Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children

Pearson, Andrew D.J.; Stegmaier, Kimberly; Bourdeaut, Franck; Reaman, Gregory H.; Heenen, Delphine; Meyers, Michael L.; Armstrong, Scott A.; Brown, Patrick; Carvalho, Daniel D. De; Jabado, Nada; Marshall, Lynley V.; Rivera, Miguel N.; Smith, Malcolm A.; Adamson, Peter C.; Barone, Amy; Baumann, Christian; Blackman, Samuel C.; Buenger, Victoria; Donoghue, Martha; Duncan, Aundrietta D.; Fox, Elizabeth; Gadbaw, Brian; Hattersley, Maureen M.; Ho, Peter; Jacobs, Ira; Kieran, Mark W.; Lesa, Giovanni; Ligas, Franca; Ludwinski, Donna; McDonough, Joe; Nikolova, Zariana; Norga, Koen; Senderowicz, Adrian M.; Taube, Tilmann; Weiner, Susan; Karres, Dominik; Vassal, Gilles

doi:10.1016/j.ejca.2020.08.014

Cited by 24 publications

(5 citation statements)

References 109 publications

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“…Innovative strategies in early drug development for children, adolescents and young adults have been proposed by several collaborative groups [64,67,[94][95][96][97]. For example, the pediatric platform ACCELERATE, comprising multiple stakeholders in pediatric oncology, is aiming for biology-driven early drug development and clinical trial design for children and adolescents with cancer [98].…”

Section: Clinical Trial Development: Innovative Global Collaborationmentioning

confidence: 99%

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Langenberg

Looze

Molenaar

2021

Cancers

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Over the last years, various precision medicine programs have been developed for pediatric patients with high-risk, relapsed, or refractory malignancies, selecting patients for targeted treatment through comprehensive molecular profiling. In this review, we describe characteristics of these initiatives, demonstrating the feasibility and potential of molecular-driven precision medicine. Actionable events are identified in a significant subset of patients, although comparing results is complicated due to the lack of a standardized definition of actionable alterations and the different molecular profiling strategies used. The first biomarker-driven trials for childhood cancer have been initiated, but until now the effect of precision medicine on clinical outcome has only been reported for a small number of patients, demonstrating clinical benefit in some. Future perspectives include the incorporation of novel approaches such as liquid biopsies and immune monitoring as well as innovative collaborative trial design including combination strategies, and the development of agents specifically targeting aberrations in childhood malignancies.

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Section: Clinical Trial Development: Innovative Global Collaborationmentioning

confidence: 99%

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Langenberg

Looze

Molenaar

2021

Cancers

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“…It underlined that targeting epigenetic mechanisms will become an essential therapeutic approach. Eight classes of drugs were discussed and prioritized based on the current level of science to support an early evaluation in children, including inhibitors of EZH2 (Pearson et al 2020).…”

Section: Discussionmentioning

confidence: 99%

A narrative review on pathogenetic mechanisms of hyperinsulinemic hypoglycemia in Kabuki syndrome

Maines

Maiorana

Leonardi

et al. 2023

Endocrine Regulations

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Objective. Kabuki syndrome (KS) is associated with hyperinsulinemic hypoglycemia (HH) in 0.3–4% of patients, thus exceeding the prevalence in the general population. HH association is stronger for KS type 2 (KDM6A-KS, OMIM #300867) than KS type 1 (KMT2D-KS, OMIM #147920). Both the disease-associated genes, KMD6A and KMT2D, modulate the chromatin dynamic. As such, KS is considered to be the best characterized pediatric chromatinopathy. However, the exact pathogenetic mechanisms leading to HH in this syndrome remain still unclear. Methods. We selected on the electronic database PubMed all articles describing or hypothesizing the mechanisms underlying the dysregulated insulin secretion in KS. Results. The impact on the gene expression due to the KDM6A or KMT2D function loss may lead to a deregulated pancreatic β-cell differentiation during embryogenesis. Moreover, both KMT2D gene and KDM6A gene are implicated in promoting the transcription of essential pancreatic β-cell genes and in regulating the metabolic pathways instrumental for insulin release. Somatic KMT2D or KDM6A mutations have also been described in several tumor types, including insulinoma, and have been associated with metabolic pathways promoting pancreatic cell proliferation. Conclusions. The impact of pathogenic variants in KDM6A and KDM2D genes on β-cell insulin release remains to be fully clarified. Understanding this phenomenon may provide valuable insight into the physiological mechanisms of insulin release and into the pathological cascade causing hyperinsulinism in KS. The identification of these molecular targets may open new therapeutic opportunities based on epigenetic modifiers.

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“…It also suggested a global master protocol to allow drug evaluation of multiple treatment strategies. The fifth, on epigenetic modifiers ( 12 ), concluded that menin inhibitors should be moved rapidly into pediatric development; a prioritization meeting on BET inhibitors resolved that further clinical development of other pan-BET inhibitors in children should await the results of the first pediatric clinical trial ( 18 ).…”

Section: Paediatric Strategy Forum Modelmentioning

confidence: 99%

Impact of ACCELERATE Paediatric Strategy Forums: a review of the value of multi-stakeholder meetings in oncology drug development

Pearson,

de Rojas,

Karres

et al. 2023

JNCI: Journal of the National Cancer Institute

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In a landscape of an increasing number of products and histology and age agnostic trials for rare patient cancer, prioritisation of products is required. Paediatric Strategy Forums, organised by ACCELERATE and the European Medicines Agency with participation of the US Food and Drug Administration, are multi-stakeholder meetings that share information to best inform paediatric drug development strategies and subsequent clinical trial decisions. Academia, industry, regulators and patient advocates are equal members with patient advocates highlighting unmet needs of children and adolescents with cancer. The eleven Paediatric Strategy Forums since 2017 have made specific and general conclusions to accelerate drug development. Conclusions on product prioritisation meetings, as well as global master protocols, have been outputs of these meetings. Forums have provided information for regulatory discussions and decisions by industry to facilitate development of high priority products; for example, 62% high-priority assets (agreed at a Forum) in contrast to 5% of those assets not considered high priority have been the subject of a Paediatric Investigational Plan or Written Request. Where there are multiple products of the same class, Forums have recommended a focused and sequential approach. Class prioritisation resulted in an increase in waivers for non-prioritised B cell products (44% to 75%) and a decrease in monotherapy trials, proposed in PIP submissions of checkpoint inhibitors from 53% to 19%. Strategy Forums could play a role in defining unmet medical needs. Multi-stakeholder forums, such as the Paediatric Strategy Forum, serve as a model to improve collaboration in the oncology drug development paradigm.

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Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children

Cited by 24 publications

References 109 publications

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

A narrative review on pathogenetic mechanisms of hyperinsulinemic hypoglycemia in Kabuki syndrome

Impact of ACCELERATE Paediatric Strategy Forums: a review of the value of multi-stakeholder meetings in oncology drug development

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