Viral Therapy in Treating Patients With Recurrent Glioblastoma Multiforme

• MTD, defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least 1/3 of patients (at least 2/6 new patients) or the highest dose level for Arm B, if =< 1/6 patients experience dose-limiting toxicity [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]
  
• Number and severity of all adverse events, per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population.
  
  
• Number and severity of grade 3+ adverse events, per NCI CTCAE version 3.0 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  The number and severity of grade 3+ adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population.
  
  
• Overall toxicity incidence, per NCI CTCAE version 3.0 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  Overall toxicity incidence will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
  
  
• Time until any treatment related toxicity [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  
• Time until hematologic nadir (white blood cells [WBC], ANC, platelets) [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  
• Time until treatment related grade 3+ toxicity [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  
• Toxicity profile by dose level, patient, and tumor site, per NCI CTCAE version 3.0 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  Toxicity profiles by dose level, patient, and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
  
  

• Best response, defined as the best objective status recorded from the start of the treatment until disease progression/recurrence [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  The number of responses will be summarized by simple descriptive summary statistics delineating response type (complete response vs partial response vs regression), as well as stable and progressive disease in this patient population.
  
  
• Progression-free survival (PFS) [ Time Frame: Length of time from date of registration to a) date of progression or death due to any cause or b) last follow-up, assessed up to 6 months ] [ Designated as safety issue: No ]
  Percentage of patients who are progression free at 3 and 6 months (PFS3 and PFS6) will be summarized descriptively.
  
  
• Survival [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  Reported using standard Kaplan-Meier estimation method.
  
  
• Time to disease progression [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  Reported using standard Kaplan-Meier estimation method.
  
  
• Time to treatment failure [ Time Frame: Time from registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 15 years ] [ Designated as safety issue: No ]
  

• CEA titers [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  
• Change in CD4 counts [ Time Frame: Baseline to day 28 ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  
• Change in CD46 status [ Time Frame: Baseline to up to day 5 ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  
• Change in CD8 counts [ Time Frame: Baseline to day 28 ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  
• Change in viral shedding [ Time Frame: Baseline to day 28 ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  
• Change in viremia [ Time Frame: Baseline to up to 15 years ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  
• Measles virus specific immunity, in terms of change in interferon gamma [ Time Frame: Baseline to day 28 ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  
• Measles virus specific immunity, in terms of change in lymphoproliferative assay results [ Time Frame: Baseline to day 28 ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  
• Viral propagation in tumor [ Time Frame: Up to day 5 ] [ Designated as safety issue: No ]
  Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlates between these laboratory values and other outcome measures like response and dose levels will be carried out in an exploratory manner.
  
  

PRIMARY OBJECTIVES:

I. To assess the safety and toxicity of intratumoral and resection cavity administration of an Edmonston's strain measles virus genetically engineered to produce CEA (MV-CEA) in patients with recurrent glioblastoma multiforme.

II. To determine the maximum tolerated dose (MTD) of MV-CEA. III. To characterize viral gene expression at each dose level as manifested by CEA titers.

IV. To assess viremia, viral replication, and measles virus shedding/persistence following intratumoral administration.

V. To assess humoral and cellular immune response to the injected virus. VI. To assess in a preliminary fashion antitumor efficacy of this approach.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 sequential treatment arms.

ARM A (RESECTION CAVITY ADMINISTRATION): Patients undergo en block resection of their tumor (after confirming diagnosis) on day 1, followed by MV-CEA administered into the resection cavity.

ARM B (INTRATUMORAL AND RESECTION CAVITY ADMINISTRATION): Patients undergo stereotactic biopsy (to confirm the diagnosis) and placement of a catheter within the tumor, followed by carcinoembryonic antigen-expressing measles virus administered into the tumor through the catheter over 10 minutes on day 1. Patients then undergo en block resection of their tumor with computer-assisted stereotactic techniques on day 5, followed by MV-CEA administered around the tumor bed.

After completion of study treatment, patients are followed up at 28 days (non-cohort I patients), 7 weeks (patients in cohort I only), every 2 months until progression, 3 months after progression, 12 months after progression, and then yearly thereafter for up to 15 years.