Phase 1/2 domatinostat class I HDAC inhibitor + sirolimus mTOR inhibitor in R/R sarcoma/osteosarcoma.

This multicenter, open-label, cohort-sequential Phase 1/2 trial tests domatinostat plus sirolimus in adolescents and adults with relapsed/refractory sarcoma (Phase 1 dose escalation) and relapsed/refractory osteosarcoma (Phase 2 dose confirmation/expansion with two cohorts: post-surgical complete remission vs unresectable measurable disease). Domatinostat (also known as 4SC-202) is an oral, class I histone deacetylase (HDAC) inhibitor that modulates epigenetic transcription programs and has been studied for potential immune–microenvironment effects; sirolimus is an mTOR inhibitor that downshifts PI3K/AKT/mTOR pathway signaling and protein synthesis. The sponsor is H. Lee Moffitt Cancer Center; commercially, domatinostat originated at 4SC AG and has been reported as out-licensed (program history includes discontinuation by 4SC, with subsequent development arrangements). The key angle is leveraging epigenetic reprogramming plus mTOR blockade to improve disease control in settings where outcomes after relapse are poor. In practice today, relapsed osteosarcoma is typically managed with aggressive metastasectomy/local control when feasible plus non-curative systemic options (e.g., ifosfamide- or gemcitabine/docetaxel-based regimens, TKIs in select contexts), and relapsed soft-tissue/bone sarcomas similarly cycle through histology-driven chemotherapy and targeted agents when available—making a tolerable oral–oral biologically rational combination attractive if signals emerge.