Phase III ASCERTAIN Trial Meets Endpoint in Topline Results for Cedazuridine and Decitabine in MDS/CMML

Mohammad Azab, MD

Mohammad Azab, MD, MSc

Topline results from the ASCERTAIN trial of the cedazuridine and decitabine (ASTX727) combination in patients with intermediate and high-risk myelodysplastic syndromes (MDS) or chronic myelomoncyctis leukemia (CMML) showed that the phase III trial met its primary endpoint. The fixed-dose combination demonstrated a decitabine exposure equivalence of total 5-day dosing compared with intravenous (IV) decitabine in the study patient population. 

Additionally, safety and clinical activity of the combination were found to be similar to what had been observed in earlier phase I/II findings. Full findings will be presented at an upcoming medical meeting. The developer of cedazuridine, Astex Pharmaceuticals, which is a member of Ostuka, plans to file a new drug application for the combination by the end of 2019.

“We are delighted with the outcome of the ASCERTAIN trial, and the demonstration that the fixed-dose combination of cedazuridine with decitabine enables successful oral delivery of decitabine, alleviating the significant burden of 5 days of monthly IV infusions for patients who may continue to benefit from the drug for several months or even years,” Mohammad Azab, MD, MSc, MBA, president and chief medical officer, Astex Pharmaceuticals, said in a press release. “Subject to regulatory review and approvals, ASTX727 could bring a new treatment option to patients with these deadly diseases. We are extremely grateful to all the patients, caregivers, partner research and manufacturing organizations, as well as the healthcare professionals who contributed to this effort.”

Cedazuridine is a cytidine deaminase inhibitor, and decitabine is an anticancer DNA hypomethylating agent; the combination ASTX727 is a novel, orally administered fixed-dose combination of both drugs. By inhibiting cytidine deaminase in the gut and the liver, ASTX727 allows for an oral administration of decitabine at exposures that are equivalent to the approved intravenous form of decitabine administered over 5 days.

In the multicenter, open-label, crossover ASCERTAIN study, researchers set out to demonstrate that ASTX727 could deliver a pharmacokinetically equivalent exposure of oral decitabine versus IV decitabine in adults with treatment-naïve or pretreated MDS, as well as patients with MDS International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2, or high-risk MDS. The patients with treatment-naïve or pretreated MDS could include all French, American, and British subtypes with refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and CMML.

Patients were randomized 1:1 to receive ASTX727 5 times per day in the first 28-day cycle followed by IV decitabine 5 times per day in the second 28-day cycle, or the opposite order. After completion of the first 2 cycles, patients continued to receive treatment with ASTX727 in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of content.

The primary endpoint was total 5-day AUC exposures of decitabine following ASTX727 therapy compared with IV decitabine, as measured across the first 2 cycles. Secondary endpoints included safety assessments, pharmacodynamic measurements, secondary pharmacokinetic (PK) parameters, clinical responses, red blood cell transfusion independence, leukemia-free survival, and overall survival. ASCERTAIN was conducted in 138 patients at 46 sites.

The combination was previously evaluated in a phase I/II PK-guided dose-escalation and dose-confirmation trial in patients with MDS and CMML. Investigators sought to define appropriate doses of cedazuridine and decitabine separately, so that decitabine exposure following oral administration of ASTX727 is similar to exposure after IV decitabine at the approved daily dose of a 1-hour infusion at 20 mg/m2.

Results of the trial demonstrated that ASTX727 allowed decitabine to be delivered orally at a dose that emulates parenteral PKs, as measured by 5-day area under the curve (AUC).²Moreover, the safety profile was similar to IV decitabine, and there was a low level of gastrointestinal-related adverse events with ASTX727.

Additional combinations of cedazuridine and decitabine are being explored in ongoing trials, the company stated in the press release.

References

1. Astex Pharmaceuticals and Otsuka Announce Results Of The Phase 3 ASCERTAIN Study Of The Novel Oral Cedazuridine And Decitabine Fixed-Dose Combination (ASTX727) in Patients With Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML). Astex Pharmaceuticals. Published June 6, 2019. https://bit.ly/2Is0meY. Accessed June 6, 2019.
2. Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study.Lancet Haematol. 2019;6(4):e194-e203. doi: doi: 10.1016/S2352-3026(19)30030-4./li>