A Phase 1b Multi-Center Study of the FLT3 Inhibitor Gilteritinib in Combination with the IDH1 Inhibitor Ivosidenib or the IDH2 Inhibitor Enasidenib for Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring FLT3/IDH1 or FLT3/IDH2 Mutations

Background: Mutations in isocitrate dehydrogenase isoenzymes 1 and 2 (IDH1 and IDH2) occur in 15- 25% of patients with acute myeloid leukemia. Enasidenib and ivosidenib, inhibitors of mutant IDH2 and IDH1 respectively, decrease intracellular levels of 2-HG, restore myeloid maturation, and lead to complete or partial remissions in approximately 40% of patients with IDH-mutant AML. While this response rate is remarkable in a relapsed and refractory AML population, nearly 60% of patients fail to respond. Approximately 30% of patients with IDH1/2 mutations have co-occurring mutations in the FMS like tyrosine kinase 3 (FLT3). Correlative science suggests that the acquisition of FLT3 mutations (either an internal tandem duplication (ITD) or tyrosine kinase domain (TKD)) is a common mechanism of resistance to IDH inhibitor monotherapy. Gilteritinib is a FLT3 inhibitor that targets the ITD and TKD mutations. This clinical trial (NCT05756777) will evaluate the safety and efficacy of concurrent IDH and FLT3 inhibition, while determining the maximum tolerated dose (MTD) for each of the combinations. Methods: NCT05756777 is a multi-center, open-label, experimental, interventional study evaluating the safety, tolerability, and preliminary efficacy of the combination of gilteritinib + ivosidenib (Cohort 1 - IDH1/FLT3 co-mutation) and gilteritinib + enasidenib (Cohort 2 - IDH2/FLT3 co-mutation) in patients with relapsed/refractory (R/R) acute myeloid leukemia with co-occurring FLT3 (ITD or TKD) and IDH1 or IDH2 mutations. Treatment with gilteritinib + ivosidenib will be administered for patients with IDH1/FLT3 co-mutations and gilteritinib + enasidenib will be administered for patients with IDH2/FLT3 co-mutations. Patients in both cohorts will dose daily throughout the 28-day cycle and without pause between cycles. The study will enroll 36 patients with relapsed/refractory AML with co-occurring FLT3 (ITD or TKD) and IDH1 or IDH2 mutations. The dose escalation schema will use the Bayesian Optimal Interval (BOIN) design. This study is open for accrual at Memorial Sloan Kettering Cancer Center. The study population will include patients with AML with dual FLT3 and IDH1/IDH2 mutations R/R to initial intensive induction therapy, or for patients treated with low intensity therapy, the patient must be refractory to treatment with a single agent hypomethylating agent (HMA) or low dose cytarabine (LDAC) (at least two cycles) or an HMA/LDAC in combination with venetoclax (at least one cycle) or another standard of care therapy (e.g. gemtuzumab ozogamicin, glasdegib/LDAC). Patients with a history of autologous or allogeneic stem cell transplant for AML are permitted to participate in the study. This study is partially supported by Astellas Pharma Global Development, Inc. Clinical trial information: https://classic.clinicaltrials.gov/ct2/show/NCT05756777