Abstract：
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/m2 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 AUC0-24 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.
RESULTS: 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]).
CONCLUSIONS: 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.
BACKGROUND: Astex Pharmaceuticals.
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/m2 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 AUC0-24 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.
RESULTS: 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]).
CONCLUSIONS: 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.
BACKGROUND: Astex Pharmaceuticals.
摘要：
背景：DNA甲基转移酶抑制剂阿扎胞苷和地西他滨可用于骨髓增生异常综合征或慢性粒单核细胞白血病患者的肠胃外形式。对这些疾病具有类似暴露的口服治疗将提供潜在的治疗益处。我们的目的是比较口服地西他滨加胞苷脱氨酶抑制剂西达嗪与静脉注射地西他滨的安全性和药代动力学。
方法：我们做了一个注册，多中心,开放标签，交叉，骨髓增生异常综合征或慢性粒单核细胞白血病和急性髓系白血病患者的3期试验，纳入单独的队列;此处仅报道骨髓增生异常综合征或慢性粒单核细胞白血病参与者的结果.在加拿大和美国的37个学术和社区诊所中，我们招募了18岁或以上的人，他们是接受静脉注射地西他滨的候选人，东部肿瘤协作组的表现状态为0或1，预期寿命至少为3个月。参与者被随机分配（1：1），在28天的治疗周期内接受口服地西他滨-切达氮嗪（每天一次，含35mg地西他滨和100mg西达氮嗪作为固定剂量组合）或静脉注射地西他滨（每天20mg/m2，连续1小时静脉输注），然后在下一个治疗周期中使用其他制剂5天。此后,从第3个周期开始,所有参与者均接受口服地西他滨-西他嗪,直至停止治疗.主要终点是在第1和第2周期中口服地西他滨-西他嗪与静脉注射地西他滨的5天总暴露量，测量为在第1和第2周期中接受全部治疗剂量并每天服用地西他滨AUC0-24口服地西他滨和静脉注射地西他滨的参与者的曲线下面积（即，成对循环)。研究完成后，所有患者均转入维持研究.这项研究在ClinicalTrials.gov注册，NCT03306264。
结果：在2018年2月8日至2021年6月7日之间，筛选了173名个体，138名(80%)参与者被随机分配到一个治疗序列，和133（96％）参与者（87[65％]男性和46[35％]女性；121[91％]白人，四名[3%]黑人或非裔美国人，三个[2%]亚洲人，5[4%]未报告)接受治疗。中位随访时间为966天（IQR917-1050）。口服地西他滨-西达嗪与静脉注射地西他滨总暴露的主要终点为98·93％（90％CI92·66-105·60），根据曲线下面积指示等效的药代动力学暴露。口服地西他滨-cedazuridine和静脉注射地西他滨的安全性相似。最常见的3级或更严重的不良事件是血小板减少症（133例参与者中的81例[61%]）。中性粒细胞减少症（76[57%]参与者），和贫血（67[50%]参与者）。第1-2周期严重不良事件的发生率为31％（130名参与者中的40名）口服地西他滨和18％（132名参与者中的24名）静脉注射地西他滨。有5例与治疗相关的死亡；2例被认为与口服治疗有关（败血症和肺炎），3例与静脉治疗有关（败血症性休克[n=2]和肺炎[n=1]）。
结论：口服地西他滨-西他嗪在药理和药效学上与静脉注射地西他滨相当。结果支持使用口服地西他滨-切达尿苷作为静脉内地西他滨的安全有效的替代药物，用于治疗患有骨髓增生异常综合征或慢性粒单核细胞白血病的个体。
背景：Astex制药。
方法：我们做了一个注册，多中心,开放标签，交叉，骨髓增生异常综合征或慢性粒单核细胞白血病和急性髓系白血病患者的3期试验，纳入单独的队列;此处仅报道骨髓增生异常综合征或慢性粒单核细胞白血病参与者的结果.在加拿大和美国的37个学术和社区诊所中，我们招募了18岁或以上的人，他们是接受静脉注射地西他滨的候选人，东部肿瘤协作组的表现状态为0或1，预期寿命至少为3个月。参与者被随机分配（1：1），在28天的治疗周期内接受口服地西他滨-切达氮嗪（每天一次，含35mg地西他滨和100mg西达氮嗪作为固定剂量组合）或静脉注射地西他滨（每天20mg/m2，连续1小时静脉输注），然后在下一个治疗周期中使用其他制剂5天。此后,从第3个周期开始,所有参与者均接受口服地西他滨-西他嗪,直至停止治疗.主要终点是在第1和第2周期中口服地西他滨-西他嗪与静脉注射地西他滨的5天总暴露量，测量为在第1和第2周期中接受全部治疗剂量并每天服用地西他滨AUC0-24口服地西他滨和静脉注射地西他滨的参与者的曲线下面积（即，成对循环)。研究完成后，所有患者均转入维持研究.这项研究在ClinicalTrials.gov注册，NCT03306264。
结果：在2018年2月8日至2021年6月7日之间，筛选了173名个体，138名(80%)参与者被随机分配到一个治疗序列，和133（96％）参与者（87[65％]男性和46[35％]女性；121[91％]白人，四名[3%]黑人或非裔美国人，三个[2%]亚洲人，5[4%]未报告)接受治疗。中位随访时间为966天（IQR917-1050）。口服地西他滨-西达嗪与静脉注射地西他滨总暴露的主要终点为98·93％（90％CI92·66-105·60），根据曲线下面积指示等效的药代动力学暴露。口服地西他滨-cedazuridine和静脉注射地西他滨的安全性相似。最常见的3级或更严重的不良事件是血小板减少症（133例参与者中的81例[61%]）。中性粒细胞减少症（76[57%]参与者），和贫血（67[50%]参与者）。第1-2周期严重不良事件的发生率为31％（130名参与者中的40名）口服地西他滨和18％（132名参与者中的24名）静脉注射地西他滨。有5例与治疗相关的死亡；2例被认为与口服治疗有关（败血症和肺炎），3例与静脉治疗有关（败血症性休克[n=2]和肺炎[n=1]）。
结论：口服地西他滨-西他嗪在药理和药效学上与静脉注射地西他滨相当。结果支持使用口服地西他滨-切达尿苷作为静脉内地西他滨的安全有效的替代药物，用于治疗患有骨髓增生异常综合征或慢性粒单核细胞白血病的个体。
背景：Astex制药。
