Mutant IDH1 inhibitor ivosidenib (IVO; AG-120) in combination with azacitidine (AZA) for newly diagnosed acute myeloid leukemia (ND AML).

Abstract

7011 Background: IVO, a mutant IDH1 (mIDH1) inhibitor, is approved for the treatment of relapsed/refractory mIDH1 AML. We report results from an ongoing phase 1b study of patients (pts) with mIDH1 ND AML ineligible for intensive treatment who received combination IVO+AZA (NCT02677922). Methods: Pts received oral IVO 500 mg daily continuously and subcutaneous AZA 75 mg/m2 on D1–7 in 28-d cycles. ORR comprised CR + CRi/CRp + PR+ MLFS. CR with partial hematologic recovery (CRh) was defined as CR with ANC > 0.5×109/L and platelets > 50×109/L. Exploratory analysis included digital PCR assessment of m IDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity). Results: As of 9Oct2018, 23 pts received IVO+AZA (11 male; median age 76 yrs [range 61–88]). Median duration of exposure was 11 mo (0.3–25.3); 12 pts remained on treatment at data cutoff. All-grade adverse events (AEs) regardless of cause in ≥30% pts were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included ECG QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% pts were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18): CR 57%, CRi/CRp 13%, and MLFS 9%. CR+CRh rate was 70% (n = 16). Median time to response was 1.8 mo (0.7–3.8) and to CR 3.5 mo (0.8–6.0); median response duration not yet reached. m IDH1 clearance was seen in 10/16 pts (63%) with CR/CRh, including 9/13 (69%) with CR. Conclusions: IVO+AZA was well tolerated with a safety profile consistent with IVO or AZA monotherapy. All-grade cytopenia-related AEs were infrequent relative to other non-intensive therapies. CR and ORR rates exceeded those of AZA alone (Dombret et al., Blood 2015) and most responders achieved m IDH1 mutation clearance. Based on these findings, a phase 3 double-blind placebo-controlled study of IVO +AZA (AGILE, NCT03173248) is actively enrolling pts. Clinical trial information: NCT02677922.