Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial.
Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial.
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DOI：
10.1016/s2352-3026(19)30029-8
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发表时间：
2019-06
影响因子：
24.7
通讯作者：
Savona, Michael R.
中科院分区：
文献类型：
--
作者：
Garcia-Manero, Guillermo;Roboz, Gail;Walsh, Katherine;Kantarjian, Hagop;Ritchie, Ellen;Kropf, Patricia;O'Connell, Casey;Tibes, Raoul;Lunin, Scott;Rosenblat, Todd;Yee, Karen;Stock, Wendy;Griffiths, Elizabeth;Mace, Joseph;Podoltsev, Nikolai;Berdeja, Jesus;Jabbour, Elias;Issa, Jean-Pierre J.;Hao, Yong;Keer, Harold N.;Azab, Mohammad;Savona, Michael R.
Guadecitabine是下一代低甲基化剂，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更长。骨髓增生异常综合征的治疗需要更有效的低甲基化药物。在本研究中，我们的目的是比较两种剂量的胍地他滨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。这项I/II期、随机、开放标签研究的II期部分招募了来自14个北美医疗中心的18岁或以上的国际预后评分系统中危、中危或高危骨髓增生异常综合征或慢性粒单核细胞白血病患者。根据研究者的判断，他们要么是未接受过低甲基化药物治疗，要么在既往低甲基化药物治疗后患有复发性或难治性疾病。合格患者的东部肿瘤协作组体能状态为0 - 2。使用计算机算法将患者随机（1：1）分配至皮下注射guadecitabine 60或90 mg/m2，28天治疗周期的第1 - 5天。根据既往低甲基化药物治疗对治疗进行分层，患者和研究者均未设盲。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缓解（完全缓解、部分缓解、骨髓完全缓解和血液学改善的复合终点）。本研究已在www.example.com上注册，编号NCT01261312。2012年7月9日至2014年4月7日期间，入组了105例患者：55例（52%）分配至胍地他滨60 mg/m2组（28例患者为初治患者，27例患者在既往低甲基化剂治疗后患有复发性或难治性疾病），50例（48%）患者接受90 mg/m2（23例患者为初治，27例患者为复发性或难治性疾病）。105例患者中有3例（3%）未接受研究治疗，从分析中排除。中位随访时间为3.2年（IQR 2.8 - 3.5）。两个剂量组之间达到总体缓解的患者比例无显著差异（60 mg/m2组53例患者中有21例[40%，95% CI 27 - 54]，90 mg/m2组49例患者中有27例[55%，95% CI 40 - 69]; p = 0.16）。49例初治患者中有25例（51%，95% CI 36 - 66）和53例复发性或难治性疾病患者中有23例（43%，30 - 58）达到总体缓解。无论与治疗的关系如何，两组中最常见的3级或更严重的不良事件是血小板减少症（60 mg/m2组53例患者中有22例[41%]，90 mg/m2组49例患者中有28例[57%]），（21例[40%]和25例[51%]）、贫血（25例[47%]和24例[49%]）、发热性腹泻（17例[32%]和21例[43%]）和肺炎（13例[25%]和15例[31%]）。102例患者中有7例（7%）因不良事件死亡（90 mg/m2组3例，60 mg/m2组4例），除1例外，所有患者均在复发或难治性队列中。2例死亡被认为与治疗相关（60 mg/m2组感染性休克; 90 mg/m2组肺炎）。在中危和高危骨髓增生异常综合征患者中，Guadecitabine具有临床活性，耐受性可接受。复发性或难治性队列的缓解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新的治疗选择。因此，我们建议这些患者使用60 mg/m2剂量的guadecitabine，为期5天。Astex Pharmaceuticals和Stand Up to Cancer。
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. 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. 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). 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. Astex Pharmaceuticals and Stand Up To Cancer.