Viral Therapy in Treating Patients With Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of carcinoembryonic antigen-expressing measles virus (MV-CEA) in treating patients with glioblastoma multiforme that has come back. A virus, called MV-CEA, which has been changed in a certain way, may be able to kill tumor cells without damaging normal cells.

Detailed Description
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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 intratumorally (IT) 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, every 3 and 12 months after progression, and then yearly thereafter for up to 15 years.

Official Title
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Phase I Trial of a Measles Virus Derivative Producing CEA (MV-CEA) in Patients With Recurrent Glioblastoma Multiforme (GBM)

Conditions
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Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Mixed Glioma, Recurrent Glioblastoma

Intervention / Treatment
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* Biological: Carcinoembryonic Antigen-Expressing Measles Virus
* Other: Laboratory Biomarker Analysis
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recurrent grade 3 or 4 glioma, including astrocytoma, oligodendroglioma or mixed glioma with histologic confirmation at initial diagnosis or recurrence Candidate for gross total or subtotal resection Absolute neutrophil count (ANC) >= 1500/uL Platelets (PLT) >= 100,000/uL Total bilirubin =< 1.5 x upper normal limit (ULN) Aspartate aminotransferase (AST) =< 2 x ULN Creatinine =< 2.0 x ULN Hemoglobin (Hgb) >= 9.0 gm/dL Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.3 x ULN Ability to provide informed consent Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Anti-measles virus immunity as demonstrated by immunoglobulin G (IgG) anti-measles antibody levels of >= 1.1 EU/ml as determined by enzyme immunoassay Normal serum CEA levels (< 3 ng/ml) at the time of registration Willing to provide biologic specimens as required by the protocol Negative serum pregnancy test done =< 7 days prior to registration (for women of childbearing potential only) Exclusion Criteria: Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Active infection =< 5 days prior to registration History of tuberculosis or history of purified protein derivative (PPD) positivity Any of the following therapies: Chemotherapy =< 4 weeks prior to registration (6 wks for nitrosourea-based chemotherapy) Immunotherapy =< 4 weeks prior to registration Biologic therapy =< 4 weeks prior to registration Bevacizumab =< 12 weeks prior to registration Non-cytotoxic antitumor drugs, i.e., small molecule cell cycle inhibitors =< 2 weeks prior to registration Radiation therapy =< 6 weeks prior to registration Any viral or gene therapy prior to registration Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment New York Heart Association classification III or IV Requiring blood product support Inadequate seizure control Expected communication between ventricles and resection cavity as a result of surgery Human immunodeficiency virus (HIV)-positive test result, or history of other immunodeficiency History of organ transplantation History of chronic hepatitis B or C Other concurrent chemotherapy, immunotherapy, radiotherapy or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) Exposure to household contacts =< 15 months old or household contact with known immunodeficiency Allergy to measles vaccine or history of severe reaction to prior measles vaccination

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (resection cavity administration)<br>Patients undergo en block resection of their tumor (after confirming diagnosis) on day 1, followed by MV-CEA administered into the resection cavity. | Biological: Carcinoembryonic Antigen-Expressing Measles Virus<br>* Given via injection into resection cavity or around tumor bed and/or IT<br>* Other names: MV-CEA;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo en bloc resection<br>|
| Experimental: Arm B (intratumoral and resection cavity administration)<br>Patients undergo stereotactic biopsy (to confirm the diagnosis) and placement of a catheter within the tumor, followed by MV-CEA IT 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. | Biological: Carcinoembryonic Antigen-Expressing Measles Virus<br>* Given via injection into resection cavity or around tumor bed and/or IT<br>* Other names: MV-CEA;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo en bloc resection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I) Maximum Tolerated Dose (MTD) (Phase I) as Measured by the Number of Participants With Dose Limiting Toxicities | The Maximum Tolerated Dose (MTD) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Dose-limiting toxicities include hematologic events grade 3 or higher (except grade 3 ANC lasting < 72 hours), non-hematologic events graded 3 or higher (except grade 3 nausea, vomiting, or diarrhea were to be considered DLT only if patient was receiving the max supportive care and alopecia was not considered dose limiting), neurologic toxicity grade 2 or higher, grade 2 allergic reactions asymptomatic bronchospasm and/or urticarial, grade 3 or higher allergic reactions, viremia lasting for 6 weeks or more from last viral administration deemed at least possibly related to treatment. The number of patients reporting a dose-limiting event are reported. | 2 weeks | 
| Number of Patients Experiencing Grade 3+ Adverse Events, Per NCI CTCAE Version 3.0 | The number of patients experiencing grade 3+ adverse events (overall and by arm) will be tabulated and summarized in this patient population. | Up to 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response, Defined as the Best Objective Status Recorded From the Start of the Treatment Until Disease Progression/Recurrence | The number of responses will be summarized by simple descriptive summary statistics delineating response type. CR = total disappearance of all tumor with patient off corticosteroids or only on adrenal replacement maintenance. PR= 50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose. REGR = unequivocal reduction in size of contrast-enhancement or decrease in mass effect as agreed upon independently by primary physician and quality control physicians; no new lesions. SD = failure to qualify for CR, PR, REGR, or PROG. PROG = >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions and/or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions. | Up to 2 weeks | 
| Progression-free Survival (PFS) | Percentage of patients who are progression free at 3 and 6 months (PFS3 and PFS6) will be summarized descriptively. Progression-free survival is defined as the length of time from date of registration to a) date of progression or death due to any cause or b) last follow-up. Progression is defined as a >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions, and/or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions. | 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 | 
| Survival | Overall survival is defined as the length of time from date of registration to a) death due to any cause or b) last follow-up. Reported using standard Kaplan-Meier estimation method. | Up to 13 years |