A Phase Ib/II Study of Olutasidenib in Patients with Relapsed/refractory IDH1 Mutant Gliomas: Safety and Efficacy As Single Agent and in Combination with Azacitidine.

2505 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in >70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent, brain penetrant (Kpuu=0.4 in intact rodent), and selective inhibitor of mutated IDH1 protein. Methods: Patients (pts) with relapsed/refractory (R/R) mIDH1 gliomas received olutasidenib 150 mg BID, orally either as single agent (SA) or in combination (CO) with azacitidine in a dose confirmation phase Ib followed by efficacy evaluation phase II study (NCT: 03684811). Results: As of 31-Oct-2019, 29 pts with R/R mIDH1 glioma were treated with olutasidenib as SA (n=24) or CO (n=5). The median age was 45 yrs (range: 23-64) & 62% were male. WHO Glioma Grade (Gr) at study entry was: II (17%), III (52%) & IV (31%). Median number of prior treatments was 2 (1-5); 86% had received prior temozolomide. mIDH1 status was locally determined (IHC, NGS or PCR): R132H (86%), R132L (7%), R132C (3.5%) & unspecified (3.5%). The median duration of olutasidenib treatment for SA & CO was 4.8 (1-11.4) & 1 (0.2-2.3) months, respectively. Fifteen pts discontinued (disease progression [n=12], AE [n=1], withdrew consent [n=1], other [n=1]). For SA, the most common (>25%) TEAEs (all grades, regardless of attribution) were: fatigue (50%), nausea (50%), diarrhea (33%), ALT increase (29%) & headache (29%). For CO, TEAEs that occurred in ≥ 2 pts were: nausea (n=4), fatigue (n=2), neutropenia (n=2), ALT increase (n=2) & AST increase (n=2). There were 2 protocol defined DLTs in the CO cohort, 1 pt with Gr 4 ALT, Gr 3 AST & Gr 3 GGT elevations & 1 pt with Gr 3 ALT elevation. No pts experienced a TEAE of QTcF prolongation. SA best responses are shown in Table; CO pts are too early for response assessment. The median PFS for SA was 8.3 months. Twenty (87%) and 11 (48%) pts were alive and progression-free at 6 & 12 months, respectively. Conclusions: SA olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in glioma pts. Evaluation of CO is ongoing. Updated safety and clinical activity, as well as evaluations of serum/CSF PK/PD will be provided. Clinical trial information: NCT03684811 . [Table: see text]