Dual FLT3 and CDK4/6 Inhibition Shows Modest Activity in Relapsed/Refractory AML
A common resistance mechanism in internal tandem duplication (ITD)-mutated FLT3 acute myeloid leukemia (AML) is the acquisition of kinase domain or gatekeeper mutations in the FLT3 gene. FLX925 is a next-generation FLT3 inhibitor developed to overcome the resistance mechanisms and to inhibit CDK4/6. The results of a phase 1 dose-escalation study of FLX925 in adult patients with relapsed or refractory AML were presented at ASH 2017.
Patients aged ≥18 years with adequate performance status (Eastern Cooperative Oncology Group ≤2) and organ function, and relapsed or treatment-refractory AML were enrolled, regardless of FLT3 mutation status.
A total of 51 eligible patients received FLX925 oral monotherapy at doses ranging from 40 mg twice daily to 720 mg 3 times daily. The median age of the study population (n = 51) at screening was 60 years (range, 19-81 years) and the majority were white (76.5%); 20 patients had FLT3-ITD–positive AML, 8 patients had FLT3-D835–mutant AML, and 5 patients carried dual mutant disease. Patients received a median of one 4-week cycle of treatment (range, <1-6 cycles).
At the FLX925 720-mg 3-times-daily dose, 1 dose-limiting toxicity (DLT) of elevated creatinine was noted; a second report of acute renal failure not meeting strict DLT criteria was also reported. The maximum tolerated dose of FLX925 was determined to be 540 mg 3 times daily. Patients in the 3 highest-dose cohorts (≥540 mg twice daily) experienced treatment-related adverse events (TRAEs). The most common TRAEs (any grade) included nausea (7.8%), diarrhea (5.9%), increased creatinine (9.8%), acute or chronic renal failure (7.8%), and decreased white blood cell count (5.9%). Of these, treatment-related serious adverse events included 1 report of increased transaminase (2%), 2 reports of increased creatinine (3.9%), and 4 reports of acute renal failure.
Pharmacokinetic studies demonstrated mean Tmax values ranging from 1.30 to 4.38 hours after the first dose, and mean T1/2 values ranging from 2.31 to 7.72 hours during cycle 1.
In terms of efficacy, there was no evidence of clinical activity in the first 5 cohorts involving 30 subjects (40-360 mg orally twice daily). In the ≥540-mg twice-daily cohorts (n = 21), 8 showed antileukemic activity, including ≥50% reductions of peripheral blasts in 6 patients (3 ITD or ITD/D835, 2 D835, and 1 FLT3 wild-type), and 2 patients who achieved a transient morphologic leukemia-free state (<5% bone marrow blasts without count recovery; 1 ITD or ITD/D835, 1 D835). No complete or partial responses were reported.
The researchers concluded that single-agent FLX925 showed modest evidence of antileukemic activity, which was hypothesized to be due to dose-limiting adverse events that precluded prolonged dosing at higher dose levels.
Daver N, et al. 2017 ASH. Abstract 1343.