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.

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with 131I-MIBG therapy in high-risk neuroblastoma.

Background: Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. Here we explore whether AURKA inhibition potentiates a response to MIBG therapy. Results: Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels. Conclusion: The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models and is a promising clinical approach in high-risk neuroblastoma.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131 I-MIBG in patients with relapsed/refractory neuroblastoma.

BACKGROUND: Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. METHODS: Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. RESULTS: Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for

Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma.

INTRODUCTION: NUT carcinoma (NC) is an underdiagnosed and aggressive poorly differentiated or squamous cell cancer. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown. Experts have recommended platinum- and ifosfamide-based therapy based on case reports. METHODS: Patients with pathologically confirmed NC with known survival outcomes after chemotherapy and consented to participate in a worldwide registry were studied. Results were summarized using descriptive methods. RESULTS: The study included 118 patients with NC. Median age was 34 (range: 1-82) years, 39% were women, and 61% harbored a BRD4::NUTM1 fusion. Patients received platinum (74%) or ifosfamide (26%, including regimens with both, 13%). Of 62 patients with nonmetastatic disease, 40% had a thoracic primary. Compared with platinum-based chemotherapy, patients who received ifosfamide-based chemotherapy had nominally higher progression-free survival (12 mo: 59% [95% CI: 32-87] versus 37% [95% CI: 22-52], hazard ratio = 0.68 [0.32, 1.42], p = 0.3) but not overall survival (OS). Among the 56 patients with metastatic disease, 80% had a thoracic primary. Ifosfamide had an objective response rate (ORR) of 75% (six of eight) and platinum had an ORR of 31% (11 of 36). Nevertheless, there was no difference in progression-free survival or OS. The 3-year OS of the entire cohort was 19% (95% CI: 10%-28%). Of the 11 patients alive greater than 3 years, all presented with nonmetastatic and operable or resectable disease. CONCLUSION: There is a numerically higher ORR for ifosfamide-based therapy compared with platinum-based therapy, with limited durability. OS at 3 years is only 19%, and development of effective therapies is an urgent unmet need for this patient population.

Reporting and impact of subsequent cycle toxicities in oncology phase I clinical trials.

BACKGROUND/AIMS: As oncology treatments evolve, classic assumptions of toxicity associated with cytotoxic agents may be less relevant, requiring new design strategies for trials intended to inform dosing strategies for agents that may be administered beyond a set number of defined cycles. We describe the overall incidence of dose-limiting toxicities during and after cycle 1, frequency of reporting subsequent cycle toxicities, and the impact of post-cycle 1 dose-limiting toxicities on conclusions drawn from oncology phase 1 clinical trials. METHODS: We conducted a systematic review of subsequent cycle toxicities in oncology phase I clinical trials published in the Journal of Clinical Oncology from 2000 to 2020. We used chi-square tests and multivariate logistic regression to describe predictors of reporting subsequent cycle toxicity data. RESULTS: From 2000 to 2020, we identified 489 articles reporting on therapeutic phase 1 clinical trials. Of these, 421 (86%) reported data regarding cycle 1 dose-limiting toxicities and 170 (35%) reported data on cycle 1 dose modifications. Of the trials that reported cycle 1 dose-limiting toxicities, the median percentage of patients that experienced cycle 1 dose-limiting toxicities was 8.89%. Only 47 (9.6%) publications reported on post-cycle 1 dose-limiting toxicities and only 92 (19%) reported on dose modifications beyond cycle 1. Of the trials that reported post-cycle 1 dose-limiting toxicities, the median percentage of patients that experienced post-cycle 1 dose-limiting toxicities was 14.8%. Among the 371 studies with a recommended phase 2 dose, 89% did not report whether post-cycle 1 toxicities impacted the recommended phase 2 dose. More recent year of publication was independently associated with reduced odds of reporting subsequent cycle toxicity. CONCLUSION: Reporting of subsequent cycle toxicity is uncommon in oncology phase I clinical trial publications and becoming less common over time. Guidelines for reporting of phase I oncology clinical trials should expand to include toxicity data beyond the first cycle.

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.

Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; PC [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.

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.

Children's Oncology Group's 2023 blueprint for research: Bone tumors.

The Children's Oncology Group (COG) Bone Tumor Committee is responsible for clinical trials and biological research on localized, metastatic, and recurrent osteosarcoma and Ewing sarcoma (EWS). Results of clinical trials in localized disease completed and published in the past 10 years have led to international standard-of-care chemotherapy for osteosarcoma and EWS. A recent focus on identifying disease subgroups has led to the identification of biological features associated with poor outcomes including the presence of circulating tumor DNA (ctDNA) at diagnosis, and specific genomic alterations-MYC amplification for osteosarcoma and STAG2 and TP53 mutation for EWS. Studies validating these potential biomarkers are under way. Clinical trials evaluating the addition of multitargeted kinase inhibitors, which are active in relapsed bone sarcomas, to standard chemotherapy are under way in osteosarcoma and planned in EWS. In addition, the Committee has data analyses and a clinical trial under way to evaluate approaches to local management of the primary tumor and metastatic sites. Given the rarity of bone sarcomas, we have prioritized international interactions and are in the process of forming an international data-sharing consortium to facilitate refinement of risk stratification and study of rare disease subtypes.

Children's Oncology Group's 2023 blueprint for research: Neuroblastoma.

Neuroblastoma is the most common extra-cranial solid tumor in children and is known for its clinical heterogeneity. A greater understanding of the biology of this disease has led to both improved risk stratification and new approaches to therapy. Outcomes for children with low and intermediate risk disease are excellent overall, and efforts to decrease therapy for such patients have been largely successful. Although survival has improved over time for patients with high-risk disease and treatments evaluated in the relapse setting are now being moved into earlier phases of treatment, much work remains to improve survival and decrease therapy-related toxicities. Studies of highly annotated biobanked samples continue to lead to important insights regarding neuroblastoma biology. Such studies, along with correlative biology studies incorporated into therapeutic trials, are expected to continue to provide insights that lead to new and more effective therapies. A focus on translational science is accompanied by an emphasis on new agent development, optimized risk stratification, and international collaboration to address questions relevant to molecularly defined subsets of patients. In addition, the COG Neuroblastoma Committee is committed to addressing the patient/family experience, mitigating late effects of therapy, and studying social determinants of health in patients with neuroblastoma.

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.

A single-institution pediatric and young adult interventional oncology collaborative: Novel therapeutic options for relapsed/refractory solid tumors.

BACKGROUND: Pediatric interventional oncology (PIO) is a growing field intended to provide additional or alternative treatment options for pediatric patients with benign or malignant tumors. Large series of patients treated uniformly and subjected to rigorous endpoints for efficacy are not available. METHODS: We designed a collaborative initiative to capture data from pediatric patients with benign and malignant tumors who underwent a therapeutic interventional radiology procedure. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized as a measure of radiologic response and data were collected regarding improvement in pain and functional endpoints. Cumulative incidence of progressive disease was calculated using both the treated site and the patient as the analytic unit. FINDINGS: Forty patients, 16 with malignant tumors and 24 with benign tumors, underwent a total of 88 procedures. Cryo- and radiofrequency ablation were the most frequently utilized techniques for both cohorts of patients. A complete or partial response, or prolonged disease stability, were achieved in approximately 40% of patients with malignant tumors and 60% of patients with benign tumors. No patients had progressive disease as their best response. Resolution of pain and improved mobility with return-to-baseline activity were demonstrated across patients from both cohorts. Only minor complications were experienced. INTERPRETATION: Interventional radiology-guided interventions can serve as an alternative or complementary approach to the treatment of benign and malignant tumors in pediatric patients. Prospective, multi-institutional trials are required to adequately study utility, treatment endpoints, and durability of response.

Clinical development of new drugs for adults and children with cancer, 2010-2020.

BACKGROUND: Many new molecular entities enter clinical development to evaluate potential therapeutic benefits for oncology patients. We characterized adult and pediatric development of the set of new molecular entities that started clinical testing in 2010-2015 worldwide. METHODS: We extracted data from AdisInsight, an extensive database of global pharmaceutical development, and the FDA.gov website. We followed the cohort of new molecular entities initiating first-in-human phase I clinical trials in 2010-2015 to the end of 2020. For each new molecular entity, we determined whether it was granted US Food and Drug Administration (FDA) approval, studied in a trial open to pediatric enrollment, or stalled during development. We characterized the cumulative incidence of these endpoints using statistical methods for censored data. RESULTS: The 572 new molecular entities starting first-in-human studies in 2010-2015 were studied in 6142 trials by the end of 2020. Most new molecular entities were small molecules (n = 316, 55.2%), antibodies (n = 148, 25.9%), or antibody-drug conjugates (n = 44, 7.7%). After a mean follow-up of 8.0 years, 173 new molecular entities did not advance beyond first-in-human trials, and 39 were approved by the FDA. New molecular entities had a 10.4% estimated probability (95% confidence interval = 6.6% to 14.1%) of being approved by the FDA within 10 years of first-in-human trials. After a median of 4.6 years since start of first-in-human trials, 67 (11.7%) new molecular entities were tested in trials open to pediatric patients, and 5 (0.9%) were approved for pediatric indications. CONCLUSIONS: More efficient clinical development strategies are needed to evaluate new cancer therapies, especially for children, and incorporate approaches to ensure knowledge gain from investigational products that stall in development.

Ewing Sarcoma Drug Therapy: Current Standard of Care and Emerging Agents.

Ewing sarcoma is a translocation-associated sarcoma mainly impacting adolescents and young adults. The classic translocation (EWSR1::FLI1) leads to a fusion oncoprotein that functions as an aberrant transcription factor. As such, the oncogenic driver of this disease has been difficult to target pharmacologically and, therefore, the systemic therapies used to treat patients with Ewing sarcoma have typically been non-selective cytotoxic chemotherapy agents. The current review highlights recent clinical trials from the last decade that provide the evidence base for contemporary drug therapy for patients with Ewing sarcoma, while also highlighting novel therapies under active clinical investigation in this disease. We review recent trials that have led to the establishment of interval-compressed chemotherapy as an international standard for patients with newly diagnosed localized disease. We further highlight recent trials that have shown a lack of demonstrable benefit from high-dose chemotherapy or IGF-1R inhibition for patients with newly diagnosed metastatic disease. Finally, we provide an overview of chemotherapy regimens and targeted therapies used in the management of patients with recurrent Ewing sarcoma.

Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents.

PURPOSE: There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders. METHODS: After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved. RESULTS: Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements. CONCLUSION: An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer.

A global collaboRAtive study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl).

BACKGROUND: Undifferentiated small round cell sarcomas (URCSs) represent a diagnostic challenge, and their optimal treatment is unknown. We aimed to define the clinical characteristics, treatment, and outcome of URCS patients. METHODS: URCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centres were retrospectively identified. Based on molecular assessment, cases were classified as follows: (1) CIC-rearranged round cell sarcomas, (2) BCOR::CCNB3-rearranged round cell sarcomas, (3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed. RESULTS: In total, 148 patients were identified [88/148 (60%) CIC-rearranged sarcoma (median age 32 years, range 7-78), 33/148 (22%) BCOR::CCNB3-rearranged (median age 17 years, range 5-91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4-70)]. One hundred-one (68.2%) cases presented with localised disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site, and a low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5-98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7-51.3) in CIC-rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1-90.6; p < 0.0001). CONCLUSIONS: This study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype.

Circulating Tumor DNA Is Prognostic in Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group.

PURPOSE: Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought to evaluate strategies for identifying circulating tumor DNA (ctDNA) in IR RMS and to determine whether ctDNA detection before therapy is associated with outcome. PATIENTS AND METHODS: Pretreatment serum and tumor samples were available from 124 patients with newly diagnosed IR RMS from the Children's Oncology Group biorepository, including 75 patients with fusion-negative rhabdomyosarcoma (FN-RMS) and 49 with fusion-positive rhabdomyosarcoma (FP-RMS) disease. We used ultralow passage whole-genome sequencing to detect copy number alterations and a new custom sequencing assay, Rhabdo-Seq, to detect rearrangements and single-nucleotide variants. RESULTS: We found that ultralow passage whole-genome sequencing was a method applicable to ctDNA detection in all patients with FN-RMS and that ctDNA was detectable in 13 of 75 serum samples (17%). However, the use of Rhabdo-Seq in FN-RMS samples also identified single-nucleotide variants, such as MYOD1L122R, previously associated with prognosis. Identification of pathognomonic translocations between PAX3 or PAX7 and FOXO1 by Rhabdo-Seq was the best method for measuring ctDNA in FP-RMS and detected ctDNA in 27 of 49 cases (55%). Patients with FN-RMS with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (event-free survival, 33.3% v 68.9%; P = .0028; overall survival, 33.3% v 83.2%; P < .0001) as did patients with FP-RMS (event-free survival, 37% v 70%; P = .045; overall survival, 39.2% v 75%; P = .023). In multivariable analysis, ctDNA was independently associated with worse prognosis in FN-RMS but not in the smaller FP-RMS cohort. CONCLUSION: Our study demonstrates that baseline ctDNA detection is feasible and is prognostic in IR RMS.

Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group.

PURPOSE: Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS: Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS: Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION: Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

Clinical and biological features prognostic of survival after relapse or progression of INRGSS stage MS pattern neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

BACKGROUND: Outcomes for patients with INRGSS metastatic special (MS) metastatic pattern neuroblastoma at initial diagnosis are well described. Prognosis after an initial event (relapse, progression, secondary malignancy) is unclear. METHODS: We investigated characteristics of MS pattern neuroblastoma patients in the International Neuroblastoma Risk Group database who subsequently experienced an event. Post-event overall survival (OS) ± standard error was calculated overall and by diagnosis era: before 2000 versus 2001 or after. Cox models were used to identify factors prognostic of post-event OS. RESULTS: Among 209 patients with an event, 88% were less than 365 days old at diagnosis; tumors were MYCN amplified in 24% and diploid in 33%. The median (range) time from diagnosis to first event was 8.16 months (7 days to 11.24 years). Of 96 patients with known relapse/progression pattern, 75% were metastatic or primary plus metastatic. Five-year post-event OS was 53% ± 3.6% and was higher for 2001 and afterwards (62% ± 5.0%) compared to before 2001 (44% ± 4.9%; p = .0046). In patients diagnosed in 2001 and after, older age, Hispanic ethnicity, MYCN amplification, 1p LOH, diploidy, high Mitotic Karyorrhexis Index, high lactate dehydrogenase (LDH), unfavorable histology, and longer time to first event were prognostic of worse post-event OS. Independent adverse prognostic factors on multivariable testing were non-White race, MYCN amplification, and diploidy. SUMMARY: Patients diagnosed in and after 2001 have substantially better post-event OS compared to before 2001. In those diagnosed in and after 2001, most well-accepted prognostic factors for OS at diagnosis are also prognostic of post-event OS. Future studies may evaluate strategies to improve outcomes in this rare population.

Early Termination of Oncology Clinical Trials in the United States.

PURPOSE: The aim of this study was to evaluate the rate of early trial discontinuation of oncology trials and reasons for early termination, to assess potential trends in rates of oncology trial termination, and to perform a comprehensive analysis of predictors of early termination. This study intends to inform efforts in improving efficiency of the oncology clinical trial enterprise. METHODS: We conducted a cross-sectional study of interventional cancer clinical trials registered in ClinicalTrials.gov database from September 27, 2007 to June 30, 2015, with at least one site listed in the United States. We evaluated predictors of early trial termination using Fisher exact or χ2 tests and logistic regression. RESULTS: Of 8687 trials, 22.74% (n = 1975) were terminated trials. Rates of early trial termination appeared stable over the study. Statistically significant univariate predictors of early termination for any reason include cancer category, phase, funding source, location, and age. In multivariable analysis, trials spanning multiple cancer categories and international trials were less likely to terminate early whereas phase 2 trials and trials funded by academia/foundation were more likely to terminate early. The most common reason for early termination was "Other, Multiple Reasons, or Unknown" (36.9%), followed by accrual issues (34.5%). In multivariate analysis among all terminated trials, supportive care trials, phase 2 trials, and non-industry funded trials had significantly higher odds of trial discontinuation specifically due to poor accrual. CONCLUSION: In this national sample of cancer clinical trials, early trial discontinuation was common. Many factors influenced early trial termination with poor accrual being a common reason. Specific trial features are associated with differential likelihood of early trial termination for any reason and for early trial termination due to poor accrual.