PB1762 A PHASE III, RANDOMIZED, DOUBLE‐BLIND STUDY OF INTENSIVE INDUCTION AND CONSOLIDATION CHEMOTHERAPY PLUS MIDOSTAURIN (PKC412) OR PLACEBO IN NEWLY DIAGNOSED PATIENTS WITH FLT3 MUTATION NEGATIVE AML

Abstract

Background:Risk stratification in AML is evolving as a consequence of characterizing cytogenetic abnormalities and mutational profiling. The latter is especially important in patients (pts) lacking karyotypic abnormalities1. Approximately 30% of adult pts with newly diagnosed AML have an activating mutation in the FLT3 gene, usually either an ITD mutation (in approximately 20% of AML pts), or an activating point mutation in the activating loop of the TKD (approximately 6‐8% of AML pts)2. FLT3‐ITD mutations are associated with poor prognosis, particularly when they are present at a high allelic ratio relative to FLT3‐WT (FLT3‐wild type)3,4.A randomized, double‐blind, multi‐center, placebo‐controlled phase III study has been initiated (currently enrolling pts) to confirm the preliminary evidence from early clinical trials that midostaurin may provide clinical benefit not only to AML pts with FLT3 mutations but also in FLT3‐WT (Signal Ratio [SR] < 0.05) AML.Aims:The study is designed to evaluate the efficacy and safety of midostaurin combined with intensive chemotherapy and post‐consolidation in pts with FLT3‐MN AML.Methods:502 adult pts with newly diagnosed AML demonstrating FLT3‐MN (SR < 0.05), as determined by a central laboratory testing, will be enrolled at approximately 150‐180 sites worldwide. Pts will be stratified by age (<60 vs. ≥ 60 years). Key exclusion criteria: central nervous system (CNS) leukemia, therapy‐related AML, isolated extramedullary leukemia, prior therapy for leukemia or myelodysplasia with exceptions. All pts/HCP will provide written consent for participation.The treatment arms will be midostaurin (PKC412) or placebo in combination with idarubicin/daunorubicin and cytarabine for induction therapy, intermediate‐dose cytarabine for consolidation therapy, followed by post‐consolidation therapy with midostaurin or placebo (figure).In induction phase, treatment will start with chemotherapy and patients will be randomized to midostaurin or placebo on day 8. Patient with CR or CRi with adequate blood count recovery with one or 2 cycles of induction will move to 4 or 3 cycles of consolidation treatment respectively.Pts will receive midostaurin (two 25 mg capsules) or placebo (2 capsules) twice daily orally from day 4 until 48 hours prior to the start of the next consolidation cycle. After the final cycle of consolidation therapy, pts will receive 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice daily at 50 mg. Pts who underwent hematopoietic cell transplantation (HCT after achieving CR or CRi with adequate blood count recovery will receive midostaurin or placebo 50 mg twice daily as post‐consolidation therapy, continuously, for up to 12 cycles (28 days/cycle). Post HCT therapy will begin >30 days but not later than 100 days following HCT.Primary outcome is to determine if the addition of midostaurin to standard induction and consolidation therapy, followed by single agent post‐consolidation therapy improves event‐free survival (EFS) in pts with newly diagnosed FLT3‐MN (SR < 0.05) AML. Key secondary outcome is to determine if Midostaurin improves OS. Other secondary endpoints includes Measurable Residual Disease negativity (MRD‐) rate.Results:‐Summary/Conclusion:This multicenter study will evaluate the efficacy and safety of midostaurin combined with intensive chemotherapy and post‐consolidation in pts with AML.image