RESULTS OF A FIRST-IN-HUMAN, PHASE 1/2 TRIAL OF ASP2215, A SELECTIVE, POTENT ORAL INHIBITOR OF FLT3/AXL, IN PATIENTS WITH RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA
(Abstract release date: 05/21/15)
EHA Library. switzer R. 06/14/15; 103407; S798
Regina switzer
Contributions
Contributions
Abstract
Abstract: S798
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:45 to 14.06.2015 09:00
Location: Room C1
Background
FMS-like tyrosine kinase-3 (FLT3) mutations, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are present in acute myeloid leukemia (AML) cells in up to 30% of patients. FLT3 inhibitors have shown promise as a therapeutic option for AML patients with FLT3 activating mutations. In vitro analyses suggest that ASP2215 is a potent inhibitor of FLT3 and AXL tyrosine kinases and demonstrates activity against both FLT3-ITD and FLT3-TKD.
Aims
A Phase 1/2 trial investigated the safety, pharmacokinetics (PK), and clinical efficacy of ASP2215 in patients with relapsed or refractory (R/R) AML.
Methods
This open-label, first-in-human study, conducted in patients ≥18 years old with R/R AML, included 2 cohorts: dose escalation (Cohort 1) and dose expansion (Cohort 2). Cohort 1 was a modified 3+3 with accelerated titration design that evaluated ascending oral doses of ASP2215 (20–450 mg). Cohort 2 was a parallel multi-dose expansion cohort that was initiated based on the efficacy observed during dose escalation and patients were stratified by FLT3 mutation status. The primary endpoints included determination of the maximum tolerated dose (MTD) and the PK profile; clinical efficacy and FLT3 phosphorylation were evaluated as secondary endpoints. All patients provided informed consent. Data from an interim analysis are presented.
Results
: A total of 166 patients (Cohort 1, n=25; Cohort 2, n=141) with a median age of 64 years (range: 21–90) were enrolled between October 2013 and December 2014. ASP2215 MTD was determined to be 300 mg after 2 out of 3 patients dosed with ASP2215 treated at 450 mg experienced dose-limiting toxicities (grade 3 diarrhea and ALT/AST elevation). Plasma concentrations of ASP2215 increased with increasing dose, with tmax between 2 and 6 hours. Accumulation was observed following repeat dosing, with estimated t1/2 values of 45 to 159 hours based on accumulation index. Approximately dose-linear PK parameters were observed over the dose range for both single and repeat dosing. Fatigue (13%), constipation (10%), anemia (8%), nausea (8%), diarrhea (7%), thrombocytopenia (6%), decreased platelet count (6%), vomiting (6%), dizziness (6%), peripheral edema (5%), increased transaminases (5%), and hypomagnesemia (5%) were the most commonly reported treatment-emergent adverse events considered “possibly” or “probably” related to drug. Further, no incidents of clinically significant QTc prolongation have been reported. Overall response rate (ORR, defined by composite complete and partial remissions) in patients with FLT3 mutations was 57% at doses between 20 and 300 mg, and 65% at doses of ≥80 mg; a lower ORR (11%) was observed in patients with wild type FLT3 (Table). In patients receiving doses ≥80 mg, a plasma inhibitory activity assay confirmed effective, consistent, and sustained FLT3 inhibition.
Summary
ASP2215, a potent oral inhibitor of FLT3/AXL, was well tolerated at doses of 20–300 mg/d in patients with R/R AML and showed a high degree of clinical activity in patients with FLT3-ITD and/or FLT3-TKD mutations. ASP2215 demonstrated a predictable PK profile consistent with once-daily dosing. Randomized phase 3 trials of ASP2215 dosed at 200 mg in newly diagnosed and R/R AML are planned.
Session topic: AML: Molecular profile and targeting
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:45 to 14.06.2015 09:00
Location: Room C1
Background
FMS-like tyrosine kinase-3 (FLT3) mutations, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are present in acute myeloid leukemia (AML) cells in up to 30% of patients. FLT3 inhibitors have shown promise as a therapeutic option for AML patients with FLT3 activating mutations. In vitro analyses suggest that ASP2215 is a potent inhibitor of FLT3 and AXL tyrosine kinases and demonstrates activity against both FLT3-ITD and FLT3-TKD.
Aims
A Phase 1/2 trial investigated the safety, pharmacokinetics (PK), and clinical efficacy of ASP2215 in patients with relapsed or refractory (R/R) AML.
Methods
This open-label, first-in-human study, conducted in patients ≥18 years old with R/R AML, included 2 cohorts: dose escalation (Cohort 1) and dose expansion (Cohort 2). Cohort 1 was a modified 3+3 with accelerated titration design that evaluated ascending oral doses of ASP2215 (20–450 mg). Cohort 2 was a parallel multi-dose expansion cohort that was initiated based on the efficacy observed during dose escalation and patients were stratified by FLT3 mutation status. The primary endpoints included determination of the maximum tolerated dose (MTD) and the PK profile; clinical efficacy and FLT3 phosphorylation were evaluated as secondary endpoints. All patients provided informed consent. Data from an interim analysis are presented.
Results
: A total of 166 patients (Cohort 1, n=25; Cohort 2, n=141) with a median age of 64 years (range: 21–90) were enrolled between October 2013 and December 2014. ASP2215 MTD was determined to be 300 mg after 2 out of 3 patients dosed with ASP2215 treated at 450 mg experienced dose-limiting toxicities (grade 3 diarrhea and ALT/AST elevation). Plasma concentrations of ASP2215 increased with increasing dose, with tmax between 2 and 6 hours. Accumulation was observed following repeat dosing, with estimated t1/2 values of 45 to 159 hours based on accumulation index. Approximately dose-linear PK parameters were observed over the dose range for both single and repeat dosing. Fatigue (13%), constipation (10%), anemia (8%), nausea (8%), diarrhea (7%), thrombocytopenia (6%), decreased platelet count (6%), vomiting (6%), dizziness (6%), peripheral edema (5%), increased transaminases (5%), and hypomagnesemia (5%) were the most commonly reported treatment-emergent adverse events considered “possibly” or “probably” related to drug. Further, no incidents of clinically significant QTc prolongation have been reported. Overall response rate (ORR, defined by composite complete and partial remissions) in patients with FLT3 mutations was 57% at doses between 20 and 300 mg, and 65% at doses of ≥80 mg; a lower ORR (11%) was observed in patients with wild type FLT3 (Table). In patients receiving doses ≥80 mg, a plasma inhibitory activity assay confirmed effective, consistent, and sustained FLT3 inhibition.
Summary
ASP2215, a potent oral inhibitor of FLT3/AXL, was well tolerated at doses of 20–300 mg/d in patients with R/R AML and showed a high degree of clinical activity in patients with FLT3-ITD and/or FLT3-TKD mutations. ASP2215 demonstrated a predictable PK profile consistent with once-daily dosing. Randomized phase 3 trials of ASP2215 dosed at 200 mg in newly diagnosed and R/R AML are planned.
Session topic: AML: Molecular profile and targeting
Abstract: S798
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:45 to 14.06.2015 09:00
Location: Room C1
Background
FMS-like tyrosine kinase-3 (FLT3) mutations, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are present in acute myeloid leukemia (AML) cells in up to 30% of patients. FLT3 inhibitors have shown promise as a therapeutic option for AML patients with FLT3 activating mutations. In vitro analyses suggest that ASP2215 is a potent inhibitor of FLT3 and AXL tyrosine kinases and demonstrates activity against both FLT3-ITD and FLT3-TKD.
Aims
A Phase 1/2 trial investigated the safety, pharmacokinetics (PK), and clinical efficacy of ASP2215 in patients with relapsed or refractory (R/R) AML.
Methods
This open-label, first-in-human study, conducted in patients ≥18 years old with R/R AML, included 2 cohorts: dose escalation (Cohort 1) and dose expansion (Cohort 2). Cohort 1 was a modified 3+3 with accelerated titration design that evaluated ascending oral doses of ASP2215 (20–450 mg). Cohort 2 was a parallel multi-dose expansion cohort that was initiated based on the efficacy observed during dose escalation and patients were stratified by FLT3 mutation status. The primary endpoints included determination of the maximum tolerated dose (MTD) and the PK profile; clinical efficacy and FLT3 phosphorylation were evaluated as secondary endpoints. All patients provided informed consent. Data from an interim analysis are presented.
Results
: A total of 166 patients (Cohort 1, n=25; Cohort 2, n=141) with a median age of 64 years (range: 21–90) were enrolled between October 2013 and December 2014. ASP2215 MTD was determined to be 300 mg after 2 out of 3 patients dosed with ASP2215 treated at 450 mg experienced dose-limiting toxicities (grade 3 diarrhea and ALT/AST elevation). Plasma concentrations of ASP2215 increased with increasing dose, with tmax between 2 and 6 hours. Accumulation was observed following repeat dosing, with estimated t1/2 values of 45 to 159 hours based on accumulation index. Approximately dose-linear PK parameters were observed over the dose range for both single and repeat dosing. Fatigue (13%), constipation (10%), anemia (8%), nausea (8%), diarrhea (7%), thrombocytopenia (6%), decreased platelet count (6%), vomiting (6%), dizziness (6%), peripheral edema (5%), increased transaminases (5%), and hypomagnesemia (5%) were the most commonly reported treatment-emergent adverse events considered “possibly” or “probably” related to drug. Further, no incidents of clinically significant QTc prolongation have been reported. Overall response rate (ORR, defined by composite complete and partial remissions) in patients with FLT3 mutations was 57% at doses between 20 and 300 mg, and 65% at doses of ≥80 mg; a lower ORR (11%) was observed in patients with wild type FLT3 (Table). In patients receiving doses ≥80 mg, a plasma inhibitory activity assay confirmed effective, consistent, and sustained FLT3 inhibition.
Summary
ASP2215, a potent oral inhibitor of FLT3/AXL, was well tolerated at doses of 20–300 mg/d in patients with R/R AML and showed a high degree of clinical activity in patients with FLT3-ITD and/or FLT3-TKD mutations. ASP2215 demonstrated a predictable PK profile consistent with once-daily dosing. Randomized phase 3 trials of ASP2215 dosed at 200 mg in newly diagnosed and R/R AML are planned.
Session topic: AML: Molecular profile and targeting
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:45 to 14.06.2015 09:00
Location: Room C1
Background
FMS-like tyrosine kinase-3 (FLT3) mutations, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are present in acute myeloid leukemia (AML) cells in up to 30% of patients. FLT3 inhibitors have shown promise as a therapeutic option for AML patients with FLT3 activating mutations. In vitro analyses suggest that ASP2215 is a potent inhibitor of FLT3 and AXL tyrosine kinases and demonstrates activity against both FLT3-ITD and FLT3-TKD.
Aims
A Phase 1/2 trial investigated the safety, pharmacokinetics (PK), and clinical efficacy of ASP2215 in patients with relapsed or refractory (R/R) AML.
Methods
This open-label, first-in-human study, conducted in patients ≥18 years old with R/R AML, included 2 cohorts: dose escalation (Cohort 1) and dose expansion (Cohort 2). Cohort 1 was a modified 3+3 with accelerated titration design that evaluated ascending oral doses of ASP2215 (20–450 mg). Cohort 2 was a parallel multi-dose expansion cohort that was initiated based on the efficacy observed during dose escalation and patients were stratified by FLT3 mutation status. The primary endpoints included determination of the maximum tolerated dose (MTD) and the PK profile; clinical efficacy and FLT3 phosphorylation were evaluated as secondary endpoints. All patients provided informed consent. Data from an interim analysis are presented.
Results
: A total of 166 patients (Cohort 1, n=25; Cohort 2, n=141) with a median age of 64 years (range: 21–90) were enrolled between October 2013 and December 2014. ASP2215 MTD was determined to be 300 mg after 2 out of 3 patients dosed with ASP2215 treated at 450 mg experienced dose-limiting toxicities (grade 3 diarrhea and ALT/AST elevation). Plasma concentrations of ASP2215 increased with increasing dose, with tmax between 2 and 6 hours. Accumulation was observed following repeat dosing, with estimated t1/2 values of 45 to 159 hours based on accumulation index. Approximately dose-linear PK parameters were observed over the dose range for both single and repeat dosing. Fatigue (13%), constipation (10%), anemia (8%), nausea (8%), diarrhea (7%), thrombocytopenia (6%), decreased platelet count (6%), vomiting (6%), dizziness (6%), peripheral edema (5%), increased transaminases (5%), and hypomagnesemia (5%) were the most commonly reported treatment-emergent adverse events considered “possibly” or “probably” related to drug. Further, no incidents of clinically significant QTc prolongation have been reported. Overall response rate (ORR, defined by composite complete and partial remissions) in patients with FLT3 mutations was 57% at doses between 20 and 300 mg, and 65% at doses of ≥80 mg; a lower ORR (11%) was observed in patients with wild type FLT3 (Table). In patients receiving doses ≥80 mg, a plasma inhibitory activity assay confirmed effective, consistent, and sustained FLT3 inhibition.
Summary
ASP2215, a potent oral inhibitor of FLT3/AXL, was well tolerated at doses of 20–300 mg/d in patients with R/R AML and showed a high degree of clinical activity in patients with FLT3-ITD and/or FLT3-TKD mutations. ASP2215 demonstrated a predictable PK profile consistent with once-daily dosing. Randomized phase 3 trials of ASP2215 dosed at 200 mg in newly diagnosed and R/R AML are planned.
Session topic: AML: Molecular profile and targeting
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