Oral cedazuridine/decitabine for MDS and CMML: A phase 2 pharmacokinetic/pharmacodynamic randomized crossover study

Guillermo Garcia-Manero, Elizabeth A. Griffiths, David P. Steensma, Gail J. Roboz, Richard Wells, James McCloskey, Olatoyosi Odenike, Amy E. DeZern, Karen Yee, Lambert Busque, Casey O’Connell, Laura C. Michaelis, Joseph Brandwein, Hagop Kantarjian, Aram Oganesian, Mohammad Azab, Michael R. Savona

Research output: Contribution to journalArticlepeer-review

Abstract

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean % LINE-1 demethylation between oral and IV were £1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ‡3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy.

Original languageEnglish (US)
Pages (from-to)674-683
Number of pages10
JournalBlood
Volume136
Issue number6
DOIs
StatePublished - Aug 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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