Contributions
Abstract: EP450
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
Acute Myeloid Leukemia (AML) in elderly unfit patients remains a challenge. Recently approved combinations have improved the treatment of unfit patients. Yet, a significant percentage of patients is refractory or relapse during the first year. Iadademstat (iada) is a first, and best in class LSD1 inhibitor that produces differentiation in leukemic stem cells. In different clinical trials, iada has been administered so far to ~100 oncology patients showing a good safety profile. Based on iada’s ADME profile and low dosing regimen, a low DDI risk is anticipated. This makes iada suitable for drug combinations with hypomethylating agents or targeted therapies and may offer additional therapeutic options for this patient population.
Aims
This is an update of the ongoing ALICE study (EudraCT 2018-000482-36).
Methods
ALICE is a Phase IIa study to assess the safety, tolerability and dose finding of iada in combination with azacitidine for the treatment of elderly AML patients. Secondary endpoints investigate anti-leukemic activity including overall response rate (ORR), time to response (TTR) and duration of responses (DOR). Additional assessments include hematological improvement, overall survival and PK/PD measures. ALICE includes adult patients diagnosed with AML (as per WHO classification), who have not received prior treatment for AML other than hydroxyurea and are ineligible for intensive chemotherapy (or refuse this treatment option).
Results
At EHA 2020, ALICE data from 18 patients (median age 78 y) were reported. Main safety events included 96 grade 3-4 AEs related to the study drugs in 12 patients, most of them neutropenia and thrombocytopenia. Only 3 non-hematological AEs were observed, asthenia and dysgeusia in one patient and weight reduction in another patient. Among the 38 SAEs reported, only one was considered related to iadademstat, a differentiation syndrome (Grade 3) and another, a fatal intracranial hemorrhage on C1D15 was considered as possibly related to the combination therapy. Besides the hematological impact, the combination was safe and well tolerated by older AML patients. From the 18 patients recruited in 2020, 13 had at least 1 bone marrow evaluation (evaluable as per protocol). Ten (77%) achieved an objective response (4 CR, 2 CRi and 4 PRs) with a mean TTR of 37 days. The longest response in CR at that time was 488 days. Those patients with longer treated periods had also improved or overcome their dependency on blood transfusions.
By the time this abstract is written, 24 patients have been included (median age 77) and 18 are evaluable; ORR has increased to 87%, TTR is now 35 days and median DOR is 335 days, with 5 patients having a response longer than one year and one longer than 2 years. 4 out of the current 8 durable responses (longer than 6 months) also show transfusion independence. The safety findings continue to support an acceptable tolerability profile of the combination, with most of the adverse effects being transient or amenable. At EHA 2021, an update on the trial results will be provided, with all patients recruited by the cut-off of May 2021.
Conclusion
ALICE data sets confirm that the combination of iadademstat with azacitidine in unfit AML patients has a manageable safety and tolerability profile. ALICE maintains encouraging response ratios as the trial progresses. Current efficacy data support iadademstat as a suitable candidate for combination therapies in AML.
Keyword(s): Differentiation therapy, Epigenetic, Phase II
Abstract: EP450
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
Acute Myeloid Leukemia (AML) in elderly unfit patients remains a challenge. Recently approved combinations have improved the treatment of unfit patients. Yet, a significant percentage of patients is refractory or relapse during the first year. Iadademstat (iada) is a first, and best in class LSD1 inhibitor that produces differentiation in leukemic stem cells. In different clinical trials, iada has been administered so far to ~100 oncology patients showing a good safety profile. Based on iada’s ADME profile and low dosing regimen, a low DDI risk is anticipated. This makes iada suitable for drug combinations with hypomethylating agents or targeted therapies and may offer additional therapeutic options for this patient population.
Aims
This is an update of the ongoing ALICE study (EudraCT 2018-000482-36).
Methods
ALICE is a Phase IIa study to assess the safety, tolerability and dose finding of iada in combination with azacitidine for the treatment of elderly AML patients. Secondary endpoints investigate anti-leukemic activity including overall response rate (ORR), time to response (TTR) and duration of responses (DOR). Additional assessments include hematological improvement, overall survival and PK/PD measures. ALICE includes adult patients diagnosed with AML (as per WHO classification), who have not received prior treatment for AML other than hydroxyurea and are ineligible for intensive chemotherapy (or refuse this treatment option).
Results
At EHA 2020, ALICE data from 18 patients (median age 78 y) were reported. Main safety events included 96 grade 3-4 AEs related to the study drugs in 12 patients, most of them neutropenia and thrombocytopenia. Only 3 non-hematological AEs were observed, asthenia and dysgeusia in one patient and weight reduction in another patient. Among the 38 SAEs reported, only one was considered related to iadademstat, a differentiation syndrome (Grade 3) and another, a fatal intracranial hemorrhage on C1D15 was considered as possibly related to the combination therapy. Besides the hematological impact, the combination was safe and well tolerated by older AML patients. From the 18 patients recruited in 2020, 13 had at least 1 bone marrow evaluation (evaluable as per protocol). Ten (77%) achieved an objective response (4 CR, 2 CRi and 4 PRs) with a mean TTR of 37 days. The longest response in CR at that time was 488 days. Those patients with longer treated periods had also improved or overcome their dependency on blood transfusions.
By the time this abstract is written, 24 patients have been included (median age 77) and 18 are evaluable; ORR has increased to 87%, TTR is now 35 days and median DOR is 335 days, with 5 patients having a response longer than one year and one longer than 2 years. 4 out of the current 8 durable responses (longer than 6 months) also show transfusion independence. The safety findings continue to support an acceptable tolerability profile of the combination, with most of the adverse effects being transient or amenable. At EHA 2021, an update on the trial results will be provided, with all patients recruited by the cut-off of May 2021.
Conclusion
ALICE data sets confirm that the combination of iadademstat with azacitidine in unfit AML patients has a manageable safety and tolerability profile. ALICE maintains encouraging response ratios as the trial progresses. Current efficacy data support iadademstat as a suitable candidate for combination therapies in AML.
Keyword(s): Differentiation therapy, Epigenetic, Phase II