Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study.
Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study.
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DOI：
10.1016/s1470-2045(13)70095-0
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发表时间：
2013-05
期刊：
影响因子：
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通讯作者：
Blaney SM
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文献类型：
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作者：
Mossé YP;Lim MS;Voss SD;Wilner K;Ruffner K;Laliberte J;Rolland D;Balis FM;Maris JM;Weigel BJ;Ingle AM;Ahern C;Adamson PC;Blaney SM
各种人类癌症都有ALK基因易位、扩增或癌基因突变，如间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、非小细胞肺癌(NSCLC)和神经母细胞瘤。因此，抑制ALK对儿童可能是一种有用的治疗策略。我们的目标是确定克里佐替尼治疗儿童难治性实体瘤和间变性大细胞淋巴瘤的安全性、推荐的2期剂量和抗肿瘤活性。在这项开放标签的第一阶段剂量递增试验中，年龄在12个月以上、22岁以下、患有可测量或可评估的实体或中枢神经系统肿瘤或间变性大细胞淋巴瘤的患者符合条件，这些患者对治疗无效，且尚无已知的根治方法。克里佐替尼每天给药两次，不间断。在研究的剂量发现阶段(A1部分)评估了6个剂量水平(每剂量100、130、165、215、280、365 mg/m2)，该研究现已完成。主要终点是估计最大耐受量，确定克里佐替尼的毒性效应，并描述克里佐替尼在难治性癌症儿童中的药代动力学。此外，确诊为ALK易位、突变或扩增的患者(研究的A2部分)或神经母细胞瘤(A3部分)的患者可以参加比A1部分目前给予的剂量水平低的一个剂量水平的试验。我们评估了肿瘤组织中ALK的基因组状态，并用定量RT-PCR检测了间变性大细胞淋巴瘤患者骨髓和血液样本中NPM-ALK融合基因的转录本。所有接受至少一剂克里佐替尼治疗的患者的反应都是可评估的；完成至少一个疗程或在此之前经历剂量限制毒性的患者被认为是完全可评估的毒性。这项研究已在临床试验中注册。GOV，NCT00939770。从2009年10月2日到2012年5月31日，79名患者参加了这项研究。中位年龄为10.1岁(1·1~21.4岁)；43例患者进入剂量递增阶段(A1)，25例患者进入A2部分，11例患者进入A3部分。克里佐替尼耐受性良好，推荐的第二阶段剂量为280 mg/m2，每日两次。周期1的4级不良反应包括中性粒细胞减少(2例)和肝酶升高(1例)。在第一周期中，超过一名患者发生的3级不良事件包括淋巴细胞减少(2例)和中性粒细胞减少(8例)。平均稳态血药浓度为630 ng/mL，达峰时间为4h(1~6)。目的79例患者中有14例出现肿瘤反应(9例完全缓解，5例部分缓解)，已知的激活ALK异常患者的抗肿瘤活性增强(9例间变性大细胞淋巴瘤中8例，11例神经母细胞瘤中1例，7例炎性肌纤维母细胞瘤中3例，2例非小细胞肺癌中1例)。研究结果表明，一种有针对性的ALK抑制剂对存在ALK易位的儿童恶性肿瘤具有抗肿瘤活性，特别是间变性大细胞淋巴瘤和炎性肌纤维母细胞瘤，有必要对存在已知ALK癌基因突变的神经母细胞瘤亚型进行进一步研究。辉瑞和国家癌症研究所向儿童肿瘤学小组提供资助。
Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2 per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials. gov, NCT00939770. 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10·1 years (range 1·1–21·4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m2 twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1–6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC). The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted. Pfizer and National Cancer Institute grant to the Children’s Oncology Group.