Evaluation of UCPVax Vaccine +/- Pembrolizumab Combined With Standard Treatment as Adjuvant Therapy in Patients With Unmethylated MGMT Glioblastoma

Official title

Evaluation of UCPVax Vaccine +/- Pembrolizumab Combined With Standard Treatment as Adjuvant Therapy in Patients With Unmethylated MGMT Glioblastoma: a Randomized Phase II Trial

Overview

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

• Drug UCPVax
  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
• Drug Pembrolizumab
  400 mg/m1 every 6 weeks since day 1 until disease progression or unacceptable toxicity for a maximum of 1 year
• Drug Temozolomide
  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.

Primary outcome measures

• 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) [Time frame: 18 months]

Secondary outcome measures (8)

• 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) [Time frame: 18 months]
• Assessment of the Overall Survival (OS) in the three arms [Time frame: from date of randomization until date of death from any cause, assessed up to 42 months]
• Assessment of the progression free survival (PFS) since randomization in the three arms [Time frame: 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]
• Assessment of the progression free survival (PFS) at 6 months since randomization in the three arms [Time frame: 6 months]
• Evaluation of incidence of treatment-emergent adverse events in the three arms [Time frame: up to 42 months]
• Assessment of the immunogenicity of the proposal combination therapy. [Time frame: average of 30 months]
• Evaluation of health-related quality of life (HrQoL) in the two arms [Time frame: up to 42 months]
• Exploratory biomarker study [Time frame: average of 30 months]

Eligibility criteria

Inclusion criteria

• 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
• Karnofsky Perfomance status (KPS) ≥ 70%
• Life expectancy ≥ 3 months
• 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
• Adequate organ function laboratory values
• 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.

• 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.
• Patient affiliated to or beneficiary of French social security system
• Ability to comply with the study protocol, in the Investigator's judgment.
• Signed and dates informed consent

Exclusion criteria

Patients will not be eligible for this study for any of the following reasons:

Cancer specific exclusion criteria:

• 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
• Previous treatment with Carmustine impregnated wafers (GliadelR)
• Previous treatment with bevacizumab or other Vascular Endothelial Growth Factor (VEGF) antagonists
• Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study.

Non-eligible to treatment by UCPVax:

• Prior therapy with an anti-PD-1, anti-PD-L1, or with an agent directed to another immune checkpoint (e.g. CTLA-4, TIGIT, Lag3…).
• Immunosuppressive treatment including CS > 10 mg prednisone or equivalent within the previous 2 weeks
• Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.
• Has a known history of Human Immunodeficiency Virus (HIV) infection.
• History of tuberculosis infection
• History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Active auto-immune disease that has required a systemic treatment in the past 2 years (i.e. corticosteroïds or immunosuppressors). Replacement therapy (e.g. thyroxine, insulin) is allowed.
• Active or history of auto-immune disease or immune deficiency
• History of solid organ transplant nor allogenic hematopoietic stem cell transplantation
• Hypersensitivity to the active substance temozolomide or to any of the excipients listed (anhydrous lactose, colloidal anhydrous silica, sodium carboxymethyl starch type A, tartaric acid, stearic acid),
• Hypersensitivity to dacarbazine (DTIC)
• Hypersensitivity to the active substance pembrolizumab or to any of the excipients listed (L-histidine, L-histidine hydrochloride monohydrate, sucrose, polysorbate 80 (E433))
• Hypersensitivity to the active substance Montanide
• Uncontrolled active systemic fungal, bacterial, viral, or other infection within the previous 4 weeks or requirement for intravenous (IV) antibiotics within the last two weeks
• Inadequate hematology and organ functions; known cardiac failure or unstable coronaropathy, respiratory failure or another life threatening condition.
• Patient with unresolved non-hematologic toxicities > Grade 1 (or > Grade 2 if deemed acceptable by the investigator and not considered a safety risk)
• Major surgery within 1 month prior randomization or planned during the study
• Vaccination with alive attenuated vaccine within 4 weeks prior the first dosing. Patient must agree not to receive live attenuated vaccine including influenza vaccine during the treatment and within 6 months following the last dose of pembrolizumab

Non-eligible to a clinical trial:

• Diagnosis of another malignant tumor within 2 years before randomization except treating resected basocellular carcinoma and carcinoma in situ such as breast cancer, endometrial or cervical carcinoma that have undergone curative therapy.
• Current or treatment with another investigational drug within the previous 4 weeks.
• Breast-feeding or pregnant women, no effective contraception if risk of conception exists (up to 4 months after end of chemotherapy)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 4 centers

• CHU de Besançon — Besançon
• Centre Georges François Leclerc — Dijon
• CHU La Timone — Marseille
• Hôpital Saint-Louis - APHP — Paris

Publications

• Laheurte C, Boullerot L, Ndao B, Malfroy M, Queiroz L, Guillaume P, Loyon R, Seffar E, Gravelin E, Renaudin A, Jacquin M, Meurisse A, Vernerey D, Ghiringhelli F, Godet Y, Genolet R, Jandus C, Borg C, Adotevi O. UCPVax, a CD4 helper peptide vaccine, induces polyfunctional Th1 cells, antibody response, and epitope spreading to improve antitumor immunity. Cell Rep Med. 2025 Jul 15;6(7):102196. doi: 1 PMID 40543509
• Adotevi O, Vernerey D, Jacoulet P, Meurisse A, Laheurte C, Almotlak H, Jacquin M, Kaulek V, Boullerot L, Malfroy M, Orillard E, Eberst G, Lagrange A, Favier L, Gainet-Brun M, Doucet L, Teixeira L, Ghrieb Z, Clairet AL, Guillaume Y, Kroemer M, Hocquet D, Moltenis M, Limat S, Quoix E, Mascaux C, Debieuvre D, Fagnoni-Legat C, Borg C, Westeel V. Safety, Immunogenicity, and 1-Year Efficacy of Universal PMID 36070539

Identifiers

NCT: NCT07347210 · 2024/894 · 2024-514399-42-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗