Incorporation of patient-reported outcomes in early-phase clinical trials for childhood and adolescent cancer.

INTRODUCTION: The assessment of quality of life (QoL) should be one of the main objectives in paediatric clinical trials. Even though researchers, regulators and advocates support the use of patient-reported outcomes (PROs), this has not been fully implemented. The aim of this study is to assess the measurement of QoL and the usage of PROs, palatability assessments and medication diaries in early-phase clinical trials for childhood and adolescent cancer. METHODS: Early-phase clinical trials for children and adolescents with cancer opened between 2005 and 2022 at the Royal Marsden Hospital (London, UK) and Vall d'Hebron University Hospital (Barcelona, Spain) were interrogated for trial characteristics and the use of QoL questionnaires, PROs, palatability assessments and medication diaries. RESULTS: Overall, 72 clinical trials were analysed: 12 (16.7%) evaluated QoL and eight (11.1%) evaluated PROs. Palatability was tested in 21/40 (52.5%) trials of oral drugs and 23/72 (31.9%) incorporated medication diaries. No studies mentioned patient involvement in the trial protocol. Use of PROs increased from one of 36 (2.8%) to seven of 36 (19.4%) between the first period (2005-2016) and the second period (2017-2022) (p = .02). Implementation of medication diaries increased from seven of 36 (19.4%) to 16/36 (44.4%) in each period, respectively (p = .02). CONCLUSION: Only a minor proportion of the international/multicentric early-phase trials evaluated included QoL/PROs and medication diaries or palatability questionnaires to help assess these, although this trend seems to be increasing over recent years. Greater implementation of QoL/PROs has the potential to improve the patient's wellbeing and facilitate symptom control, to enhance patient/parent involvement in future trial designs and to provide information for drug prioritisation.

Updating our understanding of health-related quality of life issues in children with cancer: a systematic review of patient-reported outcome measures and qualitative studies.

BACKGROUND: Health-related quality of life (HRQOL) is a key concept in pediatric oncology. This systematic review aims to update the conceptual HRQOL model by Anthony et al. (Qual Life Res 23(3):771-789, 2014), covering physical, emotional, social and general HRQOL aspects, and to present a comprehensive overview of age- and disease-specific HRQOL issues in children with cancer. METHODS: Medline, PsychINFO, the Cochrane Database for Systematic Reviews (CDSR), and the COSMIN database were searched (up to 31.12.2020) for publications using patient-reported outcome measures (PROMs) and qualitative studies in children with cancer (8-14-year) or their parents. Items and quotations were extracted and mapped onto the conceptual model for HRQOL in children with cancer mentioned above. RESULTS: Of 2038 identified studies, 221 were included for data extraction. We identified 96 PROMS with 2641 items and extracted 798 quotations from 45 qualitative studies. Most items and quotations (94.8%) could be mapped onto the conceptual model. However, some adaptations were made and the model was complemented by (sub)domains for 'treatment burden', 'treatment involvement', and 'financial issues'. Physical and psychological aspects were more frequently covered than social issues. DISCUSSION: This review provides a comprehensive overview of HRQOL issues for children with cancer. Our findings mostly support the HRQOL model by Anthony et al. (Qual Life Res 23(3):771-789, 2014), but some adaptations are suggested. This review may be considered a starting point for a refinement of our understanding of HRQOL in children with cancer. Further qualitative research will help to evaluate the comprehensiveness of the HRQOL model and the relevance of the issues it encompasses.

Clinical research tools in pediatric oncology: challenges and opportunities.

Survival for childhood cancers has improved significantly over the last decades. However, patient outcomes have plateaued over the last decade for difficult-to-treat diseases. With high cure rates, decreasing long-term toxicities and sequelae remains crucial. Since many advances in childhood cancer research come from the adult oncology world, one of the key areas is improving the adaptation of tools that are essential for clinical trial conduct that were developed for adults into pediatrics. These include tools to evaluate toxicity, quality of life, radiological response, statistical methodology, or indicators of cancer care quality. In this review, we present ongoing international efforts to validate and adapt these tools for children and adolescents and discuss remaining challenges. These efforts will hopefully accelerate and improve the quality of pediatric oncology research in the upcoming years.

Fertility status among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: results of the 58 Late Adverse Effects study.

STUDY QUESTION: What are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors? SUMMARY ANSWER: We observed similar fertility outcomes in both male and female childhood ALL survivors compared with the general population, with the exception of a higher proportion of miscarriages among partners of male survivors. WHAT IS KNOWN ALREADY: Survival after childhood ALL is currently >90% and fertility impairments are among the main concerns of the long-term survivors. Few studies have focused on the fertility issues within this selected population and the existing data are difficult to interpret due to the different treatment regimens received by the patients, the small sample sizes and the unavailability of control data in many studies. STUDY DESIGN, SIZE, DURATION: Childhood ALL patients enrolled in European Organisation for Research and Treatment of Cancer (EORTC) studies between 1971 and 1998 in France and Belgium, <18 years old at diagnosis and alive and ≥18 years at follow-up were eligible. Among 1418 eligible survivors, 507 (35.8%) participated (277 females, 230 males). Controls from the general population matched one to one by age, province, level of urbanization and sex could be identified for 503 survivors. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survivors and controls were invited to fill out a questionnaire including information about their menstrual cycles (for females), intention to have children, having children, use of medical help to become pregnant and occurrence of negative pregnancy outcomes (birth defect, miscarriage, medical abortion or stillbirth). The results were analysed separately for females and males. The association between age at diagnosis and fertility outcomes, adjusted by age at follow-up, study and country were investigated using logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: The median time since diagnosis was 20.1 years and the median age at follow-up was 25 years. There were 144 survivors (97 females, 47 males) who wanted to have children. Among these, craniospinal radiotheraphy (CRT) and haematopoietic stem cell transplantation (HSCT) were administered to 18% and 4%, respectively. Of these who tried to have children, 75% of females and 69% of males succeeded, compared with 72% and 61% of the controls, respectively. These differences were not statistically significant (P = 0.73 for females and P = 0.50 for males). Overall, fertility outcomes were comparable between survivors and controls, except that a higher proportion of miscarriages occurred in partners of male survivors (28.1% versus 5.9%, P = 0.021). Among female survivors, an older age at diagnosis (10-17 years) was associated with a greater risk of pregnancy problems (adjusted OR 5.61, P = 0.046). LIMITATIONS, REASONS FOR CAUTION: The interpretation of the incidence of miscarriage among the partners of male survivors is limited by the lack of data regarding the males' partners and by a possibly higher tendency to recall and disclose fertility issues among male survivors compared with male controls. WIDER IMPLICATIONS OF THE FINDINGS: Fertility outcomes were similar in childhood ALL survivors and controls, and the low proportion of patients treated with CRT or HSCT might explain this. Further studies should confirm the higher proportion of miscarriages in partners of male survivors. STUDY FUNDING/COMPETING INTEREST(S): This publication was supported by donations from the Fonds Cancer (FOCA) from Belgium and the KU Leuven from Belgium. G.R. has been awarded a fellowship by the EORTC Cancer Research Fund (ECRF). C.P. has been awarded a fellowship by Fonds Cancer (FOCA) from Belgium and the Kinderkankerfonds from Belgium (a non-profit childhood cancer foundation under Belgian law). No competing interests were declared. TRIAL REGISTRATION NUMBER: NCT01298388 (clinicaltrials.gov).

EORTC SPECTA-AYA: A unique molecular profiling platform for adolescents and young adults with cancer in Europe.

For most adolescent and young adult (AYA) cancers, age-specific molecular features are poorly understood. EORTC-SPECTA, an academic translational research infrastructure for biomaterial collection, will explicitly recruit AYA patients and will therefore collect empirical data to bridge the molecular gap between pediatric and adult oncology. The initial pilot study, activated in February 2019 across Europe, will recruit 100 AYA patients (aged 12-29 years) with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Formalin-fixed tumor tissue and whole blood from study participants will be prospectively collected with clinical data and stored centrally at the Integrated BioBank of Luxembourg. Whole exome sequencing of matched tumor and blood, and tumor RNA sequencing and DNA methylation profiling will be performed at the German Cancer Research Center, Heidelberg, Germany. Virtual central pathology review of scanned diagnostic slides will be undertaken by an international expert panel, and diagnostic material returned to the participating centers. A multidisciplinary molecular tumor board will release a clinically validated report to referring clinicians within 4-6 weeks after biopsy. SPECTA-AYA constitutes a major opportunity to gain knowledge about the tumor biology of this unique age group. It incorporates notable innovative aspects: AYA specificity, pan-European academic collaboration, centralized biobanking, comprehensive molecular profiling and virtual central pathology review, among others. SPECTA-AYA will help untangle the tumor particularities of AYAs with cancer and aims to improve their access to novel drugs and personalized medicine.

Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care.

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.

Rescuing Drugs That are Discontinued in Adult Oncology Development for the Benefit of Children and Adolescents With Cancer - An ACCELERATE Multistakeholder Consensus.

Better therapies for childhood cancer remain an unmet need to improve the dismal prognosis of certain malignancies and to reduce the burden of toxicity. Rescuing discontinued or shelved drugs for children, adolescents, and young adults is a strategy to identify new uses for approved or investigational medicines outside the scope of their original medical indication. Our proposed multistakeholder consensus focuses on the development of innovative, patent-protected targeted agents, sourced from previously shelved or discontinued programs that have the potential to provide significant benefit to underserved patient populations, with unmet medical needs. There are several challenges to continuing/rescuing drugs for pediatric oncology development, which include the lack of information for decision making, corporate strategy considerations underlying the decision to invest in pediatric development, and the contracting and technology transfer complexities required to enable divestment and subsequent development. The multistakeholder approach for drug development has the advantage of conveying a consensus among academia, patient advocates, and importantly industry itself. We propose three areas of action to facilitate rescuing potentially beneficial drugs for children and adolescents with cancer: (i) initiatives to provide information to companies considering developing these drugs and a standards framework; (ii) incentives both in Europe and in the United States to encourage companies to develop pediatric-only drugs, with the reform of the EU Pharmaceutical Legislation posing an important opportunity; and (iii) communication of the issues to all stakeholders. Ultimately, this will benefit children and adolescents with cancer.

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

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.

Paediatric strategy forum for medicinal product development of PI3-K, mTOR, AKT and GSK3ß inhibitors in children and adolescents with cancer.

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.

Impact of the EU Paediatric Medicine Regulation on new anti-cancer medicines for the treatment of children and adolescents.

The European Paediatric Medicine Regulation was launched in 2007, aiming to provide better medicines for children. However, its benefit for paediatric patients with cancer has been questioned and the European Paediatric and Orphan Regulations have been under review since November, 2020. To ascertain the effect of the European Paediatric Medicine Regulation, all paediatric anti-cancer medicines assessed by the European Medicines Agency from 1995 to 2022 were identified and reviewed using the agency's public assessment reports, and all Paediatric Investigation Plans granted since 2007 were analysed. 16 new molecular entities (NMEs; ie, a drug that contains an active moiety that had never been approved before) have been approved since the regulation was launched in 2007. The number of paediatric marketing authorisations increased from 2007 but represented the same 17% of all anti-cancer drug marketing authorisations before and after 2007. After 2007, nine (56%) of 16 NMEs were first authorised both in adults and children. For seven NMEs, a first paediatric indication was approved with a median lag time of 6·4 years (range 1·2-21·5 years) after the first authorisation in adults. Half of NMEs were authorised for the treatment of malignancies responsible for only 5·4% of all European childhood cancer deaths, including three medicines for melanoma and thyroid cancer-adult cancers occurring very rarely in children. The increased number of paediatric anti-cancer NMEs after 2007 is a result of the major increase in new medicines authorised for adult cancers since 2005 rather than a direct effect of the Paediatric Regulation. Paediatric development of these NMEs was driven by their adult market and did not address major unmet medical needs of children and adolescents with cancer. An improved, fit-for-purpose regulatory environment that incentivises paediatric drug development based on mechanism of action, better incentives, and a systematic multi-stakeholder engagement, with greater investment from industry, public funding, and non-governmental organisations, will increase the number of new medicines approved in the future to cure more children and adolescents with cancer.

Changing incentives to ACCELERATE drug development for paediatric cancer.

BACKGROUND: More effective incentives are needed to motivate paediatric oncology drug development, uncoupling it from dependency on adult drug development. Although the current European and North-American legislations aim to promote drug development for paediatrics and rare diseases, children and adolescents with cancer have not benefited as expected from these initiatives and cancer remains the first cause of death by disease in children older than one. Drug development for childhood cancer remains dependent on adult cancer indications and their potential market. The balance between the investment needed to execute a Paediatric Investigation Plan (PIP) in Europe and an initial Paediatric Study Plan (iPSP) in the US, coupled with the potential financial reward has not been sufficiently attractive to incite the pharmaceutical industry to develop drugs for rare indications such as childhood cancer. METHODS: We propose changes in the timing and nature of the rewards within the European Paediatric Medicine Regulation (PMR) and Regulation on Orphan Medicinal Products (both currently under review), which would drive earlier initiation of paediatric oncology studies and provide incentives for drug development specifically for childhood indications. RESULTS: We suggest modifying the PMR to ensure mechanism-of-action driven mandatory PIP and reorganization of incentives to a stepwise and incremental approach. Interim and final deliverables should be defined within a PIP or iPSP, each attracting a reward on completion. A crucial change would be the introduction of the interim deliverable requiring production of paediatric data that inform the go/no-go decisions on whether to take a drug forward to paediatric efficacy trials. CONCLUSION: Additionally, to address the critical gap in the current framework where there is a complete lack of incentives to promote paediatric-specific cancer drug development, we propose the introduction of early rewards in the Orphan Regulation, with a variant on the US-Creating Hope Act and its priority review vouchers.

Comprehensive molecular profiling of sarcomas in adolescent and young adult patients: Results of the EORTC SPECTA-AYA international proof-of-concept study.

BACKGROUND: Adolescent and young adult (AYA) patients with cancer are poorly recruited to molecularly targeted trials and have not witnessed the advances in cancer treatment and survival seen in other age groups. We report here a pan-European proof-of-concept study to identify actionable alterations in some of the worst prognosis AYA cancers: bone and soft tissue sarcomas. DESIGN: Patients aged 12-29 years with newly diagnosed or recurrent, intermediate or high-grade bone and soft tissue sarcomas were recruited from six European countries. Pathological diagnoses were centrally reviewed. Formalin-fixed tissues were analysed by whole exome sequencing, methylation profiling and RNA sequencing and were discussed in a multidisciplinary, international molecular tumour board. RESULTS: Of 71 patients recruited, 48 (median 20 years, range 12-28) met eligibility criteria. Central pathological review confirmed, modified and re-classified the diagnosis in 41, 3, and 4 cases, respectively. Median turnaround time to discussion at molecular tumour board was 8.4 weeks. whole exome sequencing (n = 48), methylation profiling (n = 44, 85%) and RNA sequencing (n = 24, 50%) led to therapeutic recommendations for 81% patients, including 4 with germ line alterations. The most common were for agents targeted towards tyrosine kinases (n = 20 recommendations), DNA repair (n = 18) and the PI3K/mTOR/AKT pathway (n = 15). Recommendations were generally based on weak evidence such as activity in a different tumour type (n = 68, 61%), reflecting the dearth of relevant molecular clinical trial data in the same tumour type. CONCLUSIONS: We demonstrate here that comprehensive molecular profiling of AYA patients' samples is feasible and deliverable in a European programme.

Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

DNA damage response inhibitors have a potentially important therapeutic role in paediatric cancers; however, their optimal use, including patient selection and combination strategy, remains unknown. Moreover, there is an imbalance between the number of drugs with diverse mechanisms of action and the limited number of paediatric patients available to be enrolled in early-phase trials, so prioritisation and a strategy are essential. While PARP inhibitors targeting homologous recombination-deficient tumours have been used primarily in the treatment of adult cancers with BRCA1/2 mutations, BRCA1/2 mutations occur infrequently in childhood tumours, and therefore, a specific response hypothesis is required. Combinations with targeted radiotherapy, ATR inhibitors, or antibody drug conjugates with DNA topoisomerase I inhibitor-related warheads warrant evaluation. Additional monotherapy trials of PARP inhibitors with the same mechanism of action are not recommended. PARP1-specific inhibitors and PARP inhibitors with very good central nervous system penetration also deserve evaluation. ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors are early in paediatric development. There should be an overall coordinated strategy for their development. Therefore, an academia/industry consensus of the relevant biomarkers will be established and a focused meeting on ATR inhibitors (as proof of principle) held. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumours and have a potential role in the treatment of other paediatric malignancies, such as neuroblastoma and Ewing sarcoma. Access to CHK1 inhibitors for paediatric clinical trials is a high priority. The three key elements in evaluating these inhibitors in children are (1) innovative trial design (design driven by a clear hypothesis with the intent to further investigate responders and non-responders with detailed retrospective molecular analyses to generate a revised or new hypothesis); (2) biomarker selection and (3) rational combination therapy, which is limited by overlapping toxicity. To maximally benefit children with cancer, investigators should work collaboratively to learn the lessons from the past and apply them to future studies. Plans should be based on the relevant biology, with a focus on simultaneous and parallel research in preclinical and clinical settings, and an overall integrated and collaborative strategy.

Patient-reported outcomes are under-utilised in evaluating supportive therapies in paediatric oncology - A systematic review of clinical trial registries.

BACKGROUND: Children with cancer suffer from numerous symptoms and side-effects, making supportive interventions indispensable to improve their quality of life. The gold standard for evaluating the latter is patient-reported outcome (PRO) assessment. This systematic review investigates the current practice of clinical outcome assessment (COA) in clinical trials on supportive interventions. METHODS: ClinicalTrials.gov and EudraCT were searched for trials including children and adolescents (≤21 years) with cancer receiving supportive care registered 2007-2020. The use of different types of COAs was analysed, focusing on PRO assessment and the domains measured with PRO measures (PROMs). Associations with trial characteristics were investigated using univariate and multivariable analyses. RESULTS: Of 4789 identified trials, 229 were included. Among them, 44.1 % relied on PROMs, the most commonly used COA. The proportion of trials using PROMs did not significantly differ over time. In the multivariable analysis, intervention type (higher PROM use in behavioural vs. medical interventional trials) and cancer type (higher PROM use in mixed and solid tumour samples vs. haematological samples) were significant predictors of PROM use. The majority of trials using PROMs (59.6 %) measured more than one health domain. 'Physical health' was the most frequently assessed domain (92.6 %). CONCLUSION: Less than half of registered clinical trials investigating supportive interventions for children with cancer used PROMs. This result is striking since supportive care explicitly focuses on patients' quality of life, which is best assessed using PROMs. Our systematic review underlines the need to identify barriers for PROM implementation and to improve PRO research in paediatric oncology.