RESUMO
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 (â¼0.1 %), 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.
Assuntos
Glicogênio Sintase Quinase 3 beta , Neoplasias , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Humanos , Criança , Adolescente , Neoplasias/tratamento farmacológico , Neoplasias/genética , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de MTOR/uso terapêutico , Inibidores de MTOR/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
Assuntos
Desenvolvimento de Medicamentos , Neoplasias , Adolescente , Criança , Humanos , Neoplasias/tratamento farmacológico , Oncologia/métodos , Linfócitos BRESUMO
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.
Assuntos
Antineoplásicos , Neuroblastoma , Estados Unidos , Adulto , Humanos , Criança , Adolescente , Antineoplásicos/uso terapêutico , Proteína BRCA1 , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , United States Food and Drug Administration , Estudos Retrospectivos , Proteína BRCA2 , Neuroblastoma/tratamento farmacológico , Biomarcadores , Dano ao DNA , Proteínas de Membrana , Proteínas Tirosina Quinases , Proteínas Serina-Treonina QuinasesRESUMO
As the mitogen-activated protein kinase (MAPK) signalling pathway is activated in many paediatric cancers, it is an important therapeutic target. Currently, a range of targeted MAPK pathway inhibitors are being developed in adults. However, MAPK signals through many cascades and feedback loops and perturbing the MAPK pathway may have substantial influence on other pathways as well as normal development. In view of these issues, the ninth Paediatric Strategy Forum focused on MAPK inhibitors. Development of MAPK pathway inhibitors to date has been predominantly driven by adult indications such as malignant melanoma. However, these inhibitors may also target unmet needs in paediatric low-grade gliomas, high-grade gliomas, Langerhans cell histiocytosis, juvenile myelomonocytic leukaemia and several other paediatric conditions. Although MAPK inhibitors have demonstrated activity in paediatric cancer, the response rates and duration of responses needs improvement and better documentation. The rapid development and evaluation of combination approaches, based on a deep understanding of biology, is required to optimise responses and to avoid paradoxical tumour growth and other unintended consequences including severe toxicity. Better inhibitors with higher central nervous systempenetration for primary brain tumours and cancers with a propensity for central nervous system metastases need to be studied to determine if they are more effective than agents currently being used, and the optimum duration of therapy with MAPK inhibition needs to be determined. Systematic and coordinated clinical investigations to inform future treatment strategies with MAPK inhibitors, rather than use outside of clinical trials, are needed to fully assess the risks and benefits of these single agents and combination strategies in both front-line and in the refractory/relapse settings. Platform trials could address the investigation of multiple similar products and combinations. Accelerating the introduction of MAPK inhibitors into front-line paediatric studies is a priority, as is ensuring that these studies generate data appropriate for scientific and regulatory purposes. Early discussions with regulators are crucial, particularly if external controls are considered as randomised control trials in small patient populations can be challenging. Functional end-points specific to the populations in which they are studied, such as visual acuity, motor and neuro psychological function are important, as these outcomes are often more reflective of benefit for lower grade tumours (such as paediatric low-grade glioma and plexiform neurofibroma) and should be included in initial study designs for paediatric low-grade glioma. Early prospective discussions and agreements with regulators are necessary. Long-term follow-up of patients receiving MAPK inhibitors is crucial in view of their prolonged administration and the important involvement of this pathway in normal development. Further rational development, with a detailed understanding of biology of this class of products, is crucial to ensure they provide optimal benefit while minimising toxicity to children and adolescents with cancer.
Assuntos
Glioma , Recidiva Local de Neoplasia , Estados Unidos , Adolescente , Adulto , Criança , Humanos , United States Food and Drug Administration , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Glioma/patologia , Proteínas Quinases Ativadas por MitógenoRESUMO
INTRODUCTION: Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs. OBJECTIVE: Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development. CONCLUSION: An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings.
Assuntos
Neoplasias , Criança , Humanos , Neoplasias/tratamento farmacológico , Oncologia/métodos , Desenvolvimento de MedicamentosRESUMO
The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Adolescente , Adulto , Neoplasias Ósseas/tratamento farmacológico , Criança , Humanos , Recidiva Local de Neoplasia , Osteossarcoma/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Estados Unidos , United States Food and Drug AdministrationRESUMO
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.
Assuntos
Desenvolvimento de Medicamentos/organização & administração , Oncologia/organização & administração , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Adolescente , Criança , Europa (Continente) , Humanos , Pediatria , Estados Unidos , United States Food and Drug AdministrationRESUMO
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.
Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Desenvolvimento de Medicamentos/organização & administração , Colaboração Intersetorial , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinase do Linfoma Anaplásico/genética , Criança , Ensaios Clínicos como Assunto , Indústria Farmacêutica/organização & administração , União Europeia/organização & administração , Humanos , Cooperação Internacional , Oncologia/organização & administração , Neoplasias/genética , Pediatria/organização & administração , Inibidores de Proteínas Quinases/farmacologia , Estados Unidos , United States Food and Drug Administration/organização & administraçãoRESUMO
The European Medicines Agency and the US Food and Drug Administration recently published a common commentary document on paediatric oncology drug development, building on the call for simultaneous submissions of paediatric investigation plans and initial pediatric study plans. The objective of this document is to guide deliberations and permit focused discussions at the monthly paediatric cluster calls, allowing early regulatory coordination of global development plans. The differences in regulations related to timeline are not considered posing a barrier in that regard.
Assuntos
Desenvolvimento de Medicamentos , Neoplasias , Criança , Humanos , Neoplasias/tratamento farmacológico , Planejamento Social , Estados Unidos , United States Food and Drug AdministrationRESUMO
The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.
Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Criança , Desenvolvimento de Medicamentos , Epigenômica/métodos , Europa (Continente) , Humanos , Oncologia/métodos , Estados Unidos , United States Food and Drug AdministrationRESUMO
PURPOSE: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. METHODS: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. RESULTS: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. CONCLUSION: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.
Assuntos
Antineoplásicos , Desenvolvimento de Medicamentos/organização & administração , Leucemia Mieloide Aguda/tratamento farmacológico , Oncologia/organização & administração , Pediatria/organização & administração , Adolescente , Idade de Início , Antineoplásicos/classificação , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/normas , Desenvolvimento de Medicamentos/tendências , Europa (Continente)/epidemiologia , Humanos , Agências Internacionais/organização & administração , Agências Internacionais/tendências , Cooperação Internacional , Leucemia Mieloide Aguda/epidemiologia , Oncologia/tendências , Pediatria/tendências , Análise de Sobrevida , Estados Unidos/epidemiologia , United States Food and Drug Administration/organização & administração , United States Food and Drug Administration/tendênciasRESUMO
Timely and successful drug development for rare cancer populations, such as pediatric oncology, requires consolidated efforts in the spirit of shared responsibility. In order to advance tailored development efforts, the concept of multistakeholder Strategy Forum involving industry, academia, patient organizations, and regulators has been developed. In this study, we review the first five pediatric oncology Strategy Forums co-organized by the European Medicines Agency between 2017 and 2020, reflecting on the outcomes and the evolution of the concept over time and providing an outline of how a "safe space" for multistakeholder engagement facilitated by regulators could be of potential value beyond pediatric oncology drug development.
Assuntos
Antineoplásicos/uso terapêutico , Tomada de Decisões , Aprovação de Drogas , Prioridades em Saúde , Participação dos Interessados , Fatores Etários , Antineoplásicos/efeitos adversos , Europa (Continente) , Órgãos Governamentais , Necessidades e Demandas de Serviços de Saúde , Humanos , Avaliação das Necessidades , Segurança do Paciente , Formulação de Políticas , Medição de RiscoRESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Órgãos Governamentais/organização & administração , Imunoterapia/métodos , Avaliação das Necessidades , Neoplasias/tratamento farmacológico , Planejamento de Assistência ao Paciente/organização & administração , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Criança , Quimioterapia Combinada , Humanos , Neoplasias/patologia , PrognósticoRESUMO
INTRODUCTION: Limited information is available on the views of children taking medicines and participating in clinical trials. These views may contribute to a better understanding of what can be improved on in the development of medicines from their perspective. OBJECTIVE: To collect children's views on taking medicines and participating in clinical trials. MATERIALS AND METHODS: A question-based survey was conducted among children living in European Union countries between January and August 2015. RESULTS: Almost 900 children aged 10-17 years from Finland, Germany, Sweden, Spain and Hungary responded. Almost 40% had a chronic health condition. The most commonly used pharmaceutical forms were solid or liquid medicines for oral use and injectable medicines. Bad taste and pain during administration were reported as common problems. Of 785 respondents, 17% had been taking part in a clinical trial. Most respondents would potentially agree to take part in a clinical trial because the investigational medicine might improve their own health or that of other children. Concern that the investigational medicine might be harmful was the main reason to refuse participation, if asked to. Over half of the respondents were willing to learn more about clinical trials, preferably online. CONCLUSIONS: It is necessary to involve children in the development of age-appropriate pharmaceutical forms and in the design of clinical trials. Children and their carers should be provided with age-appropriate medical information in the most suitable channels. We have identified some common problems that children experience when taking medicines, and we conclude that children are interested in learning more and giving their opinions on clinical trials.
Assuntos
Doença Crônica/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Consentimento Informado por Menores/psicologia , Participação do Paciente/psicologia , Sujeitos da Pesquisa/psicologia , Adolescente , Pesquisa Biomédica , Criança , Ensaios Clínicos como Assunto , Compreensão , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Finlândia , Alemanha , Pesquisa sobre Serviços de Saúde , Humanos , Hungria , Consentimento Informado por Menores/estatística & dados numéricos , Masculino , Avaliação das Necessidades , Participação do Paciente/estatística & dados numéricos , Sujeitos da Pesquisa/educação , Espanha , SuéciaRESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Linfoma de Células B/tratamento farmacológico , Adolescente , Adulto , Linfócitos B/efeitos dos fármacos , Criança , Europa (Continente) , Órgãos Governamentais , Humanos , Avaliação das Necessidades , América do Norte , Planejamento de Assistência ao PacienteRESUMO
BACKGROUND: The adverse renal effects of lithium have long been known, but glomerular insufficiency had been considered an unlikely event until recently, when new studies have raised concern regarding very long-term treatment. In this cross-sectional study, we examined glomerular function in a cohort of patients treated with lithium for up to 33 years and a control group of lithium-naïve patients treated with other mood-stabilizers. METHODS: Patients with a diagnosis of recurrent or persistent affective disorders, examined between 1 October 2007 and 31 December 2009, were screened. Demographic and clinical data were extracted from clinical charts regarding two study groups: one for patients treated with lithium for at least 12 months and the other for patients never exposed to lithium. Multivariate regression analysis was applied: the dependent variable was the estimated glomerular filtration rate (eGFR) calculated from the last available serum creatinine value using the Modification of Diet in Renal Disease Study Group equation; the following independent variables, potentially associated with renal dysfunction, were included: gender, current age, duration of lithium treatment, cigarette smoking, hypertension, diabetes and dyslipidemia. RESULTS: eGFRs lower than 60 ml/min were significantly more frequent in the group treated with lithium (38/139 = 27.3%) compared to lithium-naïve patients (4/70 = 5.7%) (P = 0.0002; Fisher's test). Regression analysis showed a significant effect on eGFR of age, gender and duration of lithium treatment but no effect of cigarette smoking, hypertension, diabetes or dyslipidemia. eGFR was estimated to decrease by 0.64 ml/min (95% confidence interval = 0.38 to 0.90; P = 0.00) for each year of lithium treatment. CONCLUSIONS: The duration of lithium treatment is a risk factor for glomerular failure, in addition to advancing age. For example, all patients aged 60 years or older may be estimated to undergo Stage 3 or more severe chronic kidney disease (namely an eGFR less than 60 ml/min) if treated with lithium for 30 years. These data may be added to the current debate on the balance between the protective effects of lithium on recurrent affective disorders and suicide and the risk of renal disease.See related commentary article here http://www.biomedcentral.com/1741-7015/11/34.