Preliminary safety and efficacy of the frida study: Iadademstat and gilteritinib in FLT3-mutated relapsed/refractory acute myeloid leukemia

Abstract

Abstract Background: Fms-related tyrosine kinase 3 (FLT3) mutations occur in 30-40% of patients (pts) with AML (frontline and relapsed/refractory (R/R)), in whom FLT3 inhibitors (FLT3i) are beneficial. Gilteritinib is approved in R/R FLT3 mutated (mut) AML based on a composite complete remission (CCR: CR+CRh) rate of 34%, median time to CCR 2.3 months, and 2.8 months EFS (Perl, et al., NEJM 2019). To improve the outcomes in this population, novel synergistic agents with FLT3i are needed. Iadademstat (iada) is a specific, potent, oral covalent inhibitor of the epigenetic Lysine-Specific Demethylase 1 (LSD1/KDM1A) enzyme. Up to 70% of recurring mutations in AML target epigenetic regulators of gene expression, resulting in myeloid differentiation blockade and enhanced leukemic stem cell renewal, underscoring the potential of epigenetic therapies. Preclinically, iada is synergistic with gilteritinib in FLT3 mut AML cells and in derived cell lines resistant to venetoclax, azacitidine or other FLT3is (Sacilotto et al., 2022 Eur J. of Cancer 174S1). More than 140 pts have been treated with iada, including treatment-naïve AML pts in the ALICE study where, in combination with azacitidine, iada produced rapid, durable, and deep responses with a manageable safety profile (Salamero et al., Lancet Hematol. 2024). The FRIDA Phase 1 study (NCT05546580) aims to establish the safety, tolerability, and the recommended Phase 2 dose (RP2D) of the combination of iada plus gilteritinib in FLT3 mut R/R AML. Methods: Adult pts with ≤ 2 prior lines of therapy (including quizartinib and gilteritinib if not refractory), received iada PO at doses of 50 to 100 μg on a 5 days ON- 2 days OFF (5+2) schedule for 3 or 4 weeks (wks), in 28-day cycles with continuous gilteritinib PO at 120 mg/day. In the expansion phase, up to 14 pts at the selected safe and pharmacologically active dose/s (PAD), based on all available data from escalation (PK, target engagement (TE), safety, tolerability, and emerging activity) will be enrolled. Primary endpoints are treatment-emergent adverse events (TEAEs) and RP2D determination. Secondary endpoints include EFS, OS, responses, and transfusion rate. Exploratory endpoints include measurable residual disease and gene mutational analysis. Results: To date the study has accrued 34 pts. Escalation consisted of 4 dose level (DL) cohorts: DL0= 100 μg iada for 4 wks/28-day cycle (n=6); DL-1= 75 μg for 4 wks (n=7); DL-2= 75 μg for 3 wks (n=8) and DL-3b= 50 μg for 4 wks (n=6). Iada DL0 was very effective in reaching the goal of LSD1 average TE > 80% and in clearing marrow blasts (83%), however recovery of peripheral counts was only achieved in 1/3 of the pts. DL-1 also reached high TE and complete remissions were achieved. A shorter exposure of that dose per cycle in DL-2 (3 out of 4 wks) could not consistently reach the goal of 80% TE and translated into fewer responses. The last DL-3b (50 μg for 4 wks) is under evaluation. No DLTs were reported within the DLT period in any cohort, but in 1 pt (DL0 dose) who proceeded to HSCT, a retrospective DLT was reported due to prolonged cytopenia. Overall, the treatment has been manageable in the clinic with no TEAEs outside of the expected safety profile for this patient population. Three serious adverse reactions reported to regulators were febrile neutropenia, myocarditis and differentiation syndrome. The study is in the expansion phase at one selected PAD of 75 μg iada for 4 weeks (5+2) in 28-day cycles (DL-1) in combination with SoC gilteritinib, for which a total of 14 patients (7 in escalation and 7 in expansion) are currently enrolled. For this cohort median age is 60 y (range 20-81), 5 females, 9 males, 64% Caucasian, with a median of 2 previous lines of therapy and 6 (43%) presented with MDS-related mutations. 50% had previous treatment with venetoclax and 50% were refractory to the last treatment. The best response results in the 12 evaluable patients were: CR (n=3), CRh (n=3), CRi (n=1); 1 additional patient achieved MLFS. Therefore, marrow response was achieved in 67% of the pts and CRR (CR+CRh+CRi) in 58% of the pts. Three pts have undergone HSCT. The median number of cycles in treatment is 4 (range 1-9). Updated expansion accrual and full escalation data will be presented. Conclusion: The combination of iada and gilteritinib at the tested doses is tolerable, and at the selected dose for expansion, shows remarkable CRR in a highly pre-treated, refractory FLT3 mut AML pt population.