Glasdegib with intensive/nonintensive chemotherapy in Japanese patients with untreated acute myeloid leukemia or high‐risk myelodysplastic syndromes

Abstract

AbstractGlasdegib is a potent, selective, oral inhibitor of the hedgehog signaling pathway. In this phase I study, previously untreated Japanese patients with acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes were treated with glasdegib (100 mg once daily) combinations: low‐dose cytarabine (20 mg twice daily; cohort 1, n = 6; expansion cohort, n = 15); daunorubicin and cytarabine (60 mg/m2 i.v.; cohort 2, n = 6); or azacitidine (100 mg/m2 i.v.; cohort 3, n = 6). Patients, except cohort 2, were ineligible for intensive chemotherapy. The primary end‐point was dose‐limiting toxicity in cohorts 1–3 and disease‐modifying response in the expansion cohort. Disease‐modifying response rate was tested with the null hypothesis of 6.8%, which was set based on the results from the phase II BRIGHT AML 1003 study (NCT01546038). No dose‐limiting toxicities were observed in cohorts 1 or 3; one patient in cohort 2 experienced a dose‐limiting toxicity of grade 3 erythroderma. The most common grade ≥3 treatment‐related adverse events were neutropenia and thrombocytopenia (66.7% each) in cohort 1 and thrombocytopenia (60.0%) in the expansion cohort. In the expansion cohort, the disease‐modifying response rate was 46.7% (90% confidence interval, 24.4–70.0; p < 0.0001), with all patients achieving either a complete response or complete response with incomplete blood count recovery. Median overall survival was 13.9 months. In this study, the primary disease‐modifying response end‐point with glasdegib plus low‐dose cytarabine was met. The study confirms the safety and efficacy of glasdegib plus low‐dose cytarabine in Japanese patients with AML ineligible for intensive chemotherapy.