NCT06712875

MAPK Inhibition Combined With Anti-PD1 Therapy for BRAF-altered Pediatric Gliomas

A Pilot Study Evaluating the Toxicity and Clinical Benefit of Mitogen-activated Protein Kinase (MAPK) Pathway Inhibition Combined With Programmed Cell Death-1 Checkpoint Blockade (Anti-PD1) for the Treatment of BRAF-altered Pediatric Gliomas

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 27 (estimated)
• Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago · Academic / Other
• Sex: All
• Age: 1 Year – 26 Years
• Healthy volunteers: Not accepted

Summary

Pediatric gliomas harboring BRAF-alterations, commonly BRAFV600 mutation or KIAA1549-BRAF fusion, are currently treated with either chemotherapy or mitogen activated protein kinase (MAPK) inhibitors, such as, dabrafenib and/or trametinib. Unfortunately, some BRAF-altered gliomas can progress or have rebound growth after discontinuation of therapy. Data from BRAFV600E-mutant melanoma has shown potential synergy between MAPK inhibition and anti-programmed cell death 1 (anti-PD1) checkpoint blockade. Anti-PD1 therapy, such as, nivolumab can block the PD1 receptor on T cells, a marker of T cell exhaustion, allowing a continued or more robust anti-tumor immune response. Here, investigators will combine MAPK inhibition with anti-PD1 therapy in recurrent, refractory low grade BRAF-altered glioma and newly diagnosed or recurrent BRAF-altered or NF-altered high grade glioma.

Detailed description

This is a pilot study evaluating the toxicity and early efficacy of dabrafenib and/or trametinib combined with nivolumab for the treatment of BRAF-altered or NF altered gliomas. While dabrafenib, trametinib, and nivolumab have been used for pediatric gliomas in previous studies, this will be the first pediatric study evaluating the combination of these agents. This study will evaluate the use of dabrafenib, trametinib, and nivolumab in patients in recurrent, refractory, or progressive low grade gliomas harboring BRAFV600 mutations who have previously been treated with MAPK inhibition alone. The same combination will be explored in newly diagnosed or recurrent BRAFV600 mutant high grade glioma. This study will also evaluate the use of trametinib and nivolumab in patients with recurrent, refractory, or progressive low grade gliomas harboring a KIAA1549 BRAF fusion who have previously been treated with MAPK inhibition alone. The same combination will be explored in NF altered transforming or high grade glioma or high grade glioma harboring a KIAA1549 BRAF fusion. The objective of this study is to understand the safety and tolerability of the combination of dabrafenib, trametinib, and/or nivolumab in pediatrics. Secondarily, this study will evaluate for an early efficacy signal of the combination therapy and compare to historical treatment response to MAPK inhibition alone.

Conditions

• Low Grade Glioma
• High Grade Glioma

Interventions

Type	Name	Description
DRUG	Trametinib and Nivolumab	Trametinib combined with nivolumab (Cohort A)
DRUG	Dabrafenib, trametinib, nivolumab	Dabrafenib + trametinib combined with nivolumab (Cohort B)

Timeline

• Start date: 2025-04-01
• Primary completion: 2028-12-01
• Completion: 2029-06-01
• First posted: 2024-12-02
• Last updated: 2025-05-29

Locations

3 sites across 1 country: United States

Regulatory

• FDA-regulated drug study