Pediatric Trials Research Articles

Evaluation and optimization of sample size of neonates and infants for pediatric clinical studies on cefiderocol using a model-based approach.

When planning pediatric clinical trials, optimizing the sample size of neonates/infants is essential because it is difficult to enroll these subjects. In this simulation study, we evaluated the sample size of neonates/infants using a model-based optimal approach for identifying their pharmacokinetics for cefiderocol. We assessed the usefulness of data for estimation performance (accuracy and variance of parameter estimation) from adults and the impact of data from very young subjects, including preterm neonates. Stochastic simulation and estimation were utilized to assess the impact of sample size allocation for age categories in estimation performance for population pharmacokinetic parameters in pediatrics. The inclusion of adult pharmacokinetic information improved the estimation performance of population pharmacokinetic parameters as the coefficient of variation (CV) range of parameter estimation decreased from 4.9%-593.7% to 2.3%-17.3%. When sample size allocation was based on the age groups of gestational age and postnatal age, the data showed 15 neonates/infants would be necessary to appropriately estimate pediatric pharmacokinetic parameters (<20%CV). By using the postmenstrual age (PMA), which is theoretically considered to be associated with the maturation of organs, the number of neonates/infants required for appropriate parameter estimation could be reduced to seven (one and six with <32 and >32 weeks PMA, respectively) to nine (three and six with <37 and >37 weeks PMA, respectively) subjects. The model-based optimal design approach allowed efficient evaluation of the sample size of neonates/infants for estimation of pediatric pharmacokinetic parameters. This approach to assessment should be useful when designing pediatric clinical trials, especially those including young children.

Weight Gain After Adenotonsillectomy in Children With Mild Obstructive Sleep-Disordered Breathing

It is unknown whether adenotonsillectomy causes undesirable weight gain in children with mild obstructive sleep-disordered breathing (oSDB). To compare changes in anthropometric measures in children with mild oSDB treated with adenotonsillectomy vs watchful waiting. This was an exploratory analysis of the Pediatric Adenotonsillectomy Trial for Snoring (PATS) randomized clinical trial of adenotonsillectomy vs watchful waiting for mild oSDB (snoring with obstructive apnea-hypopnea index of <3 events/hour) that took place at 7 pediatric tertiary care centers across the US and included 458 children aged 3.0 to 12.9 years with mild oSDB. Participants were recruited from June 29, 2016, to February 1, 2021. Anthropomorphic measures taken at baseline and 12 months after randomization were standardized for age and sex, including each participant's percentage of the 95th body mass index percentile (%BMIp95). Data analyses were performed from March 15, 2023, to April 1, 2024. Early adenotonsillectomy (eAT) vs watchful waiting with supportive care (WWSC). Twelve-month change in %BMIp95 from baseline and undesirable weight gain (defined as any weight gain in a child who already had overweight or obesity or an increase from baseline normal weight/underweight to overweight/obesity) at follow-up assessment. The study analysis included 375 children (mean [SD] age, 6.1 [2.3] years; 188 [50.2%] females), of whom 143 (38%) had overweight or obesity at baseline. At 12 months, children in the eAT group experienced a 1.25-point increase in %BMIp95 compared with a 0.59-point increase in the WWSC group (mean difference, 0.93; 95% CI, -0.39 to 2.25). Undesirable weight gain was also similar between the eAT (n = 120; 32%) and WWSC (n = 101; 27%) groups (mean difference, 4%; 95% CI, 5% to 14%). The findings of this exploratory analysis of the PATS trial indicate that adenotonsillectomy was not independently associated with an increased risk of undesirable weight gain in children with mild oSDB. However, one-third of the children gained undesirable weight during the study, which suggests that there is an opportunity to address healthy weight management during the evaluation and treatment of children with mild oSDB. ClinicalTrials.gov Identifier: NCT02562040.

Enhancing Study Power in Pediatric Research through Bayesian Extrapolation

Pediatric populations, comprising individuals aged 18 or younger, and rare disease populations pose significant challenges in clinical trial design due to limited participant numbers, patient sensitivity, and insufficient natural history data. Addressing these challenges often involves data extrapolation, leveraging existing data from adults to inform pediatric trials. Bayesian hierarchical modeling is increasingly recognized as a valuable tool for combining information across disparate sources, such as adult and pediatric datasets. This manuscript introduces an extension of an existing statistical model to enhance the efficiency of borrowing strength from multiple historical trials under consistent assumptions. A quantitative method is developed to improve the borrowing of historical information. The methods are illustrated with a simulation study motivated by real case study in pediatric clinical trial, and practical considerations are provided regarding the selection of prior distributions. This work aims to provide comprehensive insights and practical guidance for leveraging historical data effectively in clinical trial design.

Eliciting the Discount Parameter in a Power Prior Method on the Basis of the Type I Error Consideration

In Bayesian clinical trial design, the power prior methodology offers a flexible framework for incorporating historical data into the analysis. One critical aspect of this approach is determining the effective sample size, which quantifies the amount of information borrowed from the historical dataset. In this article, we derive a formula for computing the effective sample size of a power prior by eliciting the discount parameter on the basis of the Type I error consideration. Our formula takes into account various factors, including the sample size of the historical dataset and the maximally allowable Type I error rate. We demonstrate the utility of our formula through illustrative examples and provide practical guidelines for its application in clinical trial planning, using a pediatric schizophrenia trial as an example. By accurately estimating the effective sample size, researchers can enhance the efficiency and validity of Bayesian analyses in the context of historical data borrowing. Supplementary materials for this article are available online.

The reporting of social determinants of health in pediatric dermatology clinical trials: a systematic review.

Despite the acknowledgment of the importance of social determinants of health (SDOH) on clinical outcomes, few clinical trials provide information about SDOH. Including these markers in pediatric dermatologic clinical trials may lead to improved care and novel observations about the disease. Using a systematic review, assess the use of SDOH in pediatric dermatology clinical trials. CINAHL Plus, Cochrane: CENTRAL, Embase, PubMed, and Scopus were searched. English language randomized controlled trials about pediatric dermatology diseases published from January 2011 to May 2022 were included. Two authors independently screened all records using Covidence at 2 levels. Two authors independently collected data using Covidence and Microsoft Excel and assessed study quality. A protocol was registered at Open Science Framework: https://doi.org/10.17605/OSF.IO/B93VY. A total of 6463 records were retrieved and 4298 were screened at title/abstract. Next, 1738 records were screened at full text and 1085 were included. Of these, 119 reported an SDOH factor for a pediatric dermatology disease. Income or socioeconomic status was the factor most reported followed by social support, location, and health insurance. Most of the studies were conducted outside of the United States. There are a limited number of dermatology clinical trials that include a pediatric population. Despite including over 1000 pediatric dermatology clinical trials, only 119 used SDOH. Pediatric dermatology researchers must prioritize including and reporting additional SDOH in clinical trials if the goal is to impact and improve clinical care and innovate for diverse populations of patients.

Population Pharmacokinetics (PopPK) Support for Pediatric Dosing of Biological Products.

This study assesses the use of population pharmacokinetics (PopPK) in supporting pediatric dosing of novel biological drug products. The labeling for biologic drug products approved by the US Food and Drug Administration (FDA) from 2002 until 2021 was reviewed to identify those with a pediatric indication. For the drugs with a pediatric indication, the dosing regimen(s) based on age groups, dosing strategy, the use of PopPK to support the dose, and the types of pediatric clinical trials were reviewed. Data were collected from FDA's review documents and product labels on the Drugs@FDA website, and as needed, more clinical trial details were collected from PubMed and clinicaltrials.gov. The role of PopPK analyses in dosing was captured when mentioned in the label or review as playing a role in selecting the approved pediatric dose and/or in verifying the adequacy of the studied dose to support labeling. Between 2002 and 2021, FDA approved 169 biological products, and 78 of 169 (46%) products have an approved indication for which the label contains dosing recommendations for pediatric use. For the 78 products approved in pediatrics, there was a total of 180 clinical trials that included pediatric patients. Phase 3 pediatric trials commonly supported pediatric approval and dosing for the reviewed products (64%, 50/78 products; 56.1%, 101/180 trials). PopPK analyses were reported to play a critical role in dose selection, prediction, and verification for 40 of the 78 products (51%), including informing pediatric dosing in the absence of pediatric data (e.g., drugs approved under animal rule), comparing exposures to the exposure range observed in adults, and informing alternative dosing strategies in certain age or body weight groups. PopPK analyses have been applied in a variety of ways to inform pediatric dosing and support extrapolation from adult data or other pediatric age groups for biologics. Understanding and learning from these past cases on the use of pharmacometrics tools to support pediatric dosing of biological products can inform future pediatric development programs.

Supplemental Nutrition Assistance Program participation gaps within a pediatric leukemia clinical trial cohort.

Poverty-exposed children with cancer are more likely to experience adverse outcomes. Supplemental Nutrition Assistance Program (SNAP) benefits improve food insecurity and child health outcomes, and could be used to mitigate disparities. We conducted a secondary analysis of parent-reported data collected in a frontline pediatric leukemia trial (NCT03020030) to assess SNAP eligibility (proxied by other means-tested program participation) and participation. At diagnosis, 105/287 families (37%) were SNAP-eligible, of whom 53 (50%) were SNAP participants. At 6months, 104/257 families (41%) were SNAP-eligible, and 59 (57%) were SNAP participants. Interventions to increase benefits participation during childhood cancer treatment represent an immediate opportunity to reduce disparities.

Real-time cognitive performance metrics derived from a digital therapeutic for inattention predict ADHD-related clinical outcomes: Replication across three independent trials of AKL-T01

AKL-T01 is a digital therapeutic (DTx) that targets attention by generating conflict at dynamically updated difficulty levels during a multitasking game. Clinical trials support AKL-T01’s efficacy in attention-deficit/hyperactivity disorder (ADHD), but there is a need to understand how in-game data can be used to monitor patient changes in cognition. We aimed to derive a real-time measure of attention from AKL-T01 gameplay data and validate it against clinical outcomes. Trials of AKL-T01 included: STARS-ADHD-Adult (NCT05183919), a 6-week trial in adults 18 and older (n = 221; M age = 39.9; 70% female); STARS-ADHD-Adolescent (NCT04897074), a 4-week trial in adolescents ages 13–17 (n = 162; M age = 14.4; 41% female); and STARS-ADHD (NCT02674633), a 4-week trial in children ages 8–12 (n = 180; M age = 9.7; 31% female). A cognitive metric was derived from targeting response speed, targeting sensitivity (d-prime), and navigation skill level. Using multiple linear regression models, we analyzed relationships between cognitive metric change and changes in the Test of Variables of Attention (TOVA)-Attention Comparison Score (ACS), controlling for TOVA-ACS baseline, cognitive metric baseline, age, and sex. We explored associations with ADHD symptoms and quality of life. Increases in the cognitive metric significantly predicted increases in TOVA-ACS in the adult (β = 0.16, p < 0.001), adolescent (β = .09, p = 0.007), and pediatric (β = 0.06, p = 0.014) trials. Cognitive metric changes additionally related to self-reported quality of life in adults and clinician-rated ADHD symptoms in adolescents. Findings support the clinical validity of a real-time measure of attention derived from AKL-T01 patient-device interactions.

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Hodgkin lymphoma involving the extra-axial CNS: an AHOD1331, PHL-C1, and PHL-C2 report from the COG and EuroNet-PHL

AbstractHodgkin lymphoma (HL) involving the central nervous system (CNS) is exceedingly rare. Information regarding the presentation, management, treatment, and outcome of patients with CNS HL is limited to case reports or small series. We describe 45 pediatric patients with 55 extra-axial CNS lesions at diagnosis with HL from a cohort of 4995 patients enrolled on Children’s Oncology Group AHOD1331 and the European Network for Pediatric Hodgkin lymphoma C1 and C2 trials, with an overall incidence of 0.9%. Up to 82.2% of patients had a single CNS lesion in the thoracic, lumbar, or sacral spine. In the evaluated cohort, HL did not occur within the CNS parenchyma. Lesions extended into the extra-axial CNS space from adjacent soft tissue or bone and never directly infiltrated through the dura into the brain or spinal cord. Patients with CNS involvement had a twofold greater incidence of extranodal lesions than previously reported cohorts without CNS involvement. After 2 cycles of chemotherapy, 89.1% of CNS lesions demonstrated a complete metabolic response and >75% decrease in volume. Thirteen CNS lesions (23.6%) received irradiation; none were sites of disease relapse. Relapse occurred at the site of 2 lesions involving the CNS, both of which had an adequate interim response to chemotherapy. In summary, we present, to our knowledge, the largest reported cohort of systemic HL involving the CNS at diagnosis, demonstrating that these lesions originate from surrounding tissues, extend into the extra-axial CNS space, and respond similarly to other nodal and extranodal disease. The trials were registered at www.clinicaltrials.gov as #NCT02166463, #NCT00433459, and #NCT02684708.

Enrollment of underserved racial and ethnic populations in pediatric asthma clinical trials

BackgroundLimited data exist on enrollment trends of historically underserved racial and ethnic children in clinical trials. ObjectiveWe sought to evaluate documentation and representation of race and ethnicity in pediatric asthma clinical trials in the US. MethodsThis is a cross-sectional study of US-based interventional trials studying pediatric asthma completed between 2008 and 2022 and registered on ClinicalTrials.gov. Enrollment disparities were assessed using the enrollment prevalence difference (EPD) measure – the median difference between the proportion of participants enrolled and asthma prevalence in the US population by race and ethnicity. ResultsOf the 67 trials reviewed, 53 (79.2%) and 36 (53.7%) reported on race and ethnicity in ClinicalTrials.gov, respectively. Most participants were White (39.1%), Black (37.1%), and non-Hispanic (66.1%). Black, Hispanic, Multiracial, and White children were enrolled in expected proportions based on their contribution to asthma burden. However, American Indian or Alaska Native (AI/AN) (EPD: -1, 95% CI: -1, -1) and Asian children (EPD: -3, 95% CI: -3, -3) were underrepresented, relative to disease burden in these respective groups. Fewer Black children were enrolled in drug or device trials (β=-0.80; 95% CI -1.60, -0.01) than in other trials. Fewer Hispanic children were enrolled in early phase than late phase trials (β=-2.42; 95% CI -3.66, -1.19). ConclusionsEnrollment in pediatric asthma trials conducted in the US was commensurate with the demographics of children affected by asthma for most racial and ethnic groups, but AI/AN and Asian children were underrepresented. Concerted efforts are needed to promote inclusion of these underserved groups in future trials.

Diagnosing new-onset asthma in a paediatric clinical trial setting in school-age children.

Asthma is a common chronic disease in children. It is a dynamic condition-symptoms change over time, and the outcome of diagnostic tests can vary. Consequently, evaluating the onset of asthma at a single point in time, perhaps when patients are asymptomatic with limited impairment of the lung function, may result in false diagnostic conclusions. The absence of consistent gold-standard diagnostic criteria in children challenges the ability of any study to ascertain an effect of treatment on asthma prevention. A comprehensive review of the diagnostic criteria used for new-onset asthma in school-age children was conducted based on existing recommendations from published clinical guidance, alongside evidence from paediatric asthma prevention trials. Findings from the review were used to propose suggestions for diagnosing new-onset asthma in future asthma prevention trials. Despite an overall lack of consensus in the published clinical guidance, there are similarities between the various recommendations for diagnosing asthma in children, which typically involve assessing the variable symptoms and supplementing the medical history with objective measures of lung function. For future paediatric asthma prevention trials, we suggest that paediatric clinical trials should use a new-onset asthma definition that incorporates the concepts of "possible", "probable" and "confirmed" asthma. "Possible" asthma would capture self-reported features of chronic symptoms and symptom relief with β2-agonist bronchodilator (suggesting reversibility). "Probable" asthma would include symptom chronicity, self-reported symptom relief with β2-agonist bronchodilator, and objective features of asthma (reversibility or bronchial hyper-responsiveness). A "confirmed" diagnosis would be made only if there is a positive response to controller therapy. These suggestions aim to improve the diagnosis of new-onset childhood asthma in clinical trials, which will be useful in the design and conduct of future paediatric asthma prevention trials.

Pediatric Device Clinical Trials Activity: 1999-2022.

This study assessed the state of pediatric medical device (PMD) development by comparing PMD clinical trials to pediatric trials evaluating drugs and biologics, from 1999 to 2022. The site www.clinicaltrials.gov was used to identify and quantify both PMD clinical trials and pediatric trials for drugs and biologics. Clinical specialty was also assessed. The institutions included were the 7 children's hospitals primarily affiliated with the Food and Drug Administration (FDA) Pediatric Device Consortia (PDC) grant program between 2018 and 2023. For a national comparison, an additional search assessed PMD trials across all US medical institutions. A total of 243 PMD clinical trials were identified at the FDA-PDC institutions on the basis of the year of initiation; the average number of PMD trials initiated per year per institution was 1.5 from 1999 to 2022. However, PMD trials significantly increased during the period 2014 to 2022 compared with 1999 to 2013 (P < .001); the rate of initiation of drug and biologic pediatric trials demonstrated no significant differences between these time periods. A national survey of all institutions initiating PMD trials, and drugs and biologics trials, identified 1885 PMD trials out of a total 12 943. A comparable trend was noted in the national survey with initiation of PMD trials increasing significantly from 2014 to 2022 (P < .001), compared with 1999 to 2013, whereas the rate of initiation of drug and biologic trials during these periods did not demonstrate a significant change. Although pediatric clinical trial initiation for drugs and biologics remained stable from 1999 to 2022, the rate of new PMD trials significantly increased during the period 2014 to 2022 at FDA-PDC institutions and nationally.

Discussion of the classification of pediatric drug clinical trials in children's hospitals in China.

This study aimed to gain insights into pediatric clinical trials conducted in children's hospitals in China and provide valuable references for the development of children's hospitals and the research and development of pediatric drugs. A comprehensive search was performed on the Chinese Clinical Trial Registry (Chi CTR) and ChinaDrugTrials.org.cn to collect information on all clinical trials involving subjects under 18 years, including those conducted in children's hospitals. The retrieval period was extended until 31 December 2022. A total of 459 pediatric clinical trials were collected, comprising 299 from Chi CTR and 160 from the Drug Clinical Trial Registration and Information Publicity Platform (Information Platform). Post-marketing drug studies and phase III clinical trials accounted for the majority of research stages. These trials covered a wide range of diseases/systems, with a particular focus on respiratory system disorders, tumors, endocrine disorders, and nutritional or metabolic diseases. Chemical drugs constituted the most extensively studied category, while traditional Chinese medicine/natural drugs received comparatively less attention. Clinical trial activities were primarily geographically focused on the eastern coastal regions of China, with multicenter trials being the most predominant. Ethics committee approval was obtained for 427 studies. The pediatric clinical trials conducted by children's hospitals in China have shown an overall upward trend; however, there is limited research focusing on traditional Chinese medicine, along with significant regional and institutional imbalances. Furthermore, there is still room for improvement regarding ethical review processes. It is recommended that children's hospitals enhance their scientific research capabilities while optimizing resource allocation to meet medical service demands effectively. Additionally, fostering more research-focused children's hospitals will contribute to the high-quality development of children's health in China.

Compliance and Readiness to a Low Free Sugar Diet Among Latino Families: Lessons Learned From an Ongoing Pediatric NAFLD Prevention Trial

Compliance and Readiness to a Low Free Sugar Diet Among Latino Families: Lessons Learned From an Ongoing Pediatric NAFLD Prevention Trial

Leveraging a global, federated, real-world data network to optimize investigator-initiated pediatric clinical trials: the TriNetX Pediatric Collaboratory Network.

Clinical research networks facilitate collaborative research, but data sharing remains a common barrier. The TriNetX platform provides real-time access to electronic health record (EHR)-derived, anonymized data from 173 healthcare organizations (HCOs) and tools for queries and analysis. In 2022, 4 pediatric HCOs worked with TriNetX leadership to found the Pediatric Collaboratory Network (PCN), facilitated via a multi-institutional data-use agreement (DUA). The DUA enables collaborative study design and execution, with institutional review board-approved transfer of complete datasets for further analyses on a per-protocol basis. Of the 41.2 million children with TriNetX records, the PCN represents nearly 10%. The PCN assisted several early-career investigators to bring study concepts from conception to an international scientific meeting presentation and journal submission. The PCN facilitates EHR vendor-agnostic multicenter pediatric research on the global TriNetX platform. Continued growth of the PCN will advance knowledge in pediatric health.

Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.

Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.

The role of autologous stem-cell transplantation in classical Hodgkin lymphoma in the modern era

Despite excellent cure rates with modern front-line regimens, up to 20% of patients with Hodgkin lymphoma will progress through front-line therapy or experience disease relapse. Worldwide, salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) is considered the standard of care for these patients and can cure approximately 50% of relapsed or refractory (R/R) patients in the second line. Brentuximab vedotin (BV), an anti-CD30 antibody drug conjugate, and PD1 inhibitors like nivolumab and pembrolizumab, have high response rates in patients who recur after HDT/ASCT. When used prior to HDT/ASCT, BV and PD1 inhibitors appear to dramatically increase the effectiveness of salvage therapies with complete response rates often double those seen with historic chemotherapy-based regimens and durable progression free survival (PFS) post-HDT/ASCT. Emerging data in adults and from pediatric trials showing a durable PFS in a subset of relapsed patients raises the question of whether HDT/ASCT is essential for cure in R/R patients after PD1 based salvage. Future studies will help clarify if ASCT can omitted PD1 based salvage to avoid the potential toxicity of HDT/ASCT without compromising cure.

Harmonizing Quality Improvement Metrics Across Global Trial Networks to Advance Paediatric Clinical Trials Delivery

BackgroundDespite global efforts to improve paediatric clinical trials, significant delays continue in paediatric drug approvals. Collaboration between research networks is needed to address these delays. This paper is a first step to promote interoperability between paediatric networks from different jurisdictions by comparing drivers for, and content of, metrics about clinical trial conduct.MethodsThree paediatric networks, Institute for Advanced Clinical Trials for Children, the Maternal Infant Child and Youth Research Network and conect4children, have each developed metrics to address delays and create efficiencies. We identified the methodology by which each network identified metrics, described the metrics of each network, and mapped consistency to come to consensus about core metrics that networks could share.ResultsMetric selection was driven by site quality improvement in one network (11 metrics), by network performance in one network (13 metrics), and by both in one network (five metrics). The domains of metrics were research capacity/capability, site identification/feasibility, trial start-up, and recruitment/enrolment. The network driven by site quality improvement did not have indicators for capacity/capability or identification/feasibility. Fifteen metrics for trial start up and conduct were identified. Metrics related to site approvals were found in all three networks. The themes for metrics can inform the development of ‘shared’ metrics.ConclusionWe found disparity in drivers, methodology and metrics. Tackling this disparity will result in a unified approach to addressing delays in paediatric drug approvals. Collaborative work to define inter-operable metrics globally is outlined.

ATRT-15. COMBINING THE PI3K INHIBITOR PAXALISIB WITH NUCLEOSIDE ANALOG GEMCITABINE TO IMPROVE SURVIVAL OF ATYPICAL TERATOID/RHABDOID TUMORS

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRT) have a dismal overall survival. Targeting the mTORC1/2 pathway kills ATRT tumor cells and increases the survival of mice bearing orthotopic xenografts. Paxalisib is a brain penetrant PI3K inhibitor that is in pediatric clinical trials for diffuse midline glioma. Paxalisib activates the integrated stress response (ISR) in ATRT. Consistent high-level activation of the ISR leads to cell death. We hypothesize paxalisib will synergize with the DNA-damaging agent gemcitabine, which also triggers the ISR, to over-activate this pathway and drive ATRT apoptosis. METHODS We analyzed ISR gene expression following mTOR inhibition via RNA-seq. Children’s Brain Tumor Network (CBTN) provided comparative data on ISR genes in ATRT and other pediatric brain tumors. Paxalisib/gemcitabine effects were evaluated through cell-based assays, western blot for ISR markers, and survival in three murine models. RESULTS ATRT have high baseline expression of ISR genes (CBTN: ATF4, eIF2α), and mTOR inhibition leads to activation of ISR genes (ATF4, CHOP, PPP1R15A, p&amp;lt;0.05). Paxalisib monotherapy significantly extends median survival in murine models compared to vehicle controls (CHLA-06: 40 to 54 days, p=0.001; BT-12: 21 to 35 days, p=0.05). Paxalisib/gemcitabine therapy synergized to slow cell growth and induce cell death (SynergyFinder BLISS score in five ATRT cell lines). Combination therapy leads to ISR activation (western blot: p-eIF2α, ATF4, CHOP). Combination slowed tumor growth (bioluminescent imaging) and led to significant extension of survival in orthotopic xenograft models (CHLA-06: 22 to 82.5 days; BT-37 56-day vehicle median survival while undefined combination survival). A third model is ongoing and showing similar results. CONCLUSIONS Paxalisib/gemcitabine therapy shows potential for targeting ATRT by over-activating the ISR. Our findings prompted the Pediatric Neuro-Oncology Consortium to consider this combination for inclusion in an upcoming clinical trial targeting relapsed/refractory ATRT, offering a novel approach to treat this aggressive tumor.