Azacitidine and decitabine are available in parenteral form for patients with myelodysplastic syndromes or chronic myelomonocytic leukaemia. This study evaluated the safety and pharmacokinetics of oral decitabine, coupled with cedazuridine, compared to intravenous decitabine. The results showed that oral decitabine–cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine, supporting its use as a safe and effective alternative to intravenous decitabine for the treatment of these patients.
The DNA methyltransferase inhibitors azacitidine and decitabine are available in parenteral form for the treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. The possibility of oral therapy with equivalent efficacy for these conditions presents potential treatment benefits. This study aimed to evaluate and compare the safety and pharmacokinetics of oral decitabine, coupled with the cytidine deaminase inhibitor cedazuridine, to intravenous decitabine administration.
This registrational, open-label, crossover, phase 3 trial was conducted across 37 academic and community-based clinics in Canada and the USA and included adult patients with myelodysplastic syndromes or chronic myelomonocytic leukaemia eligible for intravenous decitabine. In total, 138 participants were randomly assigned (1:1) to receive five days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by five days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine–cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over five days with oral decitabine–cedazuridine vs. intravenous decitabine for cycles 1 and 2, measured as the area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0–24 for both oral decitabine–cedazuridine and intravenous decitabine (i.e., paired cycles). On completion of the study, all patients were rolled over to a maintenance study.
After a median follow-up of 2.6 years (966 days), the primary endpoint of total exposure of oral decitabine–cedazuridine vs. intravenous decitabine was reported at 98.93%, indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine–cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade ≥3 were thrombocytopenia (61%), neutropenia (57%), and anaemia (50%). The incidence of serious adverse events in cycles 1-2 was 31% vs. 18% with oral decitabine–cedazuridine and intravenous decitabine, respectively. There were five treatment-related deaths, two related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]).
In conclusion, oral decitabine–cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. These results support the use of oral decitabine–cedazuridine as a safe and effective alternative to intravenous decitabine for the treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia.
Garcia-Manero G, McCloskey J, Griffiths Oral decitabine–cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. Lancet Haematol. 2024; 11(1):e15-26.