A Phase 1a/b Dose Escalation Study of the 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 mutant forms of the FLT3 kinase, including the ITD, TKD, and F691L forms. Luxeptinib 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. 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 determine the recommended phase 2 dose in R/R AML patients. Secondary objectives include elucidation of pharmacokinetics (PK) and evaluation of a new formulation to enhance bioavailability.

METHODS: Eligible patients have relapsed or refractory de novo, secondary, or therapy-related AML or higher risk MDS. 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. A novel formulation (G3) of luxeptinib was designed to increase bioavailability (BA) in a relative BA (RBA) study. Patients enrolled in the RBA study took a single dose of G3 formulation at 50 mg, 100 mg, or 200 mg on Cycle 1 Day -3, had PK exposure monitored for 72 hours, and then received the original formulation (a single dose on Cycle 1 Day 1 followed by BID dosing thereafter).

RESULTS: As of July 8, 2022, a total of 25 patients (median age 74 years, 12 (48%) FLT3-ITD, 11 (44%) FLT3-WT, and 2 FLT3-TKD (8%) per local labs with a median of 3 prior treatments (range 1 - 10)) have been treated with luxeptinib at 450 mg BID (n=6), 600 mg BID (n=4), 750 mg BID (n=10) and 900 mg BID (n=5). Most had relapsed and refractory disease (60%), 76% were RBC transfusion dependent, and 72% were platelet transfusion dependent. Drug related TEAEs of at least Grade 3 included decreased platelet count and anemia (n=2 each, 8%) and decreased neutrophil count, pericardial effusion, decreased lymphocyte count, encephalopathy, and decreased white blood cell count (n=1 each, 4%). One patient reported a single DLT at 450 mg (grade 3 pericardial effusion, out of 6 patients dosed at 450 mg) and another at 750 mg (grade 3 encephalopathy, out of 10 patients dosed at 750 mg). No DLT was reported at any other dose levels through 900 mg. Steady-state (C_min) plasma levels in the patients treated with 600 mg BID were 0.6–1.6 µM by the end of Cycle 1 (C1D22). Two of six patients in 450 mg BID had a decrease in blast proportion whereas the remainder experienced progressive disease. At 450 mg BID, one heavily pretreated AML patient (received 8 prior regimens including alloSCT and FLT3 inhibitors gilteritinib and crenolanib) had a 99% reduction in peripheral blasts (6.4x10³/µL at C1D1 to 0.1x10³/µL at C1D15), though the blast proportion increased during Cycle 2. One heavily pretreated patient with 2 prior HSCT experienced a CR at C2D1 evolving to MRD negativity at C4D1 and remained on treatment for 14 cycles. A 750 mg BID, one patient with 2 prior regimens had stable disease at C2D1 and another patient with cytogenetic abnormalities (inv(3)q21q26.2) and 3 prior regimens had a 47% blast reduction at C2D1. Similar PK exposure was seen from a single dose in both the 50 mg G3 formulation and the 900 mg original formulation, indicating superior bioavailability of G3. This formulation may reduce pill burden and produce greater exposure, thereby potentially resulting in greater anti-tumor activity.

CONCLUSIONS: As of July 8, 2022, luxeptinib is well tolerated at dose levels of 450, 600, 750, and 900 mg BID over multiple cycles without evidence of having reached the MTD. Luxeptinib in heavily pretreated relapsed FLT3-ITD AML patients has shown anti-tumor activity including a durable, MRD negative CR. Enrollment of patients with R/R AML is ongoing and updated clinical data with the G3 formulation will be presented at the meeting.