Targeting the Myelodysplasia (MDS) Inflammasome with the Oral Wnt/β-Catenin Pathway Inhibitor, ES-3000 in Combination with Oral Decitabine/Cedazuridine (ASTX727) an Australasian Leukaemia and Lymphoma Group Trial (ALLG MDS05/D1)

Background: The role of inflammatory signaling in myelodysplasia (MDS) is emerging as an important factor that influences the disease characteristics as well as progression. The novel agent, ES-3000 (a benzylisoquinoline alkaloid) has been shown to influence marrow microenvironment interactions with leukaemic stem cells through the Wnt/β catenin pathway, NF-κB and NLRP3 inflammasome signaling.

Studies have shown that ES-3000 is able to bind competitively to calmodulin and may be a novel calmodulin antagonist. Calmodulin protein dependent kinase II γ (CaMKIIγ) is overexpressed in leukemic stem cells and blast cells and in turn regulates the Wnt/β-catenin and STAT3 signaling. In addition, dysregulated pathways like the inflammasome, focusing on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-inflammasome and Sirtuin 1 (SIRT1) overexpression are also downregulated by ES-3000. Given the above mechanistic activities, ES-3000 may offer an innovative treatment approach for MDS in combination with a backbone hypomethylating agent.

'Trial in progress' for a phase Ib/II study, combining oral anticancer agent ES-3000 with oral ASTX727 (35mg decitabine/ 100mg cedazuridine) will be presented.

Aims:

The primary objectives of the study are: 1.To assess the safety profile of ES-3000 in combination with oral ASTX727 (fixed dose Decitabine and Cedazuridine). 2.To determine the recommended phase 2 dose (RP2D) and dosing schedule of ES-3000 in combination ASTX727.

Secondary objectives are: 1.To determine event free survival 2.To determine the overall survival 3.To determine the time to first response.

Tertiary objectives are: 1.To determine the time to transfusion independence 2.To assess the quality of life and its correlation to responses and toxicity 3.To assess frailty and its correlation with responses and toxicity

Exploratory objectives are: 1.Inflammasome markers including β -catenin, Wnt and CaMKIIγ expression in higher risk MDS/low blast count AML and its correlation with response to therapy 2.Myeloid mutational profile and response to ES-3000 3. Aryl hydrocarbon reductase pathway changes and response to therapy 4.Pharmacokinetic profiling of ES-3000 in the dose determining phase.

Methods: All patients are being recruited as part of the Australasian Leukaemia and Lymphoma Group’s (ALLG) MDS05 platform study, MYDAS-T domain 1(ALLG MDS05/D1), from 5 Australian hospitals. The study is being conducted in participants with myelodysplastic syndrome, who have not previously received treatment, have an International Prognostic Scoring System (IPSS) score of 1.5 or higher, and are eligible for standard hypomethylating agent treatment in Australia. Patients with AML and blasts < 30% in bone marrow and peripheral blood were also eligible. Patients with significant other medical disorders or infections at the start of treatment are excluded.

This is a window study design with a dose escalation phase with first cycle comprising 14 days of ES-3000 at 60mg TID (180mg daily). This will be followed by combination of ES-3000 at the same dose for days 1-14 combined with fixed dose ASTX727 (oral decitabine 35mg/cedazuridine 100mg) for days 1-5. Up to 20 participants will be enrolled in this dose escalation part and treated in cohorts of three. Up to four levels of the ES-3000 dose, in combination with ASTX727 will be explored. In the dose-determination part, the BOIN design included assigning a dose to the next cohort of patients and conducting dose-escalation/de-escalation according to predetermined rules. Adverse events were graded as per CTCAE version 5. All serious adverse events are graded by site investigators and information reviewed by the trial monitoring committee as well ALLG’s safety and data monitoring committee.

Results: Clinical trial design will be discussed and presented. Recruitment data and updates including patient demographics, will be presented as per specifications in the ‘trial in progress’ category.

Conclusions: The oral-oral combination of ES-3000 and ASTX727 is attractive given the mechanisms of action and potential synergies. This study will evaluate the safety and effectiveness of this combination.