Phase 1/2a Study of A49, A52, and Litenimod Sodium in Patients with Glioblastoma

The primary objective of the NAVIG-1 study is to evaluate the **maximum tolerated dose (MTD)** and select the recommended Phase 2a dose in patients with **glioblastoma** during Phase 1. In Phase 2a, the study aims to assess anti-PTPRZ1/TERT specific T cell responses at 2 months at the selected dose level. This is clinically relevant as determining the MTD and evaluating immune responses are crucial steps in developing effective and safe therapeutic strategies for glioblastoma, a highly aggressive brain tumor.

Secondary objectives include: - Assessing anti-PTPRZ1 and anti-TERT immune T cell responses triggered by the vaccination protocol (Phase 1). - Evaluating safety. - Assessing progression-free survival using RANO 2.0 criteria. - Evaluating overall survival. - Assessing quality of life using EORTC QLQ30 and BN20 questionnaires.

The clinical trial focuses on participants diagnosed with **glioblastoma**, a type of brain cancer. The study population includes both male and female subjects, aged between 18 and 75 years. Participants are required to have a **Karnofsky Performance Status** of at least 60%, indicating they are capable of self-care and able to carry out normal activities or work. The trial does not involve a vulnerable population. Participants must have adequate organ function and a life expectancy of at least three months. They should have previously undergone concurrent radiotherapy with temozolomide and must be human leukocyte antigen (HLA)-A2 positive. The trial requires participants to have PTPRZ1 expression in the tumor and available tumor tissue for retrospective assessment of TERT promoter mutations and MGMT promoter methylation status. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the safety and efficacy of a new adjuvant vaccine in patients with **glioblastoma**. This study is structured as a Phase 1/2a trial, incorporating a randomized, double-blind, and controlled methodology. The trial aims to determine the maximum tolerated dose (MTD) in Phase 1 and assess specific T cell responses in Phase 2a. The trial is expected to commence on October 1, 2024, and conclude by February 28, 2027, with participant involvement lasting approximately 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and previous treatment history. The primary inclusion criteria include a histologically confirmed diagnosis of glioblastoma, a Karnofsky Performance Status of at least 60%, and a life expectancy of at least three months. The study will exclude individuals not meeting these criteria. Following the screening, participants will attend regular follow-up visits at specified intervals: Day 0, Week 2, Week 4, Week 6, and monthly from Month 2 to Month 12. These visits will involve clinical assessments, blood sample collection, and cerebral MRI scans to monitor safety and immune responses.

The primary endpoints focus on safety, with adverse events evaluated and graded according to CTCAE v5.0, and immune efficacy assessed through anti-PTPRZ1 and anti-TERT specific T cell responses. Secondary endpoints include the evolution of immune responses, progression-free survival, overall survival, and quality of life assessments using EORTC QLQ30 and BN20 questionnaires. Participants may be withdrawn from the study if they experience significant adverse events or fail to comply with study protocols. The investigational products, including Peptide A49, Litenimod solution, and Peptide A52, are administered via subcutaneous injection, with the trial ensuring rigorous monitoring to maintain participant safety and data integrity.

The clinical trial involves the administration of three experimental medications, each formulated as a **solution for injection**. The first experimental medication is **Peptide A49 associated to melanin**, identified by the sponsor product code A49-Mel. This medication is administered via **subcutaneous use**. The active substance, A49, is classified under the ATC code L03AX, which pertains to "Other Cytokines and Immunomodulators." The substance origin is categorized as "Protein - Other." The administration schedule and dosage frequency are determined based on the trial phase objectives, focusing on assessing the maximum tolerated dose and selecting the recommended Phase 2a dose.

The second experimental medication is **Litenimod solution**, with the sponsor product code Li28. This medication also follows a **subcutaneous route** of administration. The active substance, Litenimod Sodium, is similarly classified under the ATC code L03AX. The substance origin is identified as "Nucleic Acid." The dosing schedule is aligned with the trial's main objective to evaluate specific T cell responses at a selected dose level.

The third experimental medication is **Peptide A52 associated to melanin**, identified by the sponsor product code A52-Mel. Like the other medications, it is administered via **subcutaneous use**. The active substance, A52, shares the ATC classification L03AX and is also derived from "Protein - Other." The administration and dosage are consistent with the trial's aim to determine the maximum tolerated dose and assess specific immune responses.

All experimental medications are provided by Assistance Publique - Hôpitaux de Paris and are not formulated for pediatric use. The trial does not involve any orphan drug designations. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

The efficacy of the investigational treatment in the clinical trial titled "NAVIG-1: New adjuvant vaccine in glioblastoma, a Phase 1/2a study" will be assessed through several primary and secondary endpoints. In Phase 2a, the primary endpoint focuses on immune efficacy, specifically evaluating anti-PTPRZ1 and anti-TERT specific T cell responses in peripheral blood. This will be measured using the IFN-gamma ELISPOT assay at 2 months post the first immunizations.

Secondary endpoints include the evolution over time of these immune T cell responses, assessed at various timepoints such as week 2 (for Phase 1 only), week 4, and months 2, 3, 5, 7, 9, and 12. Additionally, progression-free survival will be monitored using cerebral MRI at baseline, month 2, month 3, and every 2 months thereafter. Overall survival and quality of life will also be evaluated, with the latter assessed using the EORTC QLQ30 and BN20 questionnaires at baseline and at 5 months.