Phase I trial and pharmacological study of a 3-hour paclitaxel infusion in children with refractory solid tumours: a SFOP study

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m2). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. © 2001 Cancer Research Campaign http://www.bjcancer.co

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m−2 for Group A and 100 mg m−2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events

Clinical, methodology, and patient/carer expert advice in pediatric drug development by conect4children.

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

The SIOPE strategic plan: A European cancer plan for children and adolescents

[EN] Within the European Network for Cancer research in Children and Adolescents (ENCCA), SIOPE and the European paediatric haematology-oncology community have established a long-term sustainable Strategic Plan to increase the cure rate and the quality of survivorship for children and young people with cancer over the next ten years. The ultimate goal is to increase the diseaseand late-effect- free survival after 10 years from the diagnosis, and beyond. As a result of several initiatives to involve all stakeholders and ensure that all their points of view would be taken into account in the document, this long-term sustainable Strategic Plan has achieved a broad consensus, and will serve as the "European Cancer Plan for Children and Adolescents".This publication has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under the project ENCCA (European Network for Cancer research in Children and Adolescents), grant agreement nr. HEALTH-F2-2011-261474.Vassal, G.; Schrappe, M.; Pritchard-Jones, K.; Arnold, F.; Basset-Salom, L.; Biondi, A.; Bode, G.... (2016). The SIOPE strategic plan: A European cancer plan for children and adolescents. Journal of Cancer Policy. 8:17-32. https://doi.org/10.1016/j.jcpo.2016.03.007S1732

Outcome of children and adolescents with central nervous system tumors in phase I trials

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses. Overall, 114 patients were included (109 evaluable for efficacy). Median age was 10.2 years (range 1.0-17.9). Main diagnoses included: medulloblastoma/primitive neuroectodermal tumors (32.5%) and high-grade gliomas (23.7%). Complete/partial responses (CR/PR) were reported in 7.3% patients and stable disease (SD) in 23.9%. Performance status of 90-100%, school/work attendance, normal ALT/AST and CR/PR/SD correlated with better overall survival (OS) in the univariate analysis. No variables assessable at screening/enrollment were associated with OS in the multivariate analysis. Five patients (4.5%) were discontinued from study due to toxicity. No toxic deaths occurred. Median OS was 11.9 months with CR/PR, 14.5 months with SD and 3.7 months with progressive disease (p < 0.001). The enrollment of children and adolescents with CNS tumors in phase I trials is feasible, safe and offers potential benefit for the patients. Sustained disease stabilization has a promising role as a marker of anti-tumor activity in children with CNS tumors participating in phase I trials

Effect of plyometric training on handspring vault performance and functional power in youth female gymnasts

This study aimed to determine the effect of plyometric training (PT) when added to habitual gymnastic training (HT) on handspring vault (HV) performance variables. Twenty youth female competitive gymnasts (Age: 12.5 ± 1.67 y) volunteered to participate and were randomly assigned to two independent groups. The experimental plyometric training group (PTG) undertook a six-week plyometric program, involving two additional 45 min PT sessions a week, alongside their HT, while the control group (CG) performed regular HT only. Videography was used (120 Hz) in the sagittal plane to record both groups performing three HVs for both the baseline and post-intervention trials. Furthermore, participants completed a countermovement jump test (CMJ) to assess the effect of PT on functional power. Through the use of Quintic biomechanics software, significant improvements (P < 0.05) were found for the PTG for run-up velocity, take-off velocity, hurdle to board distance, board contact time, table contact time and post-flight time and CMJ height. However, there were no significant improvements on pre-flight time, shoulder angle or hip angle on the vault for the PTG. The CG demonstrated no improvement for all HV measures. A sport-specific PT intervention improved handspring vault performance measures and functional power when added to the habitual training of youth female gymnasts. The additional two hours plyometric training seemingly improved the power generating capacity of movement-specific musculature, which consequently improved aspects of vaulting performance. Future research is required to examine the whether the improvements are as a consequence of the additional volume of sprinting and jumping activities, as a result of the specific PT method or a combination of these factors

Clinical, methodology, and patient/carer expert advice in pediatric drug development by conect4children

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

Early phase clinical trials of anticancer agents in children and adolescents — an ITCC perspective

In the past decade, the landscape of drug development in oncology has evolved dramatically; however, this paradigm shift remains to be adopted in early phase clinical trial designs for studies of molecularly targeted agents and immunotherapeutic agents in paediatric malignancies. In drug development, prioritization of drugs on the basis of knowledge of tumour biology, molecular 'drivers' of disease and a drug's mechanism of action, and therapeutic unmet needs are key elements; these aspects are relevant to early phase paediatric trials, in which molecular profiling is strongly encouraged. Herein, we describe the strategy of the Innovative Therapies for Children with Cancer (ITCC) Consortium, which advocates for the adoption of trial designs that enable uninterrupted patient recruitment, the extrapolation from studies in adults when possible, and the inclusion of expansion cohorts. If a drug has neither serious dose-related toxicities nor a narrow therapeutic index, then studies should generally be started at the adult recommended phase II dose corrected for body surface area, and act as dose-confirmation studies. The use of adaptive trial designs will enable drugs with promising activity to progress rapidly to randomized studies and, therefore, will substantially accelerate drug development for children and adolescents with cancer

The state of research into children with cancer across Europe : new policies for a new decade

Overcoming childhood cancers is critically dependent on the state of research. Understanding how, with whom and what the research community is doing with childhood cancers is essential for ensuring the evidence-based policies at national and European level to support children, their families and researchers. As part of the European Union funded EUROCANCERCOMS project to study and integrate cancer communications across Europe, we have carried out new research into the state of research in childhood cancers. We are very grateful for all the support we have received from colleagues in the European paediatric oncology community, and in particular from Edel Fitzgerald and Samira Essiaf from the SIOP Europe office. This report and the evidence-based policies that arise from it come at a important junction for Europe and its Member States. They provide a timely reminder that research into childhood cancers is critical and needs sustainable long-term support.peer-reviewe