PVSRIPO With/Without Lomustine
This clinical trial will investigate the use of oncolytic polio/rhinovirus recombinant (PVSRIPO) alone or in combination with lomustine (a chemotherapy drug) in adult patients with recurrent grade IV glioma.
PVSRIPO is a genetically engineered, non-pathogenic version of poliovirus that does not cause disease. Normally, poliovirus can only infect and enter cells by binding to CD155, a protein on the surface of those cells. PVSRIPO takes advantage of the observation that CD155 levels are abnormally high in certain cancer cells, like glioblastoma, and has been found to play an important role in tumor cell migration, invasion, and metastasis. When PVSRIPO is administered to the tumor site, the modified poliovirus will selectively infect, and ultimately kill, tumor cells that make CD155. Additional modifications ensure that PVSRIPO is designed to only replicate in non-neuronal cells, further biasing it towards glioblastoma cells.
The objective of this Phase II trial is to assess the efficacy of PVSRIPO with or without lomustine, in treating patients with recurrent grade IV glioma. PVSRIPO will be delivered directly to the tumor site using convection-enhanced delivery (CED). Results will be compared to a historical control group (past cases of grade IV glioma), and eligible participants will be randomized to the following treatment groups:
- Experimental Group 1: PVSRIPO
- Experimental Group 2: PVSRIPO + lomustine
- Patients must have a recurrent supratentorial WHO grade IV malignant glioma based on imaging studies with measurable disease (≥ 1 cm and ≤ 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.
- Age ≥ 18 years of age at the time of entry into the study.
- Karnofsky Performance Score (KPS) ≥ 70%.
- Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy.
- Total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase ≤ 2.5 x normal prior to biopsy.
- Neutrophil count ≥ 1000 prior to biopsy.
- Hemoglobin ≥ 9 prior to biopsy.
- Platelet count ≥ 125,000/µl prior to biopsy; Platelet count ≥ 100,000/µl prior to infusion.
- Creatinine ≤ 1.2 x normal range prior to biopsy.
- Positive serum anti-poliovirus titer prior to biopsy.
- The patient must have received a boost immunization with trivalent inactivated IPOL™ (Sanofi-Pasteur) at least 1 week prior to administration of the study agent.
- At the time of biopsy, prior to administration of virus, the presence of recurrent tumor must be confirmed by histopathological analysis.
- A signed informed consent form approved by the 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.
- Able to undergo brain MRI with and without contrast.
For the most up-to-date list of criteria, please visit clinicaltrials.gov.
- Females who are pregnant or breast-feeding. Female patients of child-bearing potential or female sexual partners (who are of child-bearing potential) of male patients must use at least one of the following methods of medically acceptable contraceptives: approved hormonal contraceptives (such as birth control pills, patches, implants or infusions), an intrauterine device (IUD), or a barrier method of contraception (such as a condom or diaphragm) used with spermicide. Because all patients are required to have a boost immunization of trivalent inactivated IPOL™, there should be no risk of transmission of a mother to her fetus after receiving intracranial PVSRIPO. As such, patients who become pregnant after receiving PVSRIPO will continue to be monitored in the same manner, i.e. per protocol, unless the assessment is contra-indicated during pregnancy. Partners who become pregnant will sign a Pregnant Partner Information Form and information regarding the pregnancy and its outcome may be collected.
- Patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons or their designate.
- Patients with severe, active co-morbidity, defined as follow:
- 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.
- Patients with impaired cardiac function or clinically significant cardiac disease, such as congestive heart failure requiring treatment (New York Heart Association Class ≥ 2), uncontrolled hypertension or clinically significant arrhythmia; QTcF > 470 msec on electrocardiogram (ECG) if performed or congenital long QT syndrome; acute myocardial infarction or unstable angina pectoris < 3 months prior to study.
- Patients with known lung (FEV1 < 50%) disease or uncontrolled diabetes mellitus.
- Patients with albumin allergy.
- Patients with gadolinium allergy.
- Patients with a previous history of neurological complications due to poliovirus infection.
- Patients who have not recovered from the toxic effects of prior chemo- and/or radiation therapy. 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 who have not completed all standard of care treatments, including surgical procedure and radiation therapy (at least 59Gy).
- If the MGMT (O(6)-methylguanine-DNA methyltransferase) 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 methylation status is unknown at time of screening, patients must have received at least one chemotherapy regimen prior to participating in this trial.
- Patients with neoplastic lesions in the brainstem, cerebellum, or spinal cord, radiological evidence of active (growing) multifocal disease, subependymal or leptomeningeal disease.
- Patients with undetectable anti-tetanus toxoid IgG (Immunoglobulin G).
- Patients with known history of agammaglobulinemia.
- Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to admission for PVSRIPO infusion.
- Patients with worsening steroid myopathy (history of gradual progression of bilateral proximal muscle weakness, and atrophy of proximal muscle groups).
- 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.
- Patients with a known history of hypersensitivity to lomustine, dacarbazine, or any components of lomustine.
For the most up-to-date list of criteria, please visit clinicaltrials.gov.