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.

Jakob Stenman,Fredrik Sundquist,Arthur Braat,Sandra Wessman,Per Grybäck,Jesper Brok,Jelena Rascon,Max van Noesel,Dan Granberg,Minna Koskenvuo,Lars Hjorth,Joachim Nilsson,Kleopatra Georgantzi,Nikolas Herold,Per Kogner,Kirsten Brunsvig Jarvis,Mikael Sundin,Mark Gaze

doi:10.3389/fped.2022.836230

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.

Highlights

Neuroblastoma (NBL) is a malignant disease that most commonly occurs in early childhood, and displays a wide heterogeneity regarding biological features, clinical presentation, morbidity, and mortality [1]
peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE is an attractive new option with potentially less adverse effects and a significantly lesser exposure to radiation for persons participating in the care of the patient, as compared to 131I-mIBG -therapy [36, 37, 44]
The aim of the current LuDO-N trial is to establish whether 177Lu-DOTATATE can be effective as a single agent, in the treatment of relapsed or primary refractory high-risk neuroblastoma, when the dose schedule is intensified to two doses delivered 2 weeks apart and the administered activity is optimized/personalized by dosimetry

Summary

Introduction

Neuroblastoma (NBL) is a malignant disease that most commonly occurs in early childhood, and displays a wide heterogeneity regarding biological features, clinical presentation, morbidity, and mortality [1]. Treatment of HR-NBL generally consists of (i) an induction phase with intensive neoadjuvant chemotherapy, (ii) establishment of local control by surgery and radiotherapy, (iii) systemic remission consolidation therapy with high-dose chemotherapy and autologous stem cell reinfusion, and (iv) maintenance therapy with anti-GD2 antibodies and retinoic acid [3–5]. In spite of this multimodal treatment, survival has remained at ∼50% in HR-NBL. “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

Methods

Discussion

Conclusion