PVSRIPO for Recurrent Glioblastoma (GBM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2015 by Duke University
National Cancer Institute (NCI)
Brain Tumor Research Charity Grant
Information provided by (Responsible Party):
Darell D. Bigner, MD, PhD, Duke University Medical Center
ClinicalTrials.gov Identifier:
First received: December 1, 2011
Last updated: November 11, 2015
Last verified: November 2015

Purpose of the Study:

To determine the maximally tolerated dose (MTD) or optimal dose 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.

Condition Intervention Phase
Malignant Glioma
Biological: PVSRIPO
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Dose-finding and Safety Study of an Oncolytic Polio/Rhinovirus Recombinant Against Recurrent WHO Grade IV Malignant Glioma

Resource links provided by NLM:

Further study details as provided by Duke University:

Primary Outcome Measures:
  • Maximum Tolerated Dose or Optimal Dose [ Time Frame: 28 days post administration of PVSRIPO ] [ Designated as safety issue: Yes ]
    The highest dose level for which the estimated probability that a patient experiences a dose-limiting toxicity (DLT) is less than 20%. Any grade 3 or any Grade 4 toxicity that is not reversible within 2 weeks, or any life-threatening event, or treatment-related death will be considered a DLT. Any grade 2 or higher serious autoimmune toxicities particularly those affecting vital organs (e.g. cardiac, renal, CNS) will be considered a DLT.

Secondary Outcome Measures:
  • Progression Free Survival [ Time Frame: Patients will be followed at a min of 2,4,8,16,24, 32,40 and 48 week intervals after infusion. ] [ Designated as safety issue: No ]
    The Progression Free Survival is defined as the time between initiation of protocol treatment and the first occurrence of disease or death.

  • Overall Survival [ Time Frame: Infusion until 5 years post-infusion ] [ Designated as safety issue: No ]
    The time between initiation of protocol treatment (i.e. infusion) and death with live patients being censored as of the last follow-up

  • Radiographic Response [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Best radiographic response observed within 6 months of infusion.

Estimated Enrollment: 65
Study Start Date: January 2012
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PVSRIPO
PVSRIPO will be delivered in a single infusion directly into the tumor via catheter placed at the time of biopsy. The current dose level is dose level minus one (5 x 10^7 TCID50 (tissue culture infectious dose)).
Biological: PVSRIPO
PVSRIPO will be delivered in a single infusion directly into the tumor via catheter placed at the time of biopsy. The current dose level is dose level minus one (5 x 10^7 TCID50 (tissue culture infectious dose)).
Other Name: Live attenuated, oral (Sabin) serotype 1 poliovirus vaccine

Detailed Description:

PVSRIPO is a genetically recombinant, non-pathogenic poliovirus:rhinovirus chimera with a tumor-specific conditional replication phenotype. It consists of the genome of the live attenuated poliovirus serotype 1 (SABIN) vaccine (PV1S) with its cognate internal ribosomal entry site (IRES) element replaced with that of human rhinovirus type 2 (HRV2). PVSRIPO has been manufactured at NCI-Frederick, NCI, NIH.

Catheter Implantation: PVSRIPO 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 a Cosman-Robert-Wells, MRI-compatible, sterotactic head frame or similar frameless device. Immediately following the stereotactically-guided tumor biopsy, a catheter will be implanted in the operating room (OR) at a site the same or different from that used for the biopsy using sterile techniques. A CT may be used to confirm catheter placement post-operatively.

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 Neuro-Surgical Intensive Care Unit (NSICU) or neuro step down unit just prior to the beginning of infusion. Drug infusion will occur in the NSICU or neuro step down unit 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 ml/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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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. 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/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
    • 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
  6. Poliovirus Immunization Booster. The subject must have received a boost immunization with trivalent inactivated IPOL™ (Sanofi-Pasteur) 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.
  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.
  9. 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 or John Sampson, 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 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 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.
    • 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 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 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, radiation therapy (at least 59Gy), and at least one chemotherapy regiment 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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01491893

Contact: Stevie Threatt 919-684-5301 stevie.threatt@duke.edu
Contact: Susan Boulton, RN 919-684-5301 susan.boulton@duke.edu

United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Stevie Threatt    919-684-5301    stevie.threatt@duke.edu   
Sponsors and Collaborators
Darell D. Bigner, MD, PhD
National Cancer Institute (NCI)
Brain Tumor Research Charity Grant
Principal Investigator: Gordana Vlahovic, MD Duke University
  More Information

No publications provided

Responsible Party: Darell D. Bigner, MD, PhD, Director, Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT01491893     History of Changes
Other Study ID Numbers: Pro00031169, NS20023
Study First Received: December 1, 2011
Last Updated: November 11, 2015
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
Brain Tumor
Poliovirus Vaccine
WHO Grade IV Malignant Glioma

Additional relevant MeSH terms:
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors

ClinicalTrials.gov processed this record on November 27, 2015