Phase 2 methotrexate dihydrofolate reductase inhibitor optimizes HD‑MTX discharge in osteosarcoma.

This Phase 2, multicenter supportive-care/operations study from Wake Forest University Health Sciences (Wake Forest Baptist) tests whether patients with newly diagnosed high‑grade osteosarcoma (children, adolescents, and young adults ≤22) can be discharged after high‑dose methotrexate at slightly higher serum MTX thresholds than many hospitals traditionally use. Methotrexate is a folate antagonist that inhibits dihydrofolate reductase, blocking thymidylate and purine synthesis (a DNA synthesis inhibitor), and here it is delivered as part of routine MAP chemotherapy alongside doxorubicin (a topoisomerase II inhibitor) and cisplatin (a DNA‑crosslinking platinum). Discharge thresholds (e.g., ≤0.10 to ≤0.20 µM) are evaluated sequentially rather than randomized, with safety judged by toxicity and hospital re-admission within 7 days, plus comparisons to historical discharge practices. A translational arm evaluates feasibility of generating patient-derived osteosarcoma tumor organoids across centers (osteosarcoma is rare, so scalable organoid generation is a key enabling platform). For newly diagnosed high‑grade osteosarcoma, today’s care is perioperative multi-agent chemotherapy (MAP-based) plus surgery; this study doesn’t change anti-cancer drugs, but may safely reduce inpatient time, burden on families, and hospital resource use while building a reusable organoid biobank.