Background

Immune checkpoint inhibitors targeting PD-1 have shown clinical benefit in adults with cancer, but data on these drugs in children are scarce. We did a phase 1–2 study of nivolumab, a PD-1 blocking monoclonal antibody, to determine its safety, pharmacokinetics, and antitumour activity in children and young adults with recurrent or refractory non-CNS solid tumours or lymphoma.

Methods

We did a multicentre, open-label, single-arm, dose-confirmation and dose-expansion, phase 1–2 trial in 23 hospitals in the USA. Eligible patients for part A (dose-confirmation phase) of the study were aged 1–18 years with solid tumours with measurable or evaluable disease (by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) regardless of histology. Eligible patients for part B (dose-expansion phase) were aged 1–30 years with measurable disease (by RECIST criteria) in the following disease cohorts: rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, neuroblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and melanoma. Patients in part A and were given nivolumab 3 mg/kg intravenously over 60 min on days 1 and 15 of a 28-day cycle in a rolling 6 study design with de-escalation upon dose-limiting toxicities to establish the recommended phase 2 dose. Patients in part B were given the recommended phase 2 dose. The primary outcomes were the tolerability, systemic exposure, maximum tolerated dose, and the antitumour activity of nivolumab at the adult recommended dose in children and young adults. This trial is registered with ClinicalTrials.gov, NCT02304458, with follow-up ongoing and is closed to new participants.

Findings

85 patients were enrolled between Feb 22, 2015, and Dec 31, 2018, and 75 patients were fully evaluable for toxicity. Median follow-up was 30 days (IQR 27–83). In part A, 13 patients were enrolled and 12 were evaluable for toxicity. There were no dose de-escalations or dose-limiting toxicities and nivolumab 3 mg/kg was confirmed as the paediatric recommended phase 2. 72 patients were enrolled in part B and 63 were evaluable for toxicity. Five (7%) patients in part B had dose-limiting toxicities. The most common overall toxicity was anaemia (35 [47%] of 75 patients; five patients had grade 3 or grade 4) and non-haematological toxicity was fatigue (28 [37%] patients; none had grade 3 or grade 4). Responses were observed in patients with lymphoma (three [30%] of ten with Hodgkin lymphoma and one [10%] of ten with non-Hodgkin lymphoma; all responders had PD-L1 expression). Objective responses were not observed in other tumour types.

Interpretation

Nivolumab was safe and well tolerated in children and young adults and showed clinical activity in lymphoma. Nivolumab showed no significant single-agent activity in the common paediatric solid tumours. This study defines the recommended phase 2 dose and establishes a favourable safety profile for nivolumab in children and young adults, which can serve as the basis for its potential study in combinatorial regimens for childhood cancer.

Funding

Bristol-Myers Squibb, Children's Oncology Group, National Institutes of Health, Cookies for Kids Cancer Foundation.

中文翻译：

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患有复发性或难治性实体瘤或淋巴瘤的儿童和青年人的Nivolumab（ADVL1412）：一项多中心，开放标签，单组，1-2期试验。

背景

针对PD-1的免疫检查点抑制剂已在患有癌症的成人中显示出临床益处，但有关儿童中这些药物的数据很少。我们对PD-1阻断性单克隆抗体nivolumab进行了1-2期研究，以确定其对患有复发性或难治性非CNS实体瘤或淋巴瘤的儿童和年轻人的安全性，药代动力学和抗肿瘤活性。

方法

我们在美国的23家医院进行了多中心，开放标签，单臂，剂量确认和剂量扩大的1-2期临床试验。符合研究A部分（剂量确认阶段）条件的患者年龄在1-18岁之间，患有可测量或可评估疾病的实体瘤（根据实体瘤反应评估标准[RECIST] 1.1版），而不论组织学如何。B部分（剂量扩展期）的合格患者年龄在1-30岁之间，患有以下疾病人群中可测量的疾病（根据RECIST标准）：横纹肌肉瘤，尤因肉瘤，骨肉瘤，神经母细胞瘤，霍奇金淋巴瘤，非霍奇金淋巴瘤和黑色素瘤。在第6轮研究设计中，在28天周期的第1天和第15天的60分钟内，对A部分的患者在60分钟内静脉给予了nivolumab 3 mg / kg的剂量，并随着剂量限制的毒性而逐步降低，以建立推荐的2期剂量。B部分的患者接受了推荐的2期剂量。主要结果是在儿童和年轻人中，成人推荐剂量下的纳武单抗的耐受性，全身暴露，最大耐受剂量和抗肿瘤活性。该临床试验已在ClinicalTrials.gov上注册，编号为NCT02304458，后续活动仍在进行中，并且不对新参与者开放。

发现

在2015年2月22日至2018年12月31日之间招募了85位患者，其中75位患者的毒性完全可评估。中位随访时间为30天（IQR 27-83）。在A部分中，招募了13例患者，其中12例可评估毒性。没有降低剂量的剂量升高或剂量限制的毒性反应，并确认儿科推荐的2期尼古鲁单抗3 mg /kg。B部分入组72例患者，其中63例可评估毒性。B部分中有五名（7％）患者具有剂量限制性毒性。最常见的总体毒性是贫血（75例患者中的35 [47％]； 5例具有3级或4级患者），非血液学毒性是疲劳（28例[37％]患者；无3或4级患者）。在淋巴瘤患者中观察到了反应（霍奇金淋巴瘤的十名患者中有三[30％]，非霍奇金淋巴瘤的十名患者中有十[10％]；所有应答者均具有PD-L1表达）。在其他类型的肿瘤中未观察到客观反应。

解释

Nivolumab在儿童和年轻人中安全且耐受良好，并在淋巴瘤中表现出临床活性。在常见的小儿实体瘤中，Nivolumab没有显示出明显的单药活性。这项研究确定了推荐的2期剂量，并为儿童和青壮年的nivolumab建立了良好的安全性，可作为其在儿童癌症联合治疗方案中进行潜在研究的基础。

资金

Bristol-Myers Squibb，美国国立卫生研究院儿童肿瘤学小组，儿童癌症曲奇饼基金会。