Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.
Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.
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DOI：
10.1016/s1470-2045(17)30576-4
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发表时间：
2017-10
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影响因子：
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通讯作者：
Issa JJ
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作者：
Kantarjian HM;Roboz GJ;Kropf PL;Yee KWL;O'Connell CL;Tibes R;Walsh KJ;Podoltsev NA;Griffiths EA;Jabbour E;Garcia-Manero G;Rizzieri D;Stock W;Savona MR;Rosenblat TL;Berdeja JG;Ravandi F;Rock EP;Hao Y;Azab M;Issa JJ
去甲基化药物阿扎替丁和地西他滨已显示出对骨髓增生异常综合征和急性髓系白血病(AML)的疗效，但反应有限，持续时间短，可能是由于半衰期短和骨髓暴露不佳所致。Guadecitabine(SGI-110)是一种由地西他滨和脱氧鸟苷组成的二核苷酸，可抵抗胞苷脱氨酶的降解，从而获得更长的半衰期和其活性代谢物地西他滨的暴露。我们的目的是评估皮下注射吉西他滨治疗不适合强化化疗的幼稚老年AML患者的安全性和临床活性。在这项多中心、开放标签、第2阶段的研究中，来自14个北美AML医疗中心的未接受强化化疗的幼稚老年患者被随机分配(1：1，使用计算机算法)，在28天的治疗周期的第1-5天(5天计划)中，以60或90 mg/m2的速度皮下注射吉西他滨。随后，患者被分成10天的顺序皮下注射60 mg/m2的吉西他滨(至少在第1-5天和第8-12天给药2个周期，后续的周期按5天的时间表给药)。目的是评估和比较两种剂量和方案的吉西他滨的活性和安全性，主要终点为复合完全缓解(包括完全缓解[CR]、CR伴血小板不完全恢复[CRP]和CR伴中性粒细胞不完全恢复[CRI])。只要一名患者接受了至少一次吉西他滨治疗，就评估了所有患者(AS治疗)的疗效。次要终点包括安全性、存活率和药效学。我们给出了最终的试验分析，尽管在数据库锁定时，15名患者仍在接受生存监测，其中包括6名继续治疗。这项研究在ClinicalTrials.gov注册，编号NCT01261312。在2012年8月24日至2014年9月15日期间，103名患者接受了治疗：51名接受了5天的吉西他滨治疗(24名接受了60 mg/m2的治疗，27名接受了90 mg/m2的治疗)，52名接受了10天的治疗。中位年龄77岁。预后不良的特征包括≥状态2(39[38%])、危险细胞遗传学不良(43[42%])和继发性急性髓细胞白血病(37[36%])。在剂量和时间表上，特征总体上是平衡的。60天、90天和10天60 mg/m2方案的结直肠癌发生率分别为54%(13例)、59%(16例)和50%(26例)。在5天和10天的时间表中，最常见的3级或更高的不良事件，无论与治疗的关系如何，分别包括发热性中性粒细胞减少症(31[61%]和36[69%])，血小板减少症(25[49%]和22[42%])，中性粒细胞减少症(20[39%]和18[35%])，肺炎(15[29%]和19[37%])，贫血(15[29%]和12[23%])，以及败血症(8[16%]和14[27%])。在5天和10天的时间表中，最常见的严重不良事件，无论与治疗的关系如何，分别是发热性中性粒细胞减少症(27[53%]和25[48%])，肺炎(14[27%]和16[31%])，以及败血症(8[16%]和14[27%])。在治疗不适合强化化疗的幼稚的老年急性髓细胞白血病患者中，吉西他滨导致高结直肠癌发生率≥为50%，在所调查的剂量和方案中安全性可接受。在这一患者群体中进行的第三阶段关键研究正在进行中，以评估5天时间表与标准治疗方案中吉西他滨60 mg/m2的疗效。ASTEX制药公司与癌症抗争
Hypomethylating agents azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia (AML), but responses are limited and of short duration, possibly due to short half-lives and suboptimal bone marrow exposure. Guadecitabine (SGI-110), a dinucleotide of decitabine and deoxyguanosine, is resistant to degradation by cytidine deaminase thus achieving longer half-life and exposure of its active metabolite, decitabine. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in treatment-naïve older patients with AML who were not candidates for intensive chemotherapy. In this multicentre, open-label, phase 2 study, treatment-naïve older patients from 14 North American medical centres with AML who were not candidates for intensive chemotherapy were randomly assigned (1:1, using a computer algorithm) to subcutaneous guadecitabine at 60 or 90 mg/m2 on days 1–5 (5-day schedule) of a 28-day treatment cycle. Subsequently, patients were assigned sequentially to subcutaneous guadecitabine at 60 mg/m2 in a 10-day schedule (at least 2 cycles administered on days 1–5 and 8–12, with subsequent cycles given on a 5-day schedule). The objective was to evaluate and compare the activity and safety of two doses and schedules of guadecitabine, with a primary endpoint of composite complete response (including complete response [CR], CR with incomplete platelet recovery [CRp], and CR with incomplete neutrophil recovery regardless of platelets [CRi]). Response was evaluated in all patients (as-treated) as long as a patient received at least one guadecitabine treatment. Secondary endpoints included safety, survival, and pharmacodynamics. We present the final trial analyses, although at time of database lock, 15 patients were still being monitored for survival including six continuing treatment. This study is registered with ClinicalTrials.gov, number NCT01261312 Between Aug 24, 2012, and Sep 15, 2014, 103 patients received treatment: 51 on a 5-day schedule of guadecitabine (24 received 60 mg/m2, 27 received 90 mg/m2) and 52 on the 10-day schedule. Median age was 77 years. Poor prognostic features included ECOG status ≥2 (39 [38%]), poor-risk cytogenetics (43 [42%]), and secondary AML (37 [36%]). Characteristics were generally balanced across doses and schedules. CRc rates were 54% (13 patients), 59% (16 patients), and 50% (26 patients) for the 5-day 60, 5-day 90, and 10-day 60 mg/m2 regimens, respectively. The most common grade 3 or higher adverse events, regardless of relationship to treatment, for the 5- and 10-day schedules, respectively, included febrile neutropenia (31 [61%] and 36 [69%]), thrombocytopenia (25 [49%] and 22 [42%]), neutropenia (20 [39%] and 18 [35%]), pneumonia (15 [29%] and 19 [37%]), anaemia (15 [29%] and 12 [23%]), and sepsis (8 [16%] and 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5- and 10-day schedules, respectively, were febrile neutropenia (27 [53%] and 25 [48%]), pneumonia (14 [27%] and 16 [31%]), and sepsis (8 [16%] and 14 [27%]). In treatment-naïve older patients with AML not candidates for intensive chemotherapy, guadecitabine resulted in high CRc rates ≥50% with acceptable safety across the doses and schedules investigated. A phase 3 pivotal study in this patient population is ongoing to evaluate guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care. Astex Pharmaceuticals, Inc., Stand Up To Cancer