Vaccine Therapy for the Treatment of Newly Diagnosed Glioblastoma Multiforme

Study Overview
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Brief Summary
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The purpose of this research study is to determine if an investigational dendritic cell vaccine, called pp65 DC, is effective for the treatment of a specific type of brain tumor called glioblastoma (GBM) when given with stronger doses of routine chemotherapy.

Detailed Description
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Dendritic cells (DC) are involved in activating, or turning-on, your body's immune system. Your immune system helps guard your body from germs, viruses, and other threats. Although dendritic cells are very strong, the number of them in the body is not high enough to cause a powerful immune response; therefore, more DC are made in a laboratory with cells collected from an individual's blood. In this study, we will make a vaccine that we hope will educate immune cells to target the pp65 antigen, a type of immune marker in GBM, thus resulting in what we call the pp65 DC vaccine. Use of a vaccine that activates your immune system is a type of immunotherapy. It is hoped that by giving the pp65 DC vaccine as a shot under the skin, the immune system will be activated to attack tumor cells in the brain while leaving normal cells alone. To see if the pp65 DC vaccine is effective for the treatment of GBM, subjects will be assigned to different treatment groups. Two groups of subjects will receive the pp65 DC vaccine and one group will receive a placebo.

Official Title
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A Phase II Randomized, Blinded, and Placebo-controlled Trial of CMV RNA-Pulsed Dendritic Cells With Tetanus-Diphtheria Toxoid Vaccine in Patients With Newly-Diagnosed Glioblastoma

Conditions
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Glioblastoma Multiforme, Glioblastoma, Malignant Glioma, Astrocytoma, Grade IV, GBM

Intervention / Treatment
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* Biological: pp65-shLAMP DC with GM-CSF
* Biological: unpulsed PBMC and saline
* Drug: Td
* Drug: Saline
* Biological: pp65-flLAMP DC with GM-CSF


Participation Criteria
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Eligibility Criteria
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Abbreviated Inclusion Criteria: To be assessed at study enrollment prior to standard of care chemo-radiation therapy: Age ≥ 18 years. Histopathologically proven newly-diagnosed de novo GBM (WHO Grade IV glioma) The tumor must have a supratentorial component. Must have undergone definitive surgical resection of tumor with less than approximately 3cm x 3cm residual enhancing tumor as product of longest perpendicular planes by MRI. Recovery from the effects of surgery, postoperative infection, and other complications. Diagnostic contrast-enhanced MRI or CT scan of the brain preoperatively and postoperatively. Karnofsky Performance Status of ≥ 70. Signed informed consent. For females of childbearing potential, negative serum pregnancy test. Women of childbearing potential and male participants must be willing to practice adequate contraception throughout the study and for at least 24 weeks after the last dose of study drug. To be assessed prior to initiation of adjuvant TMZ: Must have completed RT (targeted total dose of 59.4-60.0 Gy over ≤ 7 weeks) and concomitant TMZ (targeted dose of 75mg/m2/d for ≤ 49 days) therapy without significant toxicity that persisted over 4 weeks. History & physical with neurologic examination prior to initiation of adjuvant TMZ. For patients receiving steroids, daily dose must be ≤ 4 mg. CBC with differential with adequate bone marrow function. Adequate renal function. Adequate hepatic function. Abbreviated Exclusion Criteria: To be verified in order to randomize subject: Prior invasive malignancy unless disease free for ≥ 3 years. Metastases detected below the tentorium or beyond the cranial vault and leptomeningeal involvement. Recurrent or multifocal malignant gliomas. HIV, Hepatitis B, or Hepatitis C seropositive. Known active infection or immunosuppressive disease. Prior chemotherapy or radiosensitizers (including Gliadel wafers) for cancers of the head and neck region. Prior radiotherapy to the head or neck, resulting in overlap of radiation fields. Severe, active co-morbidity. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the entire study period. Pregnant or lactating women. Prior allergic reaction to temozolomide, GM-CSF or Td. Prior history of brachial neuritis or Guillain-Barré syndrome. Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry. To be assessed prior to initiation of adjuvant TMZ: Did not start radiation therapy and temozolomide within 7 weeks of surgery. Progression of disease as defined by modified RANO criteria. More than 45 days after completion of radiation therapy and temozolomide

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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pp65-shLAMP DC with GM-CSF and Td<br>Given under the skin at day 22-24 after the first temozolomide cycle then at 2 week intervals. Doses 4-10 will be given on day 22-24 of each temozolomide cycle. Doses will continue until a total of 10 or until progression or unacceptable toxicity. | Biological: pp65-shLAMP DC with GM-CSF<br> <br> * Other names: pp65-shLAMP mRNA DCs with GM-CSF;Drug: Td<br>* All subjects will receive a Td booster before study drug dose #1. Subjects in the experimental arms will receive Td skin prep before study drug doses #3, #6, and #9.<br>* Other names: Tetanus and Diphtheria Toxoid;|
| Experimental: pp65-flLAMP DC with GM-CSF and Td<br>Given under the skin at day 22-24 after the first temozolomide cycle then at 2 week intervals. Doses 4-10 will be given on day 22-24 of each temozolomide cycle. Doses will continue until a total of 10 or until progression or unacceptable toxicity. | Drug: Td<br>* All subjects will receive a Td booster before study drug dose #1. Subjects in the experimental arms will receive Td skin prep before study drug doses #3, #6, and #9.<br>* Other names: Tetanus and Diphtheria Toxoid;Biological: pp65-flLAMP DC with GM-CSF<br> <br> * Other names: pp65-flLAMP mRNA DCs with GM-CSF;|
| Placebo Comparator: unpulsed PBMC and Saline<br>Given under the skin at day 22-24 after the first temozolomide cycle then at 2 week intervals. Doses 4-10 will be given on day 22-24 of each temozolomide cycle. Doses will continue until a total of 10 or until progression or unacceptable toxicity. | Biological: unpulsed PBMC and saline<br> <br> * Other names: Peripheral Blood Mononuclear Cells;Drug: Saline<br> <br> * Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in median overall survival |  | From date of randomization until the date of death, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in immune response | Parameters include ELISPOT for evaluation of cellular immune responses is a sensitive detection assay for evaluation of antigen specific cytokine producing T cells | Change between baseline and vaccine #3, assessed up to 4 weeks | 
| Change in progression-free survival |  | From randomization until first documentation of either disease progression or recurrence assessed up to 24 months | 
| Changes in immune response | Parameters include peak antibody titers to the CMV pp65, reported as humoral response to the specific antigens. | Change between baseline and vaccine #3, assessed up to 4 weeks | 
| Changes in immune response | Parameters include Cytokine Bead Array analysis to detect multiple cytokines secreted by lymphocytes after in vitro stimulation with specific and control antigens, examine the spectrum of Type 0,1,2, and 3 cytokines secreted by T cells after stimulation with overlapping peptides spanning CMV pp65, PHA, and control peptides | Change between baseline and vaccine #3, assessed up to 4 weeks | 
| Changes in immune response | Parameters include cytokine flow cytometric analysis which involves the rapid early detection and analysis of the production of IFN, TNF, and IL-2 prior to cellular secretion following antigen-specific stimulation in vitro as determined by CFC | Change between baseline and vaccine #3, assessed up to 4 weeks |