Phase 2 eflornithine (DFMO) ornithine decarboxylase inhibitor added/maintenance in Ewing and osteosarcoma

This Phase 2, non-randomized, open-label basket study tests eflornithine (DFMO)—a small-molecule ornithine decarboxylase (ODC) inhibitor that suppresses polyamine synthesis—as concurrent therapy with multi-agent chemotherapy and/or as long maintenance after completion of local control/consolidation in Ewing sarcoma and osteosarcoma. Milton S. Hershey Medical Center sponsors the master protocol with five parallel cohorts spanning relapsed/refractory, metastatic-at-diagnosis, and post-local-control settings, including DFMO alone for resected lung-metastasis relapse osteosarcoma and DFMO added during post-surgery MAP-based consolidation (high-dose methotrexate + doxorubicin + cisplatin) in osteosarcoma cohorts. Ewing cohorts incorporate DFMO alongside commonly used regimens such as cyclophosphamide + topotecan and multi-agent VDC/IE-style backbones (vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide). The commercial/scientific angle is repositioning a metabolism-targeting oral agent as a long-duration maintenance strategy in AYA bone sarcomas where recurrence risk remains high despite intensive chemo plus surgery ± radiation. Today’s care for Ewing and osteosarcoma is multi-agent chemotherapy with definitive surgery when feasible and radiation in selected cases, with limited proven maintenance options after remission—this trial asks whether sustained ODC inhibition can extend event-free and overall survival versus historical outcomes.