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Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments. H3K27-alterations initiate the disease but additional drivers are required for malignant growth. Hence, there is an urgent unmet need to develop new multi-modality therapeutic strategies, including alternative methods of drug delivery. ONC201 (DRD2 antagonist and mitochondrial ClpP agonist) is the most widely evaluated investigational drug. Encouraging early data is emerging for CAR T-cells and oncolytic viruses. GD2, B7-H3 and PI3K signalling are ubiquitous targets across all subtypes and therapeutics directed to these targets would potentially benefit the largest number of children. PI3K, ACVR1, MAPK and PDGFRA pathways should be targeted in rational biological combinations. Drug discovery is a very high priority. New specific and potent epigenetic modifiers (PROTACS e.g. SMARCA4 degraders), with blood-brain penetrance are needed. Cancer neuroscience therapeutics are in early development. Overall survival is the preferred regulatory endpoint. However, the evaluation of this can be influenced by the use of re-irradiation at the time of progression. An efficient clinical trial design fit for regulatory purposes for the evaluation of new therapeutics would aid industry and facilitate more efficient therapy development. Challenges in conducting clinical trials such as the need for comparator data and defining endpoints, could be addressed through an international, first-in-child, randomised, complex innovative design trial. To achieve progress: i) drug discovery; ii) new multi-modality, efficient, collaborative, pre-clinical approaches, possibly including artificial intelligence and, iii) efficient clinical trial designs fit for regulatory purposes are required., Competing Interests: Declaration of Competing Interest MR is an employee of Novartis and holds Novartis stock. JAE is an employee of Chimerix. EB is an employee of SonALAsence. JF is an employee of Kazia Therapeutics. MJ is an employee of Brainchild Bio and holds Brainchild Bio stock. MWK is an employee of Day One Biopharmaceuticals. HK is an employee of Loxo Oncology. AGM is an employee of Laminar Pharma. AR is an employee of AstraZeneca. DZ is an employee of Biodexa Pharmaceuticals (Midatech). ADJP has consulted for Lilly, Norgine and Developmental Therapeutics Consortium Limited and been an advisor for Amgen. All remaining authors have declared no conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: In poor-prognosis children's cancers, new therapies may carry fresh hope for patients and parents. However, there is an absolute requirement for any new therapy to be properly evaluated to fulfill scientific, regulatory, and reimbursement requirements. Randomized clinical trials (RCTs) are considered the gold standard, but no consensus exists on how and when they should be deployed to best meet the needs of all stakeholders., Objective: To conduct a multistakeholder meeting to foster a greater shared understanding of perspectives regarding RCTs of new therapies for children with poor-prognosis cancers and develop consensus recommendations on when and how they should be used., Evidence Review: During October 2022 and April 2023, 2 structured workshops were convened, bringing together individuals representing the perspectives of patient advocates and academic clinician-researchers, regulators, and health technology assessment bodies. A premeeting briefing document was prepared and circulated to all attendees. During the workshops, selected attendees presented on behalf of each stakeholder group, focused topic discussions were conducted, and each meeting concluded by agreeing on a consensus set of recommendations. Meeting organizers drafted meeting summary reports that were circulated to all attendees, who commented on and revised them as a group to produce final recommendations from the workshops., Findings: Though the workshops did not reconcile all stakeholder differences, sufficient areas of agreement enabled a set of conclusions to be drawn, resulting in 8 consensus recommendations: (1) drug development strategies for new therapies, including the role of RCTs, should be established at the time of first-in-child studies; (2) engagement with regulators and health technology assessment bodies about RCT design is crucial; (3) involvement of patient advocates is necessary to ensure that an RCT is patient focused; (4) timing of an RCT is critical to preserve clinical equipoise; (5) use of crossover in an RCT can be of benefit, but with important caveats; (6) end point maturity and overall survival in an RCT may be important for regulatory and health technology assessment approvals; (7) in the absence of an RCT, contemporaneous control cohorts are preferred over historical control cohorts; and (8) quality of life should be captured in all prospective RCTs., Conclusions and Relevance: The agreed-upon workshop conclusions provide a basis for key considerations while undertaking future drug development activities for children with poor-prognosis cancers, ensuring that the needs and perspectives of all stakeholders are factored in from the outset.

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication., Competing Interests: Declaration of Competing Interest RB is an employee of Genentech, A Member of the Roche Group, South San Francisco, CA USA. JC is an employee of Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA. SGD has received consulting fees for advisory board participation from Amgen, Bayer, InhibRx, and Jazz and travel funding from Loxo, Roche, and Salarius. JF is an employee of Kazia Therapeutics. IG an employee of Celcuity. HK is an employee of Loxo Oncology at Lilly. DL is an employee of Merck Sharp & Dohme. AM is an employee of Actuate. MEM has receiving consulting fees for advisory board participation from Ymabs Therapeutics, Recordati and travel funding from Bayer. KN has received consulting fees for advisory board participation from Y-mAbs, EUSA Pharma and Bayer, fees for teaching from Bayer and serving on a data monitoring committee from Lilly. ADJP has consulted for Lilly, Norgine and Developmental Therapeutics Consortium Limited and been an advisor for Amgen. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders., Methods: After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved., Results: Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements., Conclusion: An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer.

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities., Competing Interests: Conflcits of interest statement The authors declare the following financial interests/ personal relationships which may be considered as potential competing interests: FB is an employee and stockholder of Ipsen Pharma. JC is an employee of Bayer Healthcare Pharmaceuticals. MC has served as an advisor for Astra-Zeneca, Bayer, BMS, Pfizer, and Servier. SGD has received consulting fees from Amgen, Bayer, and Loxo Oncology and has received travel reimbursement from Roche and Salarius. EG is an employee of Oncoheroes Biosciences. AH is an employee of Blueprint Medicines. KJ has received consulting fees from Bayer and Ipsen and honoraria fromTakeda and Foundation Medicine. JK is an employee of Allarity Therapeutics. SK is an employee of HUTCHMED International Corporation. CO is an employee of Eisai GmbH. ADJP has consulted for Lilly, Norgine and Developmental Therapeutics Consortium Limited and been an advisor for Amgen. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Nonprofit organizations (NPOs) play critical roles as funding sources, research partners, and disseminators of drug developments in pediatric cancer. Yet the literature provides limited guidance about ethical best practices when NPOs make trial funding decisions in this space. We conducted a systematic review of the literature indexed in PubMed and Web of Science to identify the ethical, legal, and social responsibilities of NPOs to four key stakeholder groups in funding pediatric cancer trials: (i) patients/families, (ii) researchers, (iii) industry sponsors, and (iv) donors. We applied the lifecycle framework for patient engagement in drug research and development proposed by Geissler and colleagues to analyze themes related to NPOs' responsibilities across 54 articles that met our inclusion criteria. Emergent themes included transparency surrounding conflicts of interest, the rigor of scientific review, and communication with patients/communities about trial progress. Our research identified critical gaps in best practices for negotiating research partnerships, managing competing research priorities, and pursuing alternative financing models including venture philanthropy. Results from our review informed a set of best practices to guide NPOs in making trial funding decisions that align with stakeholder values and interests., (© 2022 Wiley Periodicals LLC.)

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children., Competing Interests: Conflict of interest statement EB is an employee of Day One Biopharmaceuticals and was an employee of Pfizer. HC is an employee of Hoffmann-La Roche. SGD has consulted for Bayer and received travel expenses from Loxo Oncology, Roche, and Salarius. FD is the European principal investigator of the Roche Alectinib study and participated in advisory boards for Bayer, BMS, Roche, Celgene, LOXO Oncology, Servier and Tesaro and received travel expenses from Bayer, BMS, Roche and consultancy from Servier and received funding for research projects from Onxeo, Synth-Innove. LVM has consulted for Bayer and participated in advisory boards for BMS and Tesaro, and been a Data Monitoring Committee Member for Eisai and Merck. YM is an employee of Takeda Pharmaceuticals International. YPM has been a consultant for Pfizer. KN participated in advisory boards, consulted and taught for Bayer, Y-mAbs, and EUSA. GS is an employee of Xcovery. ADJP has participated in advisory boards for Novartis, Takeda, Merck, Lilly and Celgene and consulted for Lilly and Developmental Therapeutics Consortium Limited. KW is an employee of Pfizer. WW has consulted for Takeda and participated in an advisory board for Takeda Pharmaceuticals International. ZFZ is an employee of Turning Point Therapeutics. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 system-penetrant 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., Competing Interests: Conflict of interest statement KS has consulted for Kronos Bio and Auron Therapeutics, receives grant funding from Novartis for an unrelated project, holds stock options with Auron Therapeutics, and has given a sponsored presentation for Bristol Meyers Squibb. MK is an employee of Bristol Myers Squibb. KB is an employee of AbbVie. EG is an employee of Boehringer Ingelheim Pharma GmbH & Co KG. FG has consulted for Epigene Therapeutics. MH is an employee of Astra-Zeneca. KL is an employee of Constellation Pharmaceuticals. ZN is an employee of Celgene/Bristol Myers Squibb. AT is an employee of Plexxikon. FZ is an employee of Incyte. ADJP has participated in advisory boards for Novartis, Takeda, Merck, Lilly and Celgene. SGD has received fees for consulting and advisory board roles from Bayer and Loxo Oncology and has received travel expenses from Loxo Oncology, Roche/Genentech, and Salarius Pharmaceuticals. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner., Competing Interests: Conflicts of interest statement MLM is an employee of Syndax Pharmaceuticals Inc. PB is a scientific advisor for Novartis, Syndax and Servier. DDC and MR are consultants for Loxo Oncology and receive research support from Advanced Cell Diagnostics. PCA is an employee of Sanofi. SB is an employee of Day One Therapeutics Inc. ADD is an employee of Salarius Pharma. BG is an employee of Novartis. MH is an employee of AstraZeneca. PH is an employee of Boston Pharmaceuticals. IJ is an employee of Pfizer. MJK is an employee of Syros Pharmaceuticals. MK is an employee of Bristol Myers Squibb. ZN is an employee of Celgene. AS is an employee of Constellation Pharma. TT is an employee of Boehringer Ingelheim. ADJP has participated in advisory boards for Novartis, Takeda, Merck, Lilly and Celgene. All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)