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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme
• Intervention / Treatment: Biological: Autologous Dendritic Cell; Drug: Temozolomide; Procedure: Radiotherapy; Biological: Dendritic Cell Vaccine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Camilo E. Fadul, MD, Dartmouth-Hitchcock Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (ACTUAL): April 1, 2008
• Study Completion (ACTUAL): July 1, 2013

Study Registration Dates

• First Submitted: May 4, 2006
• First Submitted That Met QC Criteria: May 5, 2006
• First Posted (ESTIMATE): May 9, 2006

Study Record Updates

• Last Update Posted (ACTUAL): October 10, 2018
• Last Update Submitted That Met QC Criteria: October 9, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: immunotherapy; glioblastoma multiforme; cancer vaccine
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: D0536