TRLS-04. EARLY INSIGHTS FROM PNOC027: PERSONALIZED TREATMENT APPROACHES BASED ON REAL-TIME DRUG SCREENING AND GENOMIC TESTING IN PEDIATRIC AND ADOLESCENT PATIENTS WITH RECURRENT MEDULLOBLASTOMA

Abstract

Abstract BACKGROUND PNOC027, a clinical trial conducted by the Pediatric Neuro-Oncology Consortium (PNOC), explores a precision medicine strategy with up to four FDA-approved agents integrating real-time drug screening with whole exome DNA and RNA sequencing to guide personalized treatment approaches for children and young adults with relapsed medulloblastoma. METHODS Freshly isolated tumor cells from patients undergo high-throughput drug screening, evaluating responses to 232 clinically available compounds over 72 hours. In vitro drug responses are integrated with tumor genomic and transcriptomic data to predict drug combinations for each patient. Drugs are prioritized based on blood-brain barrier permeability, patient age, prior treatments, and other co-morbidities. Correlative studies include the collection of blood to assess circulating tumor DNA (ctDNA) before surgery and during treatment. Health-related quality of life (HRQOL) assessments will also be collected during therapy. RESULTS To date, nine patients have been enrolled. Eight of these have successfully completed real time drug screening with a median turnaround of 7 days from sample receipt. One patient was excluded due to ineligible (non-medulloblastoma) pathology after enrollment. Seven of these had whole exome sequencing, and six had RNA sequencing. Tumor board recommendations were rendered within 21 business days from the date of surgery. Among the diverse drug classes evaluated, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, anthracyclines, DNA crosslinkers, and kinase inhibitors showed the most robust in vitro responses. Six patients received the recommended regimens, experiencing tolerable (grade 1/2) toxicities. Two patients succumbed to disease prior to therapy initiation, three exhibited disease progression while on therapy, and three remain on therapy. CONCLUSION PNOC027 demonstrates preliminary feasibility of real-time drug screening combined with DNA/RNA sequencing to inform targeted therapy selection in clinically relevant timeframes and with potential for disease response.