Study Finds Optimal Dosing Schedule for ASTX727 in Low-Risk MDS

Researchers have formulated an optimal dosing schedule for ASTX727 in patients with lower-risk myelodysplastic syndromes (LR-MDS) and shared their results in a presentation at the 2022 American Society of Hematology Annual Meeting and Exposition.

In the first part of a phase I/II trial conducted at medical centers in the U.S. and European Union, researchers led by presenter Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center, tested several dosing schedules of low-dose ASTX727 on 48 patients with LR-MDS (defined as International Prostate Symptom Score low-risk and intermediate-1). Median patient age was 76 years (range, 51-88 years), and 65% were male.

ASTX727 is an oral fixed-dose combination of hypomethylating agent decitabine 35 mg and cytidine deaminase inhibitor cedazuridine 100 mg.

In the first stage of the phase I trial, the researchers approximated the total dose of intravenous decitabine 20 mg/m² for five days over a longer dosing period and then randomized the subjects to three cohorts of decitabine 5 mg, 10 mg, or 15 mg plus cedazuridine 100 mg for 10 days in 28-day cycles. The cohort of patients receiving decitabine 10 mg was closed due to hematologic dose-limiting toxicity. As a result, no patients were randomized to the 15 mg regimen.

The second stage—stage B—of the phase I trial involved treating 33 patients with three low-dose oral decitabine/cedazuridine regimens of shorter duration:

• Cohort B1: decitabine 10 mg plus cedazuridine 100 mg daily for five days
• Cohort B2: decitabine 10 mg plus cedazuridine 100 mg daily for seven days
• Cohort B3: decitabine 20 mg plus cedazuridine 100 mg daily for five days

Adverse events were similar to those reported for standard dose oral decitabine/cedazuridine, with the most common grade ≥3 treatment-related adverse events being neutropenia (36%), anemia (28%), and febrile neutropenia (19%).

Of the 47 treated patients, 22 (47%) had reached the event of death at data cutoff (June 17, 2022), and median overall survival was 929 days (95% CI, 526 days to not estimated). Median leukemia-free survival was 690 days (95% CI, 428-934).

“Based on the results of the phase I study, the dosing schedule of decitabine 10 mg plus cedazuridine 100 mg daily for five days, that balanced clinical efficacy with an acceptable and manageable safety profile was selected as the recommended phase II dose,” the authors wrote.

In the ongoing phase II of the study, the researchers will compare this dosing schedule with decitabine 35 mg plus cedazuridine 100 mg for three days in a 28-day cycle.

Reference

Garcia-Manero G, Bachiashvili K, Amin H, et al. ASTX727-03: Phase 1 study evaluating oral decitabine/cedazuridine (ASTX727) low-dose (LD) in lower-risk myelodysplastic syndromes (LR-MDS) patients. Abstract #461. Presented at the 64th American Society of Hematology Annual Meeting, December 10-13, 2022; New Orleans, Louisiana.