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Item does not contain fulltext, Many medicines are used "off-label" in children outside the terms of the license. Feasible pediatric clinical trials are a challenge to design. Conect4children (c4c) is an Innovative Medicines Initiative project to set up a pan-European pediatric clinical trial network aiming to facilitate the development of new medicines for children. To optimize pediatric trial development by promoting innovative trial design, c4c set up a European multidisciplinary advice service, including the voice of young patients and families, tailored to industry and academia. A network of experts was established to provide multidisciplinary advice to trial sponsors. Experts were selected to join clinical and innovative methodology expert groups. A patient and public involvement (PPI) database, to include the expert opinion of patients and parents/carers was formed. A stepwise process was developed: (1) sponsors contact c4c, (2) scoping interview takes place, (3) ad hoc advice group formed, (5) advice meeting held, and (6) advice report provided. Feedback on the process was collected. Twenty-four clinical and innovative methodology expert groups (>400 experts) and a PPI database of 135 registrants were established. As of September 30, 2022, 36 advice requests were received, with 25 requests completed. Clinical and methodology experts and PPI representatives participated in several advice requests. Sponsors appreciated the advice quality and the multidisciplinary experts from different countries, including experts not known before. Experts and PPI participants were generally satisfied with the process. The c4c project has shown successful proof of concept for a service that presents a new framework to plan innovative and feasible pediatric trials.

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.

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

[EN] Background: Essential anticancer medicines are an indispensable component of multidisciplinary treatment of paediatric malignancies. A European Society for Medical Oncology (ESMO) study reported inequalities in the availability of anticancer medicines for adult solid tumours and provided a model for the present survey. The aim of this survey was to assess the accessibility of essential medicines used in paediatric cancer patients aged 0 to 18 years across Europe from 2016 to 2018. Methods: A list of medicines was drawn with input from the European Society for Paediatric Oncology (SIOP Europe) Clinical Research Council referring to the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) 2017. A survey was sent to nominated national clinician and pharmacist rapporteurs and parent associations in up to 37 countries; answers were obtained from 34 countries. Results: The full survey list contained 68 medicines, including 24 on the WHO EMLc 2017. Health professionals reported that 35% of all medicines were prescribed off-label in at least one country and that 44% were always available in >90% of countries. Only 63% of the EMLc 2017 medicines were reported as always available. The main determinant of unavailability was shortages, reported for 72% of medicines in at least one country. Out-of-pocket costs were reported in eight countries. Twenty-seven percent of orally administered medicines were never available in childfriendly formulations. Parents detailed individual efforts and challenges of facilitating ingestion of oral medicines as prescribed. Inequalities in access to pain control during procedures were reported by parents across Europe. Conclusions: Children and adolescents with cancer in Europe experience lack of access to essential medicines. Urgent actions are needed to address shortages, financial accessibility, availability of safe age-appropriate oral formulations, and pain management across Europe.

Background: The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study. Patients and methods: Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m2 of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response [CR] + partial response [PR]). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival, 1-year overall survival, safety and pharmacokinetics. Results: Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive. Conclusions: In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed. Trial registration: NCT01962103 and EudraCT 2013-000144-26.

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.

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.