Viral Therapy in Treating Patients With Recurrent Glioblastoma Multiforme
RATIONALE: The measles virus, that has been changed in a certain way, may kill tumor cells without damaging normal cells.
PURPOSE: This phase I trial is studying the side effects and best dose of viral therapy in treating patients with recurrent glioblastoma multiforme.
Brain and Central Nervous System Tumors
Biological: carcinoembryonic antigen-expressing measles virus
Genetic: fluorescence in situ hybridization
Genetic: reverse transcriptase-polymerase chain reaction
Other: immunohistochemistry staining method
Other: immunologic technique
Other: laboratory biomarker analysis
Procedure: adjuvant therapy
Procedure: conventional surgery
Procedure: needle biopsy
Procedure: neoadjuvant therapy
|Study Design:||Primary Purpose: Treatment|
|Official Title:||Phase I Trial of a Measles Virus Derivative Producing CEA (MV-CEA) in Patients With Recurrent Glioblastoma Multiforme (GBM)|
- Adverse events profile, in terms of number and severity of all adverse events, as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
- Overall toxicity incidence and toxicity profile (by dose level, patient, and tumor site) as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
- Time until any treatment related toxicity [ Designated as safety issue: Yes ]
- Time until treatment-related toxicity ≥ grade 3 [ Designated as safety issue: Yes ]
- Time until hematologic nadirs (WBC, absolute neutrophil count, platelet count) [ Designated as safety issue: No ]
- Maximum tolerated dose of vaccine as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
- Correlate viremia, human CEA titers, viral propagation in tumor, viral shedding, CD46 status, delayed-type hypersensitivity results, CD4 and CD8 counts, lymphoproliferative assay, and ELISPOT assay with response and toxicity [ Designated as safety issue: Yes ]
- Viral gene expression at each dose level as assessed by CEA titer [ Designated as safety issue: No ]
- Viremia following intratumoral administration of vaccine as assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) of peripheral blood mononuclear cells [ Designated as safety issue: No ]
- Measles virus shedding/persistence following intratumoral administration of vaccine as assessed by RT-PCR [ Designated as safety issue: No ]
- Viral replication following intratumoral administration of vaccine as assessed by in situ hybridization and Vero cell overlay [ Designated as safety issue: No ]
- CR, PR, regress, stable dis, & prog dis by neur exam, MRI, and/or CT scan for bidimens. meas. dis & eval dis. at baseline, 28 days after resection, and then every 2 mo. until progr. [ Designated as safety issue: No ]
- Humoral and cell. imm. resp. by antimeasles virus-specific antibody level (IgG) at baseline, 28 days after resection, and every 2 mo until prog [ Designated as safety issue: No ]
- Humoral and cell. imm. resp. by lymphoproliferative assay and interferon-gamma ELISPOT assay performed at baseline and at 28 days after tumor resection [ Designated as safety issue: No ]
- Progression-free survival at 3 and 6 months [ Designated as safety issue: No ]
- Time to disease progression [ Designated as safety issue: No ]
- Time to treatment failure (due to progression, unacceptable toxicity, or refusal to continue participation by the patient) [ Designated as safety issue: Yes ]
|Study Start Date:||October 2006|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
- Determine the safety and toxicity of intratumoral and/or resection cavity administration of a recombinant, attenuated Edmonston B vaccine strain derivative of measles virus genetically engineered to produce human carcinoembryonic antigen (CEA) in patients with recurrent glioblastoma multiforme.
- Determine the maximum tolerated dose of this oncolytic virus in these patients.
- Determine viral gene expression at each dose level as manifested by CEA titers in patients treated with this oncolytic virus.
- Assess viremia, viral replication, and measles virus shedding/persistence after intratumoral administration of this oncolytic virus.
- Assess humoral and cellular immune response to the injected virus in these patients.
- Determine, preliminarily, the antitumor efficacy of this vaccine in these patients.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 sequential treatment groups.
- Group 1 (resection cavity administration): Patients undergo en block resection of their tumor (after confirming diagnosis) on day 1, followed by recombinant measles virus encoding human carcinoembryonic antigen (MV-CEA) administered into the resection cavity over 10 minutes.
- Group 2 (intratumoral and resection cavity administration): Patients undergo placement of a catheter within the tumor, followed by MV-CEA administration into the tumor through the catheter over 10 minutes on day 1. Patients undergo en block resection of their tumor with computer-assisted stereotactic techniques on day 5, followed by MV-CEA administered around the tumor bed.
In both groups, cohorts of 1-6 patients receive escalating doses of MV-CEA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD in group 1 has been determined, patients are assigned to group 2. The MTD in group 1 is used to determine the starting dose in group 2. At least 10 patients are treated at the MTD determined in group 2.
Biopsy specimen, resected tumor, normal tissue, and peripheral blood are collected during study for immunologic and biomarker correlative studies, including analysis of CD46 receptor levels (by immunohistochemistry [IHC]), measles virus N protein (by IHC), measles and viral gene expression and replication (by in situ hybridization), CEA monitoring (by immunoassay), measles virus N mRNA (by reverse transcriptase-polymerase chain reaction), and measles virus immunity. Assessments of immune competence and peripheral response to viral administration are also performed.
After completion of study treatment, patients are followed periodically for up to 15 years.
PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
|United States, Minnesota|
|Mayo Clinic Cancer Center||Recruiting|
|Rochester, Minnesota, United States, 55905|
|Contact: Clinical Trials Office - All Mayo Clinic Locations 507-538-7623|
|Study Chair:||Evanthia Galanis, MD||Mayo Clinic|