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Purpose: The aim of the Innovative Therapies for Children with Cancer (ITCC) consortium is to improve access to novel therapies for children and adolescents with cancer. The evolution of the ITCC clinical trial portfolio since 2003 was reviewed., Methods: All ITCC-labeled phase I/II trials opened between January 1, 2003 and February 3, 2018 were analyzed in two periods (2003-2010 and 2011-2018), and data were extracted from the ITCC database, regulatory agencies' registries, and publications., Results: Sixty-one trials (62% industry-sponsored) enrolled 3,198 patients. The number of trials in the second period increased by almost 300% (16 v 45). All biomarker-driven trials (n = 14) were conducted in the second period. The use of rolling six and model-based designs increased (1 of 9, 11% v 21 of 31, 68%), and that of 3 + 3 designs decreased (5 of 9, 55% v 5 of 31, 16%; P = .014). The proportion of studies evaluating chemotherapeutics only decreased (5 of 16, 31% v 4 of 45, 9%), the proportion of single-agent targeted therapies did not change (9 of 16, 56.2% v 24 of 45, 53.3%), the proportion of combination targeted therapies trials increased (2 of 16, 12%, v 17 of 45, 38%), the proportion of randomized phase II trials increased (1 of 7, 14% v 8 of 14, 57%). More trials were part of a pediatric investigation plan in the second period (4 of 16, 25% v 21 of 45, 46%). The median time for Ethics Committees' approvals was 1.7 times longer for academic compared with industry-sponsored trials., Conclusion: This study reports a shift in the paradigm of early drug development for childhood cancers, with more biologically relevant targets evaluated in biomarker-driven trials or in combination with other therapies and with more model-based or randomized designs and a greater focus on fulfilling regulatory requirements. Improvement of trial setup and recruitment could increase the number of patients benefiting from novel agents.

In a landscape of an increasing number of products and histology and age agnostic trials for rare patient cancer, prioritization of products is required. Paediatric Strategy Forums, organized 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 pediatric 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 11 Paediatric Strategy Forums since 2017 have made specific and general conclusions to accelerate drug development. Conclusions on product prioritization 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% of 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 prioritization resulted in an increase in waivers for non-prioritized B-cell products (44% to 75%) and a decrease in monotherapy trials, proposed in Paediatric Investigation Plans (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., (© The Author(s) 2023. Published by Oxford University Press.)

Despite various international regulatory initiatives over the last 20 years, many challenges remain in the field of paediatric drug development and evaluation. Indeed, drug research and development is still focused essentially on adult indications, thereby excluding many paediatric patients, limiting the feasibility of trials and favouring competing developments. Off-label prescribing persists and the development of age-appropriate dosage forms for children remains limited. Against this background, the members of this panel (TR) recommend the launch of multi-partner exchange forums on specific topics in order to focus new drug research and development on the real, unmet medical needs of children and adolescents, and in keeping with the underlying mechanisms of action. Scientific information sharing and cooperation between stakeholders are also essential for defining reference evaluation methods in each medical field. These forums can be organised through existing paediatric facilities and research networks at the French and European level. The latter are specifically dedicated to paediatric research and can facilitate clinical trial implementation and patient enrolment. Moreover, specific grants and public/private partnerships are still needed to support studies on the repositioning of drugs in paediatric indications, and pharmacokinetic studies aimed at defining appropriate dosages. The development of new pharmaceutical forms, better suited for paediatric use, and the promotion of resulting innovations will stimulate future investments. Initiatives to gather observational safety and efficacy data following off-label and/or derogatory early access should also be encouraged to compensate for the lack of information available in these situations. Finally, the creation of Ethics Committees (EC) with a specific "mother-child" advisory expertise should be promoted to ensure that the current regulation (Jardé law in France) is implemented whilst also taking into account the paediatric specificities in medical trials., (Copyright © 2022. Published by Elsevier Masson SAS.)

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ABassan is an employee of Syncopation Life Sciences. EB is an employee of Novartis. CB is an employee of Cellectis. SBC is an employee of CRISPR Therapeutics and has stock ownership in CRISPR. DSH has participated in advisory boards for AstraZeneca and Bayer and has received institutional funding from Incyte, Pfizer, Bristol Myers Squibb, Merck Sharpe Dohme, Lilly. LH is an employee of Miltenyi Biomedicine. IDH is an employee of Tessa Therapeutics. BKM is an employee of Kite, a Gilead company. YM is an employee of Takeda Pharmaceuticals International. SM has participated in advisory boards for Novartis and Wugen and received clinical trial support from Novartis. LP is an employee of GlaxoSmithKline. ADJP has participated in advisory boards for Novartis, Takeda, Merck, Lilly and Celgene and consulted for Lilly and Developmental Therapeutics Consortium Limited MP is an employee of Autolus Limited. AQ-C is an employee of TCR2 Therapeutics. RR is an employee of Celgene/Bristol Myers Squibb. CR has participated in advisory boards for Amgen, BMS, Celgene, Novartis and Pfizer. MAS is an employee and stock ownership of Gracellbiotechnologies Inc. SKT receives research funding from Incyte Corporation and Beam Therapeutics and as participated in advisory boards of Aleta Biotherapeutics and Kura Oncology. MCZ has been a constant for Incyte, Sanofi, BMS, Novartis, Pfizer, Jazz, Abbvie, Roche and Takeda; has received institutional funding from Jazz, Pfizer, Takeda, Abbvie and funding for travel from Jazz. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Since pediatric cancer drug development is a global enterprise, we sought to provide an overview of the landscape of intercontinental clinical trials in pediatric oncology opened over the last decade., Methods: ClinicalTrials.gov was systematically searched to identify all clinical therapeutic trials which opened between 2010 and 2020 and recruited pediatric patients (<18 years) with cancer., Results: Over the last 10 years, 295 (8.7%) of 3383 therapeutic pediatric cancer trials were international and 182 (5.4%) were intercontinental. Most intercontinental trials were phase-1 or 2, with 25% late-phase, 65% were sponsored by industry, and North America was involved in 92%. Industry-sponsored proportionally more phase-1 trials than academia (41% vs. 25%); conversely, academia sponsored more phase-2 and late-phase trials (39% and 31% vs. 36% and 21%, respectively) (p = 0.020). North America-Europe collaboration was predominantly industry sponsored as opposed to North America-Oceania and Europe-Oceania collaboration, more frequently academic (p < 0.0001). Most late-phase trials (18/20, 90%) focusing on pediatric malignancies were conducted by academic sponsors and 10 of these were conducted by Children's Oncology Group (COG)/National Cancer Institute in the United States and Oceania. There was no significant increase over time of intercontinental trials and a trend for a reduction in academic trials., Conclusions: Despite the relative rarity of childhood malignancies, especially within molecular subtypes, only 5.4% of pediatric cancer trials were intercontinental. The number of intercontinental trials remains small, with no significant increase over the last decade. The ACCELERATE International Collaboration Working Group aims to identify existing hurdles and propose solutions to improve intercontinental collaboration in clinical research for the benefit of children and adolescents with cancer., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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.)

Introduction: Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC)., Methods: A survey was sent to all ITCC-accredited early-phase clinical trial hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1st March and 30th April 2020., Results: Thirty-one of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared with that in 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. In addition, 26% of sites had restrictions on performing trial assessments because of local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organisational and structural changes., Conclusion: The study reveals a profound disruption of paediatric cancer early-phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises., Competing Interests: Conflict of interest statement N. André reports a consulting or advisory role for Bayer, BMS and Akina. He received funding for trial from BMS and molecules for trials from BMS and Pierre Fabre. He received travel support from BMS. K. Nysom reports a consulting or advisory role for YmAbs and Bayer and receiving honoraria from YmAbs and Bayer. L. Marshall reports a consulting or advisory role for Bayer, BMS, Eisai and Tesaro and receiving honoraria from Bayer for speaking in symposia/educational events. M. Gambart reports a consulting or advisory role for Bayer and receiving grants for travel expenses from Jazz pharmaceutical and Eusapharma. C. Rossig reports receiving honoraria for educational presentations and advice by Amgen, Pfizer, Celgene, Roche, BMS, Novartis and Genentech. F. Fagioli reports a consultant or advisory role for Amgen, Jazz Pharmaceuticals, Pfizer, Sanofi Genzyme and Takeda. I. Øra reports a consulting or advisory role for and receiving honoraria from Bayer. B. De Wilde reports a consultant or advisory role for Bayer, Roche and Novartis. C. Rizzari reports receiving personal and/or institutional grants, travel support and consultation fees from Amgen, Jazz Pharmaceuticals, SOBI and Servier. S. Palmu reports a consulting or advisory role for Boehringer Ingelheim and receiving honoraria for educational events and travel expenses from Octapharma and Sobi. L. Moreno reports being a member of a data monitoring committees for clinical trials sponsored by Novartis, Actuate Therapeutics, Shionogi, Incyte, the University of Southampton and the Royal Marsden NHS Foundation Trust; a consulting role for Novartis and Shionogi. He also reports being a member of the Executive Committee of SIOPEN (European neuroblastoma research cooperative group), organisation which receives royalties for the sales of dinutuximab beta. He reports that his institution receives funding from sponsors for DMC participation, advisory role or conducting industry-sponsored clinical trials. F. Bautista reports a consultant or advisory role for Bayer, Amgen, Sanofi and EusaPharma and receiving honoraria for speaking at symposia from Amgen and Jazz Pharmaceuticals and support for attending symposia from Takeda, EusaPharma, Shire and Jazz Pharmaceuticals. The rest of the authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy., Competing Interests: Conflict of interest statement LM has participated in advisory boards for Novartis, AstraZeneca, Roche/Genentech, Mundipharma, Bayer and Amgen, has received honoraria from Celgene and Novartis for educational events and travel grants from Mundipharma, Celgene and Amgen, and is a member of the Executive Committee of SIOPEN, a non-profit organisation that receives royalties for the sales of dinutuximab beta. SGD has received travel expenses from Loxo Oncology, Roche, and Salarius and consulting fee from Loxo Oncology. BG has participated in advisory boards for Roche/Genentech, Bayer, BMS, Celgene, Merck KG, Tesaro and Boehringer Ingelheim. MI provides advice to Bayer Canada. SB is an employee of, and owns shares in, Pfizer Ltd. HC is an employee of, and owns shares in, Hoffman La Roche. SD is an employee of Cyclacel Limited. MM and PM are employees of Astrazeneca. JS is 6-THIO-DG Scientific Founder and MAIA Scientific Advisor. GV provides advice to Roche, BMS, Celgene, Takeda, Aceta Pharma, Merck, Bayer, Servier and Novartis. ADJP provides advice to Novartis, Takeda, Merck, Lilly and Celgene., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Changes in the regulatory environment affecting pediatric cancer drug development in the United States and the European Union provide unprecedented opportunity to advance the concept of precision medicine to children with cancer. Increasing evidence suggests that new drugs and biologic products directed at molecular targets presumed to be etiologically associated with many adult cancers may well provide therapeutic options for selected subsets of children with cancer despite their histologic and biologic differences. Regulatory requirements for early evaluation of appropriate new drugs for children based on their molecular mechanism of action, rather than the specific clinical indications for which they are developed and/or approved, will shorten the unacceptable time lag between first-in-human and first-in-children studies. The relative scarcity of pediatric patients eligible for biomarker-directed studies and the ever-expanding compendium of new targeted agents mandate rational, science-based decision-making in selecting and prioritizing appropriate drugs to study early in development. A critical component of the evidence base in such decision-making includes preclinical testing of relevant drugs in pediatric tumor-specific in vitro and in vivo models. Established preclinical testing programs with academic investigator-industry collaborations are actively engaged in such activities. International collaboration is required to address the resource constraints and increasing number of potential products to be tested in a timely, efficient, nonduplicative, and cost-effective manner.

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers., Competing Interests: Conflict of interest J.A. is medical and scientific director for TC Biopharm and holds stock and share options in TC Biopharm and Autolus Ltd; M.B. is an employee of Merck Group; CB. is an employee of Tesaro; EB. is an employee of Pfizer; R.C. is an employee of Novartis; H.C. is an employee of Roche; S.J.D. is an employee of Merck & Co; M.E. is an employee of Boehringer-Ingelheimm Pharma GmbH; B.G. attended at a Roche sponsored advisory board for atezolizumab; R.I. is an employee of Celgene; M.K. is an employee and owns stock in Bristol-Myers Squibb; I.L. is an employee of Regeneron; L.V.M. has participated in advisory boards for AstraZeneca, Merck, Tesaro, Bayer and Celgene; M.M. is an employee of Syndax Pharmaceuticals; C.O. is an employee of Sanofi; A.D.J.P. has participated in advisory boards for Novartis, Taked, Merck, Lilly and Celgene; V.G.R.P. is an employee and shareholder of Autolus Ltd; C.R. attended advisory boards for Amgen, Celgen, EUSA Pharma, Genentch, Novartis and Roche, speaker honaria for Bristol Myers Squibb, Pfizer and Roche; P.K.S. is an employee of AstraZeneka; P.S. is an employee of Immunicum AB; C.v.T. participated in advisory boards for Novartis and Bayer; T.Y. is an employee of Beigene., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although outcomes for children with cancer have significantly improved over the past 40 years, there has been little progress in the treatment of some pediatric cancers, particularly when advanced. Additionally, clinical trial options and availability are often insufficient. Improved genomic and immunologic understanding of pediatric cancers, combined with innovative clinical trial designs, may provide an enhanced opportunity to study childhood cancers. Master protocols, which incorporate the use of precision medicine approaches, coupled with the ability to quickly assess the safety and effectiveness of new therapies, have the potential to accelerate early-phase clinical testing of novel therapeutics and which may result in more rapid approval of new drugs for children with cancer. Designing and conducting master protocols for children requires addressing similar principles and requirements as traditional adult oncology trials, but there are also unique considerations for master protocols conducted in children with cancer. The purpose of this paper is to define the key challenges and opportunities associated with this approach in order to ensure that master protocols can be adapted to benefit children and adolescents and ensure that adequate data are captured to advance, in parallel, the clinical development of investigational agents for children with cancer.

Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available. Therefore priority should be given to developing treatment for patients with relapsed and refractory mature B-cell lymphomas. The consensus of the clinicians attending the meeting was that CAR T-cells, T-cell engagers and antibody drug conjugates (excluding those with a vinca alkaloid-like drug) presently have the greatest probability of providing benefit in relapse in view of their mechanism of action. However, as producing autologous CAR T-cells currently takes at least 4 weeks, they are not products which could be quickly employed initially at relapse in rapidly progressing mature B-cell malignancies but only for the consolidation phase of the treatment. Global, industry-supported, academic-sponsored studies testing compounds from different pharmaceutical companies simultaneously should be considered in rare populations, and it was proposed that an international working group be formed to develop an overarching clinical trials strategy for these disease groups. Future Forums are planned for other relevant paediatric oncologic diseases with a high unmet medical need and relevant molecular targets., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Summary: Focus on new drug development over the last few years has yielded new agents that differ from unspecific classical chemotherapeutics and ionizing radiation, while still targeting the cancer cell itself. Antiangiogenesis is a totally distinct approach targeting the tumor''s blood vessels. This concept has now found its eligibility for the treatment of several adult solid tumors: the human antivascular endothelial growth factor (VEGF) antibody bevacizumab, as well as the VEGF receptor tyrosine kinase inhibitors, sunitinib and sorafinib, have recently been licensed by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of colorectal, renal, and lung cancer. Other antiangiogenic drugs are under preclinical and early clinical evaluation. However, what do we know of the use of these drugs in pediatric solid tumors, such as sarcomas and embryonal and neuronal tumors? For some time now, neuroblastoma has been shown to be dependent on angiogenesis. However, the first preclinical data on antiangiogenic drugs in neuroblastoma have not been published until recently, and clinical trials with antiangiogenic agents in neuroblastoma treatment protocols are scarce. This review adresses current knowledge on the important role and mechanisms of angiogenesis in neuroblastoma and summarizes available preclinical and clinical results of antiangiogenic agents used to treat neuroblastoma. Our review clearly demonstrates that clinical trials are urgently needed to bring forward promising antiangiogenesis concepts in neuroblastoma therapy. [Copyright &y& Elsevier]