Clinical Trial NCT02658981: Investigating Relatlimab for Recurrent Glioblastoma

A multicenter, phase 1 clinical trial (NCT02658981), conducted under the NCI Adult Brain Tumor Consortium (ABTC), evaluated the safety and immunological impact of the LAG-3 inhibitor relatlimab in patients with recurrent glioblastoma (GBM) or gliosarcoma. The study, which reached its primary completion date on April 30, 2022, explored relatlimab as both a monotherapy and in combination with the PD-1 inhibitor nivolumab, providing data on the immune microenvironment of these aggressive brain tumors.

Study Design and Patient Eligibility

The trial utilized an open-label, platform design to assess the Maximum Tolerated Dose (MTD) and safety profiles of immune checkpoint inhibitors. According to the study protocol reviewed by the NCI Cancer Therapy Evaluation Program, participants were adults with histologically confirmed recurrent GBM or gliosarcoma who had previously undergone radiation therapy and temozolomide treatment. Eligibility required measurable contrast-enhancing disease of at least 1 cm by 1 cm and a Karnofsky Performance Status (KPS) of at least 60%.

Exclusion criteria were strict to ensure patient safety and data integrity. Individuals with active or recent autoimmune disease, those requiring significant corticosteroid support (greater than 1 mg per day of dexamethasone), or patients with concurrent malignancies were ineligible. The study was approved by the Johns Hopkins Office of Human Subjects Research institutional review board (IRB) and required all participants to provide informed consent for both trial enrollment and tissue collection.

Dose Escalation and Combination Therapy

The trial was organized into three distinct parts to evaluate safety and efficacy:

• Part A: Established the MTD for relatlimab monotherapy using a modified rule-based dose escalation, testing dosages of 80 mg, 240 mg, and 800 mg.
• Part B: Investigated the combination of relatlimab and nivolumab. Initially planned to follow standard dosing, the protocol was adjusted to start relatlimab at 80 mg and escalate to 160 mg, paired with 240 mg of nivolumab, due to reported risks of immune-related adverse events like myocarditis in other immunotherapy trials.
• Part C: Examined the neoadjuvant effect of relatlimab, administering one dose prior to planned surgical resection to analyze the impact on the tumor’s immune microenvironment.

Safety and Clinical Assessment

Safety monitoring followed the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Clinical assessments included regular neurological and physical examinations, hematology, blood chemistry, and cardiac monitoring. To address the challenge of “pseudoprogression”—a phenomenon where immunotherapy causes temporary inflammation that mimics tumor growth on imaging—the study employed mRANO (modified Response Assessment in Neuro-Oncology) criteria. This required radiographic confirmation of progression within a 6-month window for non-surgical patients before classifying the disease as progressive.

Immunological Correlation Studies

The research team performed extensive molecular analysis on patient samples to understand how relatlimab alters the tumor immune microenvironment. These exploratory studies included:

• Multiplex Immunofluorescence (mIF): Used to quantify the presence of CD8+ T cells, PD-1, and LAG-3 markers within the tumor tissue.
• Gene Expression Profiling: Conducted via the NanoString nCounter platform to analyze 770 immune-related genes from surgical resection samples.
• T Cell Clonality Analysis: Utilized TCRβ sequencing to assess the diversity of the T cell repertoire.
• MIBI-TOF (Multiplexed Ion Beam Imaging by Time of Flight): Employed a custom human panel to map immune, tumor, exhaustion, and metabolic markers at a high resolution.

Key Takeaways for Future Research

The ABTC 1501 trial represents a significant effort to address the immunosuppressive nature of glioblastoma. By focusing on LAG-3 inhibition, researchers aim to overcome the limitations of traditional therapies. The data gathered from this platform trial serves as a foundation for understanding how checkpoint inhibitors can be better refined for patients facing recurrent high-grade gliomas.