Lu Suying, Que Yi, Liu Dongyang, Sun Feifei, Yao Xueting, Deng Liting, Zhan Jing, Huang Junting, Cai Ruiqing, Wang Xin, Zhu Shixing, Zhen Zijun, Zhu Jia, Wang Juan, Zhang Yizhuo
Department of Pediatric Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
Drug Clinical Trial Center, Peking University Third Hospital, Beijing, PR China.
EClinicalMedicine. 2025 May 23;84:103258. doi: 10.1016/j.eclinm.2025.103258. eCollection 2025 Jun.
Anlotinib is a novel highly potent multitargeted tyrosine kinase inhibitor. However, the safety, recommended dosage, pharmacokinetics (PK) characteristics, and efficacy of anlotinib in paediatric patients have not been fully studied. We aimed to evaluate the safety, PK, and feasibility of anlotinib in children with high risk, recurrent or refractory sarcomas.
This was an open-label, single-centre, single-arm, phase I study utilizing a "3 + 3" design. Participants were recruited at the Sun Yat-sen University Cancer Centre in China. Paediatric patients aged 5-18 years with a diagnosis of high-risk, relapsed, or refractory sarcomas were eligible for enrolment in this study. Anlotinib was administered orally once daily on a 2-week-on/1-week-off schedule. Treatment continued until disease progression, death, unacceptable toxicity, or withdrawal of consent for any reason. For patients receiving anlotinib as maintenance therapy, the maximum treatment duration was one year. The primary endpoint of phase Ia was the maximum tolerated dose (MTD) of anlotinib. The primary endpoint of phase Ib was the recommended phase II dose (RP2D) of anlotinib. Secondary endpoints included safety, PK, and efficacy. Efficacy endpoints, such as objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), were assessed at every 2 cycles for patients with measurable lesions until disease progression or intolerable toxicity. Patients with a complete response (CR) at baseline were assessed every 4 cycles until disease progression, or intolerable toxicity, or upon completion of one year of treatment. The primary analysis included all participants who received at least one dose of anlotinib, following the per protocol approach. The safety analysis included all participants who received at least one dose of anlotinib and were monitored for adverse events during the treatment period. This study is registered with ClinicalTrials.gov, NCT04659733.
Between December 29, 2020, and September 7, 2022, 34 patients were enrolled for toxicity. Among them, 61.8% (21/34) patients were evaluable for efficacy, and 38.2% (13/34) received anlotinib as maintenance therapy. Two patients (5.9%) experienced dose-limiting toxicities, including grade 3 hematuria and grade 3 hand-foot syndrome. AEs were reported in all patients, with most being grade 1 or 2 in severity. The most common AEs of any grade were hypothyroidism (58.8%, 20/34), diarrhoea (41.2%, 14/34) and abdominal pain (38.2%, 13/34). No grade 4 or treatment-related deaths occurred. PK analysis indicated a significant correlation between abdominal pain and higher steady-state trough concentrations [OR 1.08 (95% CI: 1.01-1.17), = 0.04] as well as AUCτ [OR 1.00 (95% CI: 1.00-1.01), = 0.04]. The MTD and RP2D of anlotinib for paediatric patients (5-18 years) was 8 mg for those under 35 kg and 12 mg for those 35 kg or more. The ORR and DCR for evaluable patients were 0% (95% CI: 0%-0%) and 52.4% (95% CI: 29.1%-75.7%), respectively. The 2-year PFS and OS rates for patients who received anlotinib as maintenance therapy were 84.6% (95% CI: 51.2%-95.9%) and 92.3% (95% CI: 56.6%-98.9%), respectively.
Anlotinib was well tolerated in paediatric patients. Our findings provide preliminary evidence of the efficacy of anlotinib as a maintenance therapy in paediatric patients with high risk, relapsed/refractory sarcoma who achieved a CR. Further investigation of anlotinib in larger, controlled studies is needed to determine its clinical utility.
The National Key Research and Development Program of China, the National Science and Technology Major Projects, the National Natural Science Foundation of China, the Young Science and Technology Talent Support Program of Guangdong Precision Medicine Application Association, and Capital's Funds for Health Improvement and Research.
安罗替尼是一种新型的高效多靶点酪氨酸激酶抑制剂。然而，安罗替尼在儿科患者中的安全性、推荐剂量、药代动力学（PK）特征和疗效尚未得到充分研究。我们旨在评估安罗替尼在高危、复发或难治性肉瘤患儿中的安全性、药代动力学和可行性。
这是一项采用“3+3”设计的开放标签、单中心、单臂I期研究。在中国中山大学肿瘤防治中心招募参与者。年龄在5至18岁、诊断为高危、复发或难治性肉瘤的儿科患者符合本研究的入组条件。安罗替尼按每日一次口服给药，采用2周用药/1周停药的方案。治疗持续至疾病进展、死亡、出现不可接受的毒性或因任何原因撤回同意书。对于接受安罗替尼作为维持治疗的患者，最大治疗时长为一年。Ia期的主要终点是安罗替尼的最大耐受剂量（MTD）。Ib期的主要终点是安罗替尼的推荐II期剂量（RP2D）。次要终点包括安全性、药代动力学和疗效。对于有可测量病灶的患者，每2个周期评估一次疗效终点，如客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）和总生存期（OS），直至疾病进展或出现不可耐受的毒性。基线时达到完全缓解（CR）的患者每4个周期评估一次，直至疾病进展、出现不可耐受的毒性或完成一年治疗。主要分析包括所有按照方案接受至少一剂安罗替尼的参与者。安全性分析包括所有接受至少一剂安罗替尼并在治疗期间接受不良事件监测的参与者。本研究已在ClinicalTrials.gov注册，注册号为NCT04659733。
在2020年12月29日至2022年9月7日期间，34名患者入组进行毒性评估。其中，61.8%（21/34）的患者可进行疗效评估，38.2%（13/34）的患者接受安罗替尼作为维持治疗。2名患者（5.9%）出现剂量限制性毒性，包括3级血尿和3级手足综合征。所有患者均报告了不良事件，大多数为1级或2级严重程度。任何级别最常见的不良事件为甲状腺功能减退（58.8%，20/34）、腹泻（41.2%，14/34）和腹痛（38.2%，13/34）。未发生4级或与治疗相关的死亡。药代动力学分析表明，腹痛与较高的稳态谷浓度[比值比1.08（95%可信区间：1.01-1.17），P=0.04]以及曲线下面积τ[比值比1.00（95%可信区间：1.00-1.01），P=0.04]之间存在显著相关性。儿科患者（5至18岁）中，体重低于35kg者安罗替尼的MTD和RP2D为8mg，体重35kg及以上者为12mg。可评估患者的ORR和DCR分别为0%（95%可信区间：0%-0%）和52.4%（95%可信区间：29.1%-75.7%）。接受安罗替尼作为维持治疗的患者2年PFS率和OS率分别为84.6%（95%可信区间：51.2%-95.9%）和92.3%（95%可信区间：56.6%-98.9%）。
安罗替尼在儿科患者中耐受性良好。我们的研究结果为安罗替尼作为维持治疗对达到CR的高危、复发/难治性肉瘤儿科患者的疗效提供了初步证据。需要在更大规模的对照研究中进一步研究安罗替尼以确定其临床应用价值。
国家重点研发计划、国家科技重大专项、国家自然科学基金、广东省精准医学应用协会青年科技人才支持计划以及首都健康改善与研究基金。
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