A trial to evaluate CSF ctDNA and safety of plixorafenib alone or with retifanlimab in patients with BRAF-altered glioma.

Abstract

TPS2100 Background: BRAF V600E mutant gliomas are difficult to treat in the recurrent setting due to adaptive resistance to FDA-approved targeted therapies. Emerging therapeutic approaches include novel BRAF inhibitors or combination therapies, but evaluating treatment response is limited by radiographic techniques and the infeasibility of serial tissue sampling. This two-arm study will evaluate the feasibility of using CSF and plasma circulating tumor DNA (ctDNA) as biomarkers for response to a novel-BRAF inhibitor, plixorafenib alone or in combination with PD-1 inhibitor, retifanlimab. Plixorafenib is a small-molecule selective inhibitor of BRAF-V600E and BRAF-fusion alterations without inducing paradoxical reactivation of MAPK signaling. Methods: This single institution trial of plixorafenib alone (Arm A) or combined with retifanlimab (Arm B) is enrolling patients (18+ years of age) with BRAF-V600E mutant glioma following progression on prior BRAF-targeted therapy who are recommended for a clinically-indicated diagnostic or debulking surgery. Eligible patients have recurrent BRAF-V600E mutant glioma (any grade) with measurable disease (by RANO 2.0), and a Karnofsky performance status ≥ 70. Leptomeningeal disease is allowed. All enrolled patients will undergo clinically-indicated resection or biopsy for confirmation of disease progression and characterization of putative resistance alterations with a ventricular reservoir placed at time of surgery for CSF sampling. In both arms, patients will initiate oral plixorafenib once clinically recovered from surgery. Patients will take the plixorafenib daily with food. In Arm B, enrolled patients will receive one dose of retifanlimab three weeks prior to surgery, then resume monthly retifanlimab infusions after surgery in combination with oral plixorafenib. MRI, CSF, and plasma assessments will occur approximately every two months to evaluate disease status. The primary trial endpoint is detectable ctDNA at baseline and after one month of treatment with plixorafenib. Secondary endpoints include safety of plixorafenib alone or in combination with retifanlimab, response rate in each arm, and the correlation of ctDNA with disease status over time. The trial is IRB approved and enrollment is ongoing (10 patients per arm). Clinical trial identifier NCT06610682. Clinical trial information: NCT06610682 .