A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia

Abstract

FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and unlike other inhibitors is minimally vulnerable to resistance induced by FLT3 ligand (FL). We conducted a phase 1 dose escalation study of oral FF-10101 (NCT03194685) in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities (DLT) were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose (RP2D) was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML.-

Development of Epigenetic Modifiers with Therapeutic Potential in FMS-Related Tyrosine Kinase 3/Internal Tandem Duplication (FLT3/ITD) Acute Myeloid Leukemia and Other Blood Malignancies

“…Specifically, one-third of AML patients have different FLT3 mutations: (i) FLT3-TKD, a missense point mutation in a highly conserved region, i.e., the activation loop of the tyrosine kinase domain (TKD), found in approximately 7% of AML patients; (ii) FLT3-ITD, internal tandem duplications (ITDs) of the juxtamembrane domain, found in 25% of AML patients. Patients with FLT3-ITD are classified as intermediate-risk AML, according to the 2022 European LeukemiaNet risk stratification system, and can specifically benefit from the use of the FLT3 inhibitor (FLT3i) gilteritinib as monotherapy in relapsed/refractory AML or as maintenance therapy after hematopoietic stem cell transplantation. , Therefore, mutational screening during the diagnostic process is crucial for the accurate assessment of disease prognosis. However, inhibitor-resistant FLT3 mutations can arise through on- or off-target mechanisms, often recruiting downstream pathways like JAK/STAT and PI3K/Akt, resulting in a consequent decrease in FLT3i efficacy …”