Naxitamab + GM-CSF was effective against chemo-resistant high-risk neuroblastoma (HR-NB), leading to approval by the Food and Drug Administration. We now describe toxicity and outcome of patients treated in first complete remission (CR) with naxitamab plus novel dosing of GM-CSF (nGM-CSF), initiated in February 2021, based on pharmacologic data. Treatment also included an anti-NB vaccine but no prior myeloablative therapy (MAT). This retrospective study covers all first CR HR-NB patients who started the novel naxitamab + nGM-CSF regimen from February 22, 2021 to December 11, 2023. As before, naxitamab (3 mg/kg) was infused on days 1-3-5 (i.e., 3 doses/cycle). Previously, priming doses of GM-CSF 250 μg/m2/day were subcutaneously administered ×5 (days -4 to 0), followed by step-up to 500 μg/m2/day ×5 (days 1 to 5), but now priming doses were ×3 (days -2 to 0) and stepped-up dosing was ×7 (days 1 to 7), that is, through 2 days after the last dose of naxitamab. After completing antibody treatment (5 monthly cycles), patients could receive vaccine. Event-free survival (EFS) and overall survival (OS) were calculated from start of naxitamab + nGM-CSF. Forty-three patients received 157 cycles. Acute toxicities were generally manageable, allowing outpatient treatment. Stepped-up dosing and extended administration of GM-CSF had no associated toxicity, hematological or otherwise. Human anti-human antibody developed in 5/43 (12%) patients. Thirty-four (79%) patients received the vaccine; 9 did not due to relapse (n = 4) and parental choice (n = 5). EFS/OS rates at 24 months were 88%/95% and at 36 months were 80%/95%. Naxitamab + nGM-CSF is a good option to consolidate first CR of HR-NB patients, including those who did not undergo MAT.

Relapse of high-risk neuroblastoma (HR-NB) poses a challenge to cure. Increasing numbers of HR-NB patients achieve post-relapse complete remission (CR) because close monitoring can detect localized disease and novel effective salvage therapies have emerged. We report outcome with immunotherapy using the anti-GD2 monoclonal antibody (mAb) naxitamab and granulocyte-macrophage colony-stimulating factor (GM-CSF) for consolidation of second or later CR in a phase II trial (Clinicaltrials.gov NCT01757626). Cycles included GM-CSF 250 μg/m2/day on days -4-to-0 and increased to 500 μg/m2/day on days +1-to-5, and 3 doses of naxitamab infused (30-to-90 min) on days +1/+3/+5, 3 mg/kg/infusion (9 mg/kg/cycle, i.e., ~270 mg/m2/cycle). Cycles were monthly ×5. Clinical factors assessed regarding prognosis were: MYCN amplification; localized versus widespread prior relapse; 1 versus ≥2 prior relapse(s); previous treatment with anti-GD2 mAb; and time from diagnosis to 1st relapse. Sixty patients were enrolled after 1 (n = 42) or ≥2 (n = 18) prior relapse(s); 27 (45%) had MYCN amplification. Progression-free survival (PFS) rates at 2/5 years were 55%/50%. Prior treatment with naxitamab and prior widespread relapse had significant negative impacts on PFS. Post-protocol patients in CR routinely received an investigational anti-NB vaccine. Two other patients, both with 1 prior relapse, took DFMO. Naxitamb+GM-CSF is a good option to consolidate post-relapse CR of HR-NB. The encouraging long-term outcome cannot be attributed solely to naxitamab+GM-CSF given post-protocol therapies.

10050 Background: Entrectinib is a TRK and ROS1 inhibitor that has shown rapid and durable responses in children with NTRK1/2/3 or ROS1 fusion-positive (fp) extracranial solid or primary CNS tumors in an integrated analysis of the STARTRK-NG (NCT02650401), TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267) trials. These data led to FDA and EMA approval of entrectinib in pediatric patients > 1 month with NTRK fp tumors. Here we present updated data on pediatric patients with ROS1 fp tumors based on the trials listed above to further describe the efficacy and safety of entrectinib in this population. Methods: Eligible pts were TRK/ROS1 inhibitor-naïve, < 18 years old, with locally advanced/metastatic extracranial solid or primary CNS tumors, with measurable or evaluable-only disease. All pts who received ≥1 daily dose of oral entrectinib are included in the safety-evaluable population. Pts who had a ROS1 fusion and were followed for ≥6 months are included in the ROS1 efficacy-evaluable population. Pts received entrectinib until disease progression, unacceptable toxicity, or consent withdrawal. Tumor responses were confirmed by blinded independent central review (BICR) per RECIST v1.1 or RANO criteria. Primary endpoint: confirmed objective response rate (ORR) per BICR. Key secondary endpoints: ORR in pts with baseline measurable disease per BICR; duration of confirmed response (DoR); time to confirmed response (TTR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety. Results: At clinical cut-off (16 July 2024), of the 113 safety-evaluable pts, there were 26 pts in the ROS1 efficacy-evaluable cohort. ORR was 69.2% (95% CI 48.2, 85.7). Median TTR was 1.84 months. Median OS was not evaluable. Median duration of survival follow-up was 29.4 months (range 1–80). Efficacy outcomes are shown in the table. The most common related adverse events were weight gain (37.2%), anemia (36.3%), and AST increase (26.5%). Related fracture events occurred in 23% of pts. Conclusions: Entrectinib yielded rapid and durable responses in pediatric pts with ROS1 fp extracranial solid or primary CNS tumors. The safety profile of entrectinib was consistent with previous reports. Clinical trial information: NCT02650401 ; NCT04589845 ; NCT02568267 . Efficacy ROS1 (N=26) Confirmed ORR*, N, % [95% CI] 18, 69.2 [48.2- 85.7] Complete response 4, 15.4 [4.4- 34.9] Partial response 14, 53.8 [33.4- 73.4] Median confirmed DoR*, months (95% CI) NE (16.2- NE) Median TTR*, months (range) 1.84 (1.6- 4.0) CBR*, % (95% CI) 84.6 (65.1- 95.6) Median PFS*, months (95% CI) NE (21.8- NE) Median OS, months (95% CI) NE (NE- NE) *Per BICR; CI, confidence interval; NE, not evaluable.

Purpose Little is known about local control, toxicity, and survival outcomes associated with reduced-dose radiation therapy (RT) for high-risk neuroblastoma (HR-NB). Methods and Materials In this prospective pilot study, eligible patients had HR-NB with a gross total resection (no tumor evident on postsurgery CT or MRI) of the primary site after induction systemic therapy. Patients were treated with 15 or 18 Gy to the primary site in 1.5 Gy fractions delivered twice daily. The primary outcome was to assess local failure (LF) at the primary site. The secondary outcomes included overall survival (OS), event-free survival (EFS), distant-metastasis-free survival (DMFS), and acute toxicity from RT. Results A total of 78 patients were enrolled between 2014 and 2023 at a single institution. Median follow-up from time of RT was 35 months (interquartile range [IQR] 19-67 months). Median age at the time of RT was 3.8 years (IQR, 2.4-5.6). Forty-seven patients (60%) received proton RT, 53 (68%) received 15 Gy, and 25 (32%) received 18 Gy. Three patients experienced LF at the primary site, all at 15 Gy. At 1 and 5 years post-RT, the rate of LF was 2.6 and 3.9%, respectively. There was no significant difference in the risk of LF by MYCN-amplification status (P = .5). There was no significant difference in OS, EFS, or DMFS between the 15 Gy and 18 Gy cohorts (P = .95, P = .45, and P = .45, respectively). Thirty-two patients (41%) experienced acute toxicity, which included grade 1 to 2 fatigue, nausea, and decreased appetite. Conclusions For patients with HR-NB who have a GTR of the primary site, reduced-dose RT of 15 to 18 Gy is associated with an approximately 96% local control rate with negligible acute toxicity.

Myeloablative therapy (MAT) is included in high‐risk neuroblastoma (HR‐NB) treatment programs of the Children's Oncology Group (COG) and the Societe Internationale d'Oncologie Pediatrique Europe Neuroblastoma (SIOPEN), but not at Memorial Sloan Kettering Cancer Center (MSK). COG and SIOPEN programs achieved 3–5‐year event‐free survival rates of ~50%–60%, similar to the MSK experience without MAT which involved patients treated with COG or MSK induction and anti‐G D2 mAb murine‐3F8 + granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). We now present the first report on rapid COJEC without MAT. This retrospective study covers HR‐NB patients who received rapid COJEC but not MAT and had no prior progressive disease (PD) when referred to MSK during the era of availability of anti‐G D2 mAb naxitamab. The 28 subjects were diagnosed 1/2017–6/2023. Post‐COJEC, 10 had no distant disease (Group 1) and 18 had persistence of metastases (Group 2). Group 1 patients had resection of primary tumors and received 1–2 cycles of HR‐NB regimens (cyclophosphamide‐topotecan ± vincristine), local radiotherapy, and naxitamab + GM‐CSF; 9 also received anti‐NB vaccine. All 10 remain event‐free at median 3.5+ years post‐diagnosis. Group 2 patients received second‐line therapy post‐COJEC, including high‐dose cyclophosphamide + topotecan ± vincristine or cyclophosphamide + doxorubicin + vincristine. Treatment after all chemotherapy included naxitamab + GM‐CSF ± irinotecan‐temozolomide. Thirteen received vaccine. Twelve remain relapse‐free at median 2.4+ years post‐diagnosis, including 3 who developed secondary neoplasms—myelodysplastic syndrome ( n = 2, successfully treated) or thyroid carcinoma. Six developed PD (four are again in complete remission and two died of NB). Avoiding MAT after rapid COJEC does not appear to adversely affect outcome compared to rapid COJEC + MAT.

PURPOSE:Naxitamab is a humanized form of the murine anti-GD2 mAb 3F8. In an international trial, naxitamab + GM-CSF was effective against chemoresistant high-risk neuroblastoma (HR-NB), leading to approval by the FDA. We now report results with patients in first complete remission (CR). PATIENTS AND METHODS:The primary objective of this phase II protocol 16-1643 (Clinicaltrials.gov NCT03033303) was to assess event-free survival of patients with HR-NB in first CR treated with naxitamab + GM-CSF plus isotretinoin. HR-NB was defined as MYCN-amplified disease (any age) or metastatic disease at age >18 months. Cycles of immunotherapy were administered monthly up to five cycles and comprised (i) subcutaneously administered priming doses of GM-CSF 250 μg/m2/day on days -4 to -0 (Wednesday-Sunday), followed by a step-up to 500 μg/m2/day on days +1 to +5 (Monday-Friday) and (ii) naxitamab infused intravenously (30-90") on days +1, +3, and +5 (Monday-Wednesday-Friday, i.e., three doses/cycle). The dosage of naxitamab was 3 mg/kg/infusion (9 mg/kg/cycle, i.e., ∼270 mg/m2/cycle). The dosage of isotretinoin was 160 mg/m2/day started after cycle 2, ×14 days/course, and ×6 courses. RESULTS:Fifty-nine patients with HR-NB (53 stage 4, 6 stage 3) were enrolled from February 2017 to July 2020. At 36 months, event-free/overall survival rates were 73%/93%, but 50 of 59 patients received after protocol treatment (vaccine and/or difluoromethylornithine). Six of 18 relapses were isolated in the central nervous system. Longer time from diagnosis to enrollment was a significantly adverse prognostic factor (P = 0.04). Twenty-one of 59 patients took no isotretinoin. Treatment was tolerable allowing outpatient administration. CONCLUSIONS:Naxitamab + GM-CSF is a good option to consolidate first CR of patients with HR-NB, including those who did not undergo autologous stem-cell transplantation. Efforts to prevent central nervous system relapse are warranted.

Background: Entrectinib, a central nervous system (CNS)-penetrant TRK/ROS1 inhibitor, has demonstrated clinical activity in children with NTRK1/2/3 or ROS1 fusion-positive extracranial solid and CNS tumours. We present integrated data of entrectinib in children with NTRK or ROS1 fusion-positive tumours from the STARTRK-NG, TAPISTRY, and STARTRK-2 trials. Methods: Efficacy analyses were undertaken on TRK/ROS1 inhibitor-na & iuml;ve patients aged <18 years with metastatic/locally advanced NTRK1/2/3 or ROS1 fusion-positive extracranial solid or CNS tumours who received >= 1 entrectinib dose and had >= 6 months of follow-up from enrolment. Tumour responses were confirmed by blinded independent central review (BICR) per RECIST v1.1/RANO criteria. Primary endpoint: BICR-assessed confirmed objective response rate (cORR). Key secondary endpoints: duration of response (DoR); time to response (TtR); safety. Results: As of 16 July 2023, out of 91 safety-evaluable patients, 64 (NTRK: n=44; ROS1: n=20) were efficacy evaluable. In the NTRK and ROS1 subgroups, respectively, median age was 4.0 years and 7.5 years; median survival follow-up was 24.2 months and 27.6 months. cORR was 72.7% (NTRK, 95% confidence interval [CI]: 57.2-85.0) and 65.0% (ROS1, 95% CI: 40.8-84.6). Median DoR was not reached (NTRK, 95% CI: 25.4-not evaluable [NE]); ROS1, 95% CI: 16.2-NE); median TtR was 1.9 months in both subgroups. The most frequently reported treatment-related adverse events included weight gain (35.2 %) and anaemia (31.9 %). Conclusion: Integrated data from three trials confirm entrectinib induces rapid and durable responses in children with NTRK or ROS1 fusion-positive tumours. The increased duration of safety monitoring does not demonstrate new or cumulative toxicity.

With high-risk neuroblastoma, post-induction metastases in bone marrow (BM)/bones confers a poor prognosis but can respond to anti-GD2 antibody, such as naxitamab. We report results of a phase I/II trial. Cycles included GM-CSF and naxitamab infused (30-to-90 min) on days + 1, + 3, + 5. Naxitamab was dose-escalated in the trial’s phase I portion and administered at 9 mg/kg/cycle (i.e., 270 mg/m2/cycle)—the recommended phase II dosage (RP2D)—in the phase II expansion. Cycles were monthly × 5 after a major response, i.e., complete (CR) or partial response. Among 32 subjects, CR was noted in 24 (75

Abstract BACKGROUND Entrectinib (CNS-penetrant, TRK/ROS1 inhibitor) has shown efficacy and safety in children with NTRK/ROS1-fp CNS tumors. We present updated data from an integrated analysis of children with NTRK/ROS1-fp CNS tumors enrolled in three early-phase trials: STARTRK-NG (NCT02650401), TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267). METHODS TRK/ROS1 inhibitor-naïve patients <18 years old (YO) with NTRK/ROS1-fp CNS tumors with measurable/evaluable-only disease, who received ≥1 entrectinib dose before disease progression, unacceptable toxicity, or consent withdrawal, and with ≥6 months’ follow-up were efficacy evaluable. Any <18 YO on study who received ≥1 entrectinib dose, regardless of genetic alteration and follow-up duration, was evaluable for safety. Primary endpoint: blinded independent central review (BICR)-assessed confirmed objective response rate (ORR). Key secondary endpoints: BICR-assessed confirmed ORR in patients with measurable disease; duration of confirmed response (DoR); time to confirmed response (TtR); progression-free survival (PFS); safety. RESULTS On 16 July 2023 (cut-off for analysis), 27 patients were efficacy evaluable (NTRK-fp: n=20; ROS1-fp: n=7). Median age at enrolment: 4.0 Y (NTRK-fp) and 6.0 Y (ROS1-fp); 45.0% (NTRK-fp) and 42.9% (ROS1-fp) of patients received ≥2 prior therapy lines. Median survival follow-up: 26.2 months (NTRK-fp); 36.1 months (ROS1-fp). ORR: 50.0% (NTRK-fp) and 71.4% (ROS1-fp) in efficacy-evaluable patients, and 58.8% (n=10/17; NTRK-fp) and 83.3% (n=5/6; ROS1-fp) in patients with measurable disease. Median DoR: 25.4 months, TtR: 1.9 months, PFS: 23.1 months in NTRK-fp patients. DoR and PFS were not evaluable in ROS1-fp patients; median TtR was 1.9 months. In the safety-evaluable population (N=34), the most common adverse events were weight increase (50.0%), blood creatinine increase and anemia (each 41.2%). Bone fractures were reported in 26.5% of patients. Most fractures occurred in children 2–12 YO (n=7/9). CONCLUSIONS Our analysis confirms the rapid and durable activity of entrectinib in children with NTRK/ROS1-fp primary CNS tumors. The safety profile described was in line with previous reports.

10040 Background: Neuroblastoma (NB) relapsing in the central nervous system (CNS), though uncommon, is historically incurable. However, a multimodality approach has improved long term survival (1). Timely detection of CNS relapse may reduce or prevent morbidity and mortality. In most centers, surveillance for NB includes whole-body MIBG scans but does not require dedicated anatomical brain imaging. At Memorial Sloan Kettering Cancer Center (MSK), head MRI at regular intervals is standard. The objective of this retrospective study was to determine the optimal imaging modality for detecting CNS relapse in NB. Methods: After MSK IRB approval, records of patients with CNS NB seen at MSK from 2004-2023 were evaluated. In most cases, relapse was diagnosed at other institutions before referral to MSK. Analyzed data included symptoms and findings on brain CT/MRI and MIBG scans. Results: Of 206 patients with MIBG-avid CNS NB, 7 were excluded because they had CNS disease at diagnosis. For the remaining 199 patients, median time to CNS relapse from diagnosis was 18 months. 132 (66%) patients had CNS relapse at a median of 9.8 months after achieving complete remission. In 67 patients with prior systemic progression, median time to CNS relapse was 10.9 months from the last relapse. Relapse was isolated to CNS in 130/199 (65%) patients. 118 (59%) patients had neurological symptoms at time of CNS disease; 81(41%) were asymptomatic, relapse being detected on surveillance scans. Multiple (>1) parenchymal lesions were noted in 74 (37%), diffuse leptomeningeal disease without parenchymal involvement in 15 (7%) and solitary lesions in 110 (55%) patients. Median diameter of the largest lesion was 2.7 (range <0.5-6.8) cm. Anatomical imaging was performed with MRI (65%), CT (14%) or both (34%). Of those undergoing both scans, CNS relapse was missed on CT in 4/67 (6%) patients. 137 patients had MIBG scans before resection of CNS relapse. All sites of CNS disease noted on MRI/CT were positive by MIBG in 46 (33%) patients. However, MIBG scan was either totally or partly negative in 69 (50%) and 22 (16%) patients, respectively. Even for lesions ≥2cm in diameter, MIBG was completely negative in 27/57 (47%). MIBG positivity did not correlate with age, size >2cm, MYCN amplification or ALK mutation status (p>0.05 for each). Lesions <1cm and infratentorially located were more likely to be negative on MIBG scan (p<0.05). Lesions in symptomatic patients, dural lesions and hemorrhagic lesions were more likely to be positive on MIBG scan (p< 0.05). Conclusions: CNS relapse is isolated to the brain in most patients. MIBG scan has poor sensitivity for the detection of CNS NB, regardless of size or location. Although CT or MRI are both effective in detecting CNS relapse, the former can miss some lesions. We recommend brain MRI for surveillance of high-risk NB for ≥2 years after initial diagnosis or last systemic relapse. 1. J. Neurooncology 97:409, 2010.

Radiolabeled antibody 131I-omburtamab was administered intraventricularly in patients with leptomeningeal disease under an institutionally approved study (#NCT03275402). Radiation safety precautions were tailored for individual patients, enabling outpatient treatment based on in-depth, evidence-based recommendations for such precautions. The imperative advancement of streamlined therapeutic administration procedures, eliminating the necessity for inpatient isolation and resource-intensive measures, holds pivotal significance. This development bears broader implications for analogous therapies within the pediatric patient demographic. Intraventricular radioimmunotherapy (RIT) with 925–1850 MBq (25–50 mCi) of 131I-omburtamab was administered via the Ommaya reservoir, in designated rooms within the pediatric ambulatory care center. Dosimeters were provided to staff involved in patient care to evaluate exposure during injection and post-administration. Post-administration exposure rate readings from the patient on contact, at 0.3 m, and at 1 m were taken within the first 30 min, and the room was surveyed after patient discharge. Duration of radiation exposure was calculated using standard U.S. Nuclear Regulatory Commission (US NRC) regulatory guidance recommendations combined with mean exposure rates and whole-body clearance estimates. Exposure rate measurements and clearance data provided patient-specific precautions for four cohorts by age: < 3 y/o, 3–10 y/o, 10–18 y/o, and 18+. Post-administration exposure rates for patients ranged from 0.16 to 0.46 µSv/hr/MBq at 0.3 m and 0.03–0.08 µSv/hr/MBq at 1 m. Radiation exposure precautions ranged from 1 to 10 days after release for the four evaluated cohorts. Based on the highest measured exposure rates and slowest whole-body clearance, the longest precautions were approximately 78 https://clinicaltrials.gov/study/NCT03275402 .

The carbohydrate ganglioside GD2/GD3 cancer vaccine adjuvanted by β-glucan stimulates anti-GD2 IgG1 antibodies that strongly correlate with improved progression-free survival (PFS) and overall survival (OS) among patients with high-risk neuroblastoma. Thirty-two patients who relapsed on the vaccine (first enrollment) were re-treated on the same vaccine protocol (re-enrollment). Titers during the first enrollment peaked by week 32 at 751 ± 270 ng/mL, which plateaued despite vaccine boosts at 1.2–4.5 month intervals. After a median wash-out interval of 16.1 months from the last vaccine dose during the first enrollment to the first vaccine dose during re-enrollment, the anti-GD2 IgG1 antibody rose to a peak of 4066 ± 813 ng/mL by week 3 following re-enrollment (p < 0.0001 by the Wilcoxon matched-pairs signed-rank test). Yet, these peaks dropped sharply and continually despite repeated boosts at 1.2–4.5 month intervals, before leveling off by week 20 to the first enrollment peak levels. Despite higher antibody titers, patients experienced no pain or neuropathic side effects, which were typically associated with immunotherapy using monoclonal anti-GD2 antibodies. By the Kaplan–Meier method, PFS was estimated to be 51%, and OS was 81%. The association between IgG1 titer during re-enrollment and β-glucan receptor dectin-1 SNP rs3901533 was significant (p = 0.01). A longer prime–boost interval could significantly improve antibody responses in patients treated with ganglioside conjugate cancer vaccines.

10000 Background: Entrectinib previously yielded durable responses in children with NTRK or ROS1 fusion-positive extracranial solid or primary CNS tumors in STARTRK-NG (NCT02650401). We present updated data from STARTRK-NG, TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267): pediatric patients from these trials were combined to enable an integrated efficacy and safety analysis on a larger cohort than previously. Methods: Eligible patients were TRK or ROS1 inhibitor naïve and aged < 18 years, had locally advanced or metastatic extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion, and had measurable or evaluable-only disease. Once enrolled, patients received ≥1 daily dose of oral entrectinib until disease progression, unacceptable toxicity, or consent withdrawal. Tumor responses were confirmed by blinded independent central review (BICR) per RECIST v1.1 or RANO criteria. Patients were included if they had been followed for ≥6 months. The primary endpoint was confirmed objective response rate (ORR) per BICR. Key secondary endpoints included ORR in patients with baseline measurable disease per BICR, duration of confirmed response (DoR), time to confirmed response (TTR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results: At clinical cutoff (16 July 2023), out of 91 safety-evaluable patients (regardless of fusion), 44 patients in the NTRK cohort and 20 patients in the ROS1 cohort were efficacy evaluable. Median duration of survival follow-up was 24.2 months ( NTRK: range 1–66) and 27.6 months ( ROS1: range 1–73). The ORR was 72.7% (95% CI 57.2–85.0) in the NTRK cohort and 65.0% (95% CI 40.8–84.6) in the ROS1 cohort. In patients with baseline measurable disease, the ORR was 81.1% ( NTRK: n=30/37; 95% CI 64.8–92.0) and 62.5% ( ROS1: n=10/16; 95% CI 35.4–84.8). Efficacy outcomes are shown in the Table. The most common adverse events were pyrexia (50.5%), vomiting (40.7%) and anemia (40.7%). Conclusions: Entrectinib continued to yield rapid and durable responses in pediatric patients with extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion. The safety profile of entrectinib was in line with previous reports. Clinical trial information: NCT02650401 / NCT04589845 / NCT02568267 . [Table: see text]

Objective Limited safety data have been published on fluorine-18 (18F) meta-fluorobenzylguanidine (mFBG), a new PET radiopharmaceutical for imaging neural crest and neuroendocrine tumors. As part of a prospective clinical trial, safety data in patients with neuroblastoma were collected and analyzed. Methods Between April 2015 and January 2022, 27 patients with neuroblastoma underwent 18F-mFBG PET imaging as part of an ongoing single-center phase 1/2 trial (NCT 02348749). Pre- and postinjection safety assessments were performed, including vital sign measurement and observation for occurrence of adverse events (AEs). Results mFBG administration resulted in no significant changes in measured vital signs. Two subjects had transient, grade 1 facial flushing shortly after the administration, which resolved within a few minutes. Neither subject had a clinically significant change in pulse or blood pressure on postadministration measurements. Conclusion In this investigation of the potential clinical utility of mFBG PET imaging, no significant adverse safety signals were noted. Two mild, self-limited AEs were observed, without associated changes in vital signs. No grade 2 or higher AEs were noted. The findings are consistent with a favorable safety profile for mFBG in the target population of patients with neuroblastoma.

INTRODUCTION:Data on ovarian function in neuroblastoma survivors are limited. We sought to determine the prevalence of ovarian dysfunction in a cohort of high-risk neuroblastoma survivors and compare outcomes among survivors treated with and without autologous stem cell rescue (ASCR) preceded by myeloablative chemotherapy. METHODS:Retrospective review of female survivors of high-risk neuroblastoma ≥5 years from diagnosis, diagnosed between 1982 and 2014, and followed in a tertiary cancer center. Participants were divided into two groups: individuals treated with conventional chemotherapy ± radiation ("non-ASCR") (n = 32) or with chemotherapy ± radiation followed by myeloablative chemotherapy with ASCR ("ASCR") (n = 51). Ovarian dysfunction was defined as follicle-stimulating hormone ≥15 mU/mL, while premature ovarian insufficiency (POI) was defined as persistent ovarian dysfunction requiring hormone replacement therapy. Poisson models were used to determine prevalence ratios of ovarian dysfunction and POI. RESULTS:Among 83 females (median attained age: 19 years [range, 10-36]; median follow-up: 15 years [range, 7-36]), 49 (59%) had ovarian dysfunction, and 34 (41%) developed POI. Survivors treated with ASCR were 3.2-fold more likely to develop ovarian dysfunction (95% CI: 1.8-6.0; p < 0.001) and 4.5-fold more likely to develop POI (95% CI: 1.7-11.7; p = 0.002) when compared with those treated with conventional chemotherapy, after adjusting for attained age. Two participants in the non-ASCR group and six in the ASCR group achieved at least one spontaneous pregnancy. DISCUSSION:Ovarian dysfunction is prevalent in female high-risk neuroblastoma survivors, especially after ASCR. Longitudinal follow-up of larger cohorts is needed to inform counseling about the risk of impaired ovarian function after neuroblastoma therapy.

10052 Background: N9 induction for high-risk neuroblastoma was designed to limit non-hematological toxicity (especially ototoxicity) and to prevent relapse in the central nervous system (CNS). N9 builds on 2 novel regimens: high-dose cyclophosphamide-topotecan-vincristine (CTV) and ifosfamide-carboplatin-etoposide (ICE), each with good penetration across the blood-brain barrier. Methods: N9 is a pilot study (Clinicaltrials.gov.NCT04947501) to assess feasibility and safety. Secondary/exploratory objectives include response, collection of peripheral blood stem cells (PBSCs; ≥5x106/kg CD34(+) cells sufficient for ≥2 rescues), tumor resection, and assessment of central nervous system relapse. Early stopping rules centered on excessive delay in timing of chemotherapy. Eligibility criteria included age >1-to-<13 years; 1 prior chemotherapy cycle was allowed. CTCAE Version 5.0 and International Neuroblastoma Response Criteria are used.N9 comprises 4 cycles of chemotherapy. Cycles start after absolute neutrophil count is >500/μL, platelets >100,000/μL, and non-hematologic toxicities grade ≤2. Intervals of 21-28 days between start of cycles are foreseen. PBSC collection and surgery follow >3 cycles. Cycles #1 and #4 (CTV): cyclophosphamide 70mg/kg/day, days 1-2, topotecan 2mg/m2/day, days 1-4, and vincristine 0.067mg/kg, day 1. Cycle #2 (ICE): ifosfamide 1500mg/m2/day, days 1-5, carboplatin 400mg/m2/day, days 1-2, and etoposide 100mg/m2/day, days 1-5. Cycle #3: cyclophosphamide (as in CTV) and 72-hr infusions of doxorubicin 75mg/m2 and vincristine 0.067mg/kg. Results: The target number of 15 patients were enrolled: 10/2021-9/2023; age 1.5–9.8 (median 3.3) years; 14 stage M, 1 stage L2; and 10 post-1 cycle of other chemotherapy. They completed N9 without undue toxicity: all cycles started on time, organ functions remained intact, 11/11 patients tested had no ototoxicity, and acute toxicities were typical for myelosuppression (including uncomplicated fever/neutropenia). Responses were complete (n=6), partial (n=5), and stable disease (n=4). The target number of PBSCs was collected in 12 patients (9-75, median 14 x106/kg CD34(+) cells), 4x106/kg in 2 patients, and pending in 1. All patients had gross total resections of the primary tumor. Post-N9, patients did not undergo transplant, but proceeded to immunotherapy (naxitamab) or chemoimmunotherapy (naxitamab+irinotecan-temozolomide). Of 9 with residual disease post-N9, 7 achieved CR (median of 5.6 months from study entry) and 1 achieved metabolic CR (16 months), though 3 subsequently relapsed (no CNS). Conclusions: N9 shows promise for reducing chemotherapy and long-term toxicity. Less chemotherapy without compromising survival is a realistic goal by virtue of the advances with anti-GD2 monoclonal antibodies which, in combination with GM-CSF+low-dose chemotherapy, are highly effective against chemo-resistant disease in bone/bone marrow. Clinical trial information: NCT04947501 .

Two significant obstacles hinder the advancement of Radiology AI. The first is the challenge of overfitting, where small training data sets can result in unreliable outcomes. The second challenge is the need for more generalizability, the lack of which creates difficulties in implementing the technology across various institutions and practices. A recent innovation, deep neuroevolution (DNE), has been introduced to tackle the overfitting issue by training on small data sets and producing accurate predictions. However, the generalizability of DNE has yet to be proven. This paper strives to overcome this barrier by demonstrating that DNE can achieve satisfactory results in diverse external validation sets. The main innovation of the work is thus showing that DNE can generalize to varied outside data. Our example use case is predicting brain metastasis from neuroblastoma, emphasizing the importance of AI with limited data sets. Despite image collection and labeling advancements, rare diseases will always constrain data availability. We optimized a convolutional neural network (CNN) with DNE to demonstrate generalizability. We trained the CNN with 60 MRI images and tested it on a separate diverse collection of images from over 50 institutions. For comparison, we also trained with the more traditional stochastic gradient descent (SGD) method, with the two variants of (1) training from scratch and (2) transfer learning. Our results show that DNE demonstrates excellent generalizability with 97% accuracy on the heterogeneous testing set, while neither form of SGD could reach 60% accuracy. DNE's ability to generalize from small training sets to external and diverse testing sets suggests that it or similar approaches may play an integral role in improving the clinical performance of AI.

Importance:Among patients with high-risk relapsed metastatic neuroblastoma, oral β-glucan adjuvant during GD2/GD3 ganglioside vaccine boost has stimulated IgG antibody response, which was associated with improved survival; however, the effectiveness of oral β-glucan during the vaccine priming phase remains unproven.Objective:To isolate the adjuvant effect of oral β-glucan on antibody response to GD2/GD3 ganglioside vaccine in patients with high-risk neuroblastoma.Design, Setting, and Participants:In this phase 2 randomized clinical trial, enrolled patients with high-risk neuroblastoma were randomized to 2 groups to receive the GD2/GD3 vaccine at a large cancer center in a major metropolitan area from October 2018 to September 2020. Data were analyzed from October 7, 2021, to February 28, 2022.Interventions:Eligible patients receiving GD2/GD3 vaccine were randomly assigned to group 1 (n = 54) to receive no β-glucan or group 2 (n = 53) to receive an oral β-glucan regimen during the first 5 weeks of vaccine priming. From week 6 onwards, all 107 patients received oral β-glucan during vaccine boost for 1 year or until disease progression.Main Outcomes and Measures:Primary end point was comparison of anti-GD2 IgG1 response before vaccine injection 6 (week 32) in group 1 vs group 2. Seroconversion rate and the association of antibody titer with β-glucan receptor dectin-1 single nucleotide polymorphism (SNP) rs3901533 were also assessed.Results:In all, 107 patients with high-risk neuroblastoma were randomized to the 2 groups: 54 patients (median [range] age, 5.2 [1.0-17.3] years; 28 [52%] male and 26 [48%] female) in group 1; and 53 patients (median [range] age, 6.2 [1.9-18.4] years; 25 [47%] male and 28 [53%] female) in group 2; both groups were also comparable in their first remission status at study entry (70% vs 70%). Adding oral β-glucan during the first 5 weeks of vaccine priming elicited a higher anti-GD2 IgG1 antibody response in group 2 (1.80; 90% CI, 0.12-3.39; P = .08; planned type I error, 0.10). Anti-GD2 IgG1 titer of 230 ng/mL or greater by week 8 was associated with statistically favorable PFS. Antibody titer correlated significantly with dectin-1 SNP. The genotype frequency, seroconversion rates, and vaccine-related toxic effects were similar in the 2 groups.Conclusions and Relevance:This phase 2 randomized clinical trial found that adding oral β-glucan during vaccine priming increased anti-GD2 IgG1 titer among genetic responders without added toxic effects. Because responder dectin-1 SNP was identical in the 2 randomized groups, no difference was detected in seroconversion rates. Alternative or additional adjuvants may be needed to enhance seroconversion.Trial Registration:ClinicalTrials.gov Identifier: NCT00911560.

e22012 Background: In an international trial, the humanized anti-GD2 antibody naxitamab+GM-CSF was effective against chemo-resistant HR-NB, leading to approval by the Food and Drug Administration. We subsequently modified GM-CSF dosing based on a shortened priming period and pharmacokinetics showing prolonged T½ of naxitamab. We investigated safety and efficacy of naxitamab plus GM-CSF administered by a novel schedule in HR-NB patients treated in 1 st CR (Group 1) or with primary refractory disease in bones and/or bone marrow (BM) (Group 2). Methods: Immunotherapy was administered q1-2 months up to 5 cycles in Group 1 and ≥5 cycles after major responses in Group 2. Naxitamab was infused intravenously (30-90”) on days 1/Monday-3/Wednesday-5/Friday (i.e., 3 doses/cycle), 3mg/kg/infusion (9mg/kg/cycle, i.e., ~270mg/m 2 /cycle). Previously, priming doses of GM-CSF 250µg/m 2 /day were subcutaneously-administered x5 (days -4 to 0), followed by a step-up to 500µg/m 2 /day x5 (days 1-to-5), but now priming doses were x3 days (days -2 to 0 [Friday-Saturday-Sunday]) and stepped-up dosing was x7 (days 1-to-7 [Monday-to-Sunday]), i.e., through 2 days after the last dose of naxitamab. Patients did not receive isotretinoin. Follow-up was from start of naxitamab through 1/15/23. Results: From 2/22/2021-to-12/15/22, 59 patients (32 Group 1, 27 Group 2) received 1-10 (median 5) cycles, total 250. No unexpected toxicities occurred. No patient had to discontinue GM-CSF. Treatment was outpatient, except 3 patients with hypertension. Cycles were aborted because of viral symptoms (n=3), suspected small bowel obstruction (n=3), hypoxia (n=2), and hyperbilirubinemia (n=1). Four patients received only ½ of dose 1 in cycle 1 because of agitation or hypotension. In Group 1, 4/32 patients relapsed at 4-5 months while 28 patients remain in CR at 1+-to-22+ (median 15+) months. In Group 2, disease sites and responses were: BM alone (n=7): CR in 6 (1 later relapsed); MIBG alone (Curie scores 1-11) (n=8): 1 partial response, 1 progressive disease, 2 stable (1 later relapsed), 4 non-evaluable because of radiotherapy; MIBG (Curie scores 1-26) and BM(+) (n=12): 7 CR (3 later relapsed), 4 PR, 1 stable disease (subsequently progressed). Conclusions: This large experience confirms that the new schedule is safe and, despite short follow-up, appears as effective as the prior schedule.