Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study
Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study
复制标题
DOI：
10.1016/s1470-2045(18)30010-x
复制
发表时间：
2018-02-01
期刊：
影响因子：
51.1
通讯作者：
Pollyea, Daniel A.
中科院分区：
文献类型：
--
作者：
DiNardo, Courtney L.;Pratz, Keith W.;Pollyea, Daniel A.
老年急性髓性白血病患者预后差，且无有效的标准治疗。使用低甲基化药物（如阿扎胞苷和地西他滨）治疗很常见，但反应温和且通常短暂。口服抗凋亡B细胞淋巴瘤2蛋白抑制剂维奈托克在复发性或难治性急性髓性白血病患者中显示出有希望的单药活性，临床前数据表明低甲基化剂和维奈托克之间存在协同作用，方法65岁及以上的急性髓性白血病患者，既往未经治疗，不适合标准诱导治疗，入组这项非随机、开放标签、1b期研究。要求患者的东部肿瘤协作组体能状态为0-2，细胞遗传学为中危或低危。患者入组本研究剂量递增阶段的三组之一：A组（维奈托克和静脉注射地西他滨20 mg/m2 [每个28天周期的第1-5天]），B组（维奈托克和皮下或静脉阿扎胞苷75 mg/m2 [每个28天周期的第1-7天]），和C组（一项维奈托克和地西他滨的亚组研究，口服CYP 3A抑制剂泊沙康唑，第1周期第21天300 mg，两次，第1周期第22-28天300 mg，每日一次，以评估其对维奈托克药代动力学的影响）。剂量递增遵循标准3+3设计，每个队列至少入组3例可评价患者; A组和B组的维奈托克每日目标剂量分别为400 mg（队列1）、800 mg（队列2和3）和1200 mg（队列4），C组为400 mg。主要终点是维奈托克加地西他滨或阿扎胞苷的安全性和药代动力学，并确定最大耐受剂量和推荐的II期剂量。次要终点包括维奈托克与地西他滨或阿扎胞苷的初步抗白血病活性，通过分析总体缓解、缓解持续时间和总生存期。我们分析了所有接受一次或多次维奈托克给药的患者的安全性、药代动力学和抗白血病活性。本研究的扩展阶段正在进行中，但已接近入组。该试验在ClinicalTrials.gov上注册，编号NCTO 2203773。A组23例患者和B组22例患者于2014年11月19日至2015年12月15日期间入组，C组12例患者于2015年6月14日至2016年1月16日期间入组。截至数据截止日期2016年6月15日，最常见的3-4级治疗后出现的不良事件为血小板减少症（57例患者中的27例[47%]; A组9例，B组13例，C组5例），发热性中性粒细胞减少症（57例中24例[42%]; A组11例，B组10例，C组3例）和中性粒细胞减少症（57例中23例[40%]; A组12例，B组8例，C组3例）。A组和B组中最常见的严重治疗后出现的不良事件是发热性中性粒细胞减少（23例患者中7例[30%] vs 22例患者中7例[32%]），而C组中为肺部感染（12例患者中4例[33%]）。57例患者中有49例（86%）发生了治疗相关不良事件; A组和B组中最常见的包括恶心（12例[52%]患者vs 7例[32%]患者），疲乏（6例[26%]患者vs 7例[32%]），中性粒细胞计数降低（6例[26%]患者vs 6例[27%]），而C组中最常见的是恶心（12例患者中的7例[58%]）、白细胞减少（6例[50%]）、呕吐（5例[42%]）和血小板计数降低（5例[42%]）。未达到最大耐受剂量。推荐的II期剂量为400 mg每日一次或800 mg，中断给药方案（安全性扩展）。总共有4/57例（7%）患者在首次使用维奈托克后30天内死亡，原因包括败血症（B组）、菌血症（A组）、肺部感染（C组）和呼吸衰竭（A组）。未观察到肿瘤溶解综合征。地西他滨和阿扎胞苷对维奈托克暴露量无显著影响。总体而言，57例患者中有35例（61%; 95% CI 47.6-74.0）达到完全缓解或完全缓解伴骨髓恢复不完全。在A组和B组中，45例患者中有27例（60%; 95%CI 44.3-74.3）完全缓解或完全缓解伴骨髓不完全恢复。正在使用两种低甲基化药物联合给药对400 mg和800 mg剂量的扩展队列进行评价。
Background Elderly patients (aged years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study.Methods Previously untreated patients aged 65 years and over with acute myeloid leukaemia who were ineligible for standard induction therapy were enrolled into this non-randomised, open-label, phase 1b study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and either intermediate-risk or poor-risk cytogenetics. Patients were enrolled into one of three groups for the dose-escalation phase of this study: group A (venetoclax and intravenous decitabine 20 mg/m(2) [days 1-5 of each 28-day cycle]), group B (venetoclax and subcutaneous or intravenous azacitidine 75 mg/m2 [days 1-7 of each 28-day cycle]), and group C (a venetoclax and decitabine substudy with the oral CYP3A inhibitor posaconazole, 300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22-28, to assess its effect on venetoclax pharmacokinetics). Dose escalation followed a standard 3+3 design with at least three evaluable patients enrolled per cohort; daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C. The primary endpoints were the safety and pharmacokinetics of venetoclax plus decitabine or azacitidine, and to determine the maximum tolerated dose and recommended phase 2 dose. Secondary endpoints included the preliminary anti-leukaemic activity of venetoclax with decitabine or azacitidine through the analysis of overall response, duration of response, and overall survival. We analysed safety, pharmacokinetics, and anti-leukaemic activity in all patients who received one or more venetoclax doses. The expansion phase of the study is ongoing but is closed to accrual. This trial is registered with ClinicalTrials.gov, number NCTO 2203773.Findings 57 patients were enrolled in the study. 23 patients in group A and 22 patients in group B were enrolled between Nov 19, 2014, and Dec 15, 2015, and 12 patients in group C were enrolled between June 14, 2015, and Jan 16, 2016. As of data cutoff on June 15, 2016, the most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (27 [47%] of 57 patients; nine in group A, 13 in group B, and five in group C), febrile neutropenia (24 [42%] of 57; 11 in group A, ten in group B, and three in group C), and neutropenia (23 [40%] of 57; 12 in group A, eight in group B, and three in group C). The most common serious treatment-emergent adverse event in groups A and B was febrile neutropenia (seven [30%] of 23 patients vs seven [32%] of 22), whereas in group C it was lung infection (four [33%] of 12 patients). 49 (86%) of 57 patients had treatment-related adverse events; the most common in groups A and B included nausea (12 [52%] patients vs seven [32%] patients), fatigue (six [26%] patients vs seven [32%]), and decreased neutrophil count (six [26%] patients vs six [27%]), whereas in group C the most common were nausea (seven [58%] of 12 patients), leucopenia (six [50%]), vomiting (five [42%]), and decreased platelet count (five [42%]). The maximum tolerated dose was not reached. The recommended phase 2 dose was 400 mg once a day or 800 mg with an interrupted dosing schedule (safety expansion). In total, four (7%) of 57 patients had died within 30 days of the first venetoclax dose caused by sepsis (group B), bacteraemia (group A), lung infection (group C), and respiratory failure (group A). Tumour lysis syndrome was not observed. Decitabine and azacitidine did not substantially affect venetoclax exposures. Overall, 35 (61%; 95% CI 47.6-74.0) of 57 patients achieved complete remission or complete remission with incomplete marrow recovery. In groups A and B, 27 (60%; 95% CI 44.3-74.3) of 45 patients had complete remission or complete remission with incomplete marrow recovery.Interpretation Venetoclax plus hypomethylating agent therapy seems to be a novel, well-tolerated regimen with promising activity in this underserved patient population. Evaluation of expansion cohorts is ongoing at 400 mg and 800 mg doses using both hypomethylating agent combinations.