PVSRIPO for Recurrent Glioblastoma (GBM)
Condition: GBM; Glioblastoma; Glioma; Malignant Glioma
MeSH terms: Glioblastoma; Glioma
Intervention: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)
Intervention description: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)
Intervention MeSH terms: Vaccines
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 61.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GBM; Brain Tumor; Poliovirus Vaccine; WHO Grade IV Malignant Glioma

Summary:

      Purpose of the Study:

      To determine the maximally tolerated dose (MTD) and the Recommended Phase 2 Dose (RP2D) of
      PVSRIPO when delivered intracerebrally by convection-enhanced delivery (CED). To obtain
      correlative mechanistic evidence of PVSRIPO's effects on infected WHO Grade IV malignant
      glioma tumors and to estimate progression-free survival (PFS) and overall survival (OS) in
      recurrent WHO Grade IV malignant glioma patients. To obtain information about clinical
      response rates to intratumoral inoculation of PVSRIPO. To estimate the efficacy of PVSRIPO
      administered at the optimal dose.
    

Eligibility criteria:

        Inclusion Criteria:

          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. 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 immunization
             with trivalent inactivated IPOL™ (Sanofi-Pasteur) at least 1 week prior to
             administration of the study agent.

          6. Disease Confirmation. At the time of biopsy, prior to administration of virus, the
             presence of recurrent tumor must be confirmed by histopathological analysis.

          7. 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.

          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 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 accepted birth control.
             Sexually active men, whose partner is a female of child bearing potential, must use a
             medically accepted birth control.

          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, John Sampson, or Peter Fecci, 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 intravenous treatment or having an
                  unexplained febrile illness (Tmax > 99.5 F/37.5 C).

               -  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 known 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.

               -  Current or history of anaphylactic reaction to gadolinium. 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 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.

               -  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 be less than 12 weeks from radiation therapy, unless progressive
                  d disease outside of the radiation field or 2 progressive scans at least 4 weeks
                  apart or histopathologic confirmation

               -  Patients must have completed all standard of care treatments including surgical
                  procedure and radiation therapy (at least 59Gy):

                    -  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.

                    -  If the MGMT promoter in their tumor is known to be methylated or the MGMT
                       promoter status is unknown at the time of screening, patients must have
                       received at least one chemotherapy regimen 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:

               -  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 to
             admission for PVSRIPO infusion

          9. Patient has worsening steroid myopathy (history of gradual progression of bilateral
             proximal muscle weakness, and atrophy of proximal muscle groups)

         10. 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

        Eligibility Criteria for Retreatment:

        Subjects can be considered for PVSRIPO retreatment if they meet some of the pertinent
        inclusion and exclusion criteria above. In addition, the subject must also satisfy the
        following criteria:

          -  Patient must have benefited from initial treatment with PVSRIPO (i.e. be at least 12
             months following their initial PVSRIPO infusion).

          -  Patient must have a recurrence of their supratentorial WHO grade IV malignant glioma
             based 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 recurrent
             tumor must be confirmed by histopathological analysis, unless already proven within
             the last 3 months via tissue sampling (biopsy or resection).

          -  The patient must have received a new boost immunization with trivalent inactivated
             IPOL™ (Sanofi-Pasteur) at least 1 week and no more than 4 weeks prior to
             re-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 study
             procedure via phone script.

          -  A new signed informed consent form for retreatment approved by the Duke University
             Institutional Review Board (IRB) will be required for retreatment. 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.