A basket-platform trial for neurofibromatosis type 1: A potential model for rare cancer predisposition syndromes.
Authors: Bakker Annette , Dhaenens Britt , Heimann Guenter , Nievo Marco , Ferner Rosalie , Evans Gareth D , Wolkenstein Pierre , Leubner Jonas , Blakeley Jaishri O'Neill , Plotkin Scott Randall , Fisher Michael J. , Kim AeRang , Hernáiz Driever Pablo , Azizi Amedeo A. , Potratz Cornelia , Carton Charlotte , Iloeje Uchenna , Kirk George , Legius Eric , Oostenbrink Rianne 
Published: June 2023

e22550 Background: Neurofibromatosis Type 1 (NF1) is a rare hereditary condition that predisposes to the development of a variety of tumors. Variability in disease manifestation, prevalence and severity, in combination with a low prevalence complicates the efficient conduct of clinical trials in NF1. NF1-associated tumors mainly but not exclusively affect the nervous system as well as the skin, and a percentage of those tumors exhibit a significantly increased risk of malignant transformation. There is an urgent need to identify effective treatments for NF1-associated tumors. The development of innovative trial designs that accelerate the ability to assess new investigational agents is essential. The European Patient-Centric Clinical Trial Platforms (EU-PEARL) is an Innovative Medicines Initiative (IMI) project, aiming to create platform trials for diseases with high unmet medical need. As part of EU-PEARL, we designed a basket-platform trial in NF1 that could serve as a prototype for accelerating drug studies in rare cancer predisposition syndromes. Methods: The trial was designed by NF1 experts, a dedicated statistician and a trial designer. Subprotocols were written for previously prioritized manifestations including plexiform neurofibroma, cutaneous neurofibroma, low-grade glioma, and optic pathway glioma. Collaboration with NF1 experts from the USA was sought to ensure alignment with trials for NF1 in the USA. Results: To optimally learn from a small number of potential participants, patients should be able to participate in both an observational and a treatment phase. The observational phase will serve as longitudinal natural history study, providing data that can be used as a comparator for the treatment arms. To enter the treatment phase, patients must meet additional eligibility criteria. Patients will be randomized to a sequence of available drugs, rather than one single drug. This may allow for the addition of newly identified drugs during the course of the trial. If a drug concept fails or unacceptable toxicity arises, patients may re-enter the observational phase or be re-randomized to a different treatment arm if eligible. Drug-specific eligibility criteria and endpoints are listed separately in Intervention-Specific-Appendices (ISAs), allowing flexibility and adaptability that is needed for a highly variable and progressive rare disorder like NF1. This trial design allows optimal learning from a limited number of patients. Conclusions: We designed a basket-platform trial for four manifestations of NF1. This trial design addresses challenges that may be encountered when designing a clinical trial for NF1. This trial will be the future of clinical trials for NF1 in Europe. Its design could serve as a prototype for other rare diseases: it enhances the chances of finding beneficial treatments by optimizing patient inclusion and invigorating international collaborations.