CTNI-62. EVALUATION OF SAFER-SEQS CTDNA ASSAY OPTIMIZED FOR DETECTING LOW CTDNA COUNTS FROM CSF AND PLASMA: ASSESSING SENSITIVITY AND FEASIBILITY FOR CLINICAL IMPLEMENTATION

Abstract BACKGROUND Gliomas with BRAF alterations are often difficult to treat in the recurrent setting due to emergent resistance to FDA-approved targeted therapies. Additionally, it is difficult to assess response to therapy given the limitations of radiographic techniques and the infeasibility of serial tissue sampling. This protocol will serve as a prototype for determining the feasibility of using CSF and plasma circulating tumor DNA (ctDNA) as biomarkers for response to a novel-BRAF inhibitor, plixorafenib. Plixorafenib is a small-molecule selective inhibitor of Class 1 and 2 BRAF mutations that does not induce paradoxical reactivation of MAPK signaling. METHODS This clinical trial is designed as a single institution, signal-finding study to demonstrate the feasibility and sensitivity of detecting ctDNA at baseline and after one month of treatment with plixorafenib (primary endpoint). In addition, we will evaluate the correlation of ctDNA with disease status over time and response rate to plixorafenib. Patients aged 18 years or older with measurable recurrent BRAF-V600 mutant glioma (by RANO 2.0), who have received prior BRAF and/or MEK inhibitor therapy will be screened and consented for the study prior to surgery. Leptomeningeal disease allowed. A total of 12 evaluable patients will be enrolled. Patients will undergo clinically-indicated resection or biopsy for confirmation of disease progression and characterization of putative resistance alterations. All patients will have a ventricular reservoir placed at time of surgery with CSF and plasma sampling. Patients will initiate the study drug (oral plixorafenib 900mg daily with cobicistat 150mg daily) when clinically recovered from surgery. Patients will take the drug continuously for 28-day cycles. MRI, CSF, and plasma assessments will occur approximately every two months to evaluate disease status. Enrollment is planned to begin November, 2024.