Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, NF2 -related schwannomatosis and non- NF2 -related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.
Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts.
Results: The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF.
Conclusions: These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.
Competing Interests: AAA participates in the advisory board of Alexion/AstraZeneca, and has received scientific support and speaker honoraria from the same company. AB declares no conflict of interest. JOB participates in the advisory board of SpringWorks Therapeutics. CC and BD report grants from EU-PEARL, the innovative Medicines Initiative 2 Joint Undertaking under grant agreement no 853966. PHD participates in the advisory board of Alexion/AstraZeneca and is the ICI of the SPRINKLE study sponsored by Alexion. AG reports no conflict of interest. DGE reports personal fees from AstraZeneca and personal fees from SpringWorks Therapeutics. MJF participates in advisory boards of Alexion/AstraZeneca, SpringWorks Therapeutics and DayOne, and has received research support from Alexion/AstraZeneca, Array Biopharma/Pfizer and Exelixis. REF reports grants and personal fees from AstraZeneca. GH is an employee of Novartis Pharma AG. UI is an employee of SpringWorks Therapeutics. GK is an employee of AstraZeneca. AK reports no conflict of interest. EL reports personal fees from AstraZeneca, personal fees from SpringWorks Therapeutics, and grants from EU-PEARL, the innovative Medicines Initiative 2 Joint Undertaking under grant agreement no 853966. JL declares no conflict of interest. MN declares no conflict of interest. RO reports grants from EU-PEARL, the innovative Medicines Initiative 2 Joint Undertaking under grant agreement no 853966 and has performed unpaid advisory work for Alexion. CP reports no conflict of interest. SP reports being a cofounder of NFlection Therapeutics and NF2 Therapeutics and served as a consultant for Akouos. TP reports no conflict of interest. BCW reports no conflict of interest. PW reports no conflict of interest.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)