Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan–temozolomide and dasatinib–rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1–25 years with high-risk relapsed (defined as recurrence of all stage IV and amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan–temozolomide (control group) by block randomisation, stratified by status. We compared RIST (oral rapamycin [loading 3 mg/m on day 1, maintenance 1 mg/m on days 2–4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m per day] and oral temozolomide [150 mg/m per day] for 5 days with 2 days off; one course each of rapamycin–dasatinib and irinotecan–temozolomide for four cycles over 8 weeks, then two courses of rapamycin–dasatinib followed by one course of irinotecan–temozolomide for 12 weeks) with irinotecan–temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at , , and is closed to accrual. Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7–8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31–88), the median progression-free survival was 11 months (95% CI 7–17) in the RIST group and 5 months (2–8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified (n=48) was 6 months (95% CI 4–24) in the RIST group versus 2 months (2–5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified (n=76) was 14 months (95% CI 9–7) in the RIST group versus 8 months (4–15) in the control group (HR 0·84 [95% CI 0·51–1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] 41 [68%]), and anaemia (39 [58%] 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). RIST-rNB-2011 demonstrated that targeting of -amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in -amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. Deutsche Krebshilfe.

中文翻译：

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伊立替康和替莫唑胺联合达沙替尼和雷帕霉素对比伊立替康和替莫唑胺治疗复发或难治性神经母细胞瘤患者 (RIST-rNB-2011)：一项多中心、开放标签、随机、对照、2 期试验


神经母细胞瘤是儿童中最常见的颅外实体瘤。复发性或难治性神经母细胞瘤与不良预后相关。我们评估了伊立替康-替莫唑胺和达沙替尼-雷帕霉素 (RIST) 联合治疗复发或难治性神经母细胞瘤患者的情况。这项多中心、开放标签、随机、对照、2 期 RIST-rNB-2011 试验从德国和奥地利的 40 个儿科肿瘤中心招募。年龄 1-25 岁的高风险复发（定义为对治疗有反应后所有 IV 期和扩增期的复发）或难治性（初次治疗期间疾病进展）神经母细胞瘤患者，Lansky 和 ​​Karnofsky 表现状态至少 50%，通过分块随机化将患者按状态分层（1:1）分配至 RIST（RIST 组）或伊立替康-替莫唑胺（对照组）。我们比较了 RIST（口服雷帕霉素[第 1 天负荷 3 mg/m2，第 2-4 天维持 1 mg/m2]和口服达沙替尼[每天 2 mg/kg]4 天，休息 3 天，然后静脉注射伊立替康[50 mg/m每天]和口服替莫唑胺[150 mg/m每天]持续5天，休息2天；雷帕霉素-达沙替尼和伊立替康-替莫唑胺各一个疗程，持续8周四个周期，然后雷帕霉素两个疗程– 达沙替尼后接一个疗程的伊立替康-替莫唑胺，持续 12 周）与单独使用伊立替康-替莫唑胺（剂量与实验组相同）。对所有接受至少一个疗程治疗的合格患者的无进展生存期的主要终点进行了分析。安全人群包括接受至少一个疗程且至少进行过一次基线后安全评估的所有患者。该试验的注册地址为 、 ，并且已停止计提。 2013年8月26日至2020年9月21日期间，129名患者被随机分配至RIST组（n=63）或对照组（n=66）。中位年龄为 5·4 岁（IQR 3·7–8·1）。疗效分析包括 124 名患者（78 名 [63%] 男性和 46 名 [37%] 女性）。中位随访 72 个月（IQR 31-88）时，RIST 组的中位无进展生存期为 11 个月（95% CI 7-17），对照组为 5 个月（2-8）。风险比 0·62，单侧 90% CI 0·81；p=0·019）。 RIST 组中扩增患者 (n=48) 的中位无进展生存期为 6 个月 (95% CI 4–24)，而对照组为 2 个月 (2–5) (HR 0·45 [95% CI 0·24-0·84], p=0·012); RIST 组中未扩增患者 (n=76) 的中位无进展生存期为 14 个月 (95% CI 9-7)，而对照组为 8 个月 (4-15) (HR 0·84 [95% CI) 0·51–1·38]，p=0·49）。最常见的 3 级或更严重不良事件是中性粒细胞减少症（接受 RIST 的 67 名患者中的 54 名 [81%]，接受对照的 60 名患者中的 49 名 [82%]）、血小板减少症（45 名 [67%] 41 名 [68%]）和贫血（39 [58%] 38 [63%]）。报告了 9 例与治疗相关的严重不良事件（5 名患者接受对照治疗，4 名患者接受 RIST）。对照组没有发生与治疗相关的死亡，RIST 组有 1 例（多器官衰竭）。 RIST-rNB-2011 证明，使用多激酶抑制剂和 mTOR 抑制剂的路径导向节拍组合靶向扩增的复发性或难治性神经母细胞瘤可以改善无进展生存期和总生存期。这种对放大、复发性神经母细胞瘤的独特疗效值得在一线环境中进行进一步研究。德国克雷布希尔夫。