2023 SOHO: Randomized Phase 1-2 Study to Assess Safety and Efficacy of Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients: Interim Safety Analysis
Abstract:
Background: Cedazuridine (CED), a cytidine deaminase (CDA) inhibitor allows oral availability of decitabine (DEC); 5 daily doses of the fixed-dose combination (FDC) of 35 mg DEC/100 mg CED standard dose (SD) provides equivalent exposure to an IV DEC regimen of 20 mg/m2 D1-5 (Garcia-Manero et al, 2020). Attenuated HMA regimens (e.g., 3 days IV DEC) have shown activity in LR-MDS (Jabbour, et al. 2017).
Aims: This Phase 1/2 study explores lower dose oral DEC/CED regimens in LR-MDS patients.
Methods: Phase 1/2 study in lower-risk-MDS (IPSS low risk and lntermediate-1) subjects requiring treatment. Phase 1: explored 28-day regimens, dose ranges 5-20 mg DEC/100mg CED; duration ranges 5-10 days. Primary endpoints: recommended Phase 2 dose (RP2D) based on safety and dose-limiting toxicity (DLT). Secondary endpoints: clinical activity per 2006 IWG (transfusion independence [TI], LFS, OS). Phase 2: randomized 81 LR-MDS 1:1 to receive Phase 1 RP2D vs. 35 mg DEC/100 mg CED (SD) for 3days (SD-3Day) (reflecting attenuated HMA regimen for LR-MDS). Similar efficacy and safety endpoints as Phase 1.
Results: Phase 1: 47 patients treated with five different DEC/CED regimens. DLT (myelosuppression-associated) increased with higher treatment doses and longer duration. Hematologic Improvement (HI) % across dosing regimens: 30% (14/47), 8-week RBC transfusion-independent rate: 33% (7/21); mOS: 31 months (95%Cl:19,NE); mLFS 23 months (95%Cl:14,32). Based on clinical efficacy and safety, 10mg DEC/100mgCED D1-5 every 28D (LD-5Day) was selected as RP2D.
Phase 2: Baseline: Int-1 (65-73%), 48% prior MDS treatment (21%ESA, 26% luspatercept), 46% RBC transfusion-dependent (TD); 14% platelet TD. At cutoff, 80 subjects had received a median of 4.5 treatment cycles, ~10 patients received subsequent transplant. PK data showed LD-5Day exposure about half SD-3Day exposure. Reported adverse event terms with LD-5Day were similar to SD-5day, with most common grade ≥3 from myelosuppression. By cycle 8, average neutrophil counts were higher in LD-5Day regimen vs. SD-3Day regimen; platelet changes were similar. Of 8 all-cause deaths at data cutoff, only 1 was within 30days (in SD-3Day group).
Conclusion: This Phase 1/2 study suggests LD-5Day regimen is tolerable (less neutropenia) and potentially an optimal regimen for LR-MDS (longer term efficacy analysis vs. SD-3Day regimen pending).
