Off-label prescribing of immune checkpoint inhibitor therapy at a single pediatric cancer center.

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.

Osteosarcoma Explorer: A Data Commons With Clinical, Genomic, Protein, and Tissue Imaging Data for Osteosarcoma Research.

PURPOSE: Osteosarcoma research advancement requires enhanced data integration across different modalities and sources. Current osteosarcoma research, encompassing clinical, genomic, protein, and tissue imaging data, is hindered by the siloed landscape of data generation and storage. MATERIALS AND METHODS: Clinical, molecular profiling, and tissue imaging data for 573 patients with pediatric osteosarcoma were collected from four public and institutional sources. A common data model incorporating standardized terminology was created to facilitate the transformation, integration, and load of source data into a relational database. On the basis of this database, a data commons accompanied by a user-friendly web portal was developed, enabling various data exploration and analytics functions. RESULTS: The Osteosarcoma Explorer (OSE) was released to the public in 2021. Leveraging a comprehensive and harmonized data set on the backend, the OSE offers a wide range of functions, including Cohort Discovery, Patient Dashboard, Image Visualization, and Online Analysis. Since its initial release, the OSE has experienced an increasing utilization by the osteosarcoma research community and provided solid, continuous user support. To our knowledge, the OSE is the largest (N = 573) and most comprehensive research data commons for pediatric osteosarcoma, a rare disease. This project demonstrates an effective framework for data integration and data commons development that can be readily applied to other projects sharing similar goals. CONCLUSION: The OSE offers an online exploration and analysis platform for integrated clinical, molecular profiling, and tissue imaging data of osteosarcoma. Its underlying data model, database, and web framework support continuous expansion onto new data modalities and sources.

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma.

PURPOSE: Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. METHODS: Oral cabozantinib (25 mg/m2 ) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75 mg/m2 ) and cyclophosphamide (250 mg/m2 ) were administered intravenously (IV) on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. RESULTS: Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (seven with Ewing sarcoma; five with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis, grade 3 transaminitis, and prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. CONCLUSIONS: The recommended phase 2 doses and schedules for this combination are topotecan 0.75 mg/m2 IV days 1-5, cyclophosphamide 250 mg/m2 IV days 1-5, and cabozantinib 25 mg/m2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity, while allowing for potential disease control.

Evaluation of prevalence and outcomes of serial tyrosine kinase inhibitor use in pediatric patients with advanced solid tumors.

PURPOSE: Multitargeted tyrosine kinase inhibitors (mTKIs) are increasingly utilized in the treatment of pediatric sarcomas and other solid tumors. It is unknown whether serial treatment with multiple TKIs provides a benefit and which patients are most likely to benefit from mTKI rechallenge. METHODS: We performed a retrospective cohort study of pediatric cancer patients who received serial mTKI therapy off-study between 2007 and 2020 as either monotherapy or combination therapy. We report patient characteristics, clinical outcomes, dosing patterns, and treatment-associated toxicity. RESULTS: The study cohort included 25 patients. The overall prevalence of serial mTKI therapy among all patients treated for sarcoma at our institution was 3.7%, and the response rate to second mTKI was 9%. Median 6-month progression-free survival (PFS) and overall survival (OS) from start of second mTKI were 42.1% (95% CI: 20.4%-62.5%) and 79.1% (95% CI: 57.0%-90.8%), respectively. Patients who had received 4 months or more (n = 11) of therapy with first mTKI had significantly longer PFS versus those who received less than 4 months (n = 11; p = .001). Thirty-three percent of patients discontinued second mTKI due to toxicity. Six (40%) of 15 patients who discontinued the first mTKI due to progression had either a partial response or stable disease on the second mTKI. CONCLUSIONS: We observed a low response rate to mTKI rechallenge. However, we identified patients who had been treated with first mTKI for  ≥4 months as more likely to have prolonged stable disease with second mTKI. Several patients had a response or stable disease on the second mTKI despite having progressed on the first mTKI. Though toxicity was common, only a minority of patients discontinued the second mTKI due to toxicity.

Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma.

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.

Derivation and validation of a risk classification tree for patients with synovial sarcoma.

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 <70 years of age at diagnosis. We constructed a recursive partitioning model of overall survival using a training cohort of 1063 patients with variables: Age at diagnosis, sex, race, ethnicity, primary site, tumor size, tumor grade, and stage. Based on this model, we grouped patients into three risk groups and estimated 5-year overall survival for each group. We then applied these groups to a test cohort (n = 1063). RESULTS: Our model identified three prognostic groups with significantly different overall survival: low risk (local/regional stage with either <21 years of age OR tumor <7.5 cm and female sex), intermediate-risk (local/regional stage, age ≥ 21 years with either male sex and tumor <7.5 cm OR any sex with appendicular anatomic location) and high risk (local/regional stage, age ≥ 21 years, tumor size ≥7.5 cm and non-appendicular location OR distant stage). Prognostic groups were applied to the test cohort, showing significantly different survival between groups (p < 0.0001). CONCLUSIONS: Our analysis yields an intuitive risk-classification tree with discrete groups, which may provide useful information for researchers, patients, and clinicians. Prospective validation of this model may inform efforts at risk-stratifying treatment.

Adverse prognostic impact of the loss of STAG2 protein expression in patients with newly diagnosed localised Ewing sarcoma: A report from the Children's Oncology Group.

BACKGROUND: Ewing sarcoma (EWS) is an aggressive sarcoma with no validated molecular biomarkers. We aimed to determine the frequency of STAG2 protein loss by immunohistochemistry (IHC) and whether loss of expression is associated with outcome. METHODS: We performed a retrospective cohort study of patients with EWS enrolled to Children's Oncology Group studies. We obtained unstained slides from 235 patients and DNA for sequencing from 75 patients. STAG2 expression was tested for association with clinical features and survival was estimated using Kaplan-Meier methods with log-rank tests. RESULTS: In total, 155 cases passed quality control for STAG2 IHC. STAG2 expression in 20/155 cases could not be categorised with the limited available tissue, leaving 135 patients with definitive STAG2 IHC. In localised and metastatic disease, STAG2 was lost in 29/108 and 6/27 cases, respectively. Among patients with IHC and sequencing, 0/17 STAG2 expressing cases had STAG2 mutations, and 2/7 cases with STAG2 loss had STAG2 mutations. Among patients with localised disease, 5-year event-free survival was 54% (95% CI 34-70%) and 75% (95% CI 63-84%) for patients with STAG2 loss vs. expression (P = 0.0034). CONCLUSION: STAG2 loss of expression is identified in a population of patients without identifiable STAG2 mutations and carries a poor prognosis.

An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma.

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.

Circulating Tumor DNA Is Associated with Response and Survival in Patients with Advanced Leiomyosarcoma.

PURPOSE: We sought to determine whether the detection of circulating tumor DNA (ctDNA) in samples of patients undergoing chemotherapy for advanced leiomyosarcoma (LMS) is associated with objective response or survival. EXPERIMENTAL DESIGN: Using ultra-low-passage whole-genome sequencing (ULP-WGS) of plasma cell-free DNA from patients treated on a prospective clinical trial, we tested whether detection of ctDNA evaluated prior to the start of therapy and after two cycles of chemotherapy was associated with treatment response and outcome. Associations between detection of ctDNA and pathologic measures of disease burden were evaluated. RESULTS: We found that ctDNA was detectable by ULP-WGS in 49% patients prior to treatment and in 24.6% patients after two cycles of chemotherapy. Detection of pretreatment ctDNA was significantly associated with a lower overall survival [HR, 1.55; 95% confidence interval (CI), 1.03-2.31; P = 0.03] and a significantly lower likelihood of objective response [odds ratio (OR), 0.21; 95% CI, 0.06-0.59; P = 0.005]. After two cycles of chemotherapy, patients who continued to have detectable levels of ctDNA experienced a significantly worse overall survival (HR, 1.77; 95% CI, 1-3.14; P = 0.05) and were unlikely to experience an objective response (OR, 0.05; 95% CI, 0-0.39; P = 0.001). CONCLUSIONS: Our results demonstrate that detection of ctDNA is associated with outcome and objective response to chemotherapy in patients with advanced LMS. These results suggest that liquid biopsy assays could be used to inform treatment decisions by recognizing patients who are likely and unlikely to benefit from chemotherapy. See related commentary by Kasper and Wilky, p. 2480.

Rapid and highly sensitive approach for multiplexed somatic fusion detection.

Somatic gene translocations are key to making an accurate diagnosis in many cancers including many pediatric sarcomas. Currently available molecular diagnostic approaches to identifying somatic pathognomonic translocations have limitations such as minimal multiplexing, high cost, complex computational requirements, or slow turnaround times. We sought to develop a new fusion-detection assay optimized to mitigate these challenges. To accomplish this goal, we developed a highly sensitive multiplexed digital PCR-based approach that can identify the gene partners of multiple somatic fusion transcripts. This assay was validated for specificity with cell lines and synthetized DNA fragments. Assay sensitivity was optimized using a tiered amplification approach for fusion detection from low input and/or degraded RNA. The assay was then tested for the potential application of fusion detection from FFPE tissue and liquid biopsy samples. We found that this multiplexed PCR approach was able to accurately identify the presence of seven different targeted fusion transcripts with a turnaround time of 1 to 2 days. The addition of a tiered amplification step allowed the detection of targeted fusions from as little as 1 pg of RNA input. We also identified fusions from as little as two unstained slides of FFPE tumor biopsy tissue, from circulating tumor cells collected from tumor-bearing mice, and from liquid biopsy samples from patients with known fusion-positive cancers. We also demonstrated that the assay could be easily adapted for additional fusion targets. In summary, this novel assay detects multiple somatic fusion partners in biologic samples with low tumor content and low-quality RNA in less than two days. The assay is inexpensive and could be applied to surgical and liquid biopsies, particularly in places with inadequate resources for more expensive and expertise-dependent assays such as next-generation sequencing.

Multicenter Analysis of Genomically Targeted Single Patient Use Requests for Pediatric Neoplasms.

PURPOSE: The US Food and Drug Administration-expanded access program (EAP) uses a single patient use (SPU) mechanism to provide patient access to investigational agents in situations where no satisfactory or comparable therapy is available. Genomic profiling of de novo and relapsed or refractory childhood cancer has led to increased identification of new drug targets in the last decade. The aim of this study is to examine the SPU experience for genomically targeted therapies in patients with pediatric cancer. PATIENTS AND METHODS: All genomically targeted therapeutic SPUs obtained over a 5-year period were evaluated at four large pediatric cancer programs. Data were collected on the type of neoplasm, agents requested, corresponding molecularly informed targets, and clinical outcomes. RESULTS: A total of 45 SPUs in 44 patients were identified. Requests were predominantly made for CNS and solid tumors (84.4%) compared with hematologic malignancies (15.6%). Lack of an available clinical trial was the main reason for SPU initiation (64.4%). The median time from US Food and Drug Administration submission to approval was 3 days (range, 0-12 days) and from Institutional Review Board submission to approval was 5 days (range, 0-50 days). Objective tumor response was seen in 39.5% (15 of 38) of all evaluable SPUs. Disease progression was the primary reason for discontinuation of drug (66.7%) followed by toxicity (13.3%). CONCLUSION: SPU requests remain an important mechanism for pediatric access to genomically targeted agents given the limited availability of targeted clinical trials for children with high-risk neoplasms. Furthermore, this subset of SPUs resulted in a substantial number of objective tumor responses. The development of a multi-institutional data registry of SPUs may enable systematic review of toxicity and clinical outcomes and provide evidence-based access to new drugs in rare pediatric cancers.

Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives.

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.

Retrospective evaluation of single patient investigational new drug (IND) requests in pediatric oncology.

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.

Facial Paralysis From Post-transplant Lymphoproliferative Disorder.

OBJECTIVE: We report a case of facial paresis and profound hearing loss from post-transplant lymphoproliferative disorder (PTLD) in a pediatric patient with neuroblastoma. PATIENT: Three-year-old boy with rapidly progressive right facial paresis and sensorineural hearing loss. High-risk neuroblastoma had been diagnosed 1 year earlier, treated with chemotherapy and resection of the adrenal primary tumor. Two months after two autologous hematopoietic stem cell transplantations (HSCT), the patient developed facial paralysis. Magnetic resonance imaging (MRI) showed bilateral progressive internal auditory canal (IAC) enhancing lesions with a mass lesion on the right and wispy enhancement on the left and enhancement within the right cochlea. Lumbar puncture (LP) was positive for Epstein-Barr virus (EBV) making the diagnosis of PTLD most probable. Biopsy of the right IAC lesion was deferred because of potential procedural risks including intradural spread of tumor or fungus. The patient was treated with anti-fungal therapy and systemic rituximab without improvement. Subsequent intrathecal rituximab resulted in improvement of lesions on MRI and clearance of EBV from the cerebrospinal fluid (CSF). INTERVENTIONS: Mastoidectomy for biopsies from the mastoid and middle ear. Intrathecal treatment with rituximab. MAIN OUTCOME MEASURES: Imaging assessment of IAC lesion, CSF EBV titers, facial nerve function. RESULTS: Gradual resolution of IAC mass lesions, remission of PTLD, and facial improvement from House-Brackmann score of 4 to 3. CONCLUSIONS: PTLD causing facial paresis after autologous HSCT has not been previously reported and may be considered in the differential diagnosis of lesions causing facial paresis in patients who have received a stem cell or solid organ transplant.

Derivation and validation of risk groups in patients with osteosarcoma utilizing regression tree analysis.

BACKGROUND: For patients with osteosarcoma, apart from stage and primary site, we lack reliable prognostic factors for risk stratification at diagnosis. There is a need for further defined, discrete prognostic groups using presenting clinical features. METHODS: We analyzed a cohort of 3069 patients less than 50 years of age, diagnosed with primary osteosarcoma of the bone between 1986 and 2013 from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly split into test and validation cohorts. Optimal cut points for age, tumor size, and grade were identified using classification and regression tree analysis. Manual recursive partitioning was used to identify discrete prognostic groups within the test cohort. These groups were applied to the validation cohort, and overall survival was analyzed using Cox models, Kaplan Meier methods, and log-rank tests. RESULTS: After applying recursive partitioning to the test cohort, our initial model included six groups. Application of these groups to the validation cohort resulted in four final groups. Key risk factors included presence of metastases, tumor site, tumor grade, age, and tumor size. Patients with localized axial tumors were identified as having similar outcomes to patients with metastases. Age and tumor size were only prognostically important in patients with extremity tumors when assessed in the validation cohort. CONCLUSIONS: This analysis supports prior reports that patients with axial tumors are a high-risk group, and demonstrates the importance of age and tumor size in patients with appendicular tumors. Biologic and genetic markers are needed to further define subgroups in osteosarcoma.

Role of bone marrow biopsy for staging new patients with Ewing sarcoma: A systematic review.

The incidence of bone marrow metastasis (BMM) in newly diagnosed Ewing sarcoma (ES) is variable across studies. An optimal staging strategy for detecting BMM is not defined. While bone marrow (BM) biopsy and/or aspirate (BMBA) have been the gold standard, [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) to detect BMM may decrease reliance on BMBA. We conducted a systematic review to assess incidence of BMM and the role of FDG-PET. We observed a pooled incidence of BMM by BMBA of 4.8% in all newly diagnosed ES patients and 17.5% among patients with metastatic disease. Only 1.2% of patients had BMM as their sole metastatic site. FDG-PET detection of BMM compared to BMBA demonstrated pooled 100% sensitivity and 96% specificity, positive predictive value of 75%, and negative predictive value of 100%. In the era of FDG-PET imaging, omission of BMBA may be considered in patients with otherwise localized disease after initial staging studies.

Landscape of phase 1 clinical trials for minors with cancer in the United States.

OBJECTIVES: Understanding trends in characteristics of early phase trials that allow minors with cancer to participate may inform additional efforts to improve cancer drug development for young people. METHODS: We accessed data for oncology phase 1 or phase 1/2 trials in the United States from ClinicalTrials.gov with lower age bound for eligibility <18 years. Descriptive statistics were calculated and trends over time evaluated using logistic and multinomial logistic regression. RESULTS: Six hundred twelve trials met inclusion criteria. Sixty-five percent of trials were for older adults that also allowed minors, while 9% were exclusively for patients ≤18 years of age. Eighty-three percent of trials included at least one novel agent, while 17% studied only conventional therapies. Fifty-eight percent of trials studied treatments not yet Food and Drug Administration (FDA) approved (48% if exclusively for patients ≤18 years). Fifteen percent of trials for which dose-escalation method could be determined, utilized a model-based design. Eighteen percent of all trials were industry sponsored (48% if exclusively for patients ≤18 years). Forty-nine percent of all trials were multicenter (69% if exclusively for patients ≤18 years). There was an increase in trials exclusively focused on patients with central nervous system (CNS) tumors over the study period (P ≤ .02). No other temporal trends were seen. The median times from first-in-adult to first-in-pediatric for monotherapy and combination trials were 5.7 and 3.3 years, respectively. CONCLUSION: The paucity of clear temporal trends highlights the need for innovation in early drug development for young people. Our analysis serves as a benchmark against which to evaluate initiatives to improve pediatric cancer drug development.

Off-label prescribing of targeted anticancer therapy at a large pediatric cancer center.

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 < 30 years old treated for cancer from 2007 to 2017. Dosing strategies were adjusted for body size and compared to FDA-approved adult dosing regimen. A composite toxicity endpoint was defined as a patient having unplanned clinic visits, emergency department visits, or unplanned hospital admissions that were at least possibly related to the off-label treatment. RESULTS: The overall prevalence of off-label use of targeted therapies was 9.2% (n = 374 patients). The prevalence increased significantly over the study period (P < .0001). Patients treated off-label were more likely to have neuro-oncology diagnoses compared to patients not treated off-label (46% vs 29%; P < .0001). Of the 108 potential agents, 38 (35%) were used by at least one patient. The median starting dose was below the FDA-approved normalized dose for 44.4% of agents. Fifteen percent of patients had a complete response while receiving off-label therapy, 38% experienced toxicity as defined, and 13% discontinued off-label therapy due to toxicity. CONCLUSIONS: In this real-world evaluation of prescribing at a large pediatric cancer center, off-label prescribing of FDA-approved targeted therapies was common, increasing in prevalence, encompassed a broad sample of targeted agents, and was tolerable. Clinicians commonly start dosing below the equivalent FDA-approved dose.

The use of interval-compressed chemotherapy with the addition of vincristine, irinotecan, and temozolomide for pediatric patients with newly diagnosed desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare aggressive sarcoma that affects children and young adults, and portends poor outcomes despite intensive multimodal treatment approaches. We report toxicity, response, and outcomes of patients with DSRCT treated with the addition of vincristine, irinotecan, and temozolomide (VIT) to interval-compressed chemotherapy as per Children's Oncology Group ARST08P1. METHODS: All newly diagnosed pediatric patients with DSRCT treated at Dana-Farber Cancer Institute and Boston Children's Hospital between 2014 and 2019 as per ARST08P1, Arm P2 with replacement of VAC cycles with VIT, were identified. Medical records were reviewed for clinical and disease characteristics, and treatment response and outcomes. RESULTS: Six patients were treated as per the above regimen. Median age at diagnosis was 15.1 years (range 3.2-16.4) and five patients were male. Five patients had abdominal primary tumors, of which one had exclusively intraabdominal and four had extraabdominal metastases. Two initial cycles of VIT were well tolerated with nausea, vomiting, diarrhea, and constipation as the most common adverse events. Overall response rate defined as partial or complete response after two initial cycles of VIT was 50%. For local control, all patients had surgical resection followed by radiotherapy, and two patients received hyperthermic intraperitoneal chemotherapy at the time of surgery. Of the four patients who have completed therapy to date, three remain disease-free with median follow-up time of 46.7 months. CONCLUSIONS: The addition of VIT to interval-compressed chemotherapy is tolerable and active in DSRCT, with activity warranting additional investigation.

Using Liquid Biopsy in the Treatment of Patient with OS.

Liquid biopsies encompass a number of new technologies designed to derive tumor data through the minimally invasive sampling of an accessible body fluid. These technologies remain early in their clinical development, and applications for patients with osteosarcoma are actively under investigation. In this chapter, we outline the current state of liquid biopsy technologies as they apply to cancer generally and osteosarcoma specifically, focusing on assays that detect and profile circulating tumor DNA (ctDNA), microRNAs (miRNA), and circulating tumor cells (CTCs). At present, ctDNA assays are the most mature, with multiple assays demonstrating the feasibility of detecting and quantifying ctDNA from blood samples of patients with osteosarcoma. Initial studies show that ctDNA can be detected in the majority of patients with osteosarcoma and that the detection and level of ctDNA correlates with a worse prognosis. Profiling of ctDNA can also identify specific somatic events that may have prognostic relevance, such as 8q gain in osteosarcoma. miRNAs are stable RNAs that regulate gene expression and are known to be dysregulated in cancer, and patterns of miRNA expression have been evaluated in multiple studies of patients with osteosarcoma. While studies have identified differential expression of many miRNAs in osteosarcomas compared to healthy controls, a consensus set of prognostic miRNAs has yet to be definitively validated. Recent studies have also demonstrated the feasibility of capturing CTCs in patients with osteosarcoma. The development of assays that quantify and profile CTCs for use as prognostic biomarkers or tools for biologic discovery is still in development. However, CTC technology holds incredible promise given the potential to perform multi-omic approaches in single cancer cells to understand osteosarcoma heterogeneity and tumor evolution. The next step required to move liquid biopsy technologies closer to helping patients will be wide-scale collection of patient samples from large prospective studies.