Contributions
Abstract: EP455
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
SEL24/MEN1703, a dual PIM/FLT3 kinase inhibitor shows activity in both primary Acute Myeloid Leukemia (AML) cells and AML cell lines, regardless of FLT3 status. In the dose escalation (DE) part of the First in Human, Phase I/II DIAMOND-01 trial (CLI24-001, NCT03008187, EudraCT No. 2019-000941-10), SEL24/MEN1703 demonstrated an acceptable safety profile up to the recommended dose (RD) of 125 mg along with initial evidence of single agent activity and meaningful target engagement in heavily pre-treated AML patients (pts) (Solomon et al, EHA 2020; Tomirotti et al, ASH 2020). Here we present updated data including pts enrolled in the Phase II, cohort expansion (CE) of the study.
Aims
The key objectives of the CE part of the study were the confirmation of the safety profile determined in the DE part along with further investigation of the single agent activity.
Methods
DIAMOND-01 trial enrolled pts unsuitable for chemotherapy having relapsed or refractory (R/R) (DE and CE) or previously untreated (DE) AML. Previous target therapies were allowed with the only exception of previous PIM inhibitors treatments. SEL24/MEN1703 was given orally, QD, 14 days ON / 7 days OFF until disease progression/unacceptable toxicity. In the DE of the study MEN1703 escalating doses ranging from 25 to 150 mg were tested, whereas in the CE the RD (125 mg) was administered. Adverse events (AEs) were graded according to NCI-CTCAE v.4.03; responses assessed as per ELN 2017 criteria.
Results
As of January 21, 2021 (cut-off date), n=48 pts were treated across DE (n=25) and CE (n=23). All pts signed the informed consent form prior to undergoing any study procedure. Median age was 69 (25-84) years. Overall, 20 (43%) and 15 (32%) pts had non de novo AML and primary refractory AML, respectively. Adverse karyotype was reported in 7 (15%) pts. Most frequently reported mutations were FLT3/ITD (23%, n=11), DNMT3A (15% n=7), NPM1 (15%, n=7), IDH1 (13%, n=6) and IDH2 (4%, n=2), CEBPA (4%, n=2), FLT3/TKD (2%, n=1). Median number of cycles was 2 (1-8). At the RD (n=30), most frequent serious treatment-emergent AEs (serious TEAEs) were pneumonia (23%), sepsis and febrile neutropenia (13%) and pulmonary mycosis (10%), whereas most frequent G≥3 TEAEs were febrile neutropenia and pneumonia (23%), leukocytosis (20%) and neutrophil count decrease, platelet count decrease, lymphocyte count decrease and sepsis (13%). Responses occurred in 2 pts in the CE, both with IDH1 mutant disease (naïve to IDH inhibitors) who achieved complete remission with incomplete hematologic recovery (CRi). Both responses occurred by Cycle 3, with a duration of 79 (ongoing at cut-off date) and 43 days, respectively. Across DE and CE, 4 CR/CRi occurred, three of which in pts with IDH mutations. A total of 3 out of 6 pts with IDH mutations treated at doses ≥75 mg achieved CR/CRi, including a CR in a patient with IDH2 mutant AML relapsed on Enasidenib.
Conclusion
SEL24/MEN1703 confirmed a manageable safety profile at RD and showed preliminary single agent efficacy in R/R AML, particularly clustering in pts with IDH mutant disease either naïve or previously exposed to IDH inhibitors. These results warrant further investigation of SEL24/MEN1703 in AML, with potential focus in the IDH mutated subset.
Keyword(s): AML, FLT3, Pim-1
Abstract: EP455
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
SEL24/MEN1703, a dual PIM/FLT3 kinase inhibitor shows activity in both primary Acute Myeloid Leukemia (AML) cells and AML cell lines, regardless of FLT3 status. In the dose escalation (DE) part of the First in Human, Phase I/II DIAMOND-01 trial (CLI24-001, NCT03008187, EudraCT No. 2019-000941-10), SEL24/MEN1703 demonstrated an acceptable safety profile up to the recommended dose (RD) of 125 mg along with initial evidence of single agent activity and meaningful target engagement in heavily pre-treated AML patients (pts) (Solomon et al, EHA 2020; Tomirotti et al, ASH 2020). Here we present updated data including pts enrolled in the Phase II, cohort expansion (CE) of the study.
Aims
The key objectives of the CE part of the study were the confirmation of the safety profile determined in the DE part along with further investigation of the single agent activity.
Methods
DIAMOND-01 trial enrolled pts unsuitable for chemotherapy having relapsed or refractory (R/R) (DE and CE) or previously untreated (DE) AML. Previous target therapies were allowed with the only exception of previous PIM inhibitors treatments. SEL24/MEN1703 was given orally, QD, 14 days ON / 7 days OFF until disease progression/unacceptable toxicity. In the DE of the study MEN1703 escalating doses ranging from 25 to 150 mg were tested, whereas in the CE the RD (125 mg) was administered. Adverse events (AEs) were graded according to NCI-CTCAE v.4.03; responses assessed as per ELN 2017 criteria.
Results
As of January 21, 2021 (cut-off date), n=48 pts were treated across DE (n=25) and CE (n=23). All pts signed the informed consent form prior to undergoing any study procedure. Median age was 69 (25-84) years. Overall, 20 (43%) and 15 (32%) pts had non de novo AML and primary refractory AML, respectively. Adverse karyotype was reported in 7 (15%) pts. Most frequently reported mutations were FLT3/ITD (23%, n=11), DNMT3A (15% n=7), NPM1 (15%, n=7), IDH1 (13%, n=6) and IDH2 (4%, n=2), CEBPA (4%, n=2), FLT3/TKD (2%, n=1). Median number of cycles was 2 (1-8). At the RD (n=30), most frequent serious treatment-emergent AEs (serious TEAEs) were pneumonia (23%), sepsis and febrile neutropenia (13%) and pulmonary mycosis (10%), whereas most frequent G≥3 TEAEs were febrile neutropenia and pneumonia (23%), leukocytosis (20%) and neutrophil count decrease, platelet count decrease, lymphocyte count decrease and sepsis (13%). Responses occurred in 2 pts in the CE, both with IDH1 mutant disease (naïve to IDH inhibitors) who achieved complete remission with incomplete hematologic recovery (CRi). Both responses occurred by Cycle 3, with a duration of 79 (ongoing at cut-off date) and 43 days, respectively. Across DE and CE, 4 CR/CRi occurred, three of which in pts with IDH mutations. A total of 3 out of 6 pts with IDH mutations treated at doses ≥75 mg achieved CR/CRi, including a CR in a patient with IDH2 mutant AML relapsed on Enasidenib.
Conclusion
SEL24/MEN1703 confirmed a manageable safety profile at RD and showed preliminary single agent efficacy in R/R AML, particularly clustering in pts with IDH mutant disease either naïve or previously exposed to IDH inhibitors. These results warrant further investigation of SEL24/MEN1703 in AML, with potential focus in the IDH mutated subset.
Keyword(s): AML, FLT3, Pim-1