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In this single-arm, non-randomized, phase 2 trial (NCT03363373), 74 patients with relapsed/refractory high-risk neuroblastoma and residual disease in bone/bone marrow (BM) received naxitamab on Days 1, 3, and 5 (3 mg/kg/day) with granulocyte-macrophage colony-stimulating factor (Days -4 to 5) every 4 weeks, until complete response (CR) or partial response (PR) followed by 5 additional cycles every 4 weeks. Primary endpoint in the prespecified interim analysis was overall response (2017 International Neuroblastoma Response Criteria). Among 26 responders (CR + PR) in the efficacy population ( N  = 52), 58% had refractory disease, and 42% had relapsed disease. Overall response rate (ORR) was 50% (95% CI: 36-64%), and CR and PR were observed in 38% and 12%, respectively. With the 95% CI lower limit for ORR exceeding 20%, the primary endpoint of overall response was met. Patients with evaluable bone disease had a 58% (29/50) bone compartment response (CR, 40%; PR, 18%). BM compartment response was 74% (17/23; CR, 74%). One-year overall survival and progression-free survival (secondary endpoints) were 93% (95% CI: 80-98%) and 35% (95% CI: 16-54%), respectively. Naxitamab-related Grade 3 adverse events included hypotension (58%) and pain (54%). Overall, naxitamab demonstrated clinically meaningful efficacy with manageable safety in patients with residual neuroblastoma in bone/BM. Neuroblastoma is an aggressive childhood cancer with poor prognosis and limited therapeutic options. Here the authors report the results of a phase 2 trial of the anti-GD2 monoclonal antibody naxitamab plus GM-CSF for relapsed or refractory high-risk neuroblastoma.

Realising the potentially substantial benefits of chimeric antigen receptor (CAR) T-cell therapy for children with cancer is hindered by non-scientific barriers that are also relevant for other rare diseases. A solely commercial development model will not deliver optimally due to insufficient return on investment for pharmaceutical companies. Access to therapies is restricted for patients who might benefit and advancing innovation in the academic research setting is difficult. Challenges relating to CAR T-cell therapies in paediatric malignancies and how they might be addressed were discussed in a meeting convened by ACCELERATE—an international multistakeholder organisation aiming to advance the timely investigation of new anticancer drugs. New academic and biopharma hybrid development models could benefit rare populations and coordination of early development can promote synergy and avoid duplicative efforts. Following promising first-in-child trials, new models are needed to support pivotal trials, decentralised manufacturing, registration, and reduced costs. The European Medicines Agency and the US Food and Drug Administration encourage academic development and early discussions. A biotech company funded via a pooled investment vehicle could provide access to safe and effective products for children and adolescents with cancer through registration and reimbursement.

To analyse the internal consistency of an adaption of the methotrexate intolerance severity score (MISS); and to describe and compare the level of methotrexate intolerance evaluated by the MISS in Danish children with juvenile idiopathic arthritis (JIA) or acute lymphoblastic leukaemia (ALL), treated with low-dose methotrexate (MTX). Cross-sectional study of children diagnosed with JIA or ALL, treated with low-dose MTX, aged 9 years or above, and cognitively intact. The patient's parents completed the MISS. MTX intolerance was defined as a total MISS score above 6. We enrolled 120 children with JIA and 23 children with ALL. The MISS had a good internal consistency in the JIA group. The median MISS score was higher in the JIA group than in the ALL group (JIA: 8; ALL: 1; p<0.0001); and the JIA group had a larger proportion of MTX intolerant children than the ALL group (JIA: 73/120; ALL: 4/23; p<0.001). Within both the JIA group and the ALL group, the MISS total score was not significantly correlated with age, MTX dose or the duration of low-dose MTX treatment. In the JIA group the level of MTX intolerance was higher and more attributed to anticipatory, associative and behavioural symptoms than in the ALL group. The MISS may help to uncover whether MTX intolerance is present and which aspects are affected in the individual patient, thus guiding intervention. The MISS may also be applicable within leukaemia care.

Background Naxitamab is a humanized GD2‐binding monoclonal antibody that received accelerated approval from the U.S. Food and Drug Administration for refractory or relapsed high‐risk neuroblastoma limited to bone or bone marrow. Trial 201 (NCT03363373) is an ongoing global clinical trial to evaluate the efficacy and safety of naxitamab in combination with granulocyte‐macrophage colony‐stimulating factor in this population. Aims Here, we review the safety profile and adverse event (AE) management associated with naxitamab administration in a pediatric population, based on Trial 201 protocol guidelines and clinical trial experience. Methods and Results At least 50% of patients experienced pain, hypotension, bronchospasm, cough, vomiting, diarrhea, nausea, and tachycardia, with the following reported at grade ≥3 AEs for at least 10% of patients: pain, hypotension, urticaria, and bronchospasm. These AEs were generally manageable in the outpatient setting using premedications, supportive therapies, and appropriate monitoring post‐infusion. Algorithms were established for infusion‐related AEs, including hypotension and bronchospasm, to provide guidance to investigators for early recognition and timely intervention, including medication and infusion rate modification or interruption, or treatment discontinuation, based on AE severity. Educating patients and caregivers on what to expect regarding premedication at home, experience during the infusion cycle, and post‐infusion monitoring helps optimize naxitamab treatment and supportive therapies and may reduce treatment burden. Conclusion This article highlights the protocol‐based recommendations for the management of acute AEs associated with outpatient naxitamab treatment in Trial 201. The authors recommend close monitoring and timely implementation of measures to ensure that patients can remain on treatment and obtain maximum clinical benefit from naxitamab therapy.

Background Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. Methods This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1–4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. Discussion Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. Trial registration Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.

Background Optimal alignment is of utmost importance when treating pediatric patients with craniospinal irradiation (CSI), especially with regards to field junctions and multiple isocenters and techniques applying high dose gradients. Here, we investigated the setup errors and uncertainties for pediatric CSI using different setup verification protocols. Methods A total of 38 pediatric patients treated with CSI were identified for whom treatment records and setup images were available. The setup images were registered retrospectively to the reference image using an automated tool and matching on bony anatomy, subsequently, the impact of different correction protocols was simulated. Results For an action-level (AL)-protocol and a non-action level (NAL)-protocol, the translational residual setup error can be as large as 24 mm for an individual patient during a single fraction, and the rotational error as large as 6.1°. With daily IGRT, the maximum setup errors were reduced to 1 mm translational and 5.4° rotational versus 1 mm translational and 2.4° rotational for 3- and 6- degrees of freedom (DoF) couch shifts, respectively. With a daily 6-DoF IGRT protocol for a wide field junction irradiation technique, the residual positioning uncertainty was below 1 mm and 1° for translational and rotational directions, respectively. The largest rotational uncertainty was found for the patients’ roll even though this was the least common type of rotational error, while the largest translational uncertainty was found in the patients’ anterior-posterior-axis. Conclusions These results allow for informed margin calculation and robust optimization of treatments. Daily IGRT is the superior choice for setup of pediatric patients treated with CSI, although centers that do not have this option could use the results presented here to improve their margins and uncertainty estimates for a more accurate treatment alignment.

Children with relapsed acute leukemia have a poor prognosis; current relapse treatments are toxic, and novel treatments are needed. The anti‐CD38 antibody isatuximab is approved for relapsed‐refractory multiple myeloma in adults. We present results of the ISAKIDS study (NCT03860844) investigating isatuximab in children with relapsed‐refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). This Phase 2, single‐arm, multicenter, open‐label study enrolled children aged 28 days to <18 years. Patients received isatuximab 20 mg/kg induction on Day 1, then weekly for 5 weeks (ALL) or 3 weeks (AML). Standard salvage chemotherapy was added on Day 8. Participants showing possible response could receive consolidation with every‐other‐week isatuximab (two doses) plus chemotherapy (T‐ALL, B‐ALL) or optional second induction (AML). The primary endpoint was the complete response (CR) rate (proportion with CR or CR with incomplete peripheral recovery [CRi]). CR/CRi was observed for 32/59 (54%) evaluable patients (B‐ALL, 13/25 [52%]; T‐ALL, 5/11 [45%]; and AML, 14/23 [61%]). Secondary endpoints included minimal residual disease (MRD) status and safety. Based on local and central analysis, 56% (18/32) of CR/CRi patients reached MRD negativity using 10−4 sensitivity threshold for ALL and 10−3 sensitivity threshold for AML. One event of fatal cytokine release syndrome was reported in a patient with a high baseline white blood cell count, leading to trial adaptation. The toxicity of isatuximab with chemotherapy was otherwise manageable. Despite initial evidence of efficacy of isatuximab combined with intensive chemotherapy, CR/CRi rates did not meet stringent prespecified criteria to proceed to ISAKIDS Stage 2 (≥60% [T‐ALL] and ≥70% [B‐ALL and AML]).

-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy. We studied the safety and efficacy of blinatumomab, a bispecific T-cell engager molecule targeting CD19, in infants with -rearranged ALL. Thirty patients younger than 1 year of age with newly diagnosed -rearranged ALL were given the chemotherapy used in the Interfant-06 trial with the addition of one postinduction course of blinatumomab (15 μg per square meter of body-surface area per day; 28-day continuous infusion). The primary end point was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Minimal residual disease (MRD) was measured by polymerase chain reaction. Data on adverse events were collected. Outcome data were compared with historical control data from the Interfant-06 trial. The median follow-up was 26.3 months (range, 3.9 to 48.2). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary end point occurred. Ten serious adverse events were reported (fever [4 events], infection [4], hypertension [1], and vomiting [1]). The toxic-effects profile was consistent with that reported in older patients. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (<5×10 [i.e., <5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion. All the patients who continued chemotherapy became MRD-negative during further treatment. Two-year disease-free survival was 81.6% in our study (95% confidence interval [CI], 60.8 to 92.0), as compared with 49.4% (95% CI, 42.5 to 56.0) in the Interfant-06 trial; the corresponding values for overall survival were 93.3% (95% CI, 75.9 to 98.3) and 65.8% (95% CI, 58.9 to 71.8). Blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed -rearranged ALL as compared with historical controls from the Interfant-06 trial. (Funded by the Princess Máxima Center Foundation and others; EudraCT number, 2016-004674-17.).

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 ( n  = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m − 2 once weekly; 600 mg maximum) in patients with BRAF -altered, relapsed/refractory pLGG. Arm 2 ( n  = 60) is an extension cohort, which provided treatment access for patients with RAF -altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n  = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF -altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 . In a phase 2 trial, the oral type II RAF inhibitor tovorafenib exhibited an overall response rate of 67% in patients with BRAF -altered relapsed/refractory pediatric low-grade glioma.