Phase 1 Study Of Ag-881, An Inhibitor Of Mutant Idh1/Idh2, In Patients With Advanced Idh-Mutant Solid Tumors, Including Glioma

2002Background: Isocitrate dehydrogenase 1 and 2 mutations (mIDH1/2) occur in solid tumors including glioma, and result in production of the oncometabolite 2-hydroxyglutarate (2-HG), promoting tumorigenesis. AG-881 is an oral, potent, brain-penetrant inhibitor of mIDH1/2 that reduces 2-HG by up to 98% in glioma models. Methods: Patients (pts) with recurrent/progressive mIDH1/2 glioma (G) and non-glioma (NG) solid tumors were eligible to receive AG-881 daily in continuous 28-day cycles. Dose escalation cohorts for G and NG solid tumors enrolled using a Bayesian logistic regression model (BLRM) escalation guided by the overdose control (EWOC). Blood and tumor samples were evaluated for pharmacokinetics (PK)/pharmacodynamics (PD). Dose-limiting toxicity (DLT) was defined as a Grade (Gr) ≥3 AG-881-related event in Cycle 1 or by sponsor designation. Results: As of 1Dec2017, 93 pts had received AG-881 (G: 52; NG: 41) and 20 remain on AG-881 (G: 19, NG: 1). Demographics: M/F = 40/53; median age = 51; median no. ...