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

Autor: Mohammad Azab, Amy E. DeZern, James K. McCloskey, David P. Steensma, Michael R. Savona, Lambert Busque, Richard A. Wells, Hagop M. Kantarjian, Laura C. Michaelis, Elizabeth A. Griffiths, Casey O'Connell, Gail J. Roboz, Olatoyosi Odenike, Joseph M. Brandwein, Guillermo Garcia-Manero, Aram Oganesian, Karen W.L. Yee
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Adult
Male
medicine.medical_specialty
DNA-Cytosine Methylases
Clinical Trials and Observations
Gastrointestinal Diseases
Immunology
Chronic myelomonocytic leukemia
Phases of clinical research
Decitabine
Capsules
Kaplan-Meier Estimate
Neutropenia
Biochemistry
Gastroenterology
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Least-Squares Analysis
Uridine
Aged
Aged
80 and over
Cross-Over Studies
business.industry
Leukemia
Myelomonocytic
Chronic
Cell Biology
Hematology
DNA Methylation
Middle Aged
medicine.disease
Crossover study
Hematologic Diseases
Neoplasm Proteins
Drug Combinations
Leukemia
Myeloid
Acute
Long Interspersed Nucleotide Elements
International Prognostic Scoring System
Pharmacodynamics
Area Under Curve
Myelodysplastic Syndromes
Disease Progression
Female
Drug Monitoring
business
Febrile neutropenia
medicine.drug
Tablets
Zdroj: Blood
ISSN: 0210-3478
Popis: 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. This study is registered at www.clinicaltrials.gov as #NCT02103478.
Databáze: OpenAIRE
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