Phase II Feasibility Study of Dendritic Cell Vaccination for Newly Diagnosed Glioblastoma Multiforme

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Feasibility Study of Adjuvant Intra-Nodal Autologous Dendritic Cell Vaccination for Newly Diagnosed Glioblastoma Multiforme

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Biological: Autologous Dendritic Cell
* Drug: Temozolomide
* Procedure: Radiotherapy
* Biological: Dendritic Cell Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven GBM with central pathology review at Dartmouth-Hitchcock Medical Center (DHMC) Tumor specimen obtained at the time of surgery adequate for vaccination 18 years of age or older Karnofsky Performance Status 60% or greater Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10 9th/L Platelets greater than or equal to 100 x 10 9th/L Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) less than or equal to 5 times the upper limits of normal (ULN) Total bilirubin less than or equal to 1.5 times ULN Serum creatinine less than or equal to 1.5 times ULN, OR estimated creatinine clearance greater than or equal to 60 mL/min No known immunosuppression other than chemo-related Negative HIV serologies No evidence of acute or chronic hepatitis on standard hepatitis C and B screening tests No chemotherapy within four weeks prior to leukapheresis Radiotherapy at outside institution is permitted if tissue was obtained at time of surgery at DHMC and patient is willing to follow-up per protocol Off steroids for at least two weeks before leukapheresis No second malignancies except non-melanoma skin cancer, and non-invasive cancer such at cervical CIS, superficial bladder cancer or breast CIS Negative serum or urine pregnancy test for women of childbearing potential No serious uncontrolled medical disorder or active infection All patients must give informed consent No history of clinical evidence of active autoimmune disease Exclusion Criteria: Invasive cancers in the past 5 years Rheumatologic/autoimmune disease Pregnancy or unwillingness to remain on acceptable form of birth control during study Major cardiac, pulmonary, or other systemic disease; viral hepatitis; HIV infection

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine<br> | Biological: Autologous Dendritic Cell<br>* Vaccine given by cervical lymph node injection 3 times every other week<br>Drug: Temozolomide<br>* Radiotherapy (RT) with concurrent temozolomide (TMZ) for 6 weeks before vaccine is SOC<br>Procedure: Radiotherapy<br>* RT is standard of care (SOC) post surgery<br>Biological: Dendritic Cell Vaccine<br>* Vaccine given cervical lymphnode injection 3 times every other week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor-specific Cytotoxic T-cell Response | MRI & pheresis post vaccine | Day 42 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, cancer vaccine, glioblastoma multiforme