A Phase I/II Study of Seclidemstat, an LSD1 Inhibitor, and Azacitidine for Patients with Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

INTRODUCTION: Hypomethylating agents (HMA) remain the standard of care for myelodysplastic syndromes (MDS) but responses remain transient with loss of response being associated with dismal outcomes. Lysine specific demethylase 1 (LSD1) is a histone demethylase implicated in the maintenance of pluripotency and proliferation genes which is overexpressed in MDS. Given the importance of epigenetic deregulation in MDS and chronic myelomonocytic leukemia (CMML) we hypothesized that LSD1 inhibition, in combination with HMAs, may be synergistic and lead to enhanced antileukemic and pro-differentiation potential in MDS/CMML.

METHODS: To study this we designed an open label phase I/II clinical trial of seclidemstat, a selective LSD1 inhibitor, in combination with azacytidine for patients with MDS or CMML with intermediate-1 or higher risk by International Prognostic Scoring System (IPSS) and progression or no response to 6 prior cycles of HMA. Study design includes an initial phase I dose escalation phase evaluating 6 dose levels of seclidemstat (150mg, 300mg, 450mg, 600mg, 900mg and 1200mg administered orally bid on days 1-28 of each 28 day cycle) in combination with azacytidine 75mg/m2 daily on days 1-7 of each 28 day cycle. Following the completion of phase I dose escalation the study will include a dose expansion phase (n=20) to gain further experience at the selected phase 2 recommended dose of seclidemstat. Study primary endpoint is to determine the safety, tolerability and maximum tolerated dose of seclidemstat in combination with azacytidine. Other study objectives include overall response rate and survival outcomes. Responses to therapy will be assessed following 2006 IWG response criteria. The study includes futility and safety stopping rules. This study is registered at clinicaltrials.gov (NCT04734990).

RESULTS: To date, a total of 6 patients (3 in dose level 1 of seclidemstat 150mg po bid, and 3 in dose level 2 of 300mg po bid) have been treated on study as of July 2022: 5 with MDS and 1 with CMML. Patient characteristics are shown in Table 1. A total of 4 (67%) patients had higher risk MDS with complex karyotype and/or TP53 mutations after failure to HMA. Median number of prior therapies was 2 (range 1-3). Only 5 patients are evaluable for toxicity and response at the time of data cut off. To date, no DLTs have been observed. All evaluable patients experienced treatment emergent adverse events (AEs) with no treatment-related grade 3 AEs. The most frequently observed AE was transient grade 1 (n=2) and 2 (n=1) creatinine elevation which was observed during the first week of therapy and subsequently reverted to baseline levels. One patient developed QTC prolongation in the context of a right ventricular bundle branch block which was unrelated to study treatment. Dose interruptions were required only in 1 patient due to grade 2 creatinine elevation, and treatment could be resumed after normalization of creatinine levels. With a median follow up of 4.3 months (95% CI 2.0-6.6) and a median of 3 (range 2-4) cycles of therapy, response to therapy was observed in 2 patients including 1 mCR+HI with partial cytogenetic response, who transitioned to allogeneic stem-cell transplant after 3 cycles of therapy, and 1 mCR. Two patients remain on study at the 300mg po bid dose level.

CONCLUSIONS: The combination of seclidemstat with azacitidine seems safe at the current dose levels and shows initial signs of potential activity. Further enrollment and follow up continues to further explore this combination.

DiNardo:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Takeda: Honoraria; Foghorn: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Jazz: Honoraria; Astex: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Bluebird Bio: Honoraria; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Cleave: Research Funding; Forma: Research Funding; LOXO: Research Funding. Short:Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy; Pfizer: Consultancy; Takeda Oncology: Consultancy, Research Funding; Novartis: Consultancy; Stemline Therapeutics: Research Funding; Astellas: Research Funding. Kadia:AstraZeneca: Research Funding; Astex: Honoraria; JAZZ: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genfleet: Research Funding; Amgen: Research Funding; cyclacel: Research Funding; Ascentage: Research Funding; cellenkos: Research Funding; Delta-Fly: Research Funding; Astellas: Research Funding; Novartis: Consultancy; Glycomimetics: Research Funding; Iterion: Research Funding; PinotBio: Consultancy; Servier: Consultancy; Pfizer: Research Funding; Genentech: Consultancy, Research Funding; Regeneron: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding. Ravandi:AstraZeneca: Consultancy; Syos: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Prelude: Research Funding; Novartis: Consultancy. Kantarjian:NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharmaceuticals: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria. Garcia-Manero:Gilead Sciences: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Aprea: Honoraria; Acceleron Pharma: Consultancy; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding.