Contributions
Abstract: PB1391
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
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 Phase 2 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 CTCEA and International Working Group criteria respectively.
Results
As of December 10, 2020, a total of 4 patients (mean age 67.0 + 20.9 years, 2 FLT3-ITD, 1 FLT3-ITD/TKD, and 1 FLT3-WT) with a median of 3 prior treatments (range, 2 - 8) have been treated with luxeptinib at the starting dose level of 450 mg BID. Observed possibly drug related TEAEs included nausea in 2 (50%; Gr 1), prolonged activated partial thromboplastin time in 1 (25%; Gr 1), increased blood alkaline phosphatase in 1 (25%; Gr 1), headache in 1 (25%; Gr 1), pericardial effusion in 1 (25%; Gr 3), photophobia in 1 (25%; Gr 1), and pleural effusion in 1 (25%; Gr 2). The steady-state (Cmin) plasma levels of luxeptinib in AML patients treated with 450 mg Q12 hours were generally in the 1µM range by the end of Cycle 1. PD analysis demonstrated luxeptinib in the plasma of patients significantly reduced phosphorylated FLT3, ERK, SYK and PDGFRα in EOL-1 reporter cells in a plasma inhibitor activity (PIA) assay. One heavily pretreated patient with relapsed AML with mutated NPM1, DNMT3A, and FLT3-ITD who had previously progressed after chemotherapy, alloSCT, and two FLT3 inhibitors (gilteritinib, crenolanib) demonstrated clinical anti-leukemic activity with a decrease in peripheral blood blasts from 93% to 10% during Cycle 1.
Conclusion
Luxeptinib has been well tolerated at the starting dose level of 450mg Q12 hours. Pharmacodynamic studies documented inhibition of FLT3 signaling pathway, and anti-leukemic activity has been observed in the setting of AML relapsed following therapy with multiple prior FLT3 inhibitors. Enrollment of patients with R/R AML continues and updated clinical data from this dose escalation study will be presented at the meeting.
Keyword(s): Flt3 inhibitor, Flt3-ITD, Refractory, Relapsed acute myeloid leukemia
Abstract: PB1391
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
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 Phase 2 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 CTCEA and International Working Group criteria respectively.
Results
As of December 10, 2020, a total of 4 patients (mean age 67.0 + 20.9 years, 2 FLT3-ITD, 1 FLT3-ITD/TKD, and 1 FLT3-WT) with a median of 3 prior treatments (range, 2 - 8) have been treated with luxeptinib at the starting dose level of 450 mg BID. Observed possibly drug related TEAEs included nausea in 2 (50%; Gr 1), prolonged activated partial thromboplastin time in 1 (25%; Gr 1), increased blood alkaline phosphatase in 1 (25%; Gr 1), headache in 1 (25%; Gr 1), pericardial effusion in 1 (25%; Gr 3), photophobia in 1 (25%; Gr 1), and pleural effusion in 1 (25%; Gr 2). The steady-state (Cmin) plasma levels of luxeptinib in AML patients treated with 450 mg Q12 hours were generally in the 1µM range by the end of Cycle 1. PD analysis demonstrated luxeptinib in the plasma of patients significantly reduced phosphorylated FLT3, ERK, SYK and PDGFRα in EOL-1 reporter cells in a plasma inhibitor activity (PIA) assay. One heavily pretreated patient with relapsed AML with mutated NPM1, DNMT3A, and FLT3-ITD who had previously progressed after chemotherapy, alloSCT, and two FLT3 inhibitors (gilteritinib, crenolanib) demonstrated clinical anti-leukemic activity with a decrease in peripheral blood blasts from 93% to 10% during Cycle 1.
Conclusion
Luxeptinib has been well tolerated at the starting dose level of 450mg Q12 hours. Pharmacodynamic studies documented inhibition of FLT3 signaling pathway, and anti-leukemic activity has been observed in the setting of AML relapsed following therapy with multiple prior FLT3 inhibitors. Enrollment of patients with R/R AML continues and updated clinical data from this dose escalation study will be presented at the meeting.
Keyword(s): Flt3 inhibitor, Flt3-ITD, Refractory, Relapsed acute myeloid leukemia