Pediatric Oncology Drug Development Research Articles

Pediatric oncology drug development and dosage optimization.

Oncology drug discovery and development has always been an area facing many challenges. Phase 1 oncology studies are typically small, open-label, sequential studies enrolling a small sample of adult patients (i.e., 3-6 patients/cohort) in dose escalation. Pediatric evaluations typically lag behind the adult development program. The pediatric starting dose is traditionally referenced on the recommended phase 2 dose in adults with the incorporation of body size scaling. The size of the study is also small and dependent upon the prevalence of the disease in the pediatric population. Similar to adult development, the dose is escalated or de-escalated until reaching the maximum tolerated dose (MTD) that also provides desired biological activities or efficacy. The escalation steps and identification of MTD are often rule-based and do not incorporate all the available information, such as pharmacokinetic (PK), pharmacodynamic (PD), tolerability and efficacy data. Therefore, it is doubtful if the MTD approach is optimal to determine the dosage. Hence, it is important to evaluate whether there is an optimal dosage below the MTD, especially considering the emerging complexity of combination therapies and the long-term tolerability and safety of the treatments. Identification of an optimal dosage is also vital not only for adult patients but for pediatric populations as well. Dosage-finding is much more challenging for pediatric populations due to the limited patient population and differences among the pediatric age range in terms of maturation and ontogeny that could impact PK. Many sponsors defer the pediatric strategy as they are often perplexed by the challenges presented by pediatric oncology drug development (model of action relevancy to pediatric population, budget, timeline and regulatory requirements). This leads to a limited number of approved drugs for pediatric oncology patients. This review article provides the current regulatory landscape, incentives and how they impact pediatric drug discovery and development. We also consider different pediatric cancers and potential clinical trial challenges/opportunities when designing pediatric clinical trials. An outline of how quantitative methods such as pharmacometrics/modelling & simulation can support the dosage-finding and justification is also included. Finally, we provide some reflections that we consider helpful to accelerate pediatric drug discovery and development.

Global Statistics and Data Sciences (GSDS), BeiGene USA, Fulton, MD

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.

Global Statistics and Data Sciences (GSDS), BeiGene USA, Fulton, MD

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.

Advancing drug development in pediatric oncology, a focus on cancer biology and targeted therapies: iMATRIX platform

ABSTRACT With the development of novel treatment therapies as well as evolving and innovative approaches to conduct clinical trials, the landscape of pediatric oncology drug development has dramatically changed in recent years. Despite this change, approvals for new drugs and labeling updates to ensure availability of proper treatment for pediatric patients with cancer remain slow. The context of drug development in pediatric tumors has also changed with regulatory initiatives in the US and Europe, creating a great need for faster development of novel drugs. Today, conventional study designs have been replaced or complemented by novel clinical trial designs, such as master protocols and platform trials, to optimize cancer drug development and enable faster regulatory approval. The iMATRIX platform is a mechanism-of-action (MOA)–based phase 1/2 trial framework for concurrently studying multiple molecules across a range of relevant pediatric tumor types, taking into account the biology of each pediatric tumor type. Six studies have been conducted, ongoing, or planned on the iMATRIX platform – investigating atezolizumab, cobimetinib, entrectinib, idasanutlin, alectinib, and glofitamab. A brief overview of study designs and characteristics are shared in this article, along with learnings from them.

Opportunities and Challenges in Drug Development for Pediatric Cancers.

The use of targeted small-molecule therapeutics and immunotherapeutics has been limited to date in pediatric oncology. Recently, the number of pediatric approvals has risen, and regulatory initiatives in the United States and Europe have aimed to increase the study of novel anticancer therapies in children. Challenges of drug development in children include the rarity of individual cancer diagnoses and the high prevalence of difficult-to-drug targets, including transcription factors and epigenetic regulators. Ongoing pediatric adaptation of biomarker-driven trial designs and further exploration of agents targeting non-kinase drivers constitute high-priority objectives for future pediatric oncology drug development. SIGNIFICANCE: Increasing attention to drug development for children with cancer by regulators and pharmaceutical companies holds the promise of accelerating the availability of new therapies for children with cancer, potentially improving survival and decreasing the acute and chronic toxicities of therapy. However, unique approaches are necessary to study novel therapies in children that take into account low patient numbers, the pediatric cancer genomic landscape and tumor microenvironment, and the need for pediatric formulations. It is also critical to evaluate the potential for unique toxicities in growing hosts without affecting the pace of discovery for children with these life-threatening diseases.

Can a Multistakeholder Prioritization Structure Support Regulatory Decision Making? A Review of Pediatric Oncology Strategy Forums Reflecting on Challenges and Opportunities of this Concept.

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.

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

SUMMARYAccelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)—many of which are refractory to current standard-of-care treatments—from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.

Abstract 3107: A scientific task force to generate proof-of-concept data packages for clinical trials in pediatric cancers: The hepatoblastoma example

Abstract Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Hepatoblastoma (HB) is a rare tumor that constitutes the most frequent form of childhood liver cancer. Current improvement in medical care allows 80% of children to survive this disease, but no second line treatment is available at relapse, so that 20% will not survive. Patient population small size and very low mutation rate besides beta-catenin activating mutation, which is at present undruggable, make HB an orphan disease. Very few anti-cancer drugs evaluated for adult diseases are investigated in the pediatric population, with 12 drugs approved for adult cancers every year against 6 drugs approved in childhood cancer since 1978. The need of incentives to encourage pharmaceutical industry to invest in this field has been well received by the European and US medicine agencies, and recent modification to regulations on adult and pediatric oncology drug development are expected to induce pharmaceutical companies to test their new compounds in the pediatric setting. Parallel to this initiative, it is imperative that the scientific community develops research tools and scientific rational to assist drug development as well as repositioning of drugs already approved in adult cancers. To this aim, in collaboration with the International Childhood Liver Tumour Strategy Group (SIOPEL) and the network of hospitals in the Paris area (AP-HP), XenTech has launched in 2010 the development of a panel of HB patient-derived xenografts (HB-PDXs). To date, 26 HB-PDXs have been established from 80 engraftments from patients at surgery after chemotherapy or at relapse. As these models were established from tumor cells that either evaded chemotherapy or promoted local and distant metastases, they present a biological surrogate of the recurrent disease. From these PDXs, 9 cellular models have been established to allow the exploration of the functional mechanisms of tumor growth and resistance to treatment, as well as to facilitate drug screening. This project is receiving worldwide participation from the HB scientific community including clinicians, academic researchers and parents associations. Thanks to this joint effort all the models are now fully characterized at the molecular level, PDXs pharmacological profiling has been done and is currently ongoing for many of these models, and PDXs and cellular models are being used from a growing number of collaborators to perform 3D culture, to improve our knowledge on the HB biology and to identify new drugs. The ambition of this project is to generate a reference preclinical platform that will be used for research purposes by the academic community and as a testing site for biotechs and pharmaceutical companies to accelerate the identification of anti-cancer therapies for children with aggressive HB. Citation Format: Carolina Armengol, Roland Kappler, Liqin Zhu, Nikolai Timchenko, Dina Kats, Charles Keller, Lisa Howard, Christophe Grosset, Delphine Nicolle, Olivier Déas, Martina Pigazzi, Laurence Brugières, Charlotte Mussini, Louise Galmiche-Rolland, Christophe Chardot, Sophie Brancereau, Jean-Gabriel Judde, Stefano Cairo. A scientific task force to generate proof-of-concept data packages for clinical trials in pediatric cancers: The hepatoblastoma example [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3107.

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors for TP53 and NF1 inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer.

Accelerating Drug Development in Pediatric Oncology With the Clinical Pharmacology Storehouse.

Pediatric drug development is a challenging process due to the rarity of the population, the need to meet regulatory requirements across the globe, the associated uncertainty in extrapolating data from adults, the paucity of validated biomarkers, and the lack of systematic testing of drugs in pediatric patients. In oncology, pediatric drug development has additional challenges that have historically delayed availability of safe and effective medicines for children. In particular, the traditional approach to pediatric oncology drug development involves conducting phase 1 studies in children once the drug has been characterized and in some cases approved for use in adults. The objective of this article is to describe clinical pharmacology factors that influence pediatric oncology trial design and execution and to highlight efficient approaches for designing and expediting oncology drug development in children. The topics highlighted in this article include (1) study design considerations, (2) updated dosing approaches, (3) ways to overcome the significant biopharmaceutical challenges unique to the oncology pediatric population, and (4) use of data analysis strategies for extrapolating data from adults, with case studies. Finally, suggestions for ways to use clinical pharmacology approaches to accelerate pediatric oncology drug development are provided.

Drug development in pediatric oncology – challenges and opportunities – reflections from European regulators

ABSTRACTIntroduction: Ten years of the Paediatric Regulation in Europe has resulted in progress in drug development for children. Nonetheless, drug development remains a challenge, particularly in the area of pediatric oncology, as cited by the European Commission’s 10-year Report published in 2017.Areas covered: In order to further improve the timely availability of novel medicines for children with cancer, further collaborative efforts are needed. Whilst the regulatory framework might present challenges, it provides key tools necessary to support pediatric drug development.Expert Opinion: It is the regulators together with all stakeholders who need to apply these tools by means of concerted, innovative, and inclusive ways of thinking in order to make it a true success. This requires all stakeholders to reflect on their individual responsibilities in this process, not only to create a level of understanding amongst each other but also to push their own boundaries and challenge established ways of thinking for the benefit of the patient, a principle which holds true for pediatric drug development in general. This paper reflects on these challenges and the opportunities for regulators and key stakeholders.

Evolving paradigms for new agent development in pediatric oncology.

To discuss considerations of new paradigms for clinical drug development in pediatric oncology that incorporate our expanding knowledge and complexity of molecular alterations associated with cancer; advances in cancer immunology and cellular therapy; the increasing number of new anticancer drugs, therapeutic approaches, and potential combinations; and recent initiatives by regulatory agencies to improve access to safe and effective therapies. Cancer in children and adolescents is a rare event with significant long-term impact on individuals and society. Using multimodality therapy, stratified by patient and disease characteristics, the cure rate for childhood cancer exceeds 80%. Cancer genomics has transformed anticancer drug development. Understanding the genetic basis of pediatric cancers and the use of genomics for risk stratification has changed the focus of drug development from cytotoxic drugs to targeted therapeutic approaches. Advances in cancer immunology, immune checkpoint blockade, and cellular therapy offer novel approaches to harness T cells to treat cancer. To improve the outcome for children and adolescents with cancer and accelerate drug development, understanding drug and target interactions in preclinical models of pediatric cancer should be coupled with efficient clinical trial designs that incorporate biomarker selection, assessment of toxicity and drug exposure, and improved measures of response. Clinical trials for children and adolescents with cancer evaluate cytotoxic drugs, molecularly target drugs, immunotherapy as well as combination therapies. The framework for oncology clinical trials will continually adapt to improve efficiency of trials and evaluate new therapeutic approaches.

Pediatric Development of Molecularly Targeted Oncology Drugs.

Oncology products developed for adult cancers often receive full waivers of pediatric studies. This analysis retrospectively identified products with potential pediatric development opportunities despite a full waiver. Initial pediatric study plans submitted to the US Food and Drug Administration from 2012 to 2016 for oncology products with plans to request full waivers of pediatric studies were reviewed to determine if a scientific rationale existed for pediatric evaluation based on the molecular mechanism of action (MOA), clinical experience, nonclinical evidence, or published genome sequencing data. Of the 98 oncology products reviewed, pediatric studies were eventually conducted in 55 (56%) despite having a waiver, 33 additional (34%) products were considered to have a rationale for pediatric evaluation but were not studied, and 10 (10%) products had no current evidence to support pediatric development. Conducting pediatric studies based on molecular MOA, rather than indication, provides opportunities to evaluate products earlier and accelerate pediatric oncology drug development.

More Efficient Compliance with European Medicines Agency and Food and Drug Administration Regulations for Pediatric Oncology Drug Development: Problems and Solutions

The morbidity and mortality toll of pediatric cancer affects the public health of children worldwide, but despite the gains in the fight against cancer, more progress needs to take place against this disease, which is a leading cause of death and chronic disability in children. In response, leading regulatory authorities in the developed world have been ratcheting up their efforts to induce the private sector to expand their research and development focus during drug development for adult cancers to include children. In mid-May 2016, the Center for the Study of Drug Development at Tufts University held a roundtable workshop on pediatric oncology to explore how companies could maximize the efficiency of pediatric assessment of adult cancer indications while minimizing resource expenditures to comply with regulatory requirements under the European Medicines Agency and the U.S. Food and Drug Administration. Although worldwide a child is diagnosed with cancer every 3 minutes, pediatric cancer is a rare disease, and trial participants are hard to come by. Thus, the market hardly sustains research and development expenses, advances in pharmacogenomics are not reaching down the age scale, and even in the public sector, basic research funding for pediatric cancer pales in comparison to the amount spent on cancer overall. The goal of the roundtable was to acknowledge these problems, and more importantly, to raise the level of awareness of potential solutions, including: more efficient use of the data hierarchy of informative events in clinical trials; new innovative clinical trial platforms for rapid assessment of new drugs in children; new developments in formulation technology; and optimization of speed in pediatric drug development through a multi-stakeholder network collaboration separate from the adult development plan.

Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development

Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.

Pediatric Oncology Drug Development: A Case Report and Pathways Forward

In this case report, we briefly review the treatment of a patient with metastatic, refractory Ewing's sarcoma who was treated on a Phase I clinical trial before she died from progressive disease. The case illustrates the need for early phase clinical trials programs in pediatric oncology, and the way in which investigators approach such programs.

The process of drug development in pediatric oncology: a review of basic principals and a look into the future

This article will focus on basic concepts in the development of new agents for pediatric malignancies and future directions, while considering the limitations we have today and the lessons we have learned from adult cancers. In addition, basic ethical principles for conducting trials in children are summarized. The rising numbers of targeted agents that have become available over the last few years will significantly change the way clinical studies are planned and a shift towards the use of alternative end points, different selection criteria and innovative designs is necessary. Pediatric malignancies have specific particularities and disparities that distinguish them regarding the conduction and design of clinical trials, which may influence the use of novel compounds. Due to the rarity of these diseases, international groups have cooperated to increase accrual rates, and incentives to the pharmaceutical companies have been made available by regulatory authorities; however, despite this a lack of trial p...

236 INVITED Challenges of drug development in pediatric oncology. A perspective from the pharmaceutical industry

The socioeconomic status of children (SESC) is associated with lifetime cognitive performance. Current research suggests substantial connections between SES and brain development changes, particularly in memory, executive function, and emotion, in investigating the relations between socioeconomic status and brain development. The cognitive abilities of children and their achievements at school are strongly influenced by socioeconomic status. Many studies have shown lower cognitive performance in adverse situations, and SES's impact on the child's neurological systems is little known. The proposed method suggested that, while the level of socioeconomic status performance is equally consistent, children's socioeconomic status is an essential predictor for neurocognitive performance, especially of semantic and executive function. Implications for brain science, as well as for identifying and improving childhood poverty issues, are addressed. The results show that SESC and bilingualism affect various child abilities. Bilingualism is correlated with lower vocabulary and lower performances in short-term verbal memory tasks with greater language load. And have significant clinical implications that include a further study into children's varied verbal and cognitive abilities and the diverse effects of the language and life experience. Thus the numerical result recommended SESC improves academic achievement (97.2%), Cumulative vocabulary words increases in High-SES, Stressors for poor children (66.2%) and rich children (98.2%), Cognitive functions, and Parent-children vocabulary interaction (98.4%).

New Approaches to Drug Development in Pediatric Oncology

This article reviews the changing paradigm of new drug development for childhood cancer. Although there have been dramatic improvements in the treatment and outcome for childhood cancer over the past 50 years, in some cancers, only limited progress has been made. New strategies to improve the outcome for poor-prognosis tumors and to minimize the long-term sequelae associated with therapy are required. Such strategies include a new pediatric-specific initiative for the preclinical testing of anticancer drugs for childhood malignancies, and ongoing research into the molecular heterogeneity of childhood tumors to facilitate the evaluation of molecularly targeted drugs. In addition, continued investigation into the genetic basis underlying interpatient variability in drug exposure and response is a priority. The goal of these initiatives is to improve the overall outcome for childhood cancer while minimizing the short and long-term sequelae associated with current treatment strategies.

Industry & the FDA in Pediatric Oncology Drug Development

Industry & the FDA in Pediatric Oncology Drug Development