New Adjuvant Vaccine in Glioblastoma, a Phase 1/2a Study (NAVIG-1)

Assistance Publique - Hôpitaux de Paris

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Newly Diagnosed Glioblastoma

Treatments: Biological: immunization

Study type: Interventional

Funder types: Other

Identifiers

NCT06622434

APHP240512

2024-514567-26-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

This phase I/II trial evaluates the safety and the immunological efficacy of a cancer vaccine against 2 glioma-associated antigens in newly-diagnosed glioblastomas.

The objectives of this study are as follows:

Primary objective

• phase 1:
• to assess the maximum tolerated dose (MTD) and select the recommend Phase 2a dose
• phase 2a:
• to assess anti- TERT specific T cell responses at 2 months at the selected dose level

Secondary objectives:

• To assess Short and long-time immunological safety
• To assess Evolution of anti-PTPRZ1 and anti-TERT immune T cell responses over time
• To assess Progression free survival (RANO 2.0 criteria)
• To assess Overall survival
• To assess Quality of life by EORTC QLQ30 and BN20 questionnaires

as well as objective of ancillary study: to determine the mechanism of action of potential tumour escape in GBM (T-cell lymphocyte phenotype; antigen expression and checkpoint inhibitors on tumour cells at relapse, if available), analysis of circulating antibodies against TERT epitope and/or melanin, and identification of predictive biomarkers of response.

Ultimately, this trial together will lead to the implementation of future phase III trial in GBM.

All patients enrolled in the study will receive standard treatment consisting of surgical resection of the tumor followed by radio-chemotherapy. Immunotherapy will begin 4 weeks after the completion of radiotherapy.

Full description

This therapeutic vaccine targeting 2 identified glioma-associated antigens (TERT and PTPRZ1) is based on a new formulation that contains synthetic melanin and a TLR9 agonist, which is caable to induce strong cellular immune responses.

One month after glioblastoma patients have completed the initial phase of treatment with concurrent radiochemotherapy, patients will be immunized during the adjuvant phase of monthly temozolomide. Immunizations will follow the standard schedule of a priming phase (D0, W2, W4, and W6) followed by a boost phase with one immunization every 2 months for a total of 12 months.

Phase 1: subcutaneous injections at one of 3 pre-specified dose levels of peptides

Phase 2a: subcutaneous injections at the dose selected in the phase 1 part.

Safety will be evaluated clinically and with blood samples at each treatment visit. Efficacy will be assessed with anti-PTPRZ1 and anti-TERT specific T cell responses in peripheral blood, and with cerebral MRI every other months

Enrollment: 35 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• age between 18 and 75 years old
• free, informed and written consent signed
• Histologically confirmed glioblastoma
• Patients previously treated with concurrent radiotherapy (at least 45 Gy) with concomitant temozolomide, before the beginning of the 6 additional monthly cycles of temozolomide. Radiation therapy must have been completed 28 to 45 days prior to the first study treatment
• Karnofsky Performance Status ≥ 60%
• Phase 1 only: Patients must be human leukocyte antigen (HLA)-A2 positive.
• Phase 1 only: PTPRZ1 expression in the tumor
• Available tumor tissue for post hoc (retrospective) assessment of TERT promoter mutations and MGMT promoter methylation status
• Life expectancy ≥ 3 months
• Adequate organ function laboratory values within 15 days before initiation of treatment (see table in section 6.1)
• Women or Male of childbearing potential (WOCBP) must use contraceptive methods during and for 180 days after the last dose of temozolomide or up to 120 days after the last dose of vaccine, whichever is longer (see section 6.3). No sperm donation during the study and until 7 months after the end of the treatment period.
• Patient affiliated to the social security scheme

Exclusion criteria

• Known extracranial metastatic or leptomeningeal disease
• Grade 4 astrocytoma IDH mutant
• Steroid requirement >10 mg prednisone daily (or equivalent) at time of inclusion
• Patients with prior malignancy active within the last 3 years
• Patients receiving immunomodulatory or immunosuppressive therapy
• Carmustine wafers (GliadelR) implantation during surgery
• Phase 1 only: patient eligible and willing to be treated with Optune (TTF fields)
• History of autoimmune disease (lupus, rheumatoid arthritis, inflammatory bowel disease...)
• 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.
• 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
• Breast-feeding or pregnant women.
• Contra-indications to IRM
• Contra-indications to investigational medicinal product and/or to auxiliary medicinal products
• Participation to another interventional clinical trial, clinical investigation or another interventional study or being in the exclusion period at the end of a previous study
• Patient unable to follow the procedures and constraints of the protocol
• Patient under legal protection (protection of the court, or in curatorship or guardianship).

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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35 participants in 1 patient group

A52-Mel; A49-Mel (for Phase1 only) and Litenimod, as an adjuvant

Experimental group

Description:

In Phase 1, A52-Mel and A49-Mel will be mixed just prior to the injection. Litenimod will be injected at the same site just after the injection. In phase 2a, A52-Mel will be administered, followed by Litenimod at the same injection site.

Treatment:

Biological: immunization