A Phase 2 interventional study of Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF and Temozolomide in Glioblastoma, sponsored by Mustafa Khasraw, MBChB, MD, FRCP, FRACP. Terminated at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-04-08.
Sponsored by Mustafa Khasraw, MBChB, MD, FRCP, FRACP · Phase 2, Interventional, and Treatment
This single-arm phase II study will assess the impact of tetanus pre-conditioning and adjuvant Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) on overall survival of patients newly diagnosed with World Health Organization (WHO) Grade IV glioblastoma who have undergone definitive tumor resection, are cytomegalovirus (CMV) positive and unmethylated, and completed standard temozolomide (TMZ) and radiation treatment. After completion of the standard of care radiotherapy with concurrent TMZ, patients will receive 1 cycle of dose-intensified TMZ followed by pp65-loaded dendritic cell (DC) vaccination beginning on day 23.
Approximately 64 patients with resected, newly-diagnosed WHO Grade IV glioma who are CMV positive and in which the Methylguanine Methyltransferase (MGMT) is not methylated will be accrued to this study before standard of care radiation therapy (RT) and concurrent TMZ, with the goal of treating 48 patients with dose-intensified temozolomide and pp65 loaded dendritic cell vaccine after completion of standard RT and TMZ.
All enrolled patients will undergo a leukapheresis for the generation of DCs. Patients will then receive approximately 6 weeks of the standard of care radiation therapy (RT) and concurrent TMZ at a standard targeted dose of 75 mg/m2/day. For patients whose initial leukapheresis yields less than 3 vaccines, repeat leukapheresis may be obtained. At the post-RT clinic visit, a single post-RT cycle of dose-intensified TMZ (100 mg/m2/day for 21 days) will be given. On day 23 (± 2 days) of the cycle, patients will receive the first of 3 pp65 DC vaccines. Vaccines #1-3 will be given every two weeks (± 2 days). All patients will receive up to a total of 10 DC vaccines, with vaccines administered every 35 days (± 7 days) after the third vaccine, given bilaterally at the groin site unless progression occurs with no further cycles of TMZ. DC vaccines will be given intradermally (i.d.) and divided equally to both inguinal regions. Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Patients will undergo leukapheresis again for immunologic monitoring with a specific assessment of baseline antigen-specific cellular and humoral immune responses if needed for further DC generations 14 (± 2) days after vaccine #3. Prior to pp65 DC vaccination #4,(3±1) weeks after leukapheresis 2, the vaccine site will receive a pre-conditioning intradermal injection of Td. Up to 16 patients will receive 111-Indium labeled DCs at the 4th vaccine followed by SPECT/CT imaging immediately, and at 1 and 2 days after injections.
1,920 studies on the registry are indexed under Glioblastoma; 450 are open to participants now.
This study's enrollment of 6 is below the median of 36 across 1,618 interventional studies indexed under Glioblastoma.
Browse Glioblastoma studies →Mustafa Khasraw, MBChB, MD, FRCP, FRACP is the lead sponsor of 5 studies on the registry; 1 is open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Severe, active comorbidity, including any of the following:
This single-arm phase II study will assess the impact of tetanus pre-conditioning and adjuvant GM-CSF on overall survival of newly diagnosed glioblastoma (GBM) patients who have undergone definitive resection, are unmethylated, and completed standard temozolomide and radiation treatment. All enrolled patients will undergo a leukapheresis for the generation of DCs. Patients will then receive approximately 6 weeks of standard of care radiation therapy (RT) and concurrent TMZ. A single post-RT cycle of dose intensified TMZ (100 mg/m2/day for 21 days) will then be given. On day 23 (± 2 days) of the cycle, patients will receive the first of 3 pp65 DC vaccines every 2 weeks. All patients will receive up to a total of 10 DC vaccines
Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF · Drug: Temozolomide · Biological: Tetanus-Diphtheria Toxoid (Td) · Biological: GM-CSF · Biological: 111-Indium-labeling of Cells for in vivo Trafficking Studies
2x10\^7 human CMV pp65-LAMP mRNA-pulsed autologous DCs are given intradermally and bilaterally at the groin site (divided equally to both inguinal regions). Patients will receive up to a total of 10 DC vaccines.
Also known as: CMV-specific dendritic cell vaccine, DCs
Temozolomide is a chemotherapy drug given to all enrolled patients at the post-RT clinic visit as dose-intensified TMZ (100 mg/m2/day for 21 days).
Also known as: Temodar, TMZ, Temodal
Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Prior to pp65 DC vaccination #4,(3±1) weeks after leukapheresis 2 the vaccine site will receive a pre-conditioning intradermal injection of Td (1 flocculation unit (Lf), in 0.3 mL of saline for a total of 0.4 mL).
Also known as: Td pre-conditioning, Td toxoid
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a sterile, white, preservative-free lyophilized powder in a vial containing 250 mcg that will be reconstituted in 0.5 mL of sterile water for injection and used as an adjuvant with the DC vaccine.
Also known as: LEUKINE®, Sargramostim
111-In-labeled DCs are 2 x 10\^7 pp65-LAMP mRNA loaded mature DCs labeled with 111-In (50 μCi / 5 x 10\^7 DCs) and given i.d. as the fourth vaccine. In up to 16 patients, the fourth vaccine will be labeled with 111-In (50 μCi / 5 x 10\^7 DCs) prior to injection.
Median Overall Survival (OS) of Subjects Receiving Td Pre-conditioning With GM-CSF
Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up has OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time frame: duration of the study (up to 3 years and 4.5 months)
Migration and Survival From Vaccine 4
The Cox proportional hazards model will assess the impact of migration on survival after vaccine #4. Migration is defined as the maximum percentage of 111In-labeled dendritic cells (DCs) reaching inguinal nodes during the 48 hours after the 4th vaccination. The hazard ratio associated with a 1-unit change in migration will be estimated with 95% confidence intervals.CSF to site-draining inguinal lymph nodes after Td pre-conditioning and survival after vaccine # 4.
Time frame: 5 years
Chemokine (C-C Motif) Ligand 3 (CCL3) and Survival From Vaccine 4
The Cox proportional hazards model will assess the impact of CCL3 on survival post-vaccine 4. The hazard ratio associate with a 1-unit increase in CCL3 will be estimated with 95% confidence intervals
Time frame: 5 years
Polyfunctionality and Survival From Vaccine 4
Cox proportional hazards model will assess the association between fold change increase between baseline and the leukapheresis 2 in the frequency of pp65 antigen-specific CD8+ T cells producing three or more cytokines (IFNγ, CCL3, IL-2, TNFα, CD107a), and survival post-vaccine 4. The hazard ratio associate with a 1-unit fold change in polyfunctionality will be estimated with 95% confidence intervals.
Time frame: 5 years
Maximum Peak Increase From Vaccine 1 in Percent Regulatory T Cells (TReg) of CD4+ T Cells
The mean difference in TRegs between vaccine 1 and the maximum measured level post-vaccine 1 will be reported.
Time frame: 1 year
Number of Participants With Unacceptable Toxicity
An unacceptable toxicity is defined as any grade 3 or greater toxicity that is possibly, probably, or definitely attributed to the pre-conditioning agent Td or pp65 DC vaccine that does not resolve to baseline within 3 weeks; any Grade 3 hypersensitivity reactions or autoimmune toxicity requiring steroids or hormone replacement; , and is not due to progressive disease, or any life-threatening event not attributable to concomitant medication, co-morbid event, or disease progression. Toxicities will be graded according to the National Cancer Institute Common Toxicity Criteria of Adverse Events (NCI CTCAE) version 5 criteria.
Time frame: 1 year
| Milestone | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| Started | 6 |
| Completed | 0 |
| Not completed | 6 |
| Withdrew: Progression | 3 |
| Withdrew: Cmv testing results inconclusive | 1 |
| Withdrew: Unable to generate enough vaccines | 1 |
| Withdrew: Early study termination | 1 |
Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up has OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
| months | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| Median Overall Survival (OS) of Subjects Receiving Td Pre-conditioning With GM-CSF | 17.4 (13.3 to NA) |
The Cox proportional hazards model will assess the impact of migration on survival after vaccine #4. Migration is defined as the maximum percentage of 111In-labeled dendritic cells (DCs) reaching inguinal nodes during the 48 hours after the 4th vaccination. The hazard ratio associated with a 1-unit change in migration will be estimated with 95% confidence intervals.CSF to site-draining inguinal lymph nodes after Td pre-conditioning and survival after vaccine # 4.
No measurements were reported for this outcome.
The Cox proportional hazards model will assess the impact of CCL3 on survival post-vaccine 4. The hazard ratio associate with a 1-unit increase in CCL3 will be estimated with 95% confidence intervals
No measurements were reported for this outcome.
Cox proportional hazards model will assess the association between fold change increase between baseline and the leukapheresis 2 in the frequency of pp65 antigen-specific CD8+ T cells producing three or more cytokines (IFNγ, CCL3, IL-2, TNFα, CD107a), and survival post-vaccine 4. The hazard ratio associate with a 1-unit fold change in polyfunctionality will be estimated with 95% confidence intervals.
No measurements were reported for this outcome.
The mean difference in TRegs between vaccine 1 and the maximum measured level post-vaccine 1 will be reported.
No measurements were reported for this outcome.
An unacceptable toxicity is defined as any grade 3 or greater toxicity that is possibly, probably, or definitely attributed to the pre-conditioning agent Td or pp65 DC vaccine that does not resolve to baseline within 3 weeks; any Grade 3 hypersensitivity reactions or autoimmune toxicity requiring steroids or hormone replacement; , and is not due to progressive disease, or any life-threatening event not attributable to concomitant medication, co-morbid event, or disease progression. Toxicities will be graded according to the National Cancer Institute Common Toxicity Criteria of Adverse Events (NCI CTCAE) version 5 criteria.
| Participants | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| Number of Participants With Unacceptable Toxicity | 0 |
Collected over Duration of the study (up to 3 years and 4.5 months). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| DC Vaccination With Td Preconditioning and GM CSF | 5/6 (83.3%) | 0/6 (0%) | 6/6 (100%) |
| Event | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| FatigueGeneral disorders | 5/6 |
| Gastroesophageal reflux diseaseGastrointestinal disorders | 5/6 |
| HypertensionVascular disorders | 5/6 |
| NauseaGastrointestinal disorders | 5/6 |
| AnemiaBlood and lymphatic system disorders | 4/6 |
| AnorexiaMetabolism and nutrition disorders | 4/6 |
| HeadacheNervous system disorders | 4/6 |
| Lymphocyte count decreasedInvestigations | 4/6 |
| Platelet count decreasedInvestigations | 3/6 |
| Allergic rhinitisRespiratory, thoracic and mediastinal disorders | 2/6 |
| Age, Continuous(years) | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| Mean | 63 ± 12.2 |
| Sex: Female, Male(Participants) | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| Female | 4 |
| Male | 2 |
| Ethnicity (NIH/OMB)(Participants) | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| Hispanic or Latino | 1 |
| Not Hispanic or Latino | 5 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 1 |
| White | 5 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(Participants) | DC Vaccination With Td Preconditioning and GM CSF |
|---|---|
| United States | 6 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: No
This study is terminated, as verified in Apr 2024. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Mustafa Khasraw, MBChB, MD, FRCP, FRACP