TY - JOUR
T1 - Oral cedazuridine/decitabine for MDS and CMML
T2 - A phase 2 pharmacokinetic/pharmacodynamic randomized crossover study
AU - Garcia-Manero, Guillermo
AU - Griffiths, Elizabeth A.
AU - Steensma, David P.
AU - Roboz, Gail J.
AU - Wells, Richard
AU - McCloskey, James
AU - Odenike, Olatoyosi
AU - DeZern, Amy E.
AU - Yee, Karen
AU - Busque, Lambert
AU - O’Connell, Casey
AU - Michaelis, Laura C.
AU - Brandwein, Joseph
AU - Kantarjian, Hagop
AU - Oganesian, Aram
AU - Azab, Mohammad
AU - Savona, Michael R.
N1 - Funding Information:
This trial was supported by Astex Pharmaceuticals, Inc. Geoff Marx and Barry M. Weichman of BioScience Communications, New York, NY (a medical communications company), provided medical writing and editorial assistance to the authors during preparation of this manuscript, and were funded by Astex.
Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
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U2 - 10.1182/BLOOD.2019004143
DO - 10.1182/BLOOD.2019004143
M3 - Article
C2 - 32285126
AN - SCOPUS:85089170147
SN - 0006-4971
VL - 136
SP - 674
EP - 683
JO - Blood
JF - Blood
IS - 6
ER -