Glioblastoma Multiforme, Glioblastoma, Malignant Glioma, Astrocytoma, Grade IV, GBM
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALpp65-shLAMP DC with GM-CSF
BIOLOGICALunpulsed PBMC and saline
DRUGTd
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.
DRUGSaline
BIOLOGICALpp65-flLAMP DC with GM-CSF
Sponsors
National Cancer Institute (NCI)
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Overall Survival (OS) Between the Active Treatment Group (Arms 1 and 2) and the Control Group (Arm 3) | From date of first vaccine until the date of death, up to 48 months | Kaplan-Meier survival curves and the log rank test will be used to characterize and compare OS in patients who received pp65-LAMP mRNA DC vaccine (Arms 1 and 2) and in control patients (Arm 3). OS will be defined as the time between first vaccination and death and will be censored at the last follow-up if death has not occurred. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ELISPOT Assay (pp65) | baseline, post-vaccine #3 | Within patient changes from baseline to vaccine 3. |
| Flow Cytometric Analysis (T Cell) | baseline, post-vaccine #3 | Percentage of circulating cellular subsets of T cells within PBMCs. |
| Cytokine Array Analysis (IFN-g) | baseline, post-vaccine #3 | Change in concentration (pg/mL) of IFN-g as measured by multiplex array from Baseline (V1) to post-Vaccine #3. |
| Comparison of Progression-free Survival Between the Active Treatment Group (Arms 1 and 2 Combined) and the Control Group (Arm 3) | From date of first vaccine until time disease progression or death without prior progression/recurrence, up to 48 months | Calculated as dated of first vaccine to date first progression/recurrence or death. Kaplan-Meier survival curves and the log rank test will be used to characterize and compare PFS in patients who received pp65-LAMP mRNA DC vaccine (Arms 1 and 2) and in control patients (Arm 3). PFS is defined as the time between first vaccination and first documentation of either disease progression/recurrence, or death without prior progression/recurrence. |
| Flow Cytometric Analysis (NK Cell) | baseline, post-vaccine #3 | Percentage of circulating cellular subsets of NK cells within PBMCs. |
| Flow Cytometric Analysis (CD4.CD25 T Reg) | baseline, post-vaccine #3 | Percentage of circulating cellular subsets of CD4.CD25 T Reg within PBMCs. |
| ELISPOT Assay (Actin) | baseline, post-vaccine #3 | Within patient changes from baseline to vaccine 3. |
Countries
United States
Participant flow
Recruitment details
175 participants were enrolled (consented) between 8/9/2016 and 10/5/2022.
Pre-assignment details
Participants were evaluated for inclusion. 17 were determined not eligible and 4 participants withdrew. 154 participants were randomized with an allocation ratio of 1:1:1 into one of three arms: 1) Arm 1: pp65-shLAMP mRNA DCs with GM-CSF 150 µg (Td skin prep); 2) Arm 2: pp65-flLAMP mRNA DCs with GM-CSF 150 µg (Td skin prep); or 3) Arm 3: Unpulsed PBMCs (saline skin prep).
Participants by arm
| Arm | Count |
|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) The active treatment group were Arms 1 and 2
Arm 1: pp65-shLAMP mRNA DCs with GM-CSF 150 µg (Td skin prep)
Prior to leukapheresis, patients will be randomized to receive one of three treatment regimens with dose-intensified TMZ treatment at 100 mg/m2/day for 21 days with an allocation ratio of 1:1:1 into one of three arms. | 36 |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) The active treatment group were Arms 1 and 2
Arm 2: pp65-flLAMP mRNA DCs with GM-CSF 150 µg (Td skin prep)
Prior to leukapheresis, patients will be randomized to receive one of three treatment regimens with dose-intensified TMZ treatment at 100 mg/m2/day for 21 days with an allocation ratio of 1:1:1 into one of three arms. | 34 |
| Unpulsed PBMC and Saline (Arm 3) The control group was Arm 3, Unpulsed PBMCs (saline skin prep)
Prior to leukapheresis, patients will be randomized to receive one of three treatment regimens with dose-intensified TMZ treatment at 100 mg/m2/day for 21 days with an allocation ratio of 1:1:1 into one of three arms. | 41 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | did not meet eligibility prior to Cycle #1 | 8 | 9 | 9 |
| Overall Study | Not evaluable per protocol criteria | 3 | 2 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Study drug did not pass QA/QC | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 3 | 1 |
Baseline characteristics
| Characteristic | pp65-shLAMP DC With GM-CSF and Td (Arm 1) | Total | Unpulsed PBMC and Saline (Arm 3) | pp65-flLAMP DC With GM-CSF and Td (Arm 2) |
|---|---|---|---|---|
| Age, Continuous | 61.0 years | 58.0 years | 59.0 years | 56.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 103 Participants | 35 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 100 Participants | 36 Participants | 32 Participants |
| Region of Enrollment United States | 36 participants | 111 participants | 41 participants | 34 participants |
| Sex: Female, Male Female | 8 Participants | 30 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Male | 28 Participants | 81 Participants | 28 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 28 / 36 | 31 / 34 | 31 / 41 |
| other Total, other adverse events | 16 / 36 | 11 / 34 | 13 / 41 |
| serious Total, serious adverse events | 8 / 36 | 6 / 34 | 5 / 41 |
Outcome results
Primary
Comparison of Overall Survival (OS) Between the Active Treatment Group (Arms 1 and 2) and the Control Group (Arm 3)
Kaplan-Meier survival curves and the log rank test will be used to characterize and compare OS in patients who received pp65-LAMP mRNA DC vaccine (Arms 1 and 2) and in control patients (Arm 3). OS will be defined as the time between first vaccination and death and will be censored at the last follow-up if death has not occurred.
Time frame: From date of first vaccine until the date of death, up to 48 months
Population: Survival in Patients receiving vaccine vs placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) | Comparison of Overall Survival (OS) Between the Active Treatment Group (Arms 1 and 2) and the Control Group (Arm 3) | 16.9 months |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) | Comparison of Overall Survival (OS) Between the Active Treatment Group (Arms 1 and 2) and the Control Group (Arm 3) | 16.2 months |
| Unpulsed PBMC and Saline (Arm 3) | Comparison of Overall Survival (OS) Between the Active Treatment Group (Arms 1 and 2) and the Control Group (Arm 3) | 20.6 months |
p-value: 0.19695% CI: [0.77, 2.16]Log Rank
p-value: 0.19695% CI: [0.99, 2.7]Log Rank
Secondary
Comparison of Progression-free Survival Between the Active Treatment Group (Arms 1 and 2 Combined) and the Control Group (Arm 3)
Calculated as dated of first vaccine to date first progression/recurrence or death. Kaplan-Meier survival curves and the log rank test will be used to characterize and compare PFS in patients who received pp65-LAMP mRNA DC vaccine (Arms 1 and 2) and in control patients (Arm 3). PFS is defined as the time between first vaccination and first documentation of either disease progression/recurrence, or death without prior progression/recurrence.
Time frame: From date of first vaccine until time disease progression or death without prior progression/recurrence, up to 48 months
Population: Progression free survival in patients receiving vaccine vs placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) | Comparison of Progression-free Survival Between the Active Treatment Group (Arms 1 and 2 Combined) and the Control Group (Arm 3) | 6.1 months |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) | Comparison of Progression-free Survival Between the Active Treatment Group (Arms 1 and 2 Combined) and the Control Group (Arm 3) | 6.4 months |
| Unpulsed PBMC and Saline (Arm 3) | Comparison of Progression-free Survival Between the Active Treatment Group (Arms 1 and 2 Combined) and the Control Group (Arm 3) | 7.1 months |
p-value: 0.35495% CI: [0.6, 1.61]Log Rank
p-value: 0.35495% CI: [0.87, 2.33]Log Rank
Secondary
Cytokine Array Analysis (IFN-g)
Change in concentration (pg/mL) of IFN-g as measured by multiplex array from Baseline (V1) to post-Vaccine #3.
Time frame: baseline, post-vaccine #3
Population: Only participants who received at least 3 DC vaccines are included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) | Cytokine Array Analysis (IFN-g) | -3.5 pg/mL | Standard Deviation 5 |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) | Cytokine Array Analysis (IFN-g) | 3.3 pg/mL | Standard Deviation 17.7 |
| Unpulsed PBMC and Saline (Arm 3) | Cytokine Array Analysis (IFN-g) | -1.7 pg/mL | Standard Deviation 10 |
p-value: 0.2Kruskal-Wallis
p-value: 0.2Kruskal-Wallis
p-value: 0.2Kruskal-Wallis
Secondary
ELISPOT Assay (Actin)
Within patient changes from baseline to vaccine 3.
Time frame: baseline, post-vaccine #3
Population: Participants in each arm who received at least 3 DC vaccines.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) | ELISPOT Assay (Actin) | 0.4 spot forming units (SFU) | Standard Deviation 6 |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) | ELISPOT Assay (Actin) | -0.2 spot forming units (SFU) | Standard Deviation 26.1 |
| Unpulsed PBMC and Saline (Arm 3) | ELISPOT Assay (Actin) | -0.4 spot forming units (SFU) | Standard Deviation 9.4 |
p-value: 0.6Kruskal-Wallis
p-value: 0.6Kruskal-Wallis
p-value: 0.6Kruskal-Wallis
Secondary
ELISPOT Assay (pp65)
Within patient changes from baseline to vaccine 3.
Time frame: baseline, post-vaccine #3
Population: Participants in each arm who received at least 3 DC vaccines.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) | ELISPOT Assay (pp65) | 126.3 spot forming units (SFU) | Standard Deviation 759.9 |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) | ELISPOT Assay (pp65) | 48.4 spot forming units (SFU) | Standard Deviation 377.5 |
| Unpulsed PBMC and Saline (Arm 3) | ELISPOT Assay (pp65) | -162.7 spot forming units (SFU) | Standard Deviation 1075.4 |
p-value: 0.038Kruskal-Wallis
p-value: 0.038Kruskal-Wallis
p-value: 0.038Kruskal-Wallis
Secondary
Flow Cytometric Analysis (CD4.CD25 T Reg)
Percentage of circulating cellular subsets of CD4.CD25 T Reg within PBMCs.
Time frame: baseline, post-vaccine #3
Population: Only participants who received at least 3 DC vaccines are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) | Flow Cytometric Analysis (CD4.CD25 T Reg) | -0.1 percentage of PBMC | Standard Deviation 4.3 |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) | Flow Cytometric Analysis (CD4.CD25 T Reg) | 1.4 percentage of PBMC | Standard Deviation 2.2 |
| Unpulsed PBMC and Saline (Arm 3) | Flow Cytometric Analysis (CD4.CD25 T Reg) | -0.1 percentage of PBMC | Standard Deviation 2 |
p-value: 0.13Kruskal-Wallis
p-value: 0.13Kruskal-Wallis
p-value: 0.13Kruskal-Wallis
Secondary
Flow Cytometric Analysis (NK Cell)
Percentage of circulating cellular subsets of NK cells within PBMCs.
Time frame: baseline, post-vaccine #3
Population: Only participants who received at least 3 DC vaccines are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) | Flow Cytometric Analysis (NK Cell) | -1.3 percentage of PBMC | Standard Deviation 11.1 |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) | Flow Cytometric Analysis (NK Cell) | 5.9 percentage of PBMC | Standard Deviation 16.6 |
| Unpulsed PBMC and Saline (Arm 3) | Flow Cytometric Analysis (NK Cell) | 1.7 percentage of PBMC | Standard Deviation 7 |
Secondary
Flow Cytometric Analysis (T Cell)
Percentage of circulating cellular subsets of T cells within PBMCs.
Time frame: baseline, post-vaccine #3
Population: Only participants who received at least 3 DC vaccines are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| pp65-shLAMP DC With GM-CSF and Td (Arm 1) | Flow Cytometric Analysis (T Cell) | -0.1 percentage of PBMC | Standard Deviation 11.1 |
| pp65-flLAMP DC With GM-CSF and Td (Arm 2) | Flow Cytometric Analysis (T Cell) | 5.9 percentage of PBMC | Standard Deviation 16.6 |
| Unpulsed PBMC and Saline (Arm 3) | Flow Cytometric Analysis (T Cell) | 1.7 percentage of PBMC | Standard Deviation 7 |