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ABSTRACT Purpose The fragility index (FI) is an adjunctive metric to facilitate the interpretation of p‐values in clinical trials. The FI has not been studied in phase 3 trials in pediatric oncology. Methods PubMed was used to identify phase 3 pediatric oncology trials published between 1980 and 2020. We report trial characteristics and calculate the FI for trials with a binary outcome and survival‐inferred fragility index (SIFI) for trials with a time‐to‐event outcome. FI/SIFI is the number of patients from one arm of a trial who would need to change groups for the statistical conclusion to change. We also report fragility quotients (FQ and SFQ) to normalize FI and SIFI relative to trial size. Results One hundred and thirteen trials included sufficient data for analysis. The median FI for trials with a binary outcome (n = 40) was 4.5 (range: 1–33). The median SIFI for trials with a time‐to‐event outcome (n = 73) was 13 (range: 0–61). The FI or SIFI was less than the number of patients lost to follow‐up in 25% of 36 trials. Median FQ and SFQ were 0.026 and 0.03, respectively, and did not significantly vary according to trial characteristics. While sample sizes increased over time, the FQ and SFQ remained stable. Conclusions The statistical conclusions of pediatric oncology phase 3 trials hinge on a relatively small number and proportion of patients. Despite the sample size limitations of low prevalence diseases, pediatric cancer trials are similarly or less fragile than adult oncology trials. Smaller trials do not appear more statistically fragile than larger trials. Statistical fragility appears to have remained constant over the four decades evaluated. We recommend reporting FI or SIFI, in conjunction with p‐values, for all phase 3 pediatric oncology trials.

Abstract Background Immune checkpoint inhibitors (ICI) have improved outcomes in a variety of adult cancers and are prescribed with increasing frequency across oncology. However, patterns of off‐label use of ICI in pediatrics remain unclear. Methods This is a single‐institution, retrospective cohort study evaluating off‐label ICI use in pediatric and young adult patients with cancer treated at our institution from 2014 to 2022. Response was based on clinician assessment derived from clinical records. Immune‐related adverse events (iRAEs) were classified according to CTCAE v5.0. Results We identified 50 unique patients treated with off‐label ICI (28 with solid tumors, 20 with central nervous system (CNS) tumors, 2 with hematologic malignancies). At time of ICI initiation, only five patients (10%) had localized disease, and all but one patient was treated in the relapsed/refractory setting. All patients were treated with the FDA‐approved weight‐based dosing recommendations. Overall, there was disease control in 21 patients (42%), with best response including one complete response (melanoma), two partial responses (high‐grade glioma, CNS nongerminomatous germ cell tumor), and 18 patients with stable disease. Forty‐four patients (88%) eventually experienced disease progression. Among 22 patients (44%) experiencing iRAEs, 10 (20%) had a grade ≥3 irAE, 12 (24%) required corticosteroids, and 14 (28%) required ICI discontinuation. irAE occurrence was associated with significantly improved progression‐free survival (HR 0.35; 95% CI: 0.18 to 0.68; p = 0.002) and overall survival (HR 0.33; 95% CI: 0.17 to 0.66; p = 0.002). Conclusions At our institution, ICI was most commonly prescribed in the relapsed/refractory setting to patients with metastatic disease. The treatment was generally well‐tolerated in the pediatric population. The overall response rate was low, and the majority of patients eventually experienced disease progression. A few patients, however, had durable treatment responses. Further studies are needed to identify which pediatric patients are most likely to benefit from ICI.

Abstract Background Ewing sarcoma (EWS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. Cyclin‐dependent kinase 4 (CDK4) is a genomic vulnerability in EWS that is synergistic with IGF‐1R inhibition in preclinical studies. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF‐1R monoclonal antibody) for patients with relapsed EWS. Patients and Methods This open‐label, non‐randomized, phase 2 trial enrolled patients ≥12 years with relapsed EWS. All patients had molecular confirmation of EWS and RECIST measurable disease. Patients initially received palbociclib 125 mg orally on Days 1–21 and ganitumab 18 mg/kg intravenously on Days 1 and 15 of a 28‐day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. An exact one‐stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. The study was closed following enrollment of the 10th patient due to discontinuation of ganitumab supply. Results Ten evaluable patients enrolled [median age 25.7 years (range 12.3–40.1)]. The median duration of therapy was 2.5 months (range 0.9–10.8). There were no complete or partial responders. Three of 10 patients had stable disease for >4 cycles and 2 had stable disease at completion of planned therapy or study closure. Six‐month progression‐free survival was 30% (95% CI 1.6%–58.4%). Two patients had cycle 1 hematologic dose‐limiting toxicities (DLTs) triggering palbociclib dose reduction to 100 mg daily for 21 days. Two subsequent patients had cycle 1 hematologic DLTs at the reduced dose. Eighty percent of patients had grade 3/4 AEs, including neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Serum total IGF‐1 significantly increased (p = 0.013) and ctDNA decreased during the first cycle. Conclusions This combination lacks adequate therapeutic activity for further study, though a subset of patients had prolonged stable disease.

Abstract Background Synovial sarcoma (SS) accounts for 8%–10% of all soft‐tissue sarcomas. Clinical presentation and outcomes vary, yet discrete risk groups based on validated prognostic indices are not defined for the full spectrum of patients with SS. Methods We performed a retrospective cohort study using data from the SEER (surveillance, epidemiology, and end results program) database of SS patients who were

Abstract The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60–80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment.

Abstract Background Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology. Methods We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017–2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity. Results Over the 2‐year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12‐year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0–12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4–1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three‐year overall survival was 50% (95% CI, 35–64). Conclusions Single patient INDs in pediatric oncology were universally approved in our national and single‐center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial.

Abstract Background Off‐label drug prescribing is common in pediatric clinical medicine, though the extent and impact of this practice in pediatric oncology has not yet been characterized. Methods We completed a retrospective single‐institution cohort study evaluating prevalence, characteristics, and clinical outcomes of off‐label prescribing of 108 FDA‐approved targeted anticancer drugs in patients

Abstract Background The sponsorship mix of trials relevant to young people with cancer has not been reported. Understanding this sponsorship mix may have implications for policies and regulations related to pediatric cancer drug development. Methods We analyzed sponsorship of interventional trials first opened in the United States from 2007 to 2018 using the ClinicalTrials.gov registry. A total of 51 781 trials across non‐oncology disciplines and 18 431 oncology trials were classified according to lower age of eligibility (≥18 years vs