Phase 3, randomized, placebo-controlled trials evaluating glasdegib in combination with intensive or nonintensive chemotherapy in patients with untreated acute myeloid leukemia.

Abstract

TPS7073 Background: Glasdegib is an oral Hedgehog pathway inhibitor with clinical activity in patients (pts) with untreated AML or higher-risk MDS, and improved survival when combined with low-dose cytarabine (AraC) in unfit pts with AML. BRIGHT AML1019 comprises two Phase 3, randomized (1:1), double-blind trials evaluating glasdegib 100 mg once daily (QD) or placebo (PBO) + chemotherapy in untreated adult AML (NCT03416179). The protocol includes 2 parallel, simultaneous trials: 1 with intensive chemotherapy (IC) and 1 with nonintensive chemotherapy (nIC). Methods: Both trials include pts aged ≥18 y with untreated AML (WHO 2016), including AML evolved from MDS or antecedent hematologic disease, or secondary AML. Key exclusions: inadequate organ function, acute promyelocytic leukemia, active CNS leukemia. Assignment to IC or nIC trial is per Investigator. In the IC trial, 400 pts are randomized (1:1) to glasdegib 100 mg QD or PBO on Day 1 and continue for up to 2 y or until post consolidation minimal residual disease (MRD)-negative status. Glasdegib or PBO are administered with 7+3 induction (AraC 100 mg/m2 IV for 7 days + daunorubicin 60 mg/m2 for 3 days); induction 2, if needed, will use 7+3 or 5+2. Consolidation consists of single-agent AraC 1 or 3 g/m2 IV over 3 h twice daily on Days 1, 3 and 5 every 28 days for ≤4 cycles; eligible patients may receive hematopoietic stem cell transplant. In the nIC trial, 320 pts are randomized (1:1) to glasdegib 100 mg QD or PBO, each with azacitidine 75 mg/m2 daily SC or IV for 7 days, in 28-day cycles. Treatments continue until disease progression, unacceptable toxicity, withdrawal or death. In both trials, glasdegib and PBO continue regardless of chemotherapy dose modifications/delays. The primary endpoint is overall survival. Secondary endpoints include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Clinical trial information: NCT03416179.