Trial in progress - a randomized study of ASTX727 with or without Iadademstat in accelerated/blast-phase myeloproliferative neoplasms Free

Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that carry a variable risk of evolution toward an accelerated phase (AP) or blast phase (BP) of disease. MPN-AP is defined by 10-19% blasts in the peripheral blood or bone marrow while MPN-BP is defined by ≥20% blasts in the peripheral blood or marrow in a patient with a pre-existing MPN. Even in the current era of myeloid therapies, survival outcomes are poor with a median overall survival (OS) of less than 1 year in a 202 patient cohort. Outcomes were similar in patients treated with intensive chemotherapy, DNA methyltransferase inhibitor (DNMTi) + venetoclax-based therapy, and other DNMTi-based approaches (Patel et al, Blood Adv 2024). Investigation of novel therapeutics for MPN-AP/BP is an area of unmet need.

Lysine-specific demethylase 1 (LSD1) is implicated in regulation of self-renewal and differentiation of stem cells, thereby contributing to the maintenance of hematopoiesis. Furthermore, there is overexpression of LSD1 in MPNs and clinical studies of LSD1 inhibition in chronic-phase MPNs are underway. LSD1 is also highly expressed in myeloblasts and pre-clinical studies have identified LSD1 inhibition as a therapeutic strategy in MPN-AP/BP. The oral LSD1 inhibitor iadademstat has been studied in combination with the DNMTi azacitidine in de novo acute myeloid leukemia (AML) in the context of the Phase II ALICE study; the complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 52%. Of note, responses were noted in mutational subsets enriched in MPN-AP/BP including ASXL1, TP53, and IDH1/2 (Salamero et al, Lancet Haematol 2024).

These data have led to the development of a clinical trial investigating the oral DNMTi ASTX727 with or without iadademstat in patients with MPN-AP/BP (NCT06661915). This trial is being conducted via the National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN).

The study will have a dose escalation phase to identify the recommended phase 2 dose (R2PD) of iadademstat + ASTX727 followed by a randomized phase which will investigate the efficacy of iadademstat + ASTX727 compared to ASTX727 monotherapy. Relevant inclusion criteria include age ≥ 18, ECOG ≤3, no prior DNMTi, and a diagnosis of MPN-AP/BP. Exclusion criteria of note include IDH1-mutated MPN-BP (due to the availability of ivosidenib as an approved frontline therapy).

The dose escalation phase will follow a 3+3 design. Cycles are 28 days. Enrollment will begin at dose level (DL) 1 (ASTX727 35mg-100mg Days 1-5 and iadademstat 50mcg Days 1-5, 8-12, 15-19, 22-26) with a planned escalation to DL2 (ASTX727 35mg-100mg Days 1-5 and iadademstat 75mcg Days 1-5, 8-12, 15-19, 22-26) or de-escalation to DL-1 (ASTX727 35mg-100mg Days 1-5 and iadademstat 50mcg Days 1-5, 8-12, 15-19) based on an assessment of dose limiting toxicities (DLTs). Upon the completion of the dose escalation phase all safety, efficacy, and pharmacokinetic data will be reviewed to identify the R2PD for the randomized portion of the study.

The randomized portion of the study will investigate ASTX727 monotherapy compared to ASTX727 + iadademstat. The primary endpoint will be rate of acute leukemia response-complete (ALR-C) or better within 4 cycles of therapy as defined by 2012 MPN-BP criteria (Mascarenhas et al, Leuk Res 2012). The randomization will be 1:1 with 25 patients treated on each arm during the randomized portion. The primary efficacy population will consist of all randomized patients per intent-to-treat. The randomized comparison will have 82% power to detect a 50% vs. 20% difference in ALR-C rates, based on a one-sided Fisher's exact test at the 0.15 alpha level. An interim analysis for futility will be performed after 25 patients are enrolled and followed for ALR-C; if the observed response rate in the combination arm is no better than monotherapy, then the trial would be terminated early. Secondary endpoints include event-free survival, overall survival, and percentage of patients that go onto allogeneic stem cell transplantation. Exploratory endpoints include concordance of response between European LeukemiaNet (ELN) 2022 response criteria (Dohner et al, Blood 2022) and 2012 MPN-BP criteria, assessment of LSD1 target engagement via RNA sequencing/immunoassay, and analyzing molecular pathways of resistance/progression.