A Phase I/II Study of Gilteritinib and Momelotinib for Patients with Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: A Trial in Progress

Background: Despite approval of multiple FLT3 inhibitors, the outcomes of patients with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) remain suboptimal. Several mechanisms have been implicated in resistance to currently available FLT3 inhibitors. While some relapses are driven by new genomic alterations (e.g. secondary FLT3 mutations or activating mutations in the MAPK pathway), approximately half of patients who relapse on a FLT3 inhibitor do not harbor a clear genomic driver of resistance. Aberrant signaling through cytokines that utilize JAK/STAT pathways, such as GM-CSF and IL-3, have been identified as a mechanism of resistance in many of these cases. These cytokine alterations and aberrant JAK/STAT signaling may have therapeutic implications, as both in vitro and in vivo preclinical studies have suggested that dual JAK/FLT3 inhibition may overcome resistance to gilteritinib and other FLT3 inhibitors.

Momelotinib is a small molecule inhibitor of JAK1/2 and activin A receptor type 1 (ACVR1), a member of the TGF-β superfamily, that is approved for the treatment of intermediate- or high-risk myelofibrosis in adults with anemia. In addition to its established activity against multiple JAK isoforms, momelotinib may also potently inhibit FLT3 (Azhar M et al Blood Adv 2022). Inhibition of ACVR1 has also been shown to sensitize AML cells to FLT3 inhibitors, providing additional rationale for the use of momelotinib in FLT3-mutated AML (Tyagi A et al Leukemia 2024). Given the inhibitory activity of momelotinib against multiple relevant targets, including JAK1/2, FLT3, and ACVR1, we designed this phase I/II study to evaluate the combination of momelotinib and gilteritinib in patients with R/R FLT3-mutated AML.

Methods: This is a single-arm, single-center, open-label, phase I/II study of gilteritinib and momelotinib in patients with relapsed or refractory (R/R) FLT3-mutated AML. Adult patients with either FLT3-ITD or FLT3 D835/D836 mutations are eligible. In cycle 1, patients receive momelotinib orally (dose level 1: 200mg daily; dose level 2: 400mg daily; dose level 3: 600mg daily) on days 1-35 and gilteritinib 120mg orally daily on days 8-35. The 7-day lead-in of momelotinib monotherapy will allow for early assessment of monotherapy efficacy of momelotinib and collection of PK and other correlative studies. In cycles 2-24, patients receive momelotinib orally daily at the assigned dose and gilteritinib 120mg orally daily on days 1-28.

The primary objective of phase I portion of the study is to establish the minimum safe and biologically-effective dose of momelotinib in combination with gilteritinib in R/R FLT3-mutated AML; the primary objective of the phase II portion is to determine the modified CRc (i.e. CR + CRi + MLFS) rate of the regimen within 4 cycles of treatment. Secondary objectives include determining other efficacy endpoints (including the CR rate, MRD negativity rate by flow cytometry and PCR for FLT3, relapse-free survival, and overall survival), the proportion of patients bridged to allogeneic hematopoietic stem cell transplant, and the safety of the combination regimen. Exploratory endpoints include evaluation of: 1.) the impact of baseline genomic alterations on response and survival, 2.) the impact of baseline FLT3 allelic ratio on outcomes, 3.) the PK of momelotinib when given in combination with gilteritinib, 4.) changes in circulating inflammatory cytokines with combination therapy, and 5.) characterization of the FLT3 and JAK/STAT signaling pathways using CyTOF analysis in bone marrow and peripheral blood samples.

This trial is actively accruing at MD Anderson Cancer Center with a planned enrollment of 20 patients (12 in the dose escalation phase I part of the study and 8 in the dose expansion phase II part). To date, 3 patients have been enrolled. ClinicalTrials.gov Identifier: NCT06235801.