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

Abstract Background: Parenteral hypomethylating agents such as azacitidine (AZA) and decitabine are standard treatments for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, they require frequent clinic visits, which impose a substantial burden on patients (pts). An oral regimen may decrease treatment burden in high-grade myeloid malignancies. ASTX030 is an oral combination of AZA/cedazuridine that is AUC exposure equivalent to subcutaneous (SC) AZA and is being investigated in the ASTX030-01 (NCT04256317) trial, designed to transition seamlessly from phase (Ph) 1 to Ph3. Ph1 results of ASTX030-01, previously presented at ASH 2024, demonstrated all ASTX030 dose combinations were well tolerated, with a safety profile comparable to that of SC AZA. The 140/20-mg dose of AZA/cedazuridine was selected as the recommended Ph2 dose (RP2D). Here, we report results from the Ph2 ASTX030-01 trial, showing pharmacokinetic (PK), efficacy, and safety data of oral ASTX030. Methods: Ph2 of ASTX030-01, a multicenter, randomized, open-label trial, was conducted to confirm the RP2D selected from Ph1 achieved a mean AZA AUC comparable to that of parenteral AZA. Pts with confirmed MDS, chronic myelomonocytic leukemia (CMML), MDS/myeloproliferative neoplasms (MPN), or AML who were candidates for single-agent AZA were randomized 1:1 to either Sequence A or Sequence B. In Sequence A, pts were administered ASTX030 (AZA/cedazuridine 140/20 mg) in Cycle (C) 1, SC AZA (75 mg/m2) in C2, and ASTX030 from C3 onward, whereas pts in Sequence B received SC AZA in C1 and ASTX030 for C2 onward. The primary endpoint was the ratio of AZA total cycle AUC0–24 exposures after oral ASTX030 over SC AZA. Secondary endpoints included best clinical response rate, PK, LINE-1 demethylation, and safety. Results: As of May 30, 2025, 30 pts had been treated, 22 with MDS, 5 with CMML, 1 with MDS/MPN, and 2 with AML. Pts had a median age of 74.5 years; median duration of treatment was 3.8 months. Fifteen of 30 (50%) pts had an intermediate body surface area (BSA) range of 1.55–2.15 m2, 13 (43%) had high BSA of ≥2.15 m2, and two (6.7%) pts had low BSA (≤1.55 m2). Geometric mean ratio (GMR) for the primary PK endpoint was 0.913 (90% confidence interval [CI]: 0.78, 1.07). When stratifying by BSA, the intermediate-BSA subset had a GMR of 0.980 (90% CI: 0.85, 1.13), whereas the high-BSA subset had a GMR of 0.700 (90% CI: 0.55, 0.89); both low-BSA pts had a ratio of >1.0. Further simulations using a semi-physiologic population PK model suggest BSA-based dosing will offer more optimal exposures across the disease population while ensuring the oral/SC AUC ratio for AZA total cycle AUC (GMR) is closer to 1.0. This will reduce inter- and intra-pt variability and ensure an optimal dose is used for all pts, with the total dose of ASTX030 more closely approximating the total dose of SC administration of AZA across the range of BSA in the population. Overall response in pts with MDS was 50.0% (11/22); complete responses (CRs) were achieved in 5 (22.7%) pts. One of the 2 pts with AML had a CR and the other had stable disease. Of pts who were red blood cell (RBC) transfusion dependent at baseline, 30.8% (4/13) achieved ≥56-day RBC transfusion independence. Maximum mean percentage of LINE-1 demethylation during C1 was 5.95 (ASTX030) and 7.11 (SC AZA), and 5.68 (ASTX030) and 6.37 (SC AZA) in C2. Adverse events (AEs) were reported in 100% of pts in the trial, of which 83.3% were Grade ≥3. Most common treatment-emergent AEs (TEAEs) were nausea (70.0%; of note, 96.7% of pts received prophylactic/therapeutic anti-emetics), constipation (66.7%), and fatigue (60.0%), and the majority were Grade 1 or 2 in severity. Most common Grade ≥3 TEAEs were thrombocytopenia (43.3%), neutropenia (33.3%), and anemia (30.0%). AEs leading to treatment withdrawal or dose reductions occurred in 2 (6.7%) and 4 (13.3%) pts, respectively. There were 12 (40.0%) AEs that led to treatment interruption/delay. Conclusion: Oral ASTX030 showed PK, pharmacodynamic, and clinical profiles comparable to SC AZA, supporting its potential as an oral alternative. The observed variability in drug exposures, influenced by pts' BSA, highlights the value of BSA-based dosing to better align systemic exposure with that of SC AZA. The international Ph3 trial, AZTOUND, which incorporates BSA-based dosing, is currently recruiting participants. Clinical trial registration: NCT04256317