Phase 1 study of AG-881, an inhibitor of mutant IDH1/IDH2, in patients with advanced IDH-mutant solid tumors, including glioma.

Abstract

2002 Background: 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. prior systemic therapies = 3 (range 1–7). Seven initial dose levels were tested: 25mg QD (n = 10); 50mg QD (n = 12); 100mg QD (n = 21); 200mg QD (n = 22); 200mg BID (n = 5); 300mg QD (n = 5) and 400mg QD (n = 6). To further assess safety and PK in the G cohort, a 10mg dose level was tested (n = 6) and 6 additional pts enrolled in the 50mg cohort. PK showed less than dose-proportional plasma exposure with a mean effective half-life of 71±54 hrs. Common adverse events (AEs) across all pts regardless of attribution: fatigue (38.7%), nausea (35.5%), ALT/AST increase (34.4% each). Elevated ALT/AST AEs were dose-dependent (n = 0 at 10mg, n = 7 at ≤50mg, n = 10 at 100mg, n = 20 at > 100mg). Five G pts experienced DLTs at 100mg and above: Gr ≥2 ALT/AST which resolved to Gr ≤1 with dose modification (n = 4) or discontinuation (n = 1). The MTD or RP2D were not reached by BLRM with EWOC. Conclusions: AG-881 was associated with a favorable safety profile at doses < 100mg in pts with glioma and non-glioma solid tumors. No ALT/AST AEs Gr > 2 were observed at 10mg and 50mg. These doses are being explored in an ongoing perioperative glioma study. Updated safety, PK/PD, and efficacy data will be presented. Clinical trial information: NCT02481154.