A Phase 1a/b Dose Escalation Study of the Mutation Agnostic FLT3/BTK Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

INTRODUCTION: Luxeptinib (CG-806) is a potent oral small molecule inhibitor of the wild type and all mutant forms of the FLT3 kinase, including ITD, D835Y, and F691L. Luxeptinib simultaneously suppresses additional signaling pathways in AML cells (CSF1R, PDGFRα, TRK, SYK, BTK, LYN, AKT, ERK, MAPK), kills primary AML cells insensitive to other FLT3 inhibitors at pM and low nM concentrations, and shows enhanced activity in combination with venetoclax. Patient-derived AML cells retain sensitivity to luxeptinib even when harboring mutations of NPM1, IDH1, ASXL1, or TP53. Luxeptinib is being evaluated in a Phase 1a/b trial in patients with relapsed or refractory (R/R) AML (NCT04477291).

AIMS: The primary objectives are to assess the safety and tolerability of luxeptinib and to determine the recommended expansion dose for future clinical trials in patients with R/R AML. Key secondary objectives include elucidation of the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and evidence of antitumor activity.

METHODS: The study is enrolling patients with relapsed or refractory de novo AML, secondary AML, or therapy-related AML. Luxeptinib is administered continuously as oral capsules BID in 28-day cycles, in ascending cohorts of 3 or 4 patients. Treatment emergent adverse events (TEAEs) and tumor responses are evaluated using CTCAE and European Leukemia Net criteria, respectively.

RESULTS: As of June 7, 2021, a total of 10 patients (median age 74.5 years, 6 (60%) FLT3-ITD, and 4 (40%) FLT3-WT per local labs) with a median of 3 prior treatments (range, 1 - 8) have been treated with luxeptinib at dose levels of 450 mg BID (n=6) and 600 mg BID (n=4). Majority of patients (≥ 60 %) were RBC and / or platelet transfusion dependent. Drug related TEAEs at Grade ≥ 3 included decreased platelet count, anemia, and pericardial effusion (n=1, 10% each). One patient, who received 450 mg BID (Cohort 1), had Grade 3 pericardial effusion, was assessed initially as a DLT possibly related to luxeptinib and led to expansion of Cohort 1 to treat 6 patients. No DLT was observed in the other 5 patients in Cohort 1 and supported dose escalation to 600 mg BID (Cohort 2), where no DLT was observed in 4 patients and escalated to 750 mg BID (Cohort 3). The steady-state (C _min) plasma levels of luxeptinib in the patients treated with 600 mg BID were 0.6 - 1.6 µM by the end of Cycle 1. PD analysis demonstrated luxeptinib in the plasma of patients reduced FLT3 phosphorylation > 85% at concentrations > 0.2 µM while significantly reducing phosphorylation of ERK, SYK and PDGFRα in MOLM14 and / or EOL-1 reporter cells in a plasma inhibitor activity assay, demonstrating target engagement by luxeptinib. Disease evaluation via flow cytometry, PCR-based FLT3 mutation tests and targeted exome sequencing on bone marrow and peripheral blood revealed anti-leukemic activity of luxeptinib in 3 relapsed AML patients with FLT3-ITD mutations in Cohort 1. One heavily pretreated AML patient (8 prior regimens including alloSCT and FLT3 inhibitors gilteritinib and crenolanib) had 99% reduction of blasts in peripheral blood (from 6.38x10 ³/µL at C1D1 to 0.09x10 ³/µL at C1D15), though the decrease in blasts reversed during Cycle 2. Another AML patient (2 prior regimens) had FLT3-ITD VAF 0.62 at screening, which decreased 80% to 0.12 by C4D9. This patient had simultaneous reductions of clones with mutations of GATA2 R337K, TET2 R1359C, SRSF2 P95L and ASXL1 E635R, whereas a PTPN11 mutant clone emerged. MRD-negative complete remission (CR) was confirmed in one FLT3-ITD AML patient (6 prior regimens including 2 alloSCT and FLT3 inhibitor sorafenib) at Cycle 5 of treatment evidenced by reduction of FLT3-ITD VAF and blasts in bone marrow to below limit of detection (LOD) of PCR-based FLT3-ITD assay and high-sensitivity flow cytometry (LOD < 0.1%), respectively.

CONCLUSIONS: As of June 7, 2021, luxeptinib is well tolerated at dose levels of 450 and 600 mg BID over multiple cycles and escalated to 750 mg BID (Cohort 3). Pharmacodynamic studies documented inhibition of FLT3 signaling, and anti-leukemic activity has been observed in heavily pretreated relapsed FLT3-ITD AML patients as evidenced by significant reduction of FLT3-ITD VAF and blasts in bone marrow and / or peripheral blood. One FLT3-ITD AML patient has had confirmed MRD negative CR and continues treatment. Enrollment of patients with R/R AML in Cohort 3 is ongoing and updated clinical data will be presented at the meeting.