Background: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine., Methods: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 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/m 2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 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 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC 0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264., Findings: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), 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 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1])., Interpretation: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia., Funding: Astex Pharmaceuticals., Competing Interests: Declaration of interests GG-M has consulted for Acceleron; received honoraria and research funding from AbbVie, Astex, Bristol Myers Squibb, Curis, Genentech, and Novartis; received honoraria from Aprea; and received research funding from Gilead. JMc has received research funding from Astex; consulted for AbbVie, Apellis, BMS, CTI BioPharma, Novartis, Pfizer, and Takeda; received honoraria from BMS, Blueprint, Incyte, Jazz, Novartis, Stemline, and Takeda; and is an equity holder in COTA Healthcare. EAG has received research funding from Astex, Blueprint, and Celldex; received research funding from and consulted and served on advisory committees for Alexion and BMS/Celgene; consulted for and served on advisory committees for AbbVie, Apellis, AstraZeneca, CTI BioPharma, Genentech, Novartis, Taiho, and Takeda; and received honoraria from Aplastic Anemia and MDS International Foundation, Medicom, Physician Educational Resource, and Picnic Health. KWLY has consulted for BMS/Celgene, GSK, Jazz, Novartis, Pfizer, Shattuck, Taiho, and Takeda; received research funding from Astex, Forma, Genentech, Geron, Gilead, Janssen, Jazz, Novartis, Roche, Pfizer, and Treadwell; and received honoraria from AbbVie and Novartis. AMZ has received research funding from AbbVie, ADC Therapeutics, Amgen, Aprea, Astex, AstraZeneca, BMS, Boehringer-Ingelheim, Cardiff Oncology, Celgene, Incyte, Medimmune, Novartis, Otsuka, Pfizer, Takeda, and Trovagene; consulted for AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, BMS, Boehringer-Ingelheim, Cardiff, Cardinal Health, Celgene, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; received honoraria from AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, BMS, Boehringer-Ingelheim, Cardiff, Cardinal, Celgene, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Otsuka, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; received travel expenses from Cardiff, Novartis, and Pfizer; and had leadership roles in boards or committees for AbbVie, BMS, Celgene, Geron, Gilead, Kura, and Novartis. AA-K's institution has received research support from Astex. HJD, NZ, NYG, JMa, HA, and JR declare no competing interests. PAP has served on an advisory committee for Agios. MS has served on advisory committees for AbbVie, BMS, Celgene, Jazz, Novartis, Pfizer, Roche, and Taiho and served on advisory committees for and received research funding from Actinium and Astellas. M-MK has served on advisory boards for AstraZeneca, BeiGene, BMS, Seattle Genetics, and Taiho. SF has consulted for and received honoraria from Blueprint, CTI, Gilead, GSK, Incyte, Janssen, Jazz, Karyopharm, Novartis, PharmaEssentia, Sanofi, Servier, Stemline, Taiho, and Takeda. OO has consulted for AbbVie, BMS/Celgene, CTI, Impact, Novartis, and Taiho and his institution has received research funding from AbbVie, Agios, Aprea, Astex, AstraZeneca, BMS/Celgene, CTI, Incyte, Janssen, Kartos, NS Pharma, and OncoTherapy. HK has received grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, and Novartis and received honoraria from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen, KAHR, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda. AED has consulted for Taiho; received honoraria from BMS, Novartis, and Gilead; served as chair of a data safety monitoring board for Geron; and is the 2023 American Society of Hematology Education Chair. CLO has received research funding from Astex and Genentech. GJR has consulted or served on advisory boards or data and safety monitoring committees for AbbVie, Actiunuim, Agios, Amgen, Astellas, AstraZeneca, Bluebird, Blueprint, Bluebird Bio, BMS, Catamaran, Celgene, Daiichi, GSK, Helsinn, Janssen, Jasper, Jazz, Mesoblast, Novartis, Pfizer, Roche, Syndax, Takeda, and Trovagene and received research support from Janssen. LB has consulted for Novartis. RB has received honoraria and research funding from BMS and Taiho; received research funding from Takeda; and received honoraria from AbbVie. BL has received honoraria and served on advisory committees and speakers bureaus for AbbVie, Amgen, and BMS and consulted for, received honoraria, and served on advisory committees and speakers bureaus for Novartis and Pfizer. AS has consulted for and received research funding from Kymera, consulted for Janssen and Rigel, and received honoraria from National Association for Continuing Education. K-HD, AO, and HNK are employed by Astex. YH and MA were employed in the past 24 months by and consult for Astex. MRS has consulted and served on advisory boards for and received travel expenses from BMS, CTI, Forma, Geron, GSK, and Taiho; received travel expenses from Astex; is an equity holder in and served on advisory committees for Karyopharm and Ryvu; and received research funding from ALX Oncology, Astex, Incyte, and Takeda., (Copyright © 2024 Elsevier Ltd. All rights reserved.)