A Phase 1 interventional study of 5-day TMZ and 21-day TMZ in Glioblastoma and Glioblastoma Multiforme, sponsored by Eric Thompson, M.D.. Terminated at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-06-09.
Sponsored by Eric Thompson, M.D. · Phase 1, Interventional, and Treatment
Newly diagnosed glioblastoma (GBM) patients with complete or partial surgical resection who were CMV seropositive patients were eligible to enroll on this trial. Patients were enrolled following standard of care chemoradiation and prior to initiation of post-radiation cycles of temozolomide (TMZ) provided they met all eligibility criteria. All eligible patients received a tetanus-diphtheria (Td) vaccination. Patients enrolled on study were randomized to receive either standard TMZ or dose-intensified TMZ (excluding the safety cohort who only received standard TMZ). All patients received a pre-conditioning injection of tetanus on day 22 of the first post-radiation cycle of TMZ. The following day, patients received the first of 3 intradermal (i.d.) injections of the study drug cytomegalovirus peptide (PEP-CMV), which contained either a combination of Component A and Component B or Component A only depending upon when they enrolled on study. Vaccines #2 and #3 will be given at 2 week intervals. Patients who were O[6]-methylguanine-DNA methyltransferase (MGMT) unmethylated received one adjuvant cycle of the TMZ regimen according to their assigned TMZ arm. Patients who were MGMT methylated or whose methylation status was inconclusive continue with up to 12 cycles of TMZ. After the completion of a patient's last TMZ cycle, vaccines continued every 4-6 weeks for a maximum number of 20 vaccines (unless tumor progression occurred). The study ended prematurely due to lack of funds. The preliminary results suggest that the vaccine may be capable of generating an immune response.
Patients were enrolled following radiation therapy and prior to initiation of post-radiation therapy cycles of adjuvant TMZ provided they met all eligibility criteria. After signing main consent, patients had immune monitoring blood work collected and received a Tetanus-diphtheria booster vaccination with 0.5 mL of Td (tetanus, diphtheria toxoid, adsorbed). After meeting all eligibility criteria, patients were randomized to receive either standard TMZ (150-200 mg/m\^2/day on days 1-5 of each 28-day cycle) with vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle or to receive dose-intensified TMZ (75-100 mg/m\^2/day on days 1-21 of each 28-day cycle) with vaccination on day 23 (-1 day, +2 days) of each TMZ cycle (excluding patients enrolled in the safety cohort who only received standard TMZ).
Patients began their initial cycle of adjuvant TMZ as soon as possible following randomization, if applicable. For Arm 1, the adjuvant TMZ cycle(s) will be given as described above. If a patient had an MGMT unmethylated tumor, they discontinued TMZ after the 1st cycle.
All patients received a tetanus pre-conditioning injection in the right groin on day 22 (+1 day) of cycle 1 of adjuvant TMZ. On the following day, patients receive their study vaccine (either a combination of Component A and Component B or Component A only depending upon when they enrolled on study).
Vaccines #2 and #3 were given at 2 week intervals (+ 3 days), which will resulted in a \~35-day delay before starting TMZ cycle 2. MGMT unmethylated patients did not receive subsequent cycles of TMZ, but continued to receive vaccines approximately every 4 (+2) weeks. Originally, patients received the vaccine as follows: 500 µg of PEP-CMV Component A mixed with Montanide Incomplete Freund's Adjuvant (ISA)-51 intradermally administered in the right groin and 2 hours later, 500 µg of PEP-CMV Component B mixed in 150 µg of Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) intradermally administered in the left groin. A safety cohort was added in 2017 following hypersensitivity reactions in which patient received different schedules of vaccine Components A and B to determine the source of the hypersensitivity reactions. Following this safety cohort, the randomized study was allowed to reinitiate with changes to vaccine administration procedure.
Subsequent revisions were made to the study in the latter part of 2018, due to a continuation of hypersensitivity reactions, and Component B was removed from the study. Patients then received the vaccine as follows: 500 µg of PEP-CMV Component A mixed with Montanide ISA-51 administered intradermally with half in the right groin and half in the left groin.
Patients were imaged with contrast-enhanced magnetic resonance imaging (MRI) within 2 weeks (+3 days) after vaccine 3 and then approximately every 8 weeks. RANO criteria was used for assessment of pseudo-progression, and patients demonstrating definitive progression were removed from study. Blood for immune monitoring was obtained at several time points.
The study ended prematurely due to lack of funds.
1,919 studies on the registry are indexed under Glioblastoma; 449 are open to participants now.
This study's enrollment of 27 is below the median of 36 across 1,617 interventional studies indexed under Glioblastoma.
Browse Glioblastoma studies →This is the only study on the registry with Eric Thompson, M.D. as lead sponsor.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of standard TMZ (150-200 mg/m\^2/day on days 1-5 of each 28 day cycle) with PEP-CMV vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.
Drug: 5-day TMZ · Biological: PEP-CMV: Component A · Drug: Tetanus-Diphtheria booster · Drug: Tetanus Pre-Conditioning · Biological: PEP-CMV: Component B
All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of dose-intensified TMZ (75-100 mg/m\^2/day on days 1-21 of each 28 day cycle) with PEP-CMV vaccination on day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.
Drug: 21-day TMZ · Biological: PEP-CMV: Component A · Drug: Tetanus-Diphtheria booster · Drug: Tetanus Pre-Conditioning · Biological: PEP-CMV: Component B
All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of standard TMZ (150-200 mg/m\^2/day on days 1-5 of each 28 day cycle) with PEP-CMV vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine. Vaccine components A and B were administered separately, with a delay between them, to determine if it was an individual component or a combination of the components that resulted in adverse reactions.
Drug: 5-day TMZ · Biological: PEP-CMV: Component A · Drug: Tetanus-Diphtheria booster · Drug: Tetanus Pre-Conditioning · Biological: PEP-CMV: Component B
All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of standard TMZ (150-200 mg/m\^2/day on days 1-5 of each 28 day cycle) with PEP-CMV vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.
Drug: 5-day TMZ · Biological: PEP-CMV: Component A · Drug: Tetanus-Diphtheria booster · Drug: Tetanus Pre-Conditioning
All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of dose-intensified TMZ (75-100 mg/m\^2/day on days 1-21 of each 28 day cycle) with PEP-CMV vaccination on day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.
Drug: 21-day TMZ · Biological: PEP-CMV: Component A · Drug: Tetanus-Diphtheria booster · Drug: Tetanus Pre-Conditioning
Chemotherapy agent FDA approved to treat newly-diagnosed glioblastoma given as cycles of 150-200 mg/m\^2/day on days 1-5 of each 28 day cycle
Also known as: temozolomide, Temodar
Chemotherapy agent FDA approved to treat newly-diagnosed glioblastoma given as cycles of dose-intensified TMZ (75-100 mg/m2/day on days 1-21 of each 28 day cycle)
Also known as: temozolomide, Temodar
500 µg of PEP-CMV Component A (a synthetic long peptide) mixed with Montanide ISA-51 intradermally administered
At time of enrollment, after signing consent and undergoing immune monitoring blood work, patients will receive Tetanus-diphtheria booster vaccination with 0.5 mL of Td (tetanus, diphtheria toxoid, absorbed)
Also known as: Td, tetanus
All patients will receive a tetanus pre-conditioning injection in the right groin intradermally on day 22 (±1 day) of the first post-radiation cycle of TMZ
Also known as: Td, Tetanus-Diphtheria, tetanus
500 µg of PEP-CMV Component B (a neutralizing antibody epitope from human CMV glycoprotein B conjugated to Keyhole Limpet Hemocyanin) mixed in 150 µg of GM-CSF intradermally administered
Percentage of Participants With Treatment-related Adverse Events
To assess the safety of PEP-CMV vaccination in combination with adjuvant TMZ, the percentage of patients with unacceptable toxicity will be estimated within each arm. All patients who received any PEP-CMV vaccine will be included in these analyses.
Time frame: 2 weeks after the 3rd vaccine, which is approximately 12 weeks after consent
Immunologic Response as Measured by Peak Number of T Cells That Secrete IFNγ by ELISPOT in Response to Component A of PEP-CMV
The primary analysis will focus on patients who have follow-up immunologic monitoring after the 3rd vaccination with component A alone and before initiation of the second TMZ/vaccine cycle. Such a patient is considered "evaluable" for the immunologic response primary analyses. The Wilcoxon rank sum test will compare treatment groups with regard to the median peak number of T cells that secrete IFNγ by ELISPOT in response to component A of PEP-CMV. Analyses will include only those patients who have an assessment of immune response after receiving 3 vaccinations.
Time frame: Through study completion, an average of 1.5 years
Antigen Loss
To determine if tumors are CMV antigen negative by immunohistochemical analysis for the presence of the antigen pp65 at the time of disease progression/recurrence
Time frame: Through study completion, an average of 1.5 years
| Milestone | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone |
|---|---|---|---|---|---|
| Started | 4 | 1 | 6 | 8 | 8 |
| Completed | 4 | 1 | 6 | 8 | 8 |
| Not completed | 0 | 0 | 0 | 0 | 0 |
To assess the safety of PEP-CMV vaccination in combination with adjuvant TMZ, the percentage of patients with unacceptable toxicity will be estimated within each arm. All patients who received any PEP-CMV vaccine will be included in these analyses.
| percentage of participants | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone |
|---|---|---|---|---|---|
| Percentage of Participants With Treatment-related Adverse Events | 0 | 0 | 0 | 0 | 0 |
The primary analysis will focus on patients who have follow-up immunologic monitoring after the 3rd vaccination with component A alone and before initiation of the second TMZ/vaccine cycle. Such a patient is considered "evaluable" for the immunologic response primary analyses. The Wilcoxon rank sum test will compare treatment groups with regard to the median peak number of T cells that secrete IFNγ by ELISPOT in response to component A of PEP-CMV. Analyses will include only those patients who have an assessment of immune response after receiving 3 vaccinations.
| T cells | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone |
|---|---|---|---|---|---|
| Immunologic Response as Measured by Peak Number of T Cells That Secrete IFNγ by ELISPOT in Response to Component A of PEP-CMV | — | — | — | 57.5 (13.5 to 241.5) | 71.25 (28 to 146) |
To determine if tumors are CMV antigen negative by immunohistochemical analysis for the presence of the antigen pp65 at the time of disease progression/recurrence
No measurements were reported for this outcome.
Collected over 24 Months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 5-day TMZ: Components A and B | 4/4 (100%) | 4/4 (100%) | 4/4 (100%) |
| 21-day TMZ: Components A and B | 1/1 (100%) | 1/1 (100%) | 1/1 (100%) |
| 5-day TMZ: Safety Cohort | 6/6 (100%) | 2/6 (33.3%) | 6/6 (100%) |
| 5-day TMZ: Component A Alone | 8/8 (100%) | 6/8 (75%) | 8/8 (100%) |
| 21-day TMZ: Component A Alone | 8/8 (100%) | 4/8 (50%) | 8/8 (100%) |
| Event | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone |
|---|---|---|---|---|---|
| Cytokine release syndromeImmune system disorders | 2/4 | 1/1 | 0/6 | 0/8 | 0/8 |
| Flu like symptomsGeneral disorders | 1/4 | 0/1 | 0/6 | 4/8 | 4/8 |
| HypotensionVascular disorders | 1/4 | 0/1 | 0/6 | 3/8 | 4/8 |
| Sinus tachycardiaCardiac disorders | 0/4 | 0/1 | 0/6 | 3/8 | 2/8 |
| SeizureNervous system disorders | 0/4 | 0/1 | 2/6 | 2/8 | 0/8 |
| ChillsGeneral disorders | 1/4 | 0/1 | 0/6 | 2/8 | 0/8 |
| FeverGeneral disorders | 1/4 | 0/1 | 0/6 | 1/8 | 0/8 |
| DehydrationMetabolism and nutrition disorders | 0/4 | 0/1 | 0/6 | 2/8 | 0/8 |
| HeadacheNervous system disorders | 1/4 | 0/1 | 0/6 | 1/8 | 0/8 |
| Pyramidal tract syndromeNervous system disorders | 0/4 | 0/1 | 1/6 | 0/8 | 0/8 |
| Event | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone |
|---|---|---|---|---|---|
| Sinus bradycardiaCardiac disorders | 1/4 | 1/1 | 0/6 | 3/8 | 3/8 |
| Injection site reactionGeneral disorders | 2/4 | 1/1 | 4/6 | 7/8 | 6/8 |
| Alanine aminotransferase increasedInvestigations | 0/4 | 1/1 | 2/6 | 2/8 | 2/8 |
| HyperglycemiaMetabolism and nutrition disorders | 3/4 | 1/1 | 2/6 | 8/8 | 6/8 |
| HypocalcemiaMetabolism and nutrition disorders | 2/4 | 1/1 | 2/6 | 5/8 | 2/8 |
| Lymphocyte count decreasedInvestigations | 2/4 | 0/1 | 3/6 | 7/8 | 5/8 |
| AnemiaBlood and lymphatic system disorders | 2/4 | 0/1 | 5/6 | 6/8 | 5/8 |
| Cytokine release syndromeImmune system disorders | 2/4 | 0/1 | 5/6 | 6/8 | 4/8 |
| HeadacheNervous system disorders | 0/4 | 0/1 | 5/6 | 2/8 | 2/8 |
| HypertensionVascular disorders | 2/4 | 0/1 | 5/6 | 5/8 | 4/8 |
| Age, Continuous(years) | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone | Total |
|---|---|---|---|---|---|---|
| Mean | 60.75 ± 8.14 | 40 ± NA | 57.33 ± 9.97 | 57.63 ± 11.04 | 50.25 ± 8.84 | 55.19 ± 10.23 |
| Sex: Female, Male(Participants) | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone | Total |
|---|---|---|---|---|---|---|
| Female | 3 | 0 | 2 | 2 | 4 | 11 |
| Male | 1 | 1 | 4 | 6 | 4 | 16 |
| Ethnicity (NIH/OMB)(Participants) | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone | Total |
|---|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 1 | 1 | 0 | 2 |
| Not Hispanic or Latino | 4 | 1 | 4 | 7 | 7 | 23 |
| Unknown or Not Reported | 0 | 0 | 1 | 0 | 1 | 2 |
| Race (NIH/OMB)(Participants) | 5-day TMZ: Components A and B | 21-day TMZ: Components A and B | 5-day TMZ: Safety Cohort | 5-day TMZ: Component A Alone | 21-day TMZ: Component A Alone | Total |
|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 | 0 | 0 |
| White | 4 | 0 | 4 | 7 | 7 | 22 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 1 | 2 | 1 | 1 | 5 |
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