|Phase I||Biomarker/Laboratory analysis, Treatment||Active||18 and over||NCI||Pro00031169|
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 resectable, recurrent supratentorial glioblastoma multiforme (GBM) patients. To evaluate immunologic, virologic and histopathologic parameters of the effect of virus infection on GBM tumors.
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 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 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 resectable, recurrent supratentorial GBM based on imaging studies with measurable disease (≥ 1 cm or ≤ 5 cm of contrast-enhancing tumor). Prior histopathology consistent with a World Health Organization (WHO) Grade IV GBM 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 ≥ 100,000/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 sections.
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. Barrier contraceptives must be used throughout the trial in both sexes.
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).
- 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 ≤ 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 or patients have recovered from side effects of such therapy.
- Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study drug or patients have recovered from side effects of such therapy.
- Patients may not have received investigational drugs ≤ 4 weeks prior to starting the study drug or must have 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 multifocal disease, tumors extending into or crossing the corpus callosum or leptomeningeal disease, will be excluded.
- Patients with contrast-enhancing tumors of < 1 cm or > 5 cm diameter in any plane will be excluded.
- Patients with tumor ≤ 1 cm in proximity to the ventricle.
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
Trial Lead Organizations/Sponsors
Darell D. Bigner, MD, PhDNational Cancer Institute
|Allan Friedman, MD||Principal Investigator|
|Stevie Threatt||Ph: 919-684-3657|
|Duke Cancer Institute|
|Karen Carter||Ph: 919-668-2329|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01491893
ClinicalTrials.gov processed this data on November 22, 2013
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