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Purpose Intraventricular compartmental radioimmunotherapy (cRIT) with 131-I-omburtamab is a potential therapy for recurrent primary brain tumors that can seed the thecal space. These patients often previously received external beam radiotherapy (EBRT) to a portion or full craniospinal axis (CSI) as part of upfront therapy. Little is known regarding outcomes after re-irradiation as part of multimodality therapy including cRIT. This study evaluates predictors of response, patterns of failure, and radiologic events after cRIT. Methods Patients with recurrent medulloblastoma or ependymoma who received 131-I-omburtamab on a prospective clinical trial were included. Extent of disease at cRIT initiation (no evidence of disease [NED] vs measurable disease [MD]) was assessed as associated with progression-free (PFS) and overall survival (OS) by Kaplan–Meier analysis. Results All 27 patients (20 medulloblastoma, 7 ependymoma) had EBRT preceding cRIT: most (22, 81%) included CSI (median dose 2340 cGy, boost to 5400 cGy). Twelve (44%) also received EBRT at relapse as bridging to cRIT. There were no cases of radionecrosis. At cRIT initiation, 11 (55%) medulloblastoma and 3 (43%) ependymoma patients were NED, associated with improved PFS (p = 0.002) and OS (p = 0.048) in medulloblastoma. Most relapses were multifocal. With medium follow-up of 3.0 years (95% confidence interval, 1.8–7.4), 6 patients remain alive with NED. Conclusion For patients with medulloblastoma, remission at time of cRIT was associated with significantly improved survival outcomes. Relapses are often multifocal, particularly in the setting of measurable disease at cRIT initiation. EBRT is a promising tool to achieve NED status at cRIT initiation, with no cases of radiation necrosis.

Background Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non–small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. Methods STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged Results At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). Conclusions Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

PURPOSE The tyrosine kinase receptor anaplastic lymphoma kinase (ALK) can be abnormally activated in neuroblastoma, and somatic ALK mutations occur in 6%-10% of patients. The differential clinical impact of these mutations has not been clearly elucidated. METHODS Data on patients with neuroblastoma harboring ALK mutations were retrospectively analyzed. ALK sequencing was performed by whole-genome sequencing, hybrid-based capture of targeted exomes, or hotspot ALK mutation profiling. The differential impact of ALK mutation site on clinical characteristics, response to treatment, and survival was analyzed. In a subgroup of patients with locoregional neuroblastoma diagnosed after 2014, the impact of all ALK mutations was compared with wild-type ALK. RESULTS Of 641 patients with neuroblastoma with ALK status analyzed on at least one tumor sample, 103 (16%) had tumors harboring ALK mutations. Mutations existed across all ages (birth to 67.8 years), stages (30% locoregional and 70% metastatic), and risk groups (20%, 11%, and 69% with low-, intermediate-, and high-risk disease, respectively). Mutation sites included F1174 (51%), R1275 (29%), R1245 (10%), and others (10%). Mutation site was not prognostic for progression-free survival or overall survival in the entire cohort, high-risk subgroup, or locoregional subgroup. Locoregional tumors with any ALK mutation were generally invasive: L2 by International Neuroblastoma Research Group staging in 30/31 patients with a 2-year progression-free survival (59%, 95% CI, 37.4 to 80.5) that was inferior to historical controls. This observation was corroborated in the post-2014 subgroup in which gross total resection was less likely for ALK-mutated tumors. CONCLUSION Somatic ALK mutations are present across all stages and risk groups of neuroblastoma. No specific mutation carries differential prognostic significance. Locoregional neuroblastoma has an invasive phenotype when harboring somatic ALK mutations in this population.

In high-risk neuroblastoma, multimodality therapy including craniospinal irradiation (CSI) is effective for central nervous system (CNS) relapse. Management of post-CSI CNS relapse is not clearly defined.Pediatric patients with neuroblastoma treated with CSI between 2000 and 2019 were identified. Treatment of initial CNS disease (e.g., CSI, intraventricular compartmental radioimmunotherapy [cRIT] withOf 128 patients (65% male, median age 4 years), 19 (15%) received CSI with protons and 115 (90%) had a boost. Most (103, 81%) received cRIT, associated with improved OS (hazard ratio [HR] 0.3, 95% confidence interval [CI]: 0.1-0.5, p .001). Forty (31%) developed a second CNS relapse, associated with worse OS (1-year OS 32.5%, 95% CI: 19-47; HR 3.8; 95% CI: 2.4-6.0, p .001), and more likely if the leptomeninges were initially involved (HR 2.5, 95% CI: 1.3-4.9, p = .006). Median time to second CNS relapse was 6.8 months and 51% occurred outside the CSI boost field. Twenty-five (63%) patients underwent reirradiation, most peri-operatively (18, 45%) with focal hypofractionation. Eight (20%) patients with second CNS relapse received cRIT, associated with improved OS (HR 0.1; 95% CI: 0.1-0.4, p .001).CNS relapse after CSI for neuroblastoma portends a poor prognosis. Surgery with hypofractionated radiotherapy was the most common treatment. Acknowledging the potential for selection bias, receipt of cRIT both at first and second CNS relapse was associated with improved survival. This finding necessitates further investigation.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.

Very rarely, vasoactive intestinal peptide-related diarrhea (VIP-D) is observed in patients with high-risk neuroblastoma (HR-NB) where the associated fluid and electrolyte abnormalities can pose a major clinical challenge for administering the required aggressive multimodality treatment. Two patients with HR-NB developed VIP-D during induction and were found to have a somatic BRAF V600E mutation. Serum VIP levels and diarrhea promptly resolved in both patients after initiating treatment with BRAF and MEK inhibitors. This illustrates an association of VIP-D with BRAF V600E mutations and demonstrates a therapeutic strategy in the specific context of VIP-D and BRAF V600E mutations in HR-NB patients. The addition of BRAF and MEK inhibitors allows continued conventional tumor-directed treatment by decreasing the severity of symptoms caused by this life-threatening complication.

10028 Background: Chemoresistant disease is an obstacle for cure of high-risk neuroblastoma (HR-NB). Anti-GD2 monoclonal antibodies (MoAb) dinutuximab and naxitamab in combination with cytokines are FDA-approved to consolidate remission and for chemorefractory osteomedullary HR-NB, but responses in progressive disease (PD) are rare. We investigated the combination of Humanized anti-GD2 MoAb naxitamab (Hu3F8), Irinotecan, Temozolomide and Sargramostim (GMCSF) in a phase II "HITS" protocol against resistant HR-NB (NCT03189706). Noteworthy differences between HITS and COG protocol ANBL 1221 included higher MoAb and temozolomide dosage and overlap of naxitamab with GMCSF. Methods: Patients were treated at Memorial Sloan Kettering (MSK) on protocol and at Hospital Sant Joan de Déu (HJSD) per protocol on compassionate basis. Salient eligibility criteria included evaluable or measurable chemoresistant disease. Prior anti-GD2 MoAb or irinotecan/temozolomide (IT) therapy was permitted. Each cycle, administered 3-5 weeks apart, comprised irinotecan 50 mg/m2/day intravenously (IV) plus temozolomide 150 mg/m2/day IV or orally (days 1-5); naxitamab 2.25 mg/kg/day IV, days 2,4,8 and 10, and GMCSF 250 mg/m2/day subcutaneously, days 6-10. Toxicity was measured by CTCAE v4.0 and responses by International Neuroblastoma Response Criteria. Objective responses (OR) were also noted. The primary endpoint of the phase II trial was complete (CR) and partial response (PR) after 4 cycles with a desirable rate of 40%; type I and II errors of 10% (undesirable=20%). Results: Of 90 heavily prior-treated patients (38 at MSK evaluated on trial, 52 at HJSD), 8 had HR-NB refractory to induction chemotherapy while 82 had up to 6 prior relapses (median=1). 503 cycles (median 5/patient) were administered. Toxicities included myelosuppression and diarrhea expected with IT, pain and hypertension expected with naxitamab, plus febrile neutropenia in 4%. No other >grade 2 unexpected toxicities occurred; treatment was outpatient. Primary endpoint was reached in the phase II trial: INRC response = 30.6%, lower boundary = 20.4%. In the entire cohort, best responses were CR (26%), PR (11%), mixed response (9%), stable disease (27%) and PD (27%). OR were noted in 64%, with soft tissue (48%) and skeletal MIBG uptake (66%). CR in BM was seen in 57%. OR occurred in patients with MYCN-amplified (25%), refractory (100%) and relapsed (61%) HR-NB; and patients who had previously received I/T (64%) or naxitamab (68%). In patients who had previously received dinutuximab/IT, OR rate to HITS was 42% (5/12). Human anti-human antibody did not develop in any patient (n=50). Conclusions: Naxitamab-based chemoimmunotherapy was safe without immunogenicity. It was effective against chemoresistant HR-NB in all disease compartments even in patients with multiple prior relapses, and in patients who previously received anti-GD2 MoAbs and/or IT.

PURPOSE Anti-GD2 monoclonal antibody (mAb) has proven efficacy in high-risk neuroblastoma (HR-NB). A small phase I GD2/GD3 vaccine trial (n = 15) described long-term survival and a favorable safety profile among patients with a history of disease progression (PD). The kinetics of mounting antibody response to vaccine and its prognostic impact on survival are now investigated in a phase II study (ClinicalTrials.gov identifier: NCT00911560 ). PATIENTS AND METHODS One hundred two patients with HR-NB who achieved remission after salvage therapies were enrolled in this trial. They received seven subcutaneous injections of GD2/GD3 vaccine spanning 1 year plus oral β-glucan starting at week 6 after the third dose of vaccine. Serum anti-vaccine antibody titers were quantified by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms (SNPs) were determined by quantitative polymerase chain reaction. Kaplan-Meier and landmark Cox Regression models were used for survival estimates. RESULTS Patients had a history of one (63%), two (21%), or three to six (16%) episodes of PD. 82% of them progressed following anti-GD2 mAb (m3F8/dinutuximab/naxitamab) therapy. Vaccine-related toxicities were self-limited injection–associated local reactions and fever without any > grade 3 toxicities. The progression-free survival (PFS) was 32% ± 6%, and the overall survival (OS) was 71% ± 7% at 5 years. Serum anti-GD2 (immunoglobulin G1 [IgG1] and IgM) and anti-GD3 (IgG1) titers showed notable increases following the initiation of β-glucan at week 6. There was an association between IgG1 titer and SNP rs3901533 of dectin-1, the β-glucan receptor. Multivariable analyses showed that anti-GD2-IgG1 titer ≥ 150 ng/mL by week 8 was associated with favorable PFS and OS, while having prior episodes of PD and the time from last PD to vaccine were associated with PFS. CONCLUSION GD2/GD3 vaccine plus β-glucan elicited robust antibody responses in patients with HR-NB with prior PD. Higher anti-GD2-IgG1 titer was associated with improved survival.

Objective To review the treatment and revaccination of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome (OMAS) patients at Memorial Sloan Kettering Cancer Center (MSK). Procedure Institutional Review Board approval was obtained for this retrospective study of patients with neuroblastoma-associated OMAS followed at MSK from 2000 to 2016. Results Fourteen patients (nine female) were 9-21 (median 17) months old at diagnosis of neuroblastoma and OMAS syndrome. They had stage 1 (n = 12), stage 2B, or intermediate-risk stage 4. Tumor histology was favorable in 11 patients, unfavorable in two, and unknown in one patient. No patient had amplified MYCN. All patients underwent tumor resection at diagnosis. Anti-neuroblastoma treatment was limited to chemotherapy in one patient. Overall survival is 100% at 3-16 (median 10) years. For OMAS, 13 patients received intravenous immune globulin (IVIg), adrenocorticotropic hormone (ACTH), and rituximab, and one received ACTH and IVIg. Seven patients experienced OMAS relapse. For these relapses, five patients received low-dose cyclophosphamide and two received rituximab. The mean total OMAS treatment was 20-96 (median 48) months. Seven patients started rituximab ≤3 months from diagnosis and did not relapse. The other six experienced OMAS relapse. To date, six patients have been revaccinated at a minimum of 2 years after completion of OMAS therapy without OMAS recurrence. Conclusions Patients with neuroblastoma-associated OMAS had excellent overall survival. Early initiation of rituximab, IVIg, and ACTH may reduce risks of OMAS relapse. Revaccination can be resumed without exacerbation of OMAS. Further investigation with a larger cohort of patients is needed.

Background The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. Patients and methods Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. Results Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%–62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%–51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%–46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. Conclusions TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

Purpose In patients with high-risk neuroblastoma, there is an increased recognition of relapse in the central nervous system (CNS). Craniospinal irradiation (CSI) has been an effective treatment but carries significant long-term complications. It is unclear whether reducing the CSI dose from 21 to 18 Gy can achieve similar CNS tumor control. Patients and methods A retrospective review of pediatric patients with CNS-relapsed neuroblastoma treated with CSI and boost to parenchymal lesions between 2003 and 2019 was performed. The goal was to assess CNS control comparing 18 Gy and 21 Gy regimens. Results Ninety-four patients with CNS-relapsed neuroblastoma were treated with CSI followed by intraventricular compartmental radioimmunotherapy. Median age at the time of CNS disease was 4 years (range 1-13 years). Forty-one patients (44%) received 21 Gy CSI prior to an institutional decision to lower the dose; 53 patients (56%) received 18 Gy CSI. Seventy-nine patients (84%) received additional boosts. With a median follow up of 4.1 years for surviving patients, 2-year CNS relapse-free survival was 74% for 18 Gy group versus 77% for 21 Gy group, and 5-year CNS relapse-free survival was 66% for 18 Gy versus 72% for 21 Gy group, respectively (P = .40). Five-year overall survival rate was 43% in 18 Gy group versus 47% in 21 Gy group (P = .72). Conclusion For patients with CNS-relapsed neuroblastoma, CNS disease control is comparable between 18 Gy and 21 Gy CSI dose regimens, in conjunction with radioimmunotherapy and CNS penetrating chemotherapy. More than 65% of the patients remain CNS disease free after 5 years. The findings support 18 Gy as the new standard CSI dose for CNS-relapsed neuroblastoma.

Inflammatory myofibroblastic tumor (IMT) is a rare, indolent spindle cell tumor that typically affects children and young adults.1,2 IMTs occur predominantly in visceral soft tissue and are categorized as an intermediate malignancy because they have a potential for local recurrence but rarely progress to distant metastases.2,3 Approximately 50% of IMTs harbor ALK rearrangements, although gene fusions involving ROS1, NTRK3, and PDGFRβ have also been identified.2,4–6 Previously, the presence of ALK gene fusions has typically been identified using immunohistochemistry7; however, newer techniques such as hybridization capture-based next-generation sequencing (NGS) and NGS-based anchored multiplex polymerase chain reaction (PCR) testing can now be used to detect gene fusions.8–10 The identification of patients with actionable gene fusions is important given the availability of promising therapeutic strategies.2,4 Surgical resection is the standard of care for patients with solitary IMT,11 but patients with unresectable or advanced disease have limited treatment options. The current National Comprehensive Cancer Network guidelines for soft tissue sarcoma recommend the use of ALK inhibitors for patients with ALK gene fusions12; however, there are no targeted agents approved specifically for use in fusion-positive IMT. Entrectinib is an investigational, central nervous system (CNS)-active, potent, and selective inhibitor of TRK, ROS1, and ALK.8,13,14 In phase 1 trials, entrectinib demonstrated clinical efficacy in patients with different tumor types harboring NTRK, ROS1, or ALK fusions, regardless of the fusion partner gene.8 A majority of the responses to entrectinib occurred in a rapid and durable manner, and some patients remained on study due to clinical benefit even after experiencing disease progression.8 Here, we present 2 patients with fusion-positive IMT (DCTN1-ALK and TFG-ROS1) who were enrolled in the ongoing STARTRK-NG phase 1/1b trial ({"type":"clinical-trial","attrs":{"text":"NCT02650401","term_id":"NCT02650401"}}NCT02650401) and treated with entrectinib. These patients were identified as having targetable gene fusions using 2 diagnostic testing methods, a hybrid capture-based targeted exome sequencing assay and anchored multiplex PCR,15,16 at different stages of a diagnostic testing workflow.

High-risk neuroblastoma (HR-NB) includes MYCN-amplified stage 2/3, but reports covering anti-GD2 immunotherapy, which recently became standard for HR-NB, do not provide details on this subset. We now report on all 20 MYCN-amplified stage 2/3 patients who received induction chemotherapy at our center during the era of consolidation with anti-GD2 antibody 3F8/ granulocyte-macrophage colony-stimulating factor (GM-CSF) (2000-2015). Early in this period, consolidation included autologous stem-cell transplantation (ASCT). Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier analyses. With induction, 19/20 (95%) patients achieved complete/very good partial remission (CR/VGPR) but one had progressive disease with early death. One responder did not receive consolidation and died of relapse. Five-year post-diagnosis EFS/OS rates for all 20 patients were 72%/84%. The 18 CR/VGPR patients who received consolidation had EFS/OS 81%/94% at five years from starting 3F8/GM-CSF: 4/4 ASCT patients remained relapse-free, while 11/14 non-ASCT patients remained relapse-free and two of the three relapsed patients achieved 2nd CR (consolidated by retreatment with 3F8/GM-CSF) and remained in 2nd CR at 36+ and 95+ months post-relapse. The 14 non-ASCT patients had EFS/OS 73.5%/93% at five years from starting 3F8/GM-CSF. This subset appears to have a good prognosis with contemporary multi-modality therapy, possibly even without ASCT.

The phase 1/2 STARTRK-NG trial is evaluating entrectinib, a CNS-penetrant oral inhibitor of TRK, ROS1 and ALK tyrosine kinases, in children with solid tumors, including primary CNS tumors. Eligible patients are ≤22y with recurrent/refractory solid tumors. The recommended dose was determined in all-comers, and then expansion cohorts of CNS and solid tumors with NTRK1/2/3, ROS1 or ALK gene fusions, and neuroblastomas (NBL) regardless of mutation spectrum, were enrolled. Investigator-assessed response was classified as complete (CR) or partial response (PR), stable (SD) or progressive disease using RANO (CNS), RECIST (solid tumors), or Curie score (NBL). By the clinical data cut-off, 01 April 2019, 32 patients were enrolled. As of 31 Oct 2018 (enrollment data cut-off), 29 patients were enrolled and included in the evaluable population. Median age was 7y (range 4.9m to 20y). Entrectinib was well tolerated; phase 1 dose-limiting toxicities were: elevated creatinine, dysgeusia, fatigue, and pulmonary edema. The recommended dose was 550mg/m2 daily; all responses occurred at doses ≥400mg/m2. In 6 patients with high-grade CNS tumors, all gene-fusion-positive, ORR was 100% (Investigator-assessed responses): 2 CR (ETV6-NTRK3, EML1-NTRK2); 4 PR (TPR-NTRK1, KANK1-NTRK2, EEF1G-ROS1, GOPC-ROS1). In extracranial solid tumors 6/8 had a fusion; of these, 2 achieved a confirmed CR (DCTN1-ALK, ETV6-NTRK3), and 4 achieved PR (ETV6-NTRK3, EML4-NTRK3, TFG1-ROS1, KIF5B-ALK). Central imaging review is being performed and will be provided. Duration of therapy ranged from 0.2 to 22.2 months for all 32 patients. In responding patients, time to response ranged from 1 to 8.3 months. In children with refractory CNS tumors harboring NTRK1/2/3 or ROS1 fusions, entrectinib produced striking, rapid, and durable responses. No responses were seen in tumors lacking target gene fusions. These results support the continued evaluation of entrectinib in solid tumors with target gene fusions, especially high-grade CNS neoplasms.

Purpose For patients with high-risk neuroblastoma (HR-NB), a dose of 21 Gy to the primary tumor site after gross total resection (GTR) provides excellent local control. However, no clinical trial has specifically evaluated the optimal dose of radiation therapy (RT), and RT-related long-term toxicities are of increasing concern. We sought to assess local control, survival outcomes, and toxicity after a reduction in dose to the primary site from 21 Gy to 18 Gy. Methods and Materials After induction chemotherapy and GTR, patients with HR-NB were enrolled and treated on an RT dose-reduction prospective trial with 18 Gy hyperfractionated RT given in twice-daily fractions of 1.5 Gy each. Results The 25 study subjects were 1.6 to 9.5 (median, 4.3) years old at enrollment and included 23 (92%) with stage IV and II (8%) with MYCN-amplified stage III disease. Eleven (44%) were in complete remission (CR), and 14 (56%) had persistence of osteomedullary disease postinduction. Three patients (12%) received proton therapy, and the rest received intensity modulated photon therapy. After a follow-up of 1.8 to 4.2 (median, 3.5) years from initiation of RT, no failures occurred within the RT field; 3 patients had marginal recurrences. The respective 3-year progression-free and overall survival rates were 54.5% and 90.9% for patients in first CR and 42.9% and 76.2% for patients not in metastatic CR. Acute toxicity was negligible. Conclusions Reduced-dose RT with 18 Gy did not compromise local control or survival outcomes in our cohort of patients with HR-NB after GTR. These findings support assessing further RT dose reduction and validation on a larger, multi-institutional trial.

2001 Background: Neuroblastoma (NB), a rare malignancy of the sympathetic nervous system, is a tumor of early childhood with > 90% of cases diagnosed before 5 years of age. Adult-onset NB (AON) is extremely rare and differs significantly from childhood disease. AON, while more indolent, is usually metastatic at diagnosis, generally chemotherapy-resistant, and almost invariably lethal. Additionally, standard therapies for NB such as dose-intensive chemotherapy and anti-GD2 antibody are poorly tolerated by adults. Prior studies have shown AON is enriched for genomic aberrations especially ALK (Suzuki et al 2018). Although ALK inhibitors (ALKi) are effective for therapy of lymphoma and non-small cell lung cancer, their use in AON has not previously been reported. Methods: Retrospective review of patients > 18 years old at diagnosis seen at Memorial Sloan Kettering Cancer Center (MSKCC) was performed after IRB approval. Response to ALKi was evaluated using International Neuroblastoma Response Criteria; objective responses were also noted. Progression-free (PFS) and overall survival (OS) was calculated using Kaplan-Meier methods. Results: Since 1979, 52 patients with AON were seen at MSKCC. Of 23 patients evaluated, 14 (61%), harbored somatic ALK mutations. Seven were treated with FDA-approved ALKi. One patient initially diagnosed at 12 years of age was treated with ALKi following a relapse 15 years later. Overall, all ALKi were well-tolerated; reported adverse events included grade 1-2 nausea and vomiting (n = 6), and neurologic symptoms including hallucinations, drowsiness, and dizziness (n = 1 patient each) which resolved after stopping ALKi. Four patients received > 1 ALKi either due to progressive disease or intolerance. Most patients responded to the first ALKi with objective though partial response (n = 5) while one had progressive disease (PD). Median time to progression for initial ALKi was 15.5 months (10-45). One patient with no evaluable disease after four prior relapses was treated with alectinib for 36 months without PD. Of the patients treated with a second ALKi (n = 4), 1 had CR and 2 had PR after not having progressed previously, while the other had stable disease. Median OS from beginning treatment with first ALKi was 46.5 (17-74) months. Conclusions: AON is a rare disease which is a therapeutic challenge. Enrichment of ALK mutations permits consideration of targeted therapy. ALKi were well tolerated, often associated with significant responses, and treatment with serial ALKi led to ongoing benefit. Given this, ALKi should be considered for treatment in future AON cases.

STARTRK-NG (phase 1/2) is evaluating entrectinib, a CNS-penetrant oral, TRK/ROS1/ALK tyrosine kinase inhibitor, in patients

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50-75mg/m2/day after a loading dose of 100-200mg/m2 on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal 123I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-to-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings 1) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; 2) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and 3) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable. This article is protected by copyright. All rights reserved.

Background Although nephrectomy rates are higher in children with neuroblastoma who have image-defined risk factors and/or high-risk disease who undergo resection prior to chemotherapy, no published data outline the key radiographic and clinical characteristics associated with nephrectomy. Methods With IRB approval, imaging studies of children undergoing primary resection of intraabdominal neuroblastoma between 2000 and 2014 were retrospectively reviewed. Fisher's exact and Wilcoxon rank-sum tests were used to compare categorical and continuous variables, respectively, with p-values adjusted for multiple testing using the false discovery rate approach. Results Twenty-seven of 380 consecutive patients with CT imaging obtained prior to primary neuroblastoma resection underwent partial or total nephrectomy. On preoperative imaging, renal vessel narrowing and encasement and tumor invasion of the renal hilum, pelvis, and/or parenchyma were present significantly more frequently among patients undergoing nephrectomy. Delayed renal excretion of contrast, hydronephrosis, and tumors with MYCN amplification were also more prevalent in the nephrectomy group. Conclusion Encasement and narrowing of renal vessels, delayed excretion, and tumor invasion into the kidney, particularly pelvis and capsule invasion, are significantly associated with partial or total nephrectomy at initial neuroblastoma resection. These observations provide valuable information for surgical planning as well as presurgical discussions with families prior to neuroblastoma resection.

Background Although 131I–metaiodobenzylguanidine (131I–MIBG) therapy is increasingly used for children with high-risk neuroblastoma, a paucity of lead-lined rooms limits its wider use. We implemented radiation safety procedures to comply with New York City Department of Health and Mental Hygiene regulations for therapeutic radioisotopes and administered 131I–MIBG using rolling lead shields. Procedure Patients received 0.67 GBq (18 mCi)/kg/dose 131I–MIBG on an IRB-approved protocol (NCT00107289). Radiation safety procedures included private room with installation of rolling lead shields to maintain area dose rates ≤0.02 mSv/hr outside the room, patient isolation until dose rate

Background and Aim: High-risk neuroblastoma (HR-NB) relapse carries a dismal prognosis. Recent experience, however, suggests that cure is possible when remission is achieved with salvage therapy that includes anti-GD2 monoclonal antibody (mAb). The long-term survival and the favorable safety profile of gangliosides GD2 and GD3 vaccine among these patients in a Phase I trial (n=15, Clinical Cancer Res 2014) need to be confirmed. Moreover, the kinetics of seroconversion (mounting anti-vaccine antibody response) and its prognostic impact on survival need to be explored. Patients and Methods: In this Phase II trial (Clinicaltrials.gov NCT00911560), 102 HR-NB patients who achieved complete remission after salvage therapy were enrolled. They received 7 subcutaneous vaccine injections (week 1-2-3-8-20-32-52) plus oral beta-glucan (starting in week 6 at 40 mg/kg/day, 14 days on/14 days off). Each subcutaneous vaccine injection consisted of 30 µg each of GD2 and GD3, lactonized and conjugated to keyhole limpet hemocyanin and mixed with the saponin OPT-821 adjuvant. Serum anti-vaccine antibody titers were quantified by ELISA. Kaplan-Meier statistics and landmark Cox Regression models were used for survival estimates and prognostic impact analyses. Results: Among 102 patients, 63% had one, 21% had 2, and 16% had 3-6 prior disease progressions. 83/101 patients had failed prior anti-GD2 mAb (m3F8, dinutuximab, or naxitamab) therapy before vaccine: one mAb (n=62), two mAbs (n=15), or all three (n=6). Common toxicities were self-limited injection-related local reactions and fever. No pain, neuropathy, or grade 3/4 toxicities occurred during or post treatment. Progression-free survival (PFS) was 44%±5% and overall survival (OS) was 88%±4% at 2 years, and 36%±7% and 70%±8% at 5 years, respectively. Serum anti-GD2 (IgG1 and IgM) and anti-GD3 (IgG1) titers had marked increases following the initiation of beta-glucan at week 6. In univariate analyses, favorable prognostic factors included: one versus ≥2 prior disease progressions (PFS p=0.005, OS p=0.04), none versus any prior anti-GD2 mAb failures (PFS p=0.004, OS p=0.01); and the induction of ≥150 ng/ml anti-GD2-IgG1 titers by week 8 (PFS p=0.02, OS p=0.06). Factors not prognostic included: time to first NB progression, MYCN amplification status, anti-GD2-IgM, anti-GD3-IgG1 or anti-KLH-IgG1 titers, and treatment with anti-GD2 mAb right before vaccine. In multivariate analyses, week 8 anti-GD2-IgG1 titer ≥150 ng/ml yielded a hazard ratio (HR) of 0.41 [0.20, 0.83], p=0.01 for PFS, and HR=0.15 [0.02, 1.12], p=0.06 for OS. The second independent prognostic variable was the number of prior disease progressions (≥2 vs 1), yielding HR of 2.12 [1.26, 3.58], p=0.005 for PFS, and HR=2.77 (1.03, 7.47), p=0.04 for OS. Conclusions: Even with prior disease progressions, anti-GD2 (though not anti-GD3) seroconversion was associated with notable long-term survival among HR-NB patients previously thought to be unsalvageable. A randomized trial to assess the role of beta-glucan in seroconversion is actively accruing patients. Citation Format: Irene Y. Cheung, Nai-Kong V. Cheung, Shakeel Modak, Audrey Mauguen, Ellen Basu, Stephen S. Roberts, Govind Ragupathi, Brian H. Kushner. Survival impact of anti-GD2 antibody response - A phase II ganglioside vaccine trial in relapsed neuroblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-092.

Summary There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.

INTRODUCTION Opsoclonus-myoclonus-ataxia syndrome (OMS) is a rare paraneoplastic syndrome (PNS) typically associated with low-risk pediatric neuroblastoma (NB). Overall survival is excellent but patients are at risk for long-term neurologic sequelae. As with many PNS, the etiology of NB-associated OMS is thought to be immune mediated and patients are managed with immunosuppressive therapy. The use of other immunotherapy such as checkpoint inhibitors for advanced stage cancers has been associated with sporadic reports of the development of PNS. We report a case of a child with NB-associated OMS who received anti-GD2 antibody immunotherapy for advanced relapsed NB without exacerbation of OMS. While the mechanism of action of anti-GD2 is unique, this case demonstrates that further study is required to understand which patients are at risk for PNS development/flare during therapy for advanced stage cancers. CASE: Our patient presented at 16 months of age with acute onset of tremors, irritability and ataxia and was diagnosed with OMS; at that time, evaluation revealed intermediate risk stage 4 neuroblastoma which was treated with 4 cycles of chemotherapy with complete response. His OMS was managed initially with high dose dexamethasone, followed by monthly IVIG, ACTH and rituximab with improvement in neurologic symptoms. The patient developed NB relapse (stage 4) 18 months after completion of initial chemotherapy and received chemotherapy and anti-GD2 antibody immunotherapy. Through this second course of therapy he continued to wean his immunosuppressive anti-OMS therapy without flare of his neurologic symptoms. DISCUSSION We present an unusual case of a child with NB-associated OMS whose OMS symptoms did not flare despite the use of immunotherapy to treat relapsed stage 4 disease. CONCLUSION While immunosuppression is used to treat OMS and other paraneoplastic syndromes, the use of immunotherapy to treat the underlying malignancy may be tolerated. Further study is needed.

BACKGROUND The authors exploited a large database to investigate the outcomes of patients with high-risk neuroblastoma in the contemporary era. METHODS All patients with high-risk neuroblastoma aged 18 months with MYCN-nonamplified [MYCN(−)] stage 4 disease. RESULTS A complete response/very good partial response (CR/VGPR) to induction was correlated with significantly superior event-free survival (EFS) (P

10025 Background: Chemoresistant and relapsed disease are major obstacles to curing high-risk neuroblastoma (HR-NB). Anti-GD2 monoclonal antibody (MoAb) is effective in preventing relapse after remission but responses in relapsed or progressive disease (PD) are rare. We investigated the combination of humanized anti-GD2 MoAb naxitamab, (previously termed Hu3F8), irinotecan, temozolomide and sargramostim (GM-CSF): a pilot HITS protocol against resistant HR-NB now expanded to a phase II study (NCT03189706). Methods: Salient eligibility criteria included evaluable or measurable chemoresistant disease. Prior anti-GD2 MoAb and/or irinotecan/temozolomide (I/T) therapy was permitted. Each cycle comprised of irinotecan 50 mg/m2/day intravenously (IV) plus temozolomide 150 mg/m2/day IV or orally (days 1-5); naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 8 and 10 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, days 6-10. Toxicity was measured by CTCAE v4.0 and responses by modified International Neuroblastoma Response Criteria. Results: Forty-six (23 enrolled on protocol and 23 on compassionate-use basis) heavily prior-treated patients (median age at enrollment: 6.6 years; median number of prior relapses: 2) have received 175 (median 2; range 1-12) cycles to date. At enrollment, 7 patients had HR-NB refractory to induction chemotherapy while 39 had prior relapse. Toxicities included myelosuppression and diarrhea expected with I/T, and pain and hypertension expected with naxitamab. No other > grade 2 related toxicities occurred; treatment was outpatient. Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and were complete (n = 9), partial (n = 8), and mixed (n = 1); 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and PD (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12; 75%). Conclusions: High-dose naxitamab-based chemoimmunotherapy is safe and effective against chemoresistant HR-NB. This ongoing phase II study may define a broader role for naxitamab which was recently granted breakthrough designation by the FDA. Clinical trial information: NCT03189706.

10009 Background: Entrectinib is a CNS-penetrant oral inhibitor of TrkA/B/C, ROS1 and ALK tyrosine kinases. We report the efficacy of entrectinib in children with recurrent/refractory solid or CNS tumors. Methods: Patients ≤ 20y old with recurrent/refractory solid tumors were eligible. After determination of the recommended dose in all-comers, disease-specific expansion cohorts of CNS and solid tumors harboring target aberrations in NTRK1/2/3, ROS1 or ALK, and neuroblastoma (NBL), regardless of mutation spectrum, were enrolled. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using RANO for CNS tumors, RECIST for solid tumors, and Curie score for NBL. Results: Between May 2016 and October 2018, 29 patients aged 4.9m–20y (median 7y) were enrolled and 28 were evaluated for response. Entrectinib was well tolerated. Dose limiting toxicities were elevated creatinine, dysgeusia, fatigue and pulmonary edema. The recommended dose was 550 mg/m2 daily. All responses occurred at doses ≥ 400 mg/m2. In CNS tumors (n = 6), all high-grade with gene fusions: 1 achieved a CR ( ETV6-NTRK3); 3 achieved a PR ( TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2); 1 achieved an unconfirmed PR ( GOPC-ROS1); and 1 has yet to be evaluated ( KANK1-NTRK2). In extracranial solid tumors (n = 8), 6 had a fusion of whom 1 achieved a CR ( DCTN1-ALK) and 5 achieved a PR ( TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3). In NBL (n = 15): 1 achieved a CR ( ALK F1174L). Median duration of therapy was 85d (6–592d) for all patients; 56d (6–338d) for non-responders; and 281d (56–592d) for responders. Median time to response was 57d (30–58d). Conclusions: Entrectinib produced striking, rapid and durable responses in all children with refractory CNS and solid tumors harboring NTRK1/2/3, ROS1 or ALK fusions (11 out of 11) as well as in an ALK-mutated NBL. No responses were seen in tumors lacking aberrations in target kinases. These results support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3, ROS1 and ALK fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.

Importance Chimeric and murine anti-G D2 antibodies are active against neuroblastoma, but the development of neutralizing antibodies can compromise efficacy. To decrease immunogenicity, hu3F8, a humanized anti-G D2 antibody, was constructed. Objective To find the maximum-tolerated dose of hu3F8 with granulocyte-macrophage colony-stimulating factor. Design, Setting, and Participants This phase 1 clinical trial used a 3 + 3 dose-escalation design in a single referral center (Memorial Sloan Kettering Cancer Center, New York, New York). Participants were enrolled from December 24, 2012, through May 3, 2016, with follow-up and analyses through February 28, 2018. Eligibility criteria included older than 1 year and resistant or recurrent neuroblastoma regardless of the number or kinds of prior treatments. All 57 participants met the eligibility criteria, received treatment according to the protocol, and were included in all analyses. Interventions Treatment cycles were monthly, if human antihuman antibody remained negative. Each cycle comprised hu3F8 infused intravenously for 30 minutes on Monday, Wednesday, and Friday as well as granulocyte-macrophage colony-stimulating factor administered subcutaneously daily from 5 days before infusion through the last day of infusion. After cycle 2, hu3F8 was increased to the highest dose level that had been confirmed as safe. Main Outcomes and Measures Toxicity, pharmacokinetics, immunogenicity, and disease response. Results Of the 57 participants, 34 (60%) were male and 23 (40%) were female (male-to-female ratio of 1.5), with a median (range) age of 6.8 (2.4-31.3) years at enrollment and a median (range) time of 3.1 (0.6-9.0) years since initial chemotherapy. Participants received a median (range) of 4 (1-15) cycles. Treatment was outpatient with reversible neuropathic pain and without unexpected toxic effects. No maximum-tolerated dose was identified. Dose escalation was associated with increased serum levels and proceeded through dosage of 9.6 mg/kg/cycle (approximately 288 mg/m 2 ), which is more than 2.5 times higher than the standard dosage of 75 mg/m 2 /cycle or 100 mg/m 2 /cycle of dinutuximab and m3F8. Human antihuman antibody positivity developed in 5 of 57 patients (9%) after cycle 1, including in 1 of 10 patients (10%) not previously treated with anti-G D2 antibody and in 4 of 47 patients (9%) previously exposed to 1 or 2 anti-G D2 antibodies. Antineuroblastoma activity included major responses associated with higher dosing and prolonged progression-free survival despite a history of relapses. Conclusions and Relevance This phase 1 clinical trial found hu3F8 to be associated with modest toxic effects, low immunogenicity, and substantial antineuroblastoma activity; phase 2 trials are in progress. Trial Registration ClinicalTrials.gov identifier:NCT01757626

BACKGROUND Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging reveals edematous changes in the brain (especially in the parietal and occipital lobes). In this report, the authors describe PRES associated with antidisialoganglioside (anti-GD2) monoclonal antibody (MoAb) immunotherapy, which is now standard for high-risk neuroblastoma but has not previously been implicated in PRES. METHODS Successive clinical trials using the anti-GD2 MoAb 3F8 (a murine immunoglobulin 3 MoAb specific for GD2) for patients with neuroblastoma involved multiple cycles of standard-dose 3F8 (SD-3F8) (20 mg/m2 daily for 5 days per cycle) or 2 cycles of high-dose 3F8 (HD-3F8) (80 mg/m2 daily for 5 days per cycle) followed by cycles of SD-3F8. RESULTS PRES was diagnosed in 5 of 215 patients (2.3%), including 3 of 160 (1.9%) who received SD-3F8 and 2 of 55 (3.6%) who received HD-3F8 (P = .6). All 5 patients had a rapid return to clinical-radiologic baseline. PRES occurred in 3 of 26 patients (11.5%) whose prior treatment included external-beam radiotherapy to the brain (2 of 6 patients status-post total body irradiation and 1 of 20 patients status-post craniospinal irradiation) compared with 2 of 189 patients (1.1%) who had not received prior brain irradiation (P = .01). Hypertension, which is strongly linked to PRES, reached grade 3 toxicity in 12 of 215 patients (5.6%), including the 5 patients with PRES and 7 patients without PRES. CONCLUSIONS Patients who receive anti-GD2 MoAb immunotherapy should be closely monitored for, and undergo urgent treatment or evaluation of, symptoms that may herald PRES (eg, hypertension or headaches). Prior brain irradiation may be a predisposing factor for PRES with this immunotherapy. Cancer 2013;119:2789–2795. © 2013 American Cancer Society.

Background The rationale for studying the combination of bevacizumab, irinotecan, and temozolomide (BIT) in neuroblastoma (NB) is based on the following: (i) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (ii) anti-VEGF antibody bevacizumab enhances irinotecan-mediated suppression of NB xenografts, (iii) bevacizumab safety has been established in pediatric phase I studies, and (iv) irinotecan + temozolomide (IT) is a standard salvage chemotherapy. Procedure We conducted a phase II study of BIT in patients with measurable/evaluable refractory or relapsed high-risk NB (www.clinicaltrials.gov, NCT01114555). Each cycle consisted of bevacizumab (15 mg/kg intravenously [IV]) on days 1 and 15 plus irinotecan (50 mg/m2/day IV) and temozolomide (150 mg/m2/day orally) on days 4–8. Patients could have previously received, but not relapsed on, IT. An early stopping rule mandated continuing therapy only if more than five patients of 27 evaluable patients achieved partial response (PR) or complete response (CR) after four cycles. Results Thirty-three heavily pretreated patients (nine primary refractory; 24 relapsed) received one to eight cycles of BIT. Toxicities were expected and transient. Grade 4 toxicities were neutropenia (30%) and thrombocytopenia (24%). Grade 3 toxicities included hepatic transaminitis (15%), proteinuria (9%), and diarrhea (3%). Overall responses were as follows: three CR (all in prior IT-treated patients), 18 no response, and 12 progressive disease. Only one of 23 patients assessable for the early stopping rule regarding efficacy achieved PR/CR, so patient accrual was discontinued. Median progression-free survival and overall survival was 7.7 ± 1.7 and 31.5 ± 5.6 months, respectively; all patients continued anti-NB therapy post-BIT. Conclusions BIT was well tolerated, but the addition of bevacizumab did not improve response rates in resistant NB compared to historical data for IT.

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50–75mg/m2/day after a loading dose of 100–200mg/m2 on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1–5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal 123I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-to-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings 1) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; 2) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and 3) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable.

BACKGROUND: Tumors metastasizing to the CNS are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular (131)I-labeled monoclonal antibody 8H9 targeting B7-H3 in patients with CNS tumors. METHODS: Tumor B7-H3 expression was assessed by immunohistochemistry. Patients received 2 mCi tracer of intra-Ommaya (124)I- or (131)I-8H9 followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments -phase I patients; expanded cohort 50 mCi/injection) (131)I-8H9. Dosimetry was based on serial CSF, blood samplings and ROI analyses on nuclear imaging. . Toxicity was defined by the CTCAE v.3.0. Repeat injections were permitted if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. RESULTS: 131 patients received 383 injections [median age 5.4 years (1.2- 53.6)] Injections were well tolerated. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting, biochemical elevations in AST/ALT and 1 injection with grade 3 ALT elevation (dose level 3)., Myelosuppression occurred in patients with prior craniospinal radiation and at dose levels 6 and higher (>60 mCi). Of 93 patients treated for CNS neuroblastoma, an improved overall survival was noted compared to survival reported with conventional therapies. Interpatient variability for total absorbed dose to the CSF and blood was observed; mean absorbed CSF dose was 104.9 cGy/mCi by CSF sampling, and 2.6 cGy/mCi to the blood. CONCLUSIONS: Intraventricular (131)I-8H9 is safe, has favorable dosimetry to CSF, and has clinical utility for high risk primary and metastatic CNS tumors.

Natural killer (NK) cell-mediated antibody-dependent toxicity is a potent mechanism of action of the anti-GD2 murine monoclonal antibody 3F8 (m3F8). Killer immunoglobulin-like receptor (KIR) and HLA genotypes modulate NK activity and are key prognostic markers in m3F8-treated patients with neuroblastoma. Endogenous NK-cells are suppressed in the setting of high tumor burden and chemotherapy. Allogeneic NK-cells however, demonstrate potent anti-neuroblastoma activity. We report on the results of a phase I clinical trial of haploidentical NK-cells plus m3F8 administered to patients with high-risk neuroblastoma after conditioning chemotherapy. The primary objective was to determine the maximum tolerated NK-cell dose (MTD). Secondary objectives included assessing anti-neuroblastoma activity and its relationship to donor-recipient KIR/HLA genotypes, NK function, and donor NK chimerism. Patients received a lymphodepleting regimen prior to infusion of haploidentical CD3-CD56+ NK-cells, followed by m3F8. Overall and progression free survival (PFS) were assessed from the time of first NK-cell dose. Univariate Cox regression assessed relationship between dose and outcomes. Thirty-five patients received NK-cells at one of five dose levels ranging from 10×10(6) CD56+cells/kg had improved PFS (HR: 0.36, 95%CI: 0.15–0.87, p = 0.022). Patient NK-cells displayed high NKG2A expression, leading to inhibition by HLA-E-expressing neuroblastoma cells. Adoptive NK-cell therapy in combination with m3F8 is safe and has anti-neuroblastoma activity at higher cell doses.

Purpose Treatment of progression in high-risk neuroblastoma remains challenging despite improved survival. We retrospectively evaluated outcomes in children with a first progression that included soft-tissue masses. Methods We reviewed records of 903 consecutive children with high-risk neuroblastoma diagnosed between 2004 and 2014, and identified 42 whose first progression included soft-tissue masses. Data on demographics, disease characteristics, treatment, and survival were collected. Primary outcome was 5-year overall survival (OS) from time of first progression. Secondary outcomes were local disease-free progression (LDFR) and progression-free survival (PFS) postprogression. We evaluated the prognostic significance of concomitant bone/bone marrow involvement, MYCN status, and multifocality of soft tissue relapse. Results Median age at diagnosis was 3.0 (range: 1–10.7) years. Median time to first relapse or progression was 1.2 (range: 0.1–4.5) years after complete remission or minimal stable residual disease. Twelve (29%) patients had concomitant bone or marrow involvement at progression/relapse. There were 11 (26%) patients with International Neuroblastoma Staging System stage 3 disease (all with MYCN amplification), and 31 (74%) with stage 4 disease (12 with MYCN amplification). Nine (21%) patients had multifocal soft tissue progression. R1 resection was achieved in 41 children (95%), 38 (95%) of whom also received salvage radiation therapy. Five-year OS postprogression was 35% (95% CI: 19–51%), 5-year LDFS was 52% (95% CI: 32–72%), and 5-year PFS postprogression was 20% (95% CI: 6–34%). Conclusion Among children with high-risk neuroblastoma who underwent aggressive treatment of a first soft-tissue recurrence, 5-year postprogression overall survival was 34%. Multifocality and MYCN amplification were the predominant prognostic correlates for worse survival.

// Brian H. Kushner 1 , Irina Ostrovnaya 2 , Irene Y. Cheung 1 , Deborah Kuk 2 , Shakeel Modak 1 , Kim Kramer 1 , Stephen S. Roberts 1 , Ellen M. Basu 1 , Karima Yataghene 1 , Nai-Kong V. Cheung 1 1 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 2 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA Correspondence to: Brian H. Kushner, e-mail: kushnerb@mskcc.org Keywords: immunotherapy, anti-G D2 antibody, minimal residual disease, autologous stem-cell transplantation, pediatric oncology Received: September 08, 2015 Accepted: November 09, 2015 Published: November 26, 2015 ABSTRACT Since 2003, high-risk neuroblastoma (HR-NB) patients at our center received anti-G D2 antibody 3F8/GM-CSF + isotretinoin – but not myeloablative therapy with autologous stem-cell transplantation (ASCT). Post-ASCT patients referred from elsewhere also received 3F8/GM-CSF + isotretinoin. We therefore accrued a study population of two groups treated during the same period and whose consolidative therapy, aside from ASCT, was identical. We analyzed patients enrolled in 1st complete/very good partial remission (CR/VGPR). Their event-free survival (EFS) and overall survival (OS) were calculated from study entry. Large study size allowed robust statistical analyses of key prognosticators including MYCN amplification, minimal residual disease (MRD), FCGR2A polymorphisms, and killer immunoglobulin-like receptor genotypes of natural killer cells. The 170 study patients included 60 enrolled following ASCT and 110 following conventional chemotherapy. The two cohorts had similar clinical and biological features. Five-year rates for ASCT and non-ASCT patients were, respectively: EFS 65% vs. 51% ( p = .128), and OS 76% vs. 75% ( p = .975). In multivariate analysis, ASCT was not prognostic and only MRD-negativity after two cycles of 3F8/GM-CSF correlated with significantly improved EFS and OS. Although a trend towards better EFS is seen with ASCT, OS is near identical. Cure rates may be similar, as close surveillance detects localized relapse and effective salvage treatments are applied. ASCT may not be needed to improve outcome when anti-G D2 immunotherapy is used for consolidation after dose-intensive conventional chemotherapy.

Osteochondromas are benign bony protrusions that can be spontaneous or associated with radiotherapy (RT). Current treatment of high-risk neuroblastoma includes dose-intensive chemotherapy, local RT, an anti-GD2 monoclonal antibody (MoAb), and isotretinoin. Late effects are emerging.The authors examined osteochondromas in 362 patients who were aged10 years when diagnosed with neuroblastoma, had received a MoAb plus isotretinoin since 2000, and had survived24 months from the time of the first dose of the MoAb. The incidence rate of osteochondroma was determined using the competing risks approach, in which the primary event was osteochondroma calculated from the date of neuroblastoma diagnosis and the competing event was death without osteochondroma.A total of 21 osteochondroma cases were found among 14 patients who were aged 5.7 to 15.3 years (median, 10.4 years) and 3.1 to 11.2 years (median, 8.2 years) from the time of neuroblastoma diagnosis. The cumulative incidence rate was 0.6% at 5 years and 4.9% at 10 years from the neuroblastoma diagnosis. Nine osteochondromas were revealed incidentally during assessments of neuroblastoma disease status or bone age. Thirteen osteochondromas were detected outside RT portals and had characteristics of spontaneous forms. Complications were limited to pain necessitating surgical resection in 3 patients, but follow-up was short at 0.3 to 7.7 years (median, 3.5 years).Osteochondromas in long-term survivors of neuroblastoma should be expected because these benign growths can be related to RT and these patients undergo radiologic studies over years, are monitored for late toxicities through and beyond adolescence, and receive special attention (because of concerns about disease recurrence) if they develop a bony protuberance. A pathogenic role for chemotherapy, anti-GD2 MoAbs, or isotretinoin remains speculative.

Tumors metastasizing to the central nervous system (CNS) are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular 131I-labeled monoclonal antibody 8H9 targeting surface glycoprotein B7-H3 in patients with CNS. Tumor B7-H3 expression was assessed by immunohistochemistry. CSF flow was determined by 111Indium-DTPA cisternography. 131 patients received 2 mCi tracer of intra-Ommaya 124I- or 131I-8H9 for nuclear imaging followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) 131I-8H9. Pharmacokinetics were studied by serial CSF and blood samplings over 48 hours. Dosimetry was based on pharmacokinetics and region of interest analyses on serial PET. Toxicity was defined by the CTCAE v.3.0. 8H9 dosimetry and therapy injections were repeated after 1 month if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. 129 patients with primary or metastatic CNS tumors received 383 injections [median age 5.4 years (1.2- 53.6 years)] Injections were well tolerated and routinely administered in the outpatient setting. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting, biochemical elevations in AST or ALT and 1 injection with grade 3 ALT elevation (dose level 3). Although not a dose limiting toxicity, myelosuppression occurred in patients who had received craniospinal radiation and at dose levels 6 and higher (>60 mCi). Of 93 patients treated for metastatic CNS neuroblastoma, an improved overall survival was noted compared to survival reported with conventional therapies. Interpatient variability for total absorbed dose to the CSF and blood was observed; mean absorbed CSF dose was 104.9 cGy/mCi by CSF sampling, and 2.6 cGy/mCi to the blood. We conclude that intraventricular 131I-8H9 is safe, has favorable dosimetry to CSF, and has clinical utility.

Background: The STARTRK-NG (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - Next Generation) trial is a Phase 1/1b dose-escalation and expansion study of entrectinib in pediatric patients with cancer. Entrectinib is a potent oral, CNS-penetrant, inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s < 2 nM (biochemical kinase assay). Three adult studies (Phase 1 ALKA-372-001, Phase 1 STARTRK-1, and Phase 2 STARTRK-2) have enrolled hundreds of patients with advanced or metastatic solid tumors harboring TRKA/B/C, ROS1, or ALK molecular alterations, with or without CNS disease. Previously, we reported 400 mg/m2 daily as the adult body surface area (BSA)-based Recommended Phase 2 Dose (RP2D) (Patel et al, ASCO 2015). An objective response rate of 79% was seen in 24 tyrosine kinase inhibitor-naïve patients with TRK, ROS1, or ALK fusions who were treated at doses consistent with the RP2D (Drilon et al, AACR 2016). Gene fusions have been observed in a variety of adult solid tumor types, including non-small cell lung cancer, salivary gland cancers, soft tissue sarcomas and glioneuronal tumors. These fusions have also been found in cancers that affect the pediatric population, such as infantile fibrosarcoma, juvenile breast cancer, mesoblastic nephroma, intrinsic pontine gliomas, acute leukemias and anaplastic lymphoma. In addition, overexpression of TRKB and activating ALK point mutations have been observed in neuroblastoma. Thus, a pan-TRK, ROS1, and ALK inhibitor, like entrectinib, may potentially have broad therapeutic utility in pediatric patients. Methods: This is a multicenter, dose escalation study in pediatric patients (aged 2-21 years) with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 1b) in patients with primary brain tumors harboring TRK, ROS1, or ALK molecular alterations inclusive of gene fusions, neuroblastoma, and other non-neuroblastoma, extracranial solid tumors harboring TRK, ROS1, or ALK gene fusions (NCT02650401). During dose escalation, a 3+3 schema will be used to determine the pediatric RP2D of entrectinib with a starting dose of 250 mg/m2 (approximately 60% of the adult BSA-based RP2D), administered orally once daily in repeated 4-week cycles, with concordant pharmacokinetics and pharmacodynamics studies. Up to four dose levels will be evaluated. Dose modifications, if necessary, will follow a protocol-specific dosing nomogram for each dose level. Once the pediatric RP2D is determined, the Phase 1b expansion cohorts will be opened simultaneously, and prospective molecular profiling will be performed to determine eligibility except for patients with neuroblastoma. Citation Format: Ami V. Desai, Garrett M. Brodeur, Jennifer Foster, Suzanne Shusterman, Amit J. Sabnis, Magaret Macy, Cynthia Wetmore, Ellen Basu, Zachary Hornby, Vanessa Esquibel, Edna Chow Maneval, Pratik S. Multani, Elizabeth Fox. STARTRK-NG: A phase 1/1b study of entrectinib in children and adolescents with advanced solid tumors and primary CNS tumors, with or without TRK, ROS1, or ALK fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT030. doi:10.1158/1538-7445.AM2017-CT030

10545 Background: Neuroblastoma metastatic to the central nervous system (CNS NB) is associated with significant mortality (median survival < 6 months, < 10% survival at 36 months). Intraventricular compartmental radioimmunotherapy (cRIT) with radio-iodinated murine IgG1 monoclonal antibody 131I-8H9 targeting tumor cell-surface glycoprotein B7-H3 offers a therapeutic strategy. We analyzed overall survival of patients with CNS NB treated with intraventricular 131I-8H9 cRIT at Memorial Sloan Kettering Cancer Center (MSK) since 2003. Methods: After radiographic and/or pathologic confirmation of CNS NB, and assessment of adequate CSF flow, cRIT eligible patients underwent treatment on an IRB-approved protocol with either temozolomide/irinotecan-based CNS salvage regimen incorporating craniospinal radiation therapy, 131I-8H9 cRIT plus systemic immunotherapy (group 1), or non-regimen therapies with 131I-8H9 cRIT (group 2). cRIT administration involved a 2mCi tracer of 124I- or 131I-8H9 with nuclear imaging and CSF sampling for dosimetry followed by 1 or 2 therapeutic injections up to 70 mCi 131I-8H9. Disease surveillance included serial MR brain/spine, MIBG, CT, and bone marrow evaluation. Data are presented as overall survival after detection of CNS metastasis. Results: 105 patients with CNS NB were evaluated;80 patients (76%) were treated (57 group 1, 23 group 2). Of the 25 patients who were not eligible for cRIT, survival averaged 8.6 months. Of 19 patients with radiographic evidence of disease at the time of cRIT, 7 (36%) demonstrated post cRIT radiographic improvement. At analysis, 45/80 (56%) patients were alive 4.8–152 months (median 58 months) after CNS metastasis, including 36 (45%) at 36 months and 23 (29%) > 60 months. Subgroup analyses of 131I-8H9–treated patients identified age at NB diagnosis (≤18 months), relapse restricted to CNS and group 1 status as factors positively correlated with survival. Conclusions: 76% of patients with CNS NB treated at MSK received 131I-8H9 cRIT, and approximately half completed multimodality CNS salvage regimen with 131I-8H9 cRIT. Despite advanced CNS involvement, over 50% of patients treated with 131I-8H9 cRIT are still alive and nearly 50% have survived at least 36 months. Clinical trial information: NCT00089245.

10550 Background: The diagnosis of NB in adulthood is rare and little is known about its biology and clinical course. There is no established therapy for adult NB. Anti-GD2 immunotherapy is now standard in children with HR-NB but its use has not been reported in adults. Methods: After obtaining IRB waiver, records of all patients with adult-onset (≥18 years) NB seen at MSKCC between 1983 and 2015 were reviewed. Overall survival (OS) was tested by log-rank test. Cox-regression was used for multivariate analysis. Results: The subjects were 42 adults (median: 25; range18-71 years); 23 male and 19 female. Five, 1, 1 and 35 patients had INSS stage 1, 2, 3 and 4 disease, respectively. Genetic abnormalities included somatic ATRX (59%) and ALK mutations (43%) but not MYCN-amplification. 16 patients remain alive at a median follow-up of 5.3 years. OS for non-stage 4 patients was superior to stage 4 (median survival 14.6 vs 5.3 years; p < 0.05). However 5/7 patients with < stage 4 NB progressed to stage 4. Among 35 stage 4 patients, 4 achieved complete remission (CR) after induction chemotherapy and surgery, 11 underwent autologous stem cell transplant (ASCT) and 15 received multiple cycles of anti-GD2 antibodies 3F8 or hu3F8 without complications. In univariate analysis, patients ≤ 29 years old (n = 24) at diagnosis, those achieving CR, and those receiving anti-GD2 antibodies had superior OS (p < 0.05 for each). ASCT was not beneficial (p = 0.3 for ASCT vs no ASCT). For stage 4 patients, anti-GD2 immunotherapy was associated with favorable OS in multivariate analysis (95% CI of anti-GD2 antibody: 1.270 to 7.990). Conclusions: Adult-onset stage 4 NB demonstrates a high incidence of somatic mutations and is only partially chemosensitive. However, 3F8/hu3F8-based anti-GD2 immunotherapy appears to improve long-term survival and is well tolerated.

TO THE EDITOR: We suggest that the far-reaching conclusion based on a landmark phase III trial concerning high-risk neuroblastoma (HR-NB) should be reconsidered, given the major statistical error in the recent update. 1 The initial report in 1999 prompted the worldwide adoption of myeloablative therapy with autologous stemcell transplantation (ASCT) as the standard of care for patients with HR-NB in first remission. Now, 15 years later, we learn that this intervention made no statistically significant difference in overall survival (OS) when tested in a randomized fashion (P .39 by log rank; P.08 at 5 years). 1 OS stands out as the gold standard for evaluation of treatment efficacy, the acid test for US Food and Drug Administration drug approval, and the driving force for advances in cancer therapeutics. 2 OS is 100% accurate for event and time; it takes into account both safety(toxiccomplications)andefficacy.Event-freesurvival(EFS)isa surrogateendpointthatallowsanearlierassessmentofresults,butits validity requires confirmation, either through correlation with OS or by meta-analysis. 2-4 Unless improvement in quality of life can be documented, delaying asymptomatic events without prolonging survival is not clinically meaningful. 3 In short, a surrogate end point should be used with caution as the basis to establish standard of care. In this landmark study, 1 why did OS fail to show significance, whileEFSdid?Thisdiscrepancypointstothewelcomepossibilitythat

The authors exploited a large database to investigate the outcomes of patients with high-risk neuroblastoma in the contemporary era.All patients with high-risk neuroblastoma aged12 years who were treated during induction at the authors' institution from 2000 through 2011 were studied, including 118 patients with MYCN-amplified [MYCN(+)] disease and 127 patients aged18 months with MYCN-nonamplified [MYCN(-)] stage 4 disease.A complete response/very good partial response (CR/VGPR) to induction was correlated with significantly superior event-free survival (EFS) (P .001) and overall survival (OS) (P .001) compared with a partial response or less. Patients with MYCN(+) and MYCN(-) disease had similar rates of CR/VGPR to induction (P = .366), and those with MYCN(+) and MYCN(-) disease who attained a CR/VGPR had similar EFS (P = .346) and OS (P = .542). In contrast, only MYCN(+) patients had progressive disease as a response to induction (P .001), and early death from progressive disease (366 days after diagnosis) was significantly more common (P .001) among those with MYCN(+) disease. Overall, among patients who had a partial response or less, MYCN(+) patients had significantly inferior EFS (P .001) and OS (P .001) compared with MYCN(-) patients, which accounted for the significantly worse EFS (P = .008) and OS (P = .002) for the entire MYCN(+) cohort versus the MYCN(-) cohort.Patients with MYCN(-), high-risk neuroblastoma display a broad, continuous spectrum with regard to response and outcome, whereas MYCN(+) patients either have an excellent response to induction associated with good long-term outcome or develop early progressive disease with a poor outcome. This extreme dichotomy in the clinical course of MYCN(+) patients points to underlying biologic differences with MYCN(+) neuroblastoma, the elucidation of which may have far-reaching implications, including improved risk classification at diagnosis and the identification of targets for treatment.

10554Background: The rationale for studying the combination of bevacizumab+irinotecan and temozolomide (BIT) in NB is based on: (a) VEGF expression is associated with aggressive phenotype in NB. (b...

10553Background: The literature on MYCN-amplified stage 2/3 neuroblastoma is limited because this high-risk subset is uncommon. Its prognosis improved with ASCT. Reports on anti-GD2 immunotherapy d...