FDA Grants Priority Review to Cedazuridine/Decitabine for MDS and CMML

The FDA has granted a priority review designation to a new drug application (NDA) for cedazuridine plus decitabine (ASTX727; oral C-DEC) for the treatment of adult patients with previously untreated intermediate- and high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML).¹

The NDA is based on data from the phase III ASCERTAIN trial, in which oral C-DEC demonstrated decitabine exposure equivalence of total 5-day dosing compared with intravenous (IV) decitabine in patients with intermediate- and high-risk MDS or CMML. Specifically, oral C-DEC achieved 98.9 (90% CI, 92.7- 105.6) of decitabine 5-day AUC systemic exposures compared with IV decitabine.² Among evaluable patients, the complete response (CR) rate with oral C-DEC was 12%, with an overall response rate of 64%.

Under the priority review designation, the FDA will evaluate the NDA within 6 months compared to the standard review period of 10 months.

“We are very pleased that the FDA has accepted our NDA for Priority Review,” Mohammad Azab, MD, president & chief medical officer of Astex Pharmaceuticals, Inc., the developer of oral C-DEC, said in a press release. “Subject to FDA review and regulatory approval, oral C-DEC may offer a new option for patients with MDS and CMML that saves them the burden of 5-day IV infusions every month during their treatment period. We are grateful to all the patients, investigators and other healthcare providers, and partner research and manufacturing organizations, who contributed to the clinical development program of oral C-DEC.”

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.

The multicenter, open-label, crossover ASCERTAIN study compared oral C-DEC to IV decitabine in the first 2 cycles with all patients then continuing on to receive oral C-DEC starting in cycle 3. Patients randomized to the experimental arm (n = 66) received oral C-DEC: cedazuridine at 100 mg and decitabine at 35 mg was administered in a fixed-dose combination tablet given once daily for 5 days on a 28-day cycle. In the control arm (n = 67), decitabine at 20 mg/m² was administered as a daily, 1-hour IV infusion for 5 days on a 28-day cycle.

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 parameters, clinical responses, red blood cell transfusion independence, leukemia-free survival, and overall survival. ASCERTAIN was conducted in 138 patients at 46 sites.

Baseline characteristics were well balanced between the 2 arms. Among the overall population, the median age was 71 (range, 44-88), 65% of patients were male, and 12% of patients had CMML. About 40% of patients were RBC-transfusion dependent and 7.5% were platelet transfusion dependent. The ECOG performance status was 0 for 41% of patients and 1 for 59% of patients.

Among 101 patients evaluable for response, the marrow CR was 45.5% and the hematologic improvement rate was 5.3%. Stable disease occurred in 27.7% of patients and 7.9% of patients had progressive disease. At ≥16 weeks posttreatment, 15.4% of patients were RBC transfusion independent and 1 patient (10%) was platelet transfusion independent.

The researchers reported that the safety data for IV decitabine were consistent with historical findings, and that the rates of adverse events (AEs) between the 2 treatment arms were similar. Among patients who received oral C-DEC in the first 2 cycles, the most common (≥20%) AEs were thrombocytopenia (43.8%), neutropenia (35.4%), anemia (36.9%), and fatigue (23.8%).

References

1. Astex Pharmaceuticals announces U.S. Food and Drug Administration (FDA) acceptance for review of an NDA for the combination oral hypomethylating agent cedazuridine and decitabine (ASTX727 or oral C-DEC), for the treatment of MDS and CMML. Published February 13, 2020. https://bit.ly/31RVFV1. Accessed February 13, 2020.
2. Garcia-Manero G, McCloskey J, Elizabeth Griffiths E, at al. Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross-Over Phase 3 Study (ASCERTAIN) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 846.