Background

Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes.

Methods

In this phase 1 study, we enrolled patients aged 18 years or older with myelodysplastic syndromes or chronic myelomonocytic leukaemia. Eligible patients were assigned to cohorts to receive escalating oral doses of decitabine and cedazuridine. The starting dose was decitabine 20 mg and cedazuridine 40 mg. Treatment cycles lasted 28 days, with 5 days of drug administration. In cycle 1, each patient received a cohort-defined dose of oral decitabine on day −3, a 1-h intravenous infusion of decitabine 20 mg/m² on day 1, and cohort-defined doses of oral decitabine plus cedazuridine on days 2–5. In cycles 2 and beyond, the oral decitabine and cedazuridine were given on days 1–5. The dose of cedazuridine was escalated first and decitabine was escalated once CDA inhibition by cedazuridine approached the maximum effect. The drug dose was escalated if mean decitabine area under the curve (AUC) of the oral drug was less than 90% of that for intravenous decitabine in the cohort and if no dose-limiting toxicity was observed. Dose-limiting toxicity was defined as a grade 3 or greater non-haematologic toxicity or grade 4 haematologic toxicity lasting more than 14 days and unrelated to the underlying disease. Once the decitabine AUC target range set as the primary endpoint, and established with intravenous decitabine, was reached at a dose deemed to be safe, the cohort that most closely approximated intravenous decitabine exposure was expanded to 18 evaluable patients. The primary objectives were to assess the safety of decitabine plus cedazuridine, and to determine the dose of each drug needed to achieve a mean AUC for decitabine exposure similar to that for intravenous decitabine exposure. This study is registered with ClinicalTrials.gov, number NCT02103478.

Findings

Between Oct 28, 2014, and Nov 13, 2015, we enrolled 44 eligible patients (of 75 screened) with previously treated or newly diagnosed myelodysplastic syndromes or chronic myelomonocytic leukaemia; 43 of the enrolled patients were evaluable. Participants were treated in five cohorts: cohorts 1–4 included six evaluable patients each; cohort 5 included 19 patients in a 13-patient expansion. Dose-dependent increases in decitabine AUC and peak plasma concentration occurred with each cohort dose escalation. There was no evident increase in toxicity compared with that reported for intravenous decitabine. Decitabine 30 mg and 40 mg plus cedazuridine 100 mg produced mean day-5 decitabine AUCs (146 ng × h/mL for decitabine 30 mg, and 221 ng × h/mL for decitabine 40 mg) closest to the mean intravenous-decitabine AUC (164 ng × h/mL). The most common grade 3 or more adverse events were thrombocytopenia (18 [41%] of 44 patients), neutropenia (13 [30%]), anaemia (11 [25%]), leukopenia (seven [16%]), febrile neutropenia (seven [16%]), and pneumonia (seven [16%]). Four (9%) patients died because of adverse events, none of which was considered drug related, and three (7%) patients died more than 30 days after discontinuing treatment because of progressive disease (two [5%]) and respiratory failure (one [2%]).

Interpretation

Oral decitabine plus cedazuridine emulated the pharmacokinetics of intravenous decitabine, with a similar safety profile and dose-dependent demethylation. Clinical responses were similar to intravenous decitabine treatment for 5 days. Further study of decitabine plus cedazuridine as an alternative to parenteral therapy or in combination with other new oral agents for myeloid disorders is warranted.

Funding

Astex Pharmaceuticals, Inc.

中文翻译：

---

地西他滨和西屈嘧啶口服固定剂量联合治疗骨髓增生异常综合症：一项多中心，开放标签，剂量递增的1期研究

背景

地西他滨是一种DNA甲基转移酶1抑制剂或DNA低甲基化化合物，由于肠和肝脏中的胞苷脱氨酶（CDA）快速清除，因此口服生物利用度不高。在药代动力学和药效学观察的指导下，这项剂量递增研究评估了同时口服新型CDA抑制剂cedazuridine能否提高地西他滨治疗骨髓增生异常综合症的生物利用度。

方法

在这项1期研究中，我们招募了18岁或以上患有骨髓增生异常综合症或慢性粒细胞单核细胞白血病的患者。符合条件的患者被分配到队列中接受递增剂量的地西他滨和西屈氨定的口服治疗。起始剂量为地西他滨20 mg和西屈嘧啶40 mg。治疗周期持续28天，给药5天。在第1周期中，每位患者在第-3天接受队列定义的口服地西他滨剂量，静注1小时的地西他滨20 mg / m ²静脉滴注在第1天服用队列定义剂量的口服地西他滨加西屈祖啶；在第2-5天服用。在第2个周期及以后的第1-5天，给予口服地西他滨和西屈祖啶。一旦西屈里定对CDA的抑制作用达到最大程度，西曲柳定的剂量应首先增加，地西他滨的剂量应逐渐增加。如果口服药物曲线下的平均地西他滨面积（AUC）小于队列中静脉内地西他滨的90％，并且未观察到剂量限制的毒性，则药物剂量会增加。限剂量毒性定义为持续超过14天且与基础疾病无关的3级或更高级别的非血液学毒性或4级血液学毒性。一旦将地西他滨AUC的目标范围设定为主要终点并通过静脉内地西他滨确定，则剂量被认为是安全的，最接近静脉地西他滨暴露的队列扩大到了18位可评估的患者。主要目的是评估地西他滨加西屈祖啶的安全性，并确定达到与静脉地地西他滨暴露相似的地西他滨平均AUC所需的每种药物的剂量。该研究已在ClinicalTrials.gov上注册，编号为NCT02103478。

发现

在2014年10月28日至2015年11月13日期间，我们招募了44名合格患者（筛查的75名患者），这些患者先前曾接受过治疗或新诊断出的骨髓增生异常综合症或慢性骨髓单核细胞白血病。在入组患者中有43名是可评估的。参与者分为五个队列进行治疗：队列1-4包括六个可评估的患者；每个队列中包括六个可评估的患者。队列5包括19位患者，共13位患者。每次队列剂量增加时，地西他滨AUC的剂量依赖性增加和血浆峰值浓度出现。与静脉注射地西他滨相比，毒性没有明显增加。地西他滨30 mg和40 mg加上西屈祖啶100 mg产生的平均第5天地西他滨AUCs（地西他滨30 mg为146 ng×h / mL，地西他滨40 mg为221 ng×h / mL），最接近于静脉内地西他滨AUC（ 164 ng×h / mL）。最常见的3级以上不良事件是血小板减少症（44例患者中的18例[41％]），中性粒细胞减少症（13 [30％]），贫血（11例[25％]），白细胞减少症（7例[16％]），发热中性粒细胞减少症（七[16％]）和肺炎（七[16％]）。四（9％）位患者因不良事件而死亡，没有一例被认为与药物相关，三位（7％）患者因进行性疾病（两位[5％]）和呼吸衰竭（30％）停药后死亡超过30天。 1 [2％]）。

解释

口服地西他滨加西达祖啶模拟了静脉地西他滨的药代动力学，具有相似的安全性和剂量依赖性去甲基化作用。临床反应类似于静脉地西他滨治疗5天。因此，有必要对地西他滨加西屈祖啶替代肠胃外疗法或与其他新的口服药物联合治疗髓样疾病进行进一步研究。

资金

Astex Pharmaceuticals，Inc.