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Adult patients who have surgical resection of newly diagnosed glioblastoma multiforme will be treated with radiotherapy/chemotherapy followed by dendritic cell vaccine. Chemotherapy will be administered after three vaccinations for one year or until progression of disease.
Two to six weeks after surgery, patients with newly diagnosed glioblastoma multiforme (GBM) will undergo a six-week course of radiotherapy with concurrent chemotherapy (temozolomide). Between three and seven weeks after completing radiotherapy/chemotherapy, patients will undergo leukapheresis to collect white blood cells. These cells will be grown into dendritic cells, and cultured with tumor cells from the individual patient. Vaccinations will be given every two weeks for a total of three vaccinations. Four weeks after the third vaccination patients will resume chemotherapy for one year or until disease progression.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vaccine | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Autologous Dendritic Cell | Biological | Vaccine given by cervical lymph node injection 3 times every other week |
|
| Measure | Description | Time Frame |
|---|---|---|
| Tumor-specific Cytotoxic T-cell Response | MRI & pheresis post vaccine | Day 42 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Adverse Events: Toxicity Profile of Intra-nodal DC/Tumor Lysate Vaccination | Adverse events attributed to vaccination. Collected and attributed adverse events at each study visit; monitored participants for adverse events for two hours following vaccination procedure. | Until death or approximately 24 months after diagnosis |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Camilo E. Fadul, MD | Dartmouth-Hitchcock Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dartmouth-Hitchcock Medical Center | Lebanon | New Hampshire | 03756 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21499132 | Result | Fadul CE, Fisher JL, Hampton TH, Lallana EC, Li Z, Gui J, Szczepiorkowski ZM, Tosteson TD, Rhodes CH, Wishart HA, Lewis LD, Ernstoff MS. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J Immunother. 2011 May;34(4):382-9. doi: 10.1097/CJI.0b013e318215e300. |
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Between May 2006 and February 2008, 60 patients were diagnosed with GBM at our institution. Of 11 patients who entered the study, 1 had a seizure with neurologic deterioration several weeks after leukapheresis and did not receive any DC vaccinations.
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| ID | Title | Description |
|---|---|---|
| FG000 | Vaccine | Adult patients who have surgical resection of newly diagnosed glioblastoma multiforme (GBM) will be treated with radiotherapy and concurrent chemotherapy followed by intranodal vaccine with autologous dendritic cells (DCs) primed with tumor lysate. Adjuvant chemotherapy will be administered after vaccination for 1 year or until tumor progression |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Vaccine Administration |
|
| ||||||||||||||||||
| Adjuvant Therapy & Survival Follow-Up |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Vaccine | Adult patients who have surgical resection of newly diagnosed glioblastoma multiforme (GBM) will be treated with radiotherapy and concurrent chemotherapy followed by intranodal vaccine with autologous dendritic cells (DCs) primed with tumor lysate. Adjuvant chemotherapy will be administered after vaccination for 1 year or until tumor progression |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Tumor-specific Cytotoxic T-cell Response | MRI & pheresis post vaccine | All participants who received all 3 vaccine administrations were used in this data analysis. | Posted | Median | Full Range | 10^9 cells/L | Day 42 |
|
|
From Baseline through 30 days after last administration of vaccine.
Participants who started in the "Adjuvant Therapy" Period were assessed for Other/Non-Serious Adverse Events
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Vaccine | Adult patients who have surgical resection of newly diagnosed glioblastoma multiforme (GBM) will be treated with radiotherapy and concurrent chemotherapy followed by intranodal vaccine with autologous dendritic cells (DCs) primed with tumor lysate. Adjuvant chemotherapy will be administered after vaccination for 1 year or until tumor progression |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pain, neck, unilateral, Grade 2 | Musculoskeletal and connective tissue disorders | CTCAE v3.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Camilo Fadul | Dartmouth-Hitchcock Medical Center | 603-653-6312 | camilo.e.fadul@hitchcock.org |
Not provided
| ID | Term |
|---|---|
| D005909 | Glioblastoma |
| ID | Term |
|---|---|
| D001254 | Astrocytoma |
| D005910 | Glioma |
| D018302 | Neoplasms, Neuroepithelial |
| D017599 | Neuroectodermal Tumors |
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| ID | Term |
|---|---|
| D000077204 | Temozolomide |
| D011878 | Radiotherapy |
| ID | Term |
|---|---|
| D003606 | Dacarbazine |
| D014226 | Triazenes |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
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| Temozolomide | Drug | Radiotherapy (RT) with concurrent temozolomide (TMZ) for 6 weeks before vaccine is SOC |
|
| Radiotherapy | Procedure | RT is standard of care (SOC) post surgery |
|
| Dendritic Cell Vaccine | Biological | Vaccine given cervical lymphnode injection 3 times every other week |
|
| Number of Participants With Evaluable Data: Feasibility of Vaccination |
To determine the feasibility of this approach, the investigators hypothesize that at least 2/3 of the patients included in the study will be evaluable, meaning that the participants would have received the 3 vaccinations with immunologic outcome parameters measured before and after vaccination. Therefore a maximum of 15 patients would be enrolled in the study to obtain 10 evaluable patients. If after enrolling 15 patients the investigators are unable to obtain 10 evaluable patients, the investigators would consider this approach not feasible. |
| Through enrollment, approximately 2 years |
| Progression Free Survival (PFS) | Progression-free survival will be assessed for each patient as the time from surgery until the patient reaches objective disease progression by MRI criteria. Death will be regarded as a progression event in those patients that die before disease progression. Patients without documented objective progression at the time of the analysis will be censored at the date of their last objective tumor assessment. Since disease free survival and overall survival are secondary endpoints all patients will be followed until death or for a period of 5 years following enrollment. | Approximately 42 months |
| Number of Participants With Significant Difference in Tumor Volume Size Pre- and Postvaccination: Neuroimaging and Tumor Assessment | Patients with evidence of evaluable enhancing disease on contrast-enhanced MRI performed within four weeks of study entry will be evaluated for response rate. Patients will be evaluated for objective tumor assessments by gadolinium-enhanced magnetic resonance imaging (Gd-MRI). Comparisons of objective assessments, excluding progressive disease, are based upon major changes in tumor size on the Gd-MRI compared to the baseline scan. Determination of progressive disease is based upon comparison to the previous scan with volumetric analysis. | baseline and 4 weeks |
| Overall Survival Duration: Efficacy Parameters | Overall survival will also be followed. Survival will be assessed from the date of surgery to the date of patient death, due to any cause, or to the last date the patient was known to be alive. | Approximately 42 months |
| Frequency of CD4+ and CD8+ T Cells - the Proportion of Cells in the Parent Population Responding to Glioblastoma Multiforme (GBM) - Median | Pre- and post-vaccine immune assay results (Tumor-specific T-cells ) are summarized on a continuous scale as median. | Day 7 (pre-vaccination) and Day 42 (post-vaccination). |
| Percentage of Tumor-specific T-cells - Correlation Between Immunological Parameters and Efficacy- Median | Pre- and post-vaccine immune assay results (Tumor-specific T-cell Responses) are summarized on a continuous scale as median. | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
| Number of Enzyme-linked Immunosorbent Spots (ELISPOT) - Correlation Between Immunological Parameters and Efficacy - Median | Pre- and post-vaccine immune assay results (Tumor-specific T-cell Responses) are summarized on a continuous scale as mean. | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
| Frequency of CD4+ and CD8+ T Cells - the Proportion of Cells in the Parent Population Responding to Glioblastoma Multiforme (GBM) - Mean | Pre- and post-vaccine immune assay results (Tumor-specific T-cells ) are summarized on a continuous scale as mean. | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
| Percentage of Tumor-specific T-cells - Correlation Between Immunological Parameters and Efficacy- Mean | Pre- and post-vaccine immune assay results (Tumor-specific T-cell Responses) are summarized on a continuous scale as median. IFN = interferon. | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
| Number of Enzyme-linked Immunosorbent Spots (ELISPOT) - Correlation Between Immunological Parameters and Efficacy - Mean | Pre- and post-vaccine immune assay results (Tumor-specific T-cell Responses) are summarized on a continuous scale as mean. | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
| Evaluation of T Cell Characteristics | Peripheral blood obtained before starting radiation/ temozolomide (TMZ), and at first and second leukapheresis will be used to do lymphocyte phenotyping. We will determine percentages of CD3+/CD8+/CD45RO+ (memory T-cells), CD3+/CD8+/CD28- (CD8 suppressor T cell phenotype), and CD4+/CD25+ cells at those 3 time points. An anti-human Foxp3 antibody will be used to determine if the CD4+/CD25+ cells are T regulatory cells (TREG) and how the compartmental shift correlates with immunoresponse by other immune parameters as well as to efficacy. | Before starting radiation/Temozolomide and at Day 7 and Day 42. |
| Immunohistochemistry | Pathologic specimen obtained from patients who require of another surgical resection after vaccination will be examined to determine the characteristics of infiltrating tumor cells. Paraffin sections of tumor specimen will be stained by immunohistochemistry with antibodies to identify the components of the inflammatory response. This specimen will be compared to the one obtained at the time of initial surgery and changes in inflammation and inflammatory cellular components will be noted. | Approximately 42 months |
|
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Participants |
|
|
| Secondary | Number of Adverse Events: Toxicity Profile of Intra-nodal DC/Tumor Lysate Vaccination | Adverse events attributed to vaccination. Collected and attributed adverse events at each study visit; monitored participants for adverse events for two hours following vaccination procedure. | Participants were monitored for adverse events at each visit and observed for 2 hours after intranodal injections. Toxicities were graded using the Common Terminology Criteria for Adverse Events (version 3.0) and Common Toxicity Criteria (version 3.0). | Posted | Number | attributable adverse events | Until death or approximately 24 months after diagnosis |
|
|
|
| Secondary | Number of Participants With Evaluable Data: Feasibility of Vaccination | To determine the feasibility of this approach, the investigators hypothesize that at least 2/3 of the patients included in the study will be evaluable, meaning that the participants would have received the 3 vaccinations with immunologic outcome parameters measured before and after vaccination. Therefore a maximum of 15 patients would be enrolled in the study to obtain 10 evaluable patients. If after enrolling 15 patients the investigators are unable to obtain 10 evaluable patients, the investigators would consider this approach not feasible. | Posted | Count of Participants | Participants | Through enrollment, approximately 2 years |
|
|
|
| Secondary | Progression Free Survival (PFS) | Progression-free survival will be assessed for each patient as the time from surgery until the patient reaches objective disease progression by MRI criteria. Death will be regarded as a progression event in those patients that die before disease progression. Patients without documented objective progression at the time of the analysis will be censored at the date of their last objective tumor assessment. Since disease free survival and overall survival are secondary endpoints all patients will be followed until death or for a period of 5 years following enrollment. | Posted | Median | Full Range | Months | Approximately 42 months |
|
|
|
| Secondary | Number of Participants With Significant Difference in Tumor Volume Size Pre- and Postvaccination: Neuroimaging and Tumor Assessment | Patients with evidence of evaluable enhancing disease on contrast-enhanced MRI performed within four weeks of study entry will be evaluated for response rate. Patients will be evaluated for objective tumor assessments by gadolinium-enhanced magnetic resonance imaging (Gd-MRI). Comparisons of objective assessments, excluding progressive disease, are based upon major changes in tumor size on the Gd-MRI compared to the baseline scan. Determination of progressive disease is based upon comparison to the previous scan with volumetric analysis. | Posted | Count of Participants | Participants | baseline and 4 weeks |
|
|
|
| Secondary | Overall Survival Duration: Efficacy Parameters | Overall survival will also be followed. Survival will be assessed from the date of surgery to the date of patient death, due to any cause, or to the last date the patient was known to be alive. | There were 4 patients alive when data collection ended, including the patient the longest overall survival. | Posted | Median | Full Range | Months | Approximately 42 months |
|
|
|
| Secondary | Frequency of CD4+ and CD8+ T Cells - the Proportion of Cells in the Parent Population Responding to Glioblastoma Multiforme (GBM) - Median | Pre- and post-vaccine immune assay results (Tumor-specific T-cells ) are summarized on a continuous scale as median. | proportion of cells responding to GBM; GBM = glioblastoma multiforme | Posted | Median | Full Range | proportion of cells | Day 7 (pre-vaccination) and Day 42 (post-vaccination). |
|
|
|
| Secondary | Percentage of Tumor-specific T-cells - Correlation Between Immunological Parameters and Efficacy- Median | Pre- and post-vaccine immune assay results (Tumor-specific T-cell Responses) are summarized on a continuous scale as median. | Posted | Median | Full Range | percentage of cells | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
|
|
|
| Secondary | Number of Enzyme-linked Immunosorbent Spots (ELISPOT) - Correlation Between Immunological Parameters and Efficacy - Median | Pre- and post-vaccine immune assay results (Tumor-specific T-cell Responses) are summarized on a continuous scale as mean. | Posted | Median | Full Range | spots | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
|
|
|
| Secondary | Frequency of CD4+ and CD8+ T Cells - the Proportion of Cells in the Parent Population Responding to Glioblastoma Multiforme (GBM) - Mean | Pre- and post-vaccine immune assay results (Tumor-specific T-cells ) are summarized on a continuous scale as mean. | proportion of cells responding to GBM; GBM = glioblastoma multiforme | Posted | Mean | Standard Deviation | proportion of cells | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
|
|
|
| Secondary | Percentage of Tumor-specific T-cells - Correlation Between Immunological Parameters and Efficacy- Mean | Pre- and post-vaccine immune assay results (Tumor-specific T-cell Responses) are summarized on a continuous scale as median. IFN = interferon. | Posted | Mean | Standard Deviation | percentage of cells | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
|
|
|
| Secondary | Number of Enzyme-linked Immunosorbent Spots (ELISPOT) - Correlation Between Immunological Parameters and Efficacy - Mean | Pre- and post-vaccine immune assay results (Tumor-specific T-cell Responses) are summarized on a continuous scale as mean. | Posted | Mean | Standard Deviation | spots | Day 7 (pre-vaccination) and Day 42 (post-vaccination) |
|
|
|
| Secondary | Evaluation of T Cell Characteristics | Peripheral blood obtained before starting radiation/ temozolomide (TMZ), and at first and second leukapheresis will be used to do lymphocyte phenotyping. We will determine percentages of CD3+/CD8+/CD45RO+ (memory T-cells), CD3+/CD8+/CD28- (CD8 suppressor T cell phenotype), and CD4+/CD25+ cells at those 3 time points. An anti-human Foxp3 antibody will be used to determine if the CD4+/CD25+ cells are T regulatory cells (TREG) and how the compartmental shift correlates with immunoresponse by other immune parameters as well as to efficacy. | Posted | Mean | Standard Deviation | percentage of cells | Before starting radiation/Temozolomide and at Day 7 and Day 42. |
|
|
|
| Secondary | Immunohistochemistry | Pathologic specimen obtained from patients who require of another surgical resection after vaccination will be examined to determine the characteristics of infiltrating tumor cells. Paraffin sections of tumor specimen will be stained by immunohistochemistry with antibodies to identify the components of the inflammatory response. This specimen will be compared to the one obtained at the time of initial surgery and changes in inflammation and inflammatory cellular components will be noted. | Number of patients with pre- and post-tumor tissue procured, to undertake a meaningful analysis of the tumor immunohistochemistry slides inflammatory cells was insufficient. No data was collected. | Posted | Approximately 42 months |
|
|
| 0 |
| 11 |
| 1 |
| 10 |
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| D009373 |
| Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009380 | Neoplasms, Nerve Tissue |
| D001393 |
| Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D013812 | Therapeutics |
|
| %CD4+/CD25+ cells |
|
| % of are T regulatory cells (TREG) |
|