Final Results of a Phase 1b Study of BET Inhibitor PLX2853 in Patients with Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Background: Relapsed and refractory myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a clinical challenge due to high mortality, morbidity, and lack of effective therapeutic agents. PLX2853 is an orally available, non-benzodiazepine bromodomain and extraterminal domain (BET) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second of the double bromodomains of the BET proteins. By regulating genes (e.g., BCL2 and MYC) central to leukemic cell proliferation and survival, PLX2853 has demonstrated broad anti-leukemic activity both as a single agent and in combination with other agents in preclinical models. The pharmacokinetic (PK) profiles in patients with solid tumors revealed high peak plasma concentrations, a short terminal half-life (T 1/2 < 3 hour), and nearly complete elimination from the plasma by 9 hours post dose. This PK profile is hypothesized to improve tolerability by allowing transient target engagement followed by time for recovery after daily dosing.