Oral Azacitidine Yields Similar PK to Subcutaneous Azacitidine in MDS/CMML

The pharmacokinetic profile of a fixed-dose oral combination of 140 mg of azacitidine and 20 mg of cedazuridine (together, ASTX030) appeared similar to subcutaneous azacitidine in patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) with intermediate or low body surface area (BSA), according to data from the phase 2 ASTX030-01 trial (NCT04256317) that were presented at the 2025 ASH Annual Meeting.

The geometric mean ratio (GMR) for ASTX030 vs subcutaneous azacitidine was 0.913 (90% CI, 0.78-1.07; intra-coefficient of variant [CV], 39%) in the general population (n = 29), and when stratifying for BSA, the intermediate-BSA subgroup had a GMR of 0.980 (90% CI, 0.85-1.13; intra-CV, 24%), and the high-BSA subgroup had a GMR of 0.700 (90% CI, 0.55-0.89; intra-CV, 37%). Two patients had a low BSA, and both saw a GMR of over 1.0 with ASTX030. Azacitidine exposure following ASTX030 was similar on days 1, 2, and 7.

“What you see from this data is that [ASTX030] approximates around 90% of the exposure that you saw with the subcutaneous azacitidine, indicating that pharmacologically, we’re very close to the target that we wanted,” said Guillermo Garcia-Manero, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston, who presented the data. “It’s worth noticing that here we saw some variations based on the BSA of the patients.”

Maximum mean percentage of long interspersed nuclear element-1 (LINE-1) demethylation was 5.95 for ASTX030 and 7.11 for subcutaneous azacitidine during cycle 1 and 5.68 and 6.37, respectively, in cycle 2. After 7-day dosing, maximum LINE-1 demethylation effect was comparable across treatment types.

“We thought that this would enable us to … proceed into the phase 3 study of this compound,” he said, noting that the phase 3 study is now underway and close to its conclusion.

Response Rates Across MDS and CMML

The overall response rate (ORR) in patients with MDS (n = 11) was 50.0%, including 5 who achieved complete response (CR) and 2 who achieved marrow complete response. Additionally, 4 patients achieved hematologic improvement (HI), including 3 erythroid, 2 neutrophil, and 3 platelet HIs. Eight patients with MDS achieved stable disease, 2 had progressive disease, and 1 was not evaluable.

No patients with CMML responded to treatment. Five had stable disease, none had progressive disease, and 1 was not evaluable. Of 2 patients with AML, 1 achieved CR, and 1 was not evaluable.

Thirteen patients were red blood cell (RBC) transfusion-dependent at baseline; of those, 30.8% achieved 8 or more weeks of RBC transfusion independence. Median overall survival (OS) had not been reached as of most recent follow-up.

ASTX030-01 Trial Design

ASTX030-01 is an ongoing, multicenter, randomized, open-label crossover study of single-agent oral ASTX030 or subcutaneous azacitidine, with 2 periods and 2 sequences.

Patients had MDS, CMML, other MDS/myeloproliferative neoplasms, or acute myeloid lymphoma if the patient would be considered a candidate for treatment with azacitidine monotherapy.

Enrolled patients were required to have ECOG performance statuses of 0 or 1, have adequate organ function, not have graft-versus-host disease, have a life expectancy of at least 12 weeks, and have had fewer than 2 prior cycles of a DNA methyltransferase inhibitor.

Garcia-Manero noted, however, that patients were allowed to have up to 2 prior lines of a hypomethylating agent (HMA).

Patients (n = 30) were randomized 1:1 to 1 of 2 treatment sequences. Patients in sequence A (n = 14) received ASTX030 days 1 to 7 in cycle 1, then received subcutaneous azacitidine at 75 mg/m² in days 1 to 7 of cycle 2, and went back to ASTX030 for all remaining cycles. Sequence B (n = 16) reversed the first 2 cycles, where patients received subcutaneous azacitidine for cycle 1, then received ASTX030 for cycle 2 and all remaining cycles.

The study’s primary end point was GMR of azacitidine total cycle, confirming that dose of oral ASTX030 achieved a mean area under the plasma concentration-time curve from 0 to 24 hours (AUC_0-24) comparable with that of subcutaneous azacitidine.

Secondary end points included clinical response rate, pharmacodynamics (LINE-1 demethylation), safety, transfusion independence, duration of response (DOR), overall survival (OS), and time to response.

Safety of ASTX030

No significant difference was observed between safety profiles of ASTX030 and subcutaneous azacitidine. Adverse events (AEs) were largely gastrointestinal and hematologic. The most common treatment-emergent AEs (TEAEs) were nausea (56.7%), diarrhea (50.0%), anemia (46.7%), constipation (46.7%), fatigue (46.7%), peripheral edema (30.0%), vomiting (30.0%), and thrombocytopenia (26.7%).

Any-grade AEs occurred in, including in 90.0% of patients receiving subcutaneous azacitidine in cycles 1 or 2 (n = 30), in 96.7% of patients receiving ASTX030 in cycles 1 or 2 (n = 30), in 87.5% of patients in cycle 3 or beyond (n = 24), and in 100.0% of all patients; 73.3%, 76.7%, 70.8%, and 96.7%, respectively, were related to the study drug. Grade 3 or higher AEs occurred in 60.0%, 63.3%, 54.2%, and 83.3% of patients in those groups, respectively, and 43.3%, 40.0%, 29.2%, and 63.3% were related to study drug.

Serious AEs occurred in 20.0%, 36.7%, 37.5%, and 66.7% of patients, respectively, and 3.3%, 3.3%, 4.2%, and 10.0 were related to the study drug; 2 serious AEs were fatal in patients receiving subcutaneous azacitidine in cycle 1 or 2. AEs led to study drug dose adjustment in 7 total patients. No early deaths occurred.

Key Patient Characteristics

Garcia-Manero made note that half of all patients, including 5 receiving sequence A and 10 receiving sequence B, had intermediate BSA, defined as BSA between 1.55 and 2.15 m². Twelve evaluable patients had high BSA, defined as at least 2.15 m², and 2 patients had low BSA, defined as at most 1.55 m².

Of note, the study included a larger BSA compared with historical demographic data in patients with MDS/AML, according to Garcia-Manero.

Further, most patients (73.3%) had MDS, and 4 patients (sequence A, 3; sequence B, 1) had received prior HMAs, and 3 patients receiving sequence B had been exposed to luspatercept.

In terms of MDS risk classification, all patients with MDS receiving sequence A (n = 11) and 54.5% of patients with MDS receiving sequence B (n = 11) had an International Prognostic Staging System-Revised score over 3.5.

All patients received at least 2 full-dose treatment cycles. The median and mean treatment durations were 3.8 months and 5.6 months, respectively (range, 1.1-13.5). Twenty-one patients discontinued treatment, including 8 who transitioned to transplant, of whom 7 had MDS and 1 had CMML, and 4 patients who had disease progression.

At the data cutoff of July 1, 2025, 9 patients remained on treatment.

Reference

Garcia-Maner G, Borate U, Brunner A, et al. A phase 2 dose confirmation trial of oral ASTX030, a combination of oral azacitidine with cedazuridine among patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. Blood. 2025;146(supplement 1):491. doi:10.1182/blood-2025-491