2023 Intl. Congress on MDS: PHASE 1 STUDY EVALUATING LOW-DOSE (LD) ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS

View Presentation: Phase 1 Study Evaluating Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) In Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

Abstract:

Introduction and Aims: Cedazuridine (CED), a cytidine deaminase inhibitor allows oral availability of decitabine (DEC); 5 daily doses of the fixed-dose combination of 35mg DEC/100mg CED provides equivalent exposure to an IV DEC regimen of 20mg/m² D1-5 every 28 days(Garcia-Manero et al, 2020). This study explores the optimal dosing schedule of LD oral DEC/CED in LR-MDS patients.

Methods: A two-part Phase 1/2 study is being conducted in LR-MDS (IPSS low risk and lnt-1). Phase 1A, subjects were assigned to three regimens of DEC/CED (5mg/100mg, 10mg/100mg, and 15mg/100mg) for 10 days in a 28-day cycle. Phase 1B, subjects were assigned to three LD regimens with shorter durations of DEC/CED (10mg/100mg for 5 days, 10mg/100mg for 7 days, and 20mg/100mg for 5 days). The primary endpoints were dose-limiting toxicities (DLTs), safety, and the determination of the recommended phase 2 dose (RP2D). Secondary endpoints were pharmacokinetics, pharmacodynamic, and efficacy. Sub-analysis was performed based on genomic mutation profiles.

Results: 47 subjects received study treatment in various LD DEC/CED regimens. DLT associated with prolonged neutropenia were associated with higher dose and number of treatment days per cycle. The safety profile was generally consistent with decitabine treatment (myelosuppression). Neutropenia was less common with the low-dose/short-dose regimens. Clinical activity was observed in all dosing cohorts.

Conclusion: Based on the clinical efficacy and safety profile, 10mg DEC/100mg CED for 5 days was selected as the RP2D for further study. The RP2D regimen is being currently compared to 35mg DEC/100mg CED for 3 days in an ongoing Phase 2 study.