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PVSRIPO for Recurrent Glioblastoma (GBM) (PVSRIPO)

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ClinicalTrials.gov Identifier: NCT01491893
Recruitment Status : Active, not recruiting
First Posted : December 14, 2011
Last Update Posted : September 12, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
Brief Summary:

Purpose of the Study:

To determine the maximally tolerated dose (MTD) or the Phase II 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 or disease Intervention/treatment Phase
GBM Glioblastoma Glioma Malignant Glioma Biological: PVSRIPO Phase 1

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, stereotactic 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 or 3010 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 following the post-PVSRIPO infusion MRI.

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.

Selected patients who benefited from the initial infusion of PVSRIPO within this protocol will be eligible for a second infusion. Catheter implantation, PVSRIPO infusion at dose level -1, gadolinium distribution quantitation, and biopsy sampling will occur according to the procedures previously described in this protocol. In addition to the PVSRIPO retreat infusion, the patients will also receive a single dose of lomustine at approximately 8 weeks post-infusion of PVSRIPO. All procedures previously described will be followed; however, the addition of the single dose of lomustine will alter the schedule of events that was previously described.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 61 participants
Intervention Model: Single Group Assignment
Masking: None (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
Actual Study Start Date : April 25, 2012
Primary Completion Date : June 27, 2017
Estimated Study Completion Date : January 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
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


Outcome Measures

Primary Outcome Measures :
  1. Maximum Tolerated Dose or Optimal Dose [ Time Frame: 28 days post administration of PVSRIPO ]
    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 :
  1. 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. ]
    The Progression Free Survival is defined as the time between initiation of protocol treatment and the first occurrence of disease or death.

  2. Overall Survival [ Time Frame: Infusion until 5 years post-infusion ]
    The time between initiation of protocol treatment (i.e. infusion) and death with live patients being censored as of the last follow-up

  3. Radiographic Response [ Time Frame: 6 months ]
    Best radiographic response observed within 6 months of infusion.


Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
    • 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 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.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01491893


Locations
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
National Cancer Institute (NCI)
Brain Tumor Research Charity Grant
Istari Oncology, Inc.
Investigators
Principal Investigator: Dina Randazzo, DO Duke University
Study Director: Darell D Bigner, MD, PhD Istari Oncology, Inc.
More Information

Additional Information:
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT01491893     History of Changes
Other Study ID Numbers: Pro00031169
NS20023 ( Other Grant/Funding Number: National Institute of Neurological Disorders and Stroke )
First Posted: December 14, 2011    Key Record Dates
Last Update Posted: September 12, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

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

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Vaccines
Immunologic Factors
Physiological Effects of Drugs