Iadademstat Shows Efficacy in Elderly AML Patients in Combination with Azacitidine. Alice Trial

Introduction:

Acute Myeloid Leukemia (AML) is an elderly disease with a rising incidence in the past decades. Probability to achieve complete remission and survival rates decrease with age with standard chemotherapy options leading to very poor outcomes with less than 20% 5-year overall survival rates. It has been shown that Lysine-specific demethylase 1 (LSD1) is a partner in some gene transformation in AML and helps sustain the oncogenic process. Iadademstat is a potent and selective LSD1 inhibitor that has shown to be effective in preclinical models, both alone and in combination with other compounds, including azacitidine (Aza). A Phase I FiM study in acute leukemia showed that iadademstat exhibits a good safety profile and preliminary anti-leukemic activity as monotherapy. Iadademstat in combination with Aza may thus offer an alternative option for such a population with limited therapeutic options.

Methods:

ALICE is a Phase IIa clinical trial to assess the safety, tolerability and dose finding of iadademstat in combination with Aza and also to measure the clinical activity of the combination as overall response rate (ORR), time to response (TTR) and duration of response (DOR). Other assessments include hematological improvement and overall survival, along with PK/PD measures (including a set of 6 blood biomarkers).

The dose finding stage (Part 1) planned to dose a maximum 18 patients with a starting dose of iadademstat of 90 μg/m²/d in combination with Aza. Iadademstat may be escalated or de-escalated depending on the observed dose limiting toxicities. Once the Recommended Dose (RD) is identified, an expansion cohort of 18 patients will be enrolled and treated with iadademstat combined with Aza (Part 2).

ALICE includes subjects ≥ 60 years of age with AML according to World Health Organization (WHO) classification, who are considered by the investigator to be ineligible for intensive chemotherapy at that time or have refused standard chemotherapy and who have not received prior treatment for AML other than hydroxyurea.

Results:

According to the Safety Monitoring Committee of the study, the selected RD of iadademstat was 90μg/m²/d. This decision was made based on first dose finding cohort including 6 subjects with the observation of 1 DLT due to a differentiation syndrome (the sole SAE reported due to treatment) and based on the fact that the selected dose: i) was able to saturate LSD1 target engagement in PBMCs after 5 days of treatment; ii) was well tolerated (11 treatment cycles were completed at the moment of decision) and iii) demonstrated the first signs of efficacy. A short median time to first response was observed (around 1.5 months). Analysis of the first patients yielded an ORR in 4 of 5 evaluable patients (80%): in all of them the best observed response was CRi as per July 2019. A lower maintenance regime has been established for those patients that had attained CRi. The first patient that has followed this strategy has become transfusion independent. To date, no grade 3-4 non-hematological adverse events have been reported.

The patient assessments of the still-ongoing subjects from Part 1 and all new enrolled study subjects in the expansion cohort will be presented following a November 2019 cut-off, with particular emphasis on available preliminary efficacy outcomes.

Conclusions:

To date, data from this Phase II study supports that iadademstat in combination with azacitidine in elderly previously untreated AML patients has a manageable toxicity and is a meaningful candidate for specific combinations in this and future leukemia studies.

These encouraging results will be enriched with the inclusion of up to 18 additional patients in the expansion cohort and with longer clinical observation periods to better assess the frequency, deepness and duration of the responses.