Viral Therapy in Treating Patients With Recurrent Glioblastoma Multiforme

Phase 1

Completed

Conditions: Anaplastic Astrocytoma
Recurrent Glioblastoma
Anaplastic Oligodendroglioma
Mixed Glioma

Interventions: Biological: Carcinoembryonic Antigen-Expressing Measles Virus
Other: Laboratory Biomarker Analysis
Procedure: Therapeutic Conventional Surgery

Registration Number: NCT00390299

Lead Sponsor: Mayo Clinic

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (resection cavity administration)	Carcinoembryonic Antigen-Expressing Measles Virus	Patients undergo en block resection of their tumor (after confirming diagnosis) on day 1, followed by MV-CEA administered into the resection cavity.
Arm A (resection cavity administration)	Laboratory Biomarker Analysis	Patients undergo en block resection of their tumor (after confirming diagnosis) on day 1, followed by MV-CEA administered into the resection cavity.
Arm A (resection cavity administration)	Therapeutic Conventional Surgery	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)	Therapeutic Conventional Surgery	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.
Arm B (intratumoral and resection cavity administration)	Carcinoembryonic Antigen-Expressing Measles Virus	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.
Arm B (intratumoral and resection cavity administration)	Laboratory Biomarker Analysis	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.

Primary Outcome Measures

Name	Time	Method
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	2 weeks	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.
Number of Patients Experiencing Grade 3+ Adverse Events, Per NCI CTCAE Version 3.0	Up to 2 weeks	The number of patients experiencing grade 3+ adverse events (overall and by arm) will be tabulated and summarized in this patient population.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	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	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.
Best Response, Defined as the Best Objective Status Recorded From the Start of the Treatment Until Disease Progression/Recurrence	Up to 2 weeks	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.
Survival	Up to 13 years	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.