Blood Cancers Today (BCT) speaks with Guillermo Garcia-Manero, MD, University of Texas MD Anderson Center, Houston, Texas) at the ASH Annual Meeting 2024, where he presented the rationale behind ASTX030, an innovative oral therapy for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).1 By combining azacitidine with cedazuridine, a cytidine deaminase (CDA) inhibitor, ASTX030 offers a more convenient alternative to traditional subcutaneous administration while maintaining efficacy and safety. Dr. Garcia-Manero shares insights from the phase 1 trial, highlighting pharmacokinetic (PK) findings, safety profiles, and the next steps for this promising treatment.
BCT: Let’s start with the basics. Can you explain the rationale behind developing ASTX030 and how it fits into the treatment landscape for MDS and AML?
“Thank you. Hypomethylating agents like azacitidine and decitabine have long been the backbone of treatment for MDS and AML. However, their administration is limited to parenteral routes due to the enzymatic degradation of these drugs, particularly by CDA. This has always posed a challenge in terms of convenience and accessibility.”
“The rationale for ASTX030 was to combine azacitidine with cedazuridine, a CDA inhibitor, to create an oral formulation. This combination would allow for similar PK exposure to subcutaneous (SC) azacitidine while preserving the efficacy and safety profile. This builds on our prior success with ASTX727, the oral decitabine-cedazuridine combination, which has already been approved for MDS and AML.”
BCT: You mentioned ASTX727. How does ASTX030 differ, and what were the primary objectives of this phase 1 trial?
“ASTX030 is focused on azacitidine rather than decitabine. The objective of this phase 1 trial was to identify the recommended phase 2 dose by comparing the PK profile of oral azacitidine with SC azacitidine. Secondary objectives included evaluating safety, tolerability, preliminary efficacy, and the impact on global DNA methylation.”
“We also aimed to optimize the formulation. Initially, we tested an immediate-release version but later focused on a delayed-release formulation to better mimic the pharmacodynamics of SC azacitidine.”
BCT: Can you share some details about the patient population included in this trial?
“We enrolled 88 patients with MDS, chronic myelomonocytic leukemia, or other myelodysplastic/myeloproliferative neoplasms (MDS/MPN) overlap syndromes. The median age was 72 years, reflecting the real-world population for these diseases. The IPSS [International Prognostic Scoring System] risk distribution was balanced, with most patients being intermediate or high risk. Importantly, patients previously treated with hypomethylating agents were eligible, which added complexity but also provided valuable insights into this population.”
BCT: Let’s talk about the PK findings. How did the oral formulation compare to the SC version?
“The DR formulation of ASTX030 showed promise. Using 20 mg of cedazuridine, we achieved sufficient CDA inhibition to significantly enhance the oral bioavailability of azacitidine.”
“The PK target was to match the AUC [area under the curve] of SC azacitidine, and we achieved this with the combination of 140 mg azacitidine and 20 mg cedazuridine. This dose, selected as the recommended phase 2 dose, demonstrated PK and pharmacodynamic profiles comparable with the parenteral formulation.”
BCT: What about safety? Were there any unexpected adverse events?
“The safety profile of ASTX030 mirrored that of SC azacitidine. The most common grade ≥3 adverse events were related to myelosuppression, including leukopenia (27%), neutropenia (26%), and thrombocytopenia (23%). Gastrointestinal side effects, such as nausea and vomiting, were also observed but were manageable with supportive care.”
“Importantly, there were no significant differences in toxicity profiles between the oral and SC formulations. This consistency is reassuring, especially given the convenience of oral administration.”
BCT: How did ASTX030 perform in terms of efficacy?
“The efficacy data were consistent with what we expect from parenteral azacitidine. For patients with MDS, the complete remission rate was 8%, while patients with CMML [chronic myelomonocytic leukemia] or MDS/MPN had a complete remission rate of 20%. The overall response rate was approximately 56% across all cohorts.”
“Median overall survival for the entire cohort was 29 months, with 20 months for MDS and slightly lower for CMML and MDS/MPN. These results are encouraging, particularly given the inclusion of patients with prior treatment or hypomethylating agent failure.”
BCT: Can you comment on the drug’s impact on global DNA methylation and what this implies?
“Global DNA methylation was assessed using LINE-1 assays, and the results demonstrated a pattern virtually identical to that of SC azacitidine. This confirms that the oral formulation achieves similar pharmacodynamic effects, targeting DNA methyltransferase with comparable efficiency.”
BCT: With these results, what are the next steps for ASTX030?
“The phase 1 data provided a solid foundation to move forward. We are now conducting a randomized, open-label, crossover phase 2 trial comparing oral azacitidine to the SC formulation. Beyond that, a phase 3 trial is in the pipeline, set to begin early next year. This trial, named STAM, will evaluate ASTX030 not only in MDS but also in AML and in combination with agents like BCL-2 inhibitors.
BCT: Lastly, any thoughts on tailoring treatment schedules for different risk groups?
“That’s an important question. For higher-risk MDS, a standard 7-day schedule seems appropriate, but for lower-risk disease, shorter schedules like 5 or even 3 days may suffice. Ongoing trials and registry data will help clarify this. However, overdosing lower-risk patients could compromise quality of life without additional benefit, so this requires careful consideration.”
“It’s an exciting time in the field, and I appreciate the opportunity to discuss these findings.”
- Garcia-Manero G, McCloskey J, Scott BL, et al. Results from a phase 1 open-label dose escalation and expansion trial of oral azacitidine + cedazuridine (ASTX030) in patients with myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN). Abstract #662. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.
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