Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Viral Therapy in Treating Patients With Recurrent Glioblastoma Multiforme

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	MAYO-MC0671 MAYO-06-004440, NCT00390299

Objectives

Primary

1. 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.
2. Determine the maximum tolerated dose of this oncolytic virus in these patients.
3. Determine viral gene expression at each dose level as manifested by CEA titers in patients treated with this oncolytic virus.
4. Assess viremia, viral replication, and measles virus shedding/persistence after intratumoral administration of this oncolytic virus.
5. Assess humoral and cellular immune response to the injected virus in these patients.

Secondary

1. Determine, preliminarily, the antitumor efficacy of this vaccine in these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed grade 4 astrocytoma (glioblastoma multiforme) at primary diagnosis and/or recurrence



• Recurrent disease



• Candidate for gross total or subtotal resection
  • No expected communication between ventricles and resection cavity as a result of surgery



• Antimeasles virus immunity as demonstrated by IgG antimeasles antibody levels of ≥ 20 EU/mL as determined by enzyme immunoassay



• Human carcinoembryonic antigen (CEA) < 3 ng/mL

Prior/Concurrent Therapy:

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosourea-based chemotherapy) and recovered
• More than 4 weeks since prior immunotherapy
• More than 4 weeks since prior biologic therapy
• More than 2 weeks since prior noncytotoxic antitumor drugs (i.e., small molecule cell cycle inhibitors)
• More than 6 weeks since prior radiotherapy
• No prior viral or gene therapy
• No history of organ transplantation
• No concurrent chemotherapy, other immunotherapy, radiotherapy, or any other ancillary therapy considered investigational (utilized for a non-FDA-approved indication and in the context of a research investigation)
• No concurrent enrollment on any other study involving a pharmacologic agent (e.g., drugs, biologics), immunotherapy approaches, or gene therapy whether for symptom control or therapeutic intent

Patient Characteristics:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST ≤ 2 times ULN
• Creatinine ≤ 2.0 times ULN
• Hemoglobin ≥ 9.0 g/dL
• PT and aPTT ≤ 1.3 times ULN
• Willing to provide biological specimens as required by the study
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active infection within the past 5 days
• No history of tuberculosis or purified protein derivative positivity
• No New York Heart Association class III or IV cardiac disease
• Adequate seizure control
• HIV negative
• No history of other immunodeficiency
• No history of chronic hepatitis B or C
• No exposure (household contacts) to children ≤ 15 months of age or to people with known immunodeficiency
• No allergy to measles vaccine or history of severe reaction to prior measles vaccination
• No requirement for blood product support

Expected Enrollment

A total of 40 patients will be accrued for this study.

Outcomes

Adverse events profile, in terms of number and severity of all adverse events, as assessed by NCI CTCAE v3.0
Overall toxicity incidence and toxicity profile (by dose level, patient, and tumor site) as assessed by NCI CTCAE v3.0
Time until any treatment related toxicity
Time until treatment-related toxicity ≥ grade 3
Time until hematologic nadirs (WBC, absolute neutrophil count, platelet count)
Maximum tolerated dose of vaccine as assessed by NCI CTCAE v3.0
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
Viral gene expression at each dose level as assessed by CEA titer
Viremia following intratumoral administration of vaccine as assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) of peripheral blood mononuclear cells
Measles virus shedding/persistence following intratumoral administration of vaccine as assessed by RT-PCR
Viral replication following intratumoral administration of vaccine as assessed by in situ hybridization and Vero cell overlay

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.
Humoral and cell. imm. resp. by antimeasles virus-specific antibody level (IgG) at baseline, 28 days after resection, and every 2 mo until prog
Humoral and cell. imm. resp. by lymphoproliferative assay and interferon-gamma ELISPOT assay performed at baseline and at 28 days after tumor resection
Progression-free survival at 3 and 6 months
Time to disease progression
Time to treatment failure (due to progression, unacceptable toxicity, or refusal to continue participation by the patient)

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 stereotactic biopsy (to confirm the diagnosis) and 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.

Trial Contact Information

Trial Lead Organizations

Mayo Clinic Cancer Center

Evanthia Galanis, MD, Protocol chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Jan Buckner, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Brian O'Neill, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Corey Raffel, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Frederic Meyer, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
John Atkinson, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Richard Marsh, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
David Piepgras, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Timothy Kaufmann, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu
Gregory Poland, MD, Protocol co-chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu

U.S.A.
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623

Registry Information
Official Title		Phase I Trial of a Measles Virus Derivative Producing CEA (MV-CEA) in Patients with Recurrent Glioblastoma Multiforme (GBM)
Trial Start Date		2006-10-30
Trial Completion Date		2011-06-30 (estimated)
Registered in ClinicalTrials.gov		NCT00390299
Date Submitted to PDQ		2006-08-30
Information Last Verified		2009-07-05
NCI Grant/Contract Number		CA15083

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