Background

Guadecitabine is a next-generation hypomethylating agent whose active metabolite decitabine has a longer in-vivo exposure time than intravenous decitabine. More effective hypomethylating agents are needed for the treatment of myelodysplastic syndromes. In the present study, we aimed to compare the activity and safety of two doses of guadecitabine in hypomethylating agent treatment-naive or relapsed or refractory patients with intermediate-risk or high-risk myelodysplastic syndromes.

Methods

This phase 2 part of the phase 1/2, randomised, open-label study enrolled patients aged 18 years or older from 14 North American medical centres with International Prognostic Scoring System intermediate-1-risk, intermediate-2-risk, or high-risk myelodysplastic syndromes, or chronic myelomonocytic leukaemia. They were either hypomethylating agent treatment-naive or had relapsed or refractory disease after previous hypomethylating agent treatment as determined by the investigators' judgment. Eligible patients had Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1) using a computer algorithm for dynamic randomisation to subcutaneous guadecitabine 60 or 90 mg/m² on days 1–5 of a 28-day treatment cycle. Treatment was stratified by previous treatment with hypomethylating agents and neither patients nor investigators were masked. The primary endpoint was overall response (a composite of complete response, partial response, marrow complete response, and haematological improvement) assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01261312.

Findings

Between July 9, 2012, and April 7, 2014, 105 patients were enrolled: 55 (52%) were allocated to guadecitabine 60 mg/m² (28 patients were treatment-naive and 27 had relapsed or refractory disease after previous hypomethylating agent treatment) and 50 (48%) patients to 90 mg/m² (23 patients were treatment-naive and 27 had relapsed or refractory disease). Three (3%) patients of 105 did not receive study treatment and were excluded from analyses. Median follow-up was 3·2 years (IQR 2·8–3·5). The proportion of patients achieving an overall response did not significantly differ between dose groups (21 of 53 [40%, 95% CI 27–54] with 60 mg/m² and 27 of 49 [55%, 95% CI 40–69] with 90 mg/m²; p=0·16). 25 of 49 (51%, 95% CI 36–66) patients who were treatment-naive and 23 of 53 (43%, 30–58) patients with relapsed or refractory disease achieved an overall response. The most common grade 3 or worse adverse events in both groups, regardless of relationship to treatment, were thrombocytopenia (22 [41%] of 53 patients in the 60 mg/m² group and 28 [57%] of 49 in the 90 mg/m² group), neutropaenia (21 [40%] and 25 [51%]), anaemia (25 [47%] and 24 [49%]), febrile neutropaenia (17 [32%] and 21 [43%]), and pneumonia (13 [25%] and 15 [31%]). Seven (7%) of 102 patients died due to adverse events (three with 90 mg/m² and four with 60 mg/m²), and all except one were in the relapsed or refractory cohort. Two deaths were deemed treatment related (septic shock with 60 mg/m²; pneumonia with 90 mg/m²).

Interpretation

Guadecitabine was clinically active with acceptable tolerability in patients with intermediate-risk and high-risk myelodysplastic syndromes. Responses and overall survival in the relapsed or refractory cohort offer the potential of a new therapeutic option for patients for whom currently available hypomethylating agents are not successful. We therefore recommend guadecitabine at a dose of 60 mg/m² on a 5-day schedule for these patients.

Funding

Astex Pharmaceuticals and Stand Up To Cancer.

中文翻译：

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Guadecitabine (SGI-110) 用于中度或高危骨髓增生异常综合征患者：2 期结果来自多中心、开放标签、随机、1/2 期试验。

背景

瓜地西他滨是下一代去甲基化药物，其活性代谢物地西他滨的体内暴露时间比静脉内地西他滨长。治疗骨髓增生异常综合征需要更有效的去甲基化药物。在本研究中，我们旨在比较两种剂量的 guadecitabine 在低甲基化药物治疗初治或复发或难治性中危或高危骨髓增生异常综合征患者中的活性和安全性。

方法

1/2 期随机开放标签研究的第 2 期部分招募了来自 14 个北美医疗中心的 18 岁或以上的患者，这些患者采用国际预后评分系统中度 1 风险、中度 2 风险或高风险患骨髓增生异常综合征或慢性粒单核细胞白血病的风险。根据研究人员的判断，他们要么未接受过低甲基化药物治疗，要么在先前的低甲基化药物治疗后出现复发或难治性疾病。符合条件的患者的东部肿瘤协作组体能状态为 0-2。患者被随机分配（1:1），使用计算机算法进行动态随机分配，皮下注射瓜地他滨 60 或 90 mg/m ²在 28 天治疗周期的第 1-5 天。治疗按先前使用低甲基化剂的治疗进行分层，患者和研究人员均未蒙面。主要终点是在接受至少一剂研究药物的所有患者中评估的总体反应（完全反应、部分反应、骨髓完全反应和血液学改善的复合物）。该研究已在 ClinicalTrials.gov 注册，编号为 NCT01261312。

发现

2012 年 7 月 9 日至 2014 年 4 月 7 日，105 名患者入组：55 名 (52%) 被分配到 60 mg/m ²的瓜地他滨组（28 名患者未接受过治疗，27 名患者在先前的低甲基化药物治疗后出现复发或难治性疾病) 和 50 (48%) 名患者至 90 mg/m ²（23 名患者未接受过治疗，27 名患有复发或难治性疾病）。105 名患者中有 3 名 (3%) 未接受研究治疗并被排除在分析之外。中位随访时间为 3·2 年（IQR 2·8-3·5）。达到总体反应的患者比例在剂量组之间没有显着差异（53 人中有 21 人 [40%, 95% CI 27-54] 60 mg/m ²和 49 人中有 27 人 [55%, 95% CI 40-69 ] 90 毫克/米²; p=0·16)。49 名 (51%, 95% CI 36-66) 未接受过治疗的患者中的 25 名和 53 名 (43%, 30-58) 名复发或难治性疾病患者中的 23 名获得了总体缓解。无论与治疗的关系如何，两组最常见的 3 级或更严重的不良事件是血小板减少症（60 mg/m ²组 53 名患者中的 22 名 [41%] 和 90 mg/m 2 组 49 名患者中的 28 名 [57%] /m ²组）、中性粒细胞减少症（21 [40%] 和 25 [51%]）、贫血（25 [47%] 和 24 [49%]）、发热性中性粒细胞减少症（17 [32%] 和 21 [43%] ) 和肺炎 (13 [25%] 和 15 [31%])。102 名患者中有 7 名 (7%) 死于不良事件（3 名 90 mg/m ²和 4 名 60 mg/m ²)，除一位外，其他所有人都在复发或难治性队列中。两例死亡被认为与治疗相关（感染性休克 60 mg/m ²；肺炎 90 mg/m ²）。

解释

瓜地西他滨在中危和高危骨髓增生异常综合征患者中具有临床活性，耐受性可接受。复发或难治性队列中的反应和总生存期为目前可用的低甲基化药物不成功的患者提供了一种新的治疗选择的潜力。^{因此，我们建议这些患者服用 60 mg/m 2}的 guadecitabine，为期 5 天。

资金

Astex Pharmaceuticals 与癌症抗争。