A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma–LuDO-N

Abstract

BackgroundHalf the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177Lutetium 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 177Lu-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 177Lutetium-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.MethodsThe 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.ResultsThe pediatric use of the Investigational Medicinal Product (IMP) 177Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (68Ga-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.DiscussionIn 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.

The Impact of PET/CT on Paediatric Oncology

“…Finally the special resolution with PET tracers is better than that of [ 123 I]mIBG, Figure 2 [31]. There is growing interest in the use of PRRT in these patients [32,33].…”

“…If a tumour is ([ 68 Ga]DOTA-SSA-avid, this opens up the possibility of PRRT with either [ 177 Lu]DOTATATE or [ 90 Y]DOTANOC[31]. There is growing interest in the use of PRRT in these patients[32,33].…”

Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE

“…Among those, two trials are designed to investigate an intensified dosing schedule in pediatric patients affected by neuroblastoma. Indeed, trials investigating [ 177 Lu]Lu-DOTATATE in neuroblastoma patients failed so far, and this can be due both to the insufficient activities administered and to the too long intervals between the cycles of therapy [109]. Therefore, following the example of [ 131 I]MIBG, current trials are evaluating intensified cycles for this poor prognosis rapidly proliferating tumor.…”

Pediatric Neuroendocrine Neoplasms: Rare Malignancies with Incredible Variability

“…In a form of concordance with the movement towards personalized medicine, many of these patients are included in clinical trials if they have refractory or relapsed disease with certain genetic mutation profiles that can be targeted with the investigational chemotherapeutics (e.g., MDM2, MDMX, RET, BCL-2, and many others) [ 163 ]. Current ongoing therapeutic clinical trials focused on NENs are investigating the clinical efficacy and safety of 177Lu-DOTATATE in children with gastroenteropancreatic NENs, paragangliomas, and neuroblastomas (NCT04711135, NCT03966651) [ 164 , 165 , 166 ]. Prior Phase I and II clinical trials with 90Y-DOTATOC and 177Lu-DOTATATE in children with solid tumors have shown minimal dose-limiting toxicities with a good safety profile indicating their safety in this population [ 167 , 168 ].…”