Primary Glioblastoma
Conditions
Keywords
GBM, UCPVax, pembrolizumab, cancer vaccine, telomerase, CD4 T cell
Brief summary
Glioblastomas (GBM) are the most frequent brain tumors and one of the most lethal adult cancers despite maximal multimodal therapy. Despite maximal safe resection followed by radiotherapy and temozolomide (TMZ) ± tumor-treating fields, median overall survival for newly diagnosed GBM remains around 18 months and long-term survival is rare, and recurrence is nearly universal. So, the development of new therapeutic strategies is a critical unmet need in GBM. Despite the limited success of anti-PD(L)-1 therapy, immunotherapy remains a promising option in GBM. Current challenge supports to develop combinatorial therapy approaches considering the particular immune tumor microenvironment in GBM. Anticancer vaccines have shown promising signs of efficacy in GBM but critical factors challenge their efficacy. CD4 T help is of major interest for cancer vaccine effectiveness and for immune checkpoint inhibitors success. We previously designed UCPVax a CD4 T helper-targeted cancer vaccine derived from telomerase (TERT), a very attractive GBM-associated antigen (Adotévi O, J Clin Oncol 2023 ; Laheurte C, Cell Report Med 2025). The induction of robust tumor reactive CD4 T cell response with UCPVax together with TMZ-mediated immune effects will promote recruitment of effectors immune cells into tumor bed creating a more suitable microenvironment for anti-PD-1 action. This is a proof-of-concept phase II trial to evaluate the efficacy of maintenance therapy evaluating UCPVax +/- pembrolizumab combined to standard treatment in newly diagnosed unmethylated MGMT glioblastoma. A translational research network will be implemented to better understand the therapeutic efficacy of this combination.
Interventions
DRUGUCPVax
Priming : UCPVax (two helper peptides UCP2 and UCP4 + Montanide ISA51) at 0.5 mg subcutaneously at day 1, 8, 15, 29, 36 and 43 Boost : UCPVax at 0.5 mg subcutaneously one month after priming and then every 8 weeks for 12 months maximum
DRUGPembrolizumab
400 mg/m1 every 6 weeks since day 1 until disease progression or unacceptable toxicity for a maximum of 1 year
DRUGTemozolomide
150-200 mg/m2/day x 5 days per month x 6 months according to best standard of care starting at day 1 of week 1 (with vaccine 1 of UCPVax). Additional treatment with NOVO-TTF200A will be allowed.
Sponsors
Centre Hospitalier Universitaire de Besancon
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomization 2:2:1
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, age ≥ 18 with informed consent signed 2. Patient with a confirmed histological diagnosis of non-mutated IDH primary glioblastoma (surgical resection or biopsy). 3. Tumor with unmethylated MGMT promoter status 4. Patients having completed the concomitant phase of radiotherapy + temozolomide regimen (standard radiotherapy with 60 Gy in 30 fractions or hypofractionated radiotherapy with 40 Gy in 15 fractions), and eligible for the 6 monthly cycles of maintenance temozolomide 5. Karnofsky Perfomance status (KPS) ≥ 70% 6. Life expectancy ≥ 3 months 7. If patient is treated by corticosteroïds (CS), patient must be on stable CS dose for 15 days and total daily dose ≤ 10 mg prednisone, or equivalent 8. Adequate organ function laboratory values 9. Females must be using highly effective contraceptive measures, and have a negative pregnancy test prior to the start of dosing if of childbearing potential, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening : * Post-menopausal is defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments. * Women under the age of 50 years would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution. * Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but tubal ligation. Female with childbearing potential must use effective contraception during study treatment and after the end of treatment based on the last study drug administrated: 6 months after the last dose of Temozolomide; 4 months after the last dose of pembrolizumab and 1 month after the last injection of UCPVax. 10. Male patients with a female partner of childbearing potential should be willing to use barrier contraception and to refrain from donating sperm during the study and and post-treatment based on the last study drug administrated: 3 months after the last dose of temozolomide; 4 months after the last pembrolizumab dose; 1 month after the last UCPVax injection. 11. Patient affiliated to or beneficiary of French social security system 12. Ability to comply with the study protocol, in the Investigator's judgment. 13. Signed and dates informed consent
Exclusion criteria
Patients will not be eligible for this study for any of the following reasons: Cancer specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of the Overall Survival (OS) at 18 months since randomization of patients with GBM treated in the experimental arm with UCPVax +/- pembrolizumab combined with standard treatment (Temozolomide +/- Novo-TTF-200A) | 18 months | Rate for patients alive at 18 months post-randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of the Overall Survival (OS) at 18 months since randomization of patients with GBM treated in the control arm receiving standard treatment( Temozolomide +/- NovoTTF-200A) | 18 months | The rate of patients alive at 18 months post randomization |
| Assessment of the Overall Survival (OS) in the three arms | from date of randomization until date of death from any cause, assessed up to 42 months | Overall survival (OS) defined as the time interval from randomization to the date of death from any cause. Alive patients will be censored at the last date known to be alive, either during study treatment period or during follow-up period |
| Assessment of the progression free survival (PFS) since randomization in the three arms | From date of randomization until the date of first documented disease progression or death from any cause, whichever occurs first, assessed up to 42 months | Progression free survival (PFS) according to RANO 2.0 criteria: defined as the time interval from the date of randomization to the date of first documented disease progression or death from any cause, whichever occurs first. Alive patients without progression will be censored at last radiological evaluation showing no progression during study treatment follow-up. |
| Assessment of the progression free survival (PFS) at 6 months since randomization in the three arms | 6 months | Progression free survival (PFS) according to RANO 2.0 criteria: defined as the time interval from the date of randomization to the date of first documented disease progression or death from any cause, whichever occurs first. Alive patients without progression will be censored at last radiological evaluation showing no progression during study treatment follow-up. |
| Evaluation of incidence of treatment-emergent adverse events in the three arms | up to 42 months | Adverse events and routine lab abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), timing, seriousness and relationship to study treatments at each visit. |
| Assessment of the immunogenicity of the proposal combination therapy. | average of 30 months | UCP specific TCD4 T-cell response will be assess by ex vivo IFN-γ ELISpot in peripheral blood (Adotevi JCO 2023). |
| Evaluation of health-related quality of life (HrQoL) in the two arms | up to 42 months | Health related Quality of life will be evaluated with EORTC-QLQC30 questionnaire and BN20 module at randomization and at 6 months. |
| Exploratory biomarker study | average of 30 months | — |
Countries
France
Contacts
CONTACTSophie DEPIERRE
PRINCIPAL_INVESTIGATOROlivier ADOTEVI, MD
University Hospital of Besançon
PRINCIPAL_INVESTIGATORAntoine CARPENTIER, MD
University Hospital of Besançon
Outcome results
None listed