contrast-enhancing tumor).
• At the time of biopsy, prior to administration of virus, the presence of recurrenttumor must be confirmed by histopathological analysis, unless already proven withinthe last 3 months via tissue sampling (biopsy or resection).
• The patient must have received a new boost immunization with trivalent inactivatedIPOL™ (Sanofi-Pasteur) at least 1 week and no more than 4 weeks prior tore-administration of the study agent. The boost immunization may be obtained locally,prior to signing consent, as long as the patient has been informed about this studyprocedure via phone script.
• A new signed informed consent form for retreatment approved by the Duke UniversityInstitutional Review Board (IRB) will be required for retreatment. Patients must beable to read and understand the informed consent document and must sign the informedconsent indicating that they are aware of the investigational nature of this study.