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.
Male or female, age ≥ 18 with informed consent signed
Patient with a confirmed histological diagnosis of non-mutated IDH primary glioblastoma (surgical resection or biopsy).
Tumor with unmethylated MGMT promoter status
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
IDH1 or IDH2 mutated tumor
Presence of extracranial metastasis
Leptomeningeal disease on MRI
Contrast enhancement ≥4 cm (largest diameter on axial T1 sequences) on inclusion MRI
Parallel
UCPVax
DrugPriming : 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
Pembrolizumab
Drug400 mg/m1 every 6 weeks since day 1 until disease progression or unacceptable toxicity for a maximum of 1 year
Temozolomide
Drug150-200 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.
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)
Rate for patients alive at 18 months post-randomization
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)
The rate of patients alive at 18 months post randomization
Assessment of the Overall Survival (OS) in the three arms
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
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
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.
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Centre Hospitalier Universitaire de Besancon
Lead sponsor
Merck Sharp & Dohme LLC
Collaborator
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