ES-3000, A WNT/ beta CATENIN/INFLAMMASOME PATHWAY INHIBITOR COMBINED with ORAL DECITABINE/CEDAZURIDINE(ASTX727) for PATIENTS with MYELODYSPLASIA.

Abstract

Background: The role of inflammatory signalling in myelodysplasia (MDS) is emerging as an important factor that influences the disease characteristics as well as progression. A novel agent ES-3000 (a benzylisoquinoline alkaloid) has been shown to influence marrow microenvironment interaction with leukaemic stem cells through the Wnt/ beta catenin pathway, NF-kappaB as well as NLRP3 inflammasome signalling. Preliminary results from the first 8 evaluable patients of this phase Ib/II study, combining oral anticancer agent ES-3000 with oral ASTX727 is being presented. Aim(s): \1. To assess the safety profile of ES-3000 in combination with fixed dose ASTX727 including dose-limiting toxicities and serious adverse events 2. To determine the recommended phase 2 dose and dosing schedule of ES-3000 in combination with fixed dose ASTX727. Method(s): All patients were recruited as part of Australasian Leukaemia and Lymphoma Group's (ALLG) MDS platform study, MYDAS-T MDS05 domain 1, from three 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, including AML with blasts < 30%. Patients with significant other medical disorders or infections at the screening were excluded. This was a window study design (see figure) in the dose escalation phase with first cycle comprising single agent ES-3000 60mg TID (total daily dose of 180mg) from day 1-14 of a 28-day cycle. This was followed by ES-3000 at the same dose from days1-14 in combination with fixed-dose ASTX727 (oral decitabine 35mg/cedazuridine 100mg) from day 1-5. Up to 20 participants will be enrolled to the dose escalation phase and treated in cohorts of three. Up to four dose levels of ES-3000 will be examined, in combination with ASTX727. In the dose-determination phase, a BOIN design will be followed, assigning a dose to the next cohort of patients and conducting dose-escalation/de-escalation according to predetermined rules. Adverse events will be graded as per CTCAE V5. All adverse events will be graded by site investigators and information reviewed by the trial monitoring committee as well ALLG's safety and data monitoring committee. Result(s): A total of eight evaluable patients have been recruited by the cut-off date (9th Feb 2024) with a median age of 72.9 years (range 66.3-82.8). There were five males and three females. The median duration of follow up is 2.4 months (range 0.3-5.2). All participants were in the first dose cohort of ES-3000 receiving 60mg TID daily days 1-14. A total of sixteen grade 3 or higher AEs were observed. One patient discontinued ES-3000 due to persistent rash (grade 3), thought to be due to underlying vasculitis, and was considered to be a dose limiting toxicity(n=1). One patient progressed and subsequently died of infective complications (colitis) attributable to progressive disease in cycle 2. Adverse events that led to dose delay or dosing modification included one grade 2 (fever) and three grade 4 (neutropenia). Summary/Conclusion: The trial has escalated to the next ES-3000 dose of 80mg TID daily days 1-14. The oral-oral combination of ES-3000 and ASTX727 is attractive given the mechanisms of action and potential synergies. (Table present).