Bromodomain and extra-terminal inhibitors—A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children—ACCELERATE

Abstract

Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children.Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations.There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors.However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults.Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous systemepenetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation.This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.

ACCELERATE – Five years accelerating cancer drug development for children and adolescents

“…Frequently after a Paediatric Strategy Forum, product, rather than class prioritisation is required, via a Prioritisation meeting that is held without the active participation of regulators, e.g. with bromodomain and extra-terminal inhibitors following the Forum on epigenetic modifiers [31].…”

“…It is paramount to focus competition when too many trials with similar patient enrolment criteria for drugs within the same class or for the same molecular targets exist. It is important to note that FDA [32] and EMA [30,31] report that companies take into account the scientific recommendations from ACCELERATE's Paediatric Strategy Forums to guide prioritisation for the development of drugs for children in high value targets. There is a need for clear, multistakeholder endorsed criteria for second or third generation products to be developed.…”

The Current Landscape of Targeted Clinical Trials in Non-WNT/Non-SHH Medulloblastoma

“…The basis to overcome these challenges lies in extensive international cooperation and a shared strategy between academia and industry. A blueprint on how research activities can be coordinated and hastened to benefit non-WNT/non-SHH MB patients represents the international ACCELERATE platform, which, for instance, recently published a roadmap for the development of BRT/BET inhibitors [112]. Further efforts are necessary to standardize preclinical models and to determine criteria to choose the most promising amongst several drug candidates with the same target as this, for example, is realized by the pediatric preclinical proof-of-concept platform ITCC-P4 (https://www.itccp4.eu, accessed on 12 December 2021).…”

“…Amongst many other functions, BRD/BET bromodomains recognize histone acetylation and subsequently activate gene expression mechanisms. Targeting BRD/BET proteins interferes with MYC-dependent transcription and was shown to be a promising strategy in a number of MYC(N)-driven cancers, including MB and neuroblastoma [56,[106][107][108][109][110][111][112][113]. Currently, a number of BRD/BET inhibitors are developed, with promising preclinical results and importantly also in a pediatric setting [112].…”

“…Targeting BRD/BET proteins interferes with MYC-dependent transcription and was shown to be a promising strategy in a number of MYC(N)-driven cancers, including MB and neuroblastoma [56,[106][107][108][109][110][111][112][113]. Currently, a number of BRD/BET inhibitors are developed, with promising preclinical results and importantly also in a pediatric setting [112]. Additionally, the first pediatric phase I trial testing the BRD/BET inhibitor BMS-986158 was started in 2019 and is open for participation of pediatric cancer patients with MYC(N)-amplification or high copy number gain, thus potentially offering a new therapeutic option for the most aggressive form of non-WNT/non-SHH MB (NCT03936465) (Table 1).…”