ALBERT

Description: 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. Disclosures Buesa: Oryzon Genomics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Mendelion SL: Membership on an entity's Board of Directors or advisory committees. Somervaille:Novartis: Consultancy. Arevalo:Oryzon Genomics: Employment. Xaus:Oryzon Genomics: Employment. Gutierrez:Oryzon Genomics: Employment. Bullock:Oryzon Genomics: Consultancy.

Description: Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a higher incidence in older people. Most elderly AML patients are unfit for intensive chemotherapy and their treatment remains a challenge. Remission and survival rates decrease with age, and there is rather limited treatment success with standard (chemo)therapy, leading to 5-year survival rates of 20% or lower. Recent combinations of hypomethylating agents with pro-apoptotic agents such as venetoclax, a Bcl-2 inhibitor, have shown improved therapeutic prospects in early phase clinical trials, which still need to be supported by data from ongoing phase III confirmatory trials. Lysine-specific demethylase 1 (LSD1) participates in malignant transformation in AML. Iadademstat is a differentiating drug that selectively inhibits LSD1 and has shown efficacy in preclinical models, both alone and in combination with other compounds including azacitidine and Bcl-2 inhibitors. A First-in-Man phase I study in refractory-relapsed acute leukemia patients treated with iadademstat in monotherapy showed a good safety profile, strong differentiating activity and preliminary signs of anti-leukemic activity. In the last year, we have reported interim results of the ongoing ALICE clinical trial with progressively more patients treated with iadademstat combined with azacitidine. Now, we report additional positive results in this hard-to-treat population. The efficacy of this combination may offer an alternative therapeutic option for previously untreated elderly AML population. Methods: ALICE is an open-label, single arm, phase IIa clinical trial to assess the safety, tolerability and dose finding of iadademstat in combination with azacitidine for the treatment of elderly AML patients. Secondary end points of the study are to describe the anti-leukemic activity of the combination (overall response rate, time to response and duration of response), to assess the hematological improvement along with PK/PD measures. ALICE includes patients older than 60 yrs, diagnosed with AML according to the WHO classification, who have not received prior treatment for AML other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or refuse this treatment option. Results: At ASH2020 we will report compiled results of the ALICE study based on a November cut-off, when we expect to have recruited around 24 subjects. At the time this abstract is written, among the 18 currently recruited patients, 13 have had at least 1 bone marrow evaluation and achieved a 77% objective response rate (ORR): 4 Complete Remissions, 2 Complete Remissions with incomplete hematological recovery and 4 Partial Remissions. The current mean duration in the study is 20 weeks, with a mean Time to Response of only 37 days. The Progression Free Survival in the patients under remission is, so far, 250 days and the longest response in CR is above 550 days (still under treatment and in CR). Moreover, those patients with longer treatment periods have also improved or overcome their dependency on blood transfusions. Main safety events include neutropenia and thrombocytopenia in most of the patients, whereas only 3 non-hematological AEs (asthenia, dysgeusia and weight reduction) have been observed. Among the 38 serious AEs reported so far, only 2 were considered as related to iadademstat, corresponding to a differentiation syndrome (Grade 3) and a fatal intracranial hemorrhage on C1D15. Besides the expected hematological impact, the combination appears to be safe and well tolerated. Conclusions: Data to-date support iadademstat as an effective oral agent with a good safety profile compared with other anti-leukemic agents and hence as a meaningful candidate for selective combinations with other agents. Toxicity appears to be predictable, manageable and restricted only to the hematologic compartment. Under azacitidine alone, the historical response rates were 27% in this elderly AML population; the current results are supportive of a significant synergistic effect for iadademstat. The ORR of this combo is, so far, in line with the one shown by venetoclax combinations in similar early phase clinical trials. A confirmatory phase IIb trial is planned. With its oral administration, safety profile and novel MoA, iadademstat combo therapy may increase the therapeutic options for this AML population. Disclosures Salamero: Daichii Sankyo: Honoraria; Pfizer: Consultancy; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Somervaille:Novartis: Consultancy, Honoraria; Imago Bioscience: Research Funding. Gutierrez:Oryzon Genomics: Current Employment. Bullock:Oryzon Genomics: Current Employment. Buesa:Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch:Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Astra Zeneca: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Jansen: Honoraria. Montesinos:Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau; Celgene, Pfizer, Abbvie: Consultancy.