Phase 3 randomized trial of high-dose methotrexate for young children with high-risk embryonal brain tumors: A report from the Children’s Oncology Group

Mazewski C, Leary SES, Kang G, Li BK, Kellie S, Hayes L, Shaw D, Ho B, Reddy A, Gossett J, Burger PC, Judkins AR, Aridgides P, Geyer JR, Gajjar A, Pollack IF, Fouladi M, Huang A. Phase 3 randomized trial of high-dose methotrexate for young children with high-risk embryonal brain tumors: A report from the Children’s Oncology Group. Neuro Oncol. 2025 Oct 1;27(10):2726-2737. doi: 10.1093/neuonc/noaf132. PMID: 40485042; PMCID: PMC12833527.

Embryonal brain tumors are the leading cause of cancer death in young children. Methods: ACNS0334 was a phase 3 randomized study evaluating high-dose methotrexate in young children < 36 months old with newly diagnosed high-risk embryonal brain tumors. Treatment included 3 cycles of induction chemotherapy with or without methotrexate followed by 3 cycles of high-dose consolidation chemotherapy with hematopoietic stem-cell infusion. Primary endpoint was complete response (CR) at the end of therapy. Secondary endpoints included a comparison of event-free survival (EFS) between arms and to historical controls. Molecular characterization was conducted retrospectively. Tests of significance were one-sided.