Sundquist Fredrik, Georgantzi Kleopatra, Jarvis Kirsten Brunsvig, Brok Jesper, Koskenvuo Minna, Rascon Jelena, van Noesel Max, Grybäck Per, Nilsson Joachim, Braat Arthur, Sundin Mikael, Wessman Sandra, Herold Nikolas, Hjorth Lars, Kogner Per, Granberg Dan, Gaze Mark, Stenman Jakob
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Pediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
Front Pediatr. 2022 Mar 10;10:836230. doi: 10.3389/fped.2022.836230. eCollection 2022.
Half the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. "A phase II trial of Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N" (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule.
The LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022.
The pediatric use of the Investigational Medicinal Product (IMP) Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3-5 years.
In this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.
半数高危神经母细胞瘤患儿死于广泛转移。分子放疗是针对这种相对放射敏感肿瘤的一种有吸引力的全身治疗方法。I-间碘苄胍（I-mIBG）是目前使用最广泛的形式，但并非普遍有效。镥[177Lu]奥曲肽（Lutetium DOTATATE）的临床试验迄今结果令人失望，可能是因为给药活度太低，且疗程分布时间过长，不适用于快速增殖的肿瘤。我们设计了一种替代给药方案以克服这些局限性。这包括间隔2周进行两次单药Lu-DOTATATE的高活度给药，规定为个性化的全身辐射吸收剂量，而非固定的给药活度。“镥[177Lu]奥曲肽治疗原发性难治性或复发性高危神经母细胞瘤患儿的II期试验 - LuDO-N”（欧洲药品管理局临床试验编号：2020-004445-36，美国国立医学图书馆临床试验标识符：NCT04903899）对这种新的给药方案进行评估。
LuDO-N试验是一项II期、开放标签、多中心、单臂、两阶段设计的临床试验。年龄在18个月至18岁的儿童符合条件。该试验由北欧儿科血液学和肿瘤学会（NOPHO）开展，并得到国际小儿肿瘤学会（SIOPEN，https://www.siopen.net）的认可。卡罗林斯卡大学医院是LuDO-N试验的申办方，该试验与诺华公司的先进加速器应用公司合作进行。所有斯堪的纳维亚国家、立陶宛和荷兰都参与了该试验，英国已表示有兴趣在2022年加入。
研究用药品（IMP）Lu-DOTATATE以及非研究用药品SomaKit TOC®（镓[68Ga]奥曲肽，Ga-DOTATOC）和用于肾脏保护的LysaKare®氨基酸溶液在儿科的使用已在LuDO-N试验中获得欧洲药品管理局（EMA）批准用于儿科。该试验目前正在招募患者。预计招募工作将在3至5年内完成。
在本文中，我们介绍了LuDO-N试验的方案。结合其他正在进行的或计划中的具有类似目标的试验，讨论了该试验的基本原理和设计。此外，我们还讨论了靶向放射性药物治疗的快速发展以及开发高危神经母细胞瘤和其他儿科实体瘤新疗法的未来前景。
