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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.

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.

Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody 131I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya 131I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases. Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of 131I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [CIAR(t)], (b) the AUC of the unbound “harmful” antibody, AUC [CIA(t)], and (c) the therapeutic index, AUC [CIAR(t)] ÷ AUC [CIA(t)]. The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of 131I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [CIA(t)]) was predicted to increase more quickly than AUC [CIAR(t)] as a function of 131I-omburtamab dose, but the balance of therapeutic index and AUC [CIAR(t)] remained favorable over a broad range of administered doses (0.48–1.40 mg or 881–2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%. The 2-compartmental pharmacokinetic model when applied to intraOmmaya 131I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. ClinicalTrials.gov , NCT00089245.

Background Safe sampling of central nervous system tumor tissue for diagnostic purposes may be difficult if not impossible, especially in pediatric patients, and an unmet need exists to develop less invasive diagnostic tests. Methods We report our clinical experience with minimally invasive molecular diagnostics using a clinically validated assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA). All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. Results We analyzed 64 CSF samples from 45 pediatric, adolescent and young adult (AYA) patients (pediatric = 25; AYA = 20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n = 10), medulloblastoma (n = 10), pineoblastoma (n = 5), low-grade glioma (n = 4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n = 4), retinoblastoma (n = 4), ependymoma (n = 3), and other (n = 5). Somatic alterations were detected in 30/64 samples (46.9%) and in at least one sample per unique patient in 21/45 patients (46.6%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (81.5% of samples from patients with disseminated disease were positive). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient’s disease course. Conclusions We identified three general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: (1) diagnosis and/or identification of actionable alterations; (2) monitor response to therapy; and (3) tracking tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population to improve care.

Simple Summary Beta glucans, complex polysaccharides, can prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of monoclonal antibodies. In a phase I study (clinicaltrials.gov NCT00492167), we treated patients with intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles of therapy with 3F8 + BG. One patient developed DLT: transient self-limiting hepatic transaminase elevation at a BG dose of 120 mg/kg/day. Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. BG lacked major toxicity and, in combination with 3F8, demonstrated anti-neuroblastoma activity against resistant disease. The recommended phase II dose was established at 40 mg/kg/day. Abstract Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose.

BACKGROUND: Median survival from DIPG is less than one year. In a phase 1 dose escalation study (clinicaltrials.gov NCT01502917) 124I-omburtamab targeting B7-H3 was administered intratumorally using CED. METHODS: CED was performed between 4-14 weeks post radiation therapy. Using a 3 + 3 design, 124I-omburtamab was escalated from 0.25-10.0 mCi and infusion volumes (Vi) from 250-10,000 µl with serial 124I PET/CT performed up to ~1 week post-administration. Toxicities were assessed for 30 days. Dose escalation safety was evaluated. Survival was calculated using Kaplan-Meier statistics. RESULTS: 46 children were treated and evaluable for toxicity and survival;4 patients received partial doses and were evaluable for toxicity only. Three patients experienced dose limiting toxicities. Eleven patients had transient treatment related grade 3 toxicities with no grade 4 or 5 toxicities. Grade 3 nervous system toxicities included: muscular weakness(n=8), dysarthria(n=4), ataxia(n=3), dysphagia(n=3), and gait disturbance(n=1). Lesion absorbed doses ranged from 1,000-1,500cGy/mCi, with lesion-to-whole body radiation absorbed-dose ratios of ~900. A dose of 8mCi and infusion volume of 8,000 µl is safe and may provide a distribution volume up to 20cm3. Median survival was 15.3 months (n =46, 95% CI 12.7, 17.3). Survival rate estimates (95% CI) at 1, 2, 3 and 5 years were 0.67 (0.55;0.82); 0.18 (0.09;0.35); 0.10 (0.04;0.26); and 0.05 (0.01;0.20). Four patients survived >3 years; two remain alive (61+ and 106+ months);two have died (44 and 53 month) with distant CNS disease and one with extra-CNS metastasis. CONCLUSION: Administration of escalating doses and volumes of 124I-omburtamab via CED was a viable option for this patient subgroup. The median overall survival was increased 3-4 months compared to historical controls. Anecdotal long-term survival if validated with a planned phase 2 trial would support the concept of whole neuroaxis treatment in combination with CED in a subset of DIPG patients.

The incidence of abnormal cerebrospinal fluid (CSF) flow dynamics in children with central nervous system (CNS) tumors before intraventricular therapy has not been described. Methods: We performed a single-institution, retrospective review of patients with primary or metastatic CNS tumors treated between 2003 and 2018 (15 y). Patients underwent (111)In-diethylenetriaminepentaacetic acid injection into the CSF intraventricular space followed by nuclear medicine imaging at 90 min, 4 h, 24 h, and 48 h (if required). CSF flow was classified as normal, delayed, asymmetric, or obstructed. Results: In total, 278 CSF flow studies were performed on 224 patients, 202 of whom (90%) were less than 18 y old. Of these, 116 patients (52%) had metastatic CNS neuroblastoma, 57 (25%) had medulloblastoma, and 51 (23%) had other histologic types of CNS tumors. Of the 278 studies, 237 (85%) were normal, 9 (3%) required neurosurgical intervention, 25 (9%) were delayed, and 7 (3%) were asymmetric. Conclusion: Abnormal CSF flow and the necessity for neurosurgical intervention must be considered when attempting to ensure appropriate intraventricular therapy in the pediatric population.

Radiation dose estimations are key for optimizing therapies. We studied the role of 124I-omburtamab (8H9) given intraventricularly in assessing the distribution and radiation doses before 131I-omburtamab therapy in patients with metastatic leptomeningeal disease and compared it with the estimates from cerebrospinal fluid (CSF) sampling. Methods: Patients with histologically proven malignancy and metastatic disease to the central nervous system or leptomeninges who met eligibility criteria for 131I-omburtamab therapy underwent immuno-PET imaging with 124I-8H9 followed by 131I-8H9 antibody therapy. Patients were imaged with approximately 74 MBq of intraventricular 124I-omburtamab via an Ommaya reservoir. Whole-body PET images were acquired at approximately 4, 24, and 48 h after administration and analyzed for dosimetry calculations. Peripheral blood and CSF samples were obtained at multiple time points for dosimetry estimation. Results: Forty-two patients with complete dosimetry and therapy data were analyzed. 124I-omburtamab PET-based radiation dosimetry estimations revealed mean (±SD) absorbed dose to the CSF for 131I-8H9 of 0.62 ± 0.40 cGy/MBq, compared with 2.22 ± 2.19 cGy/MBq based on 124I-omburtamab CSF samples and 1.53 ± 1.37 cGy/MBq based on 131I-omburtamab CSF samples. The mean absorbed dose to the blood was 0.051 ± 0.11 cGy/MBq for 124I-omburtamab samples and 0.07 ± 0.04 cGy/MBq for 131I-omburtamab samples. The effective whole-body radiation dose for 124I-omburtamab was 0.49 ± 0.27 mSv/MBq. The mean whole-body clearance half-time was 44.98 ± 16.29 h. Conclusion: PET imaging with 124I-omburtamab antibody administered intraventricularly allows for noninvasive estimation of dose to CSF and normal organs. High CSF-to-blood absorbed-dose ratios are noted, allowing for an improved therapeutic index to leptomeningeal disease and reduced systemic doses. PET imaging-based estimates were less variable and more reliable than CSF sample-based dosimetry.

PURPOSE: We explored the use of intraventricular (131)I-8H9 targeting B7-H3 in patients with ETMR. METHODS: Patients were enrolled in an IRB approved, phase 1, 3+3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3, were eligible. We report on a cohort of 3 patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi (131)I-Omburtamab as a tracer followed by 1 or 2 therapeutic (131)I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after (131)I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received (131)I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to (131)I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then (131)I-Omburtamab (36 mCi). (131)I-Omburtamab was well-tolerated. Mean dose delivered by (131)I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 month after therapy (2 years after diagnosis). CONCLUSIONS: (131)I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, (131)I-Omburtamab may have therapeutic benefit for patients with ETMR.

INTRODUCTION: Patients receiving cranial radiotherapy (RT) are at risk for a subsequent radiation-induced glioma (RIG). RIGs are rare, generally develop with a latency of 2 years to several decades, display high-grade histology and an aggressive clinical course with poor prognosis. METHODS: We retrospectively analyzed patients with a diagnosis of RIG seen at our institution from 2001-2021, analyzing clinical, histological, molecular, and genetic characteristics. RESULTS: Twenty-one patients (n=15 male) with a history of ALL (n=6), medulloblastoma (n=5), germ cell tumors (n=4), or other (n=6) diagnosed at a median age of 8.3 years (range 1.6 to 36.4) were identified. Median age at RIG diagnosis was 18 years (range 7.8 to 66.9). Prior RT was focal+craniospinal (n=7), whole brain (n=5), total body (n=3), focal (n=1), or unknown (n=5). Median radiation dose received was 2,340 cGy (range 1,200 to 5,400). The median time from RT to RIG diagnosis was 7.7 years (range 1.6 to 23.8). All RIGs were histologically high grade (WHO Grade III or IV). Immunohistochemistry did not reveal IDH(R132H) (n=9) or H3K27M (n=8) in any tumor. Some tumors demonstrated loss of expression of ATRX (1/9) and/or H3K27me3 (3/6), and/or strong diffuse expression of p53 (0/3). Targeted panel sequencing (n=10) revealed recurrent somatic alterations including CDKN2A/B, PDGFRa/KIT/KDR, TEK, MTAP, ATM and NF1. Germline alterations were detected in 4/12 patients (pathogenetic variants in ATM, CHEK2, HOXB13 and NF1). With median follow-up of 4.5 years, two-year PFS and OS for the cohort (n=20) were 10% and 44% respectively. Two patients (with anaplastic oligodendroglioma and anaplastic astrocytoma) are alive without progression 5.4 and 13.6 years after diagnosis following surgery, RT and chemotherapy. CONCLUSION: Although RIGs are associated with a poor prognosis, they are not always fatal. Our findings suggest aggressive therapy should be considered for these patients.

Background: The Neurologic Assessment in Neuro-Oncology (NANO) scale, a standardized metric to objectively measure neurologic function in adult brain tumor patients, complements radiographic assessment in evaluating outcomes of neuro-oncology patients in clinical trials and clinical practice. Currently, there is no standardized measure for neurologic function in pediatric neuro-oncology patients despite their distinct clinical presentations and tumor locations. Therefore, we developed a dedicated pediatric NANO (pNANO) scale. Methods: An international group of pediatric neurologists and adult and pediatric neuro-oncologists convened bi-weekly over 5 months to draft the pNANO scale as an objective and quantifiable measure of neurologic function in children that can be administered during routine examination by pediatric-trained providers of any sub-specialty and be utilized together with other indicators to assess response in clinical trials. Results: Ten relevant domains of neurologic function were identified based on common pediatric brain tumor locations: gait, strength, cerebellar function, visual fields, visual acuity, facial strength, level of consciousness, extraocular movements, dysarthria and dysphagia. For each domain, developmental age appropriate levels of function were defined and categorized. Each domain, based on direct observation and testing during any routine neurological exam, can be used for longitudinal monitoring. Conclusions: The pNANO scale has been developed and aims to provide an objective metric of neurologic function for pediatric brain tumor patients. This scale will be tested for reliability, feasibility and inter-observer variability. Consistent evaluation of neurologic function using pNANO along with radiographic assessment will enable more comprehensive and standardized response assessment in pediatric neuro-oncology patients enrolled in clinical trials.

Radiation dose estimations are key for optimizing therapies. We studied the role of (124)I-omburtamab (8H9) given intraventricularly in assessing the distribution and radiation doses before (131)I-omburtamab therapy in patients with metastatic leptomeningeal disease and compared it with the estimates from cerebrospinal fluid (CSF) sampling. Methods: Patients with histologically proven malignancy and metastatic disease to the central nervous system or leptomeninges who met eligibility criteria for (131)I-omburtamab therapy underwent immuno-PET imaging with (124)I-8H9 followed by (131)I-8H9 antibody therapy. Patients were imaged with approximately 74 MBq of intraventricular (124)I-omburtamab via an Ommaya reservoir. Whole-body PET images were acquired at approximately 4, 24, and 48 h after administration and analyzed for dosimetry calculations. Peripheral blood and CSF samples were obtained at multiple time points for dosimetry estimation. Results: Forty-two patients with complete dosimetry and therapy data were analyzed. (124)I-omburtamab PET–based radiation dosimetry estimations revealed mean (±SD) absorbed dose to the CSF for (131)I-8H9 of 0.62 ± 0.40 cGy/MBq, compared with 2.22 ± 2.19 cGy/MBq based on (124)I-omburtamab CSF samples and 1.53 ± 1.37 cGy/MBq based on (131)I-omburtamab CSF samples. The mean absorbed dose to the blood was 0.051 ± 0.11 cGy/MBq for (124)I-omburtamab samples and 0.07 ± 0.04 cGy/MBq for (131)I-omburtamab samples. The effective whole-body radiation dose for (124)I-omburtamab was 0.49 ± 0.27 mSv/MBq. The mean whole-body clearance half-time was 44.98 ± 16.29 h. Conclusion: PET imaging with (124)I-omburtamab antibody administered intraventricularly allows for noninvasive estimation of dose to CSF and normal organs. High CSF-to-blood absorbed-dose ratios are noted, allowing for an improved therapeutic index to leptomeningeal disease and reduced systemic doses. PET imaging–based estimates were less variable and more reliable than CSF sample–based dosimetry.

Omburtamab is a B7H3-specific murine monoclonal antibody. B7H3 (CD 276) is a member of the B7 family of immune checkpoint co-inhibitory receptors overexpressed on many human malignancies. Radioimmunotherapy with 124I- or 131I-omburtamab administered in the cerebrospinal fluid (CSF), intraperitoneal or intratumoral cavity is currently under investigation for the treatment of CNS malignancies. The immunologic effects of anti-B7H3 therapy are not fully elucidated. A 6-year-old male was diagnosed with metastates of neuroblastoma to the received intraventricular 131I-omburtamab on an IRB-approved protocol. A treatment cycle consisted of a 2 mCi dosimetry dose and a 50 mCi treatment dose. Dosimetry by serial imaging, pharmacokinetics and safety were investigated. Clinical status, magnetic resonance imaging, CSF cell count and cytology were evaluated pre- and post-131I-omburtamab at 5 and 26 weeks. The patient did well with cycle 1. Three hours after the dosimetry dose of cycle 2, he developed a fever (39 °C), chills and headache. Blood and CSF samples were sent for culture. CSF was notable for nucleated cell pleocytosis with profound mast cell proliferation consistent with chemical meningitis. He was treated with supportive care; symptoms resolved over 48 h. Further therapy with 131I-omburtamab was electively discontinued. CSF cell count 5 weeks later demonstrated resolution of CSF pleocytosis. Local–regional administration of intraventricular 131I-omburtamab targeting B7H3 can result in a profound nucleated CSF pleocytosis with mastocytosis consistent with an acute allergic reaction.

PURPOSE: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intra-Ommaya anti-GD2 monoclonal antibody (131)I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intra-Ommaya (131)I-omburtamab (8H9), an anti-B7-H3 antibody which has shown promise in RIT of leptomeningeal metastases. METHODS: Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intra-Ommaya administrations of (131)I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC[C(IAR)(t)], (b) the AUC of the unbound “harmful” antibody, AUC[C(IA)(t)], and (c) the therapeutic index, AUC[C(IAR)(t)]÷AUC[C(IA)(t)]. RESULTS: The model fit CSF radioactivity data well (mean R=96.4%). The median immunoreactivity of (131)I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC[C(IA)(t)]) was predicted to increase more quickly than AUC[C(IAR)(t)] as a function of (131)I-omburtamab dose, but the balance of therapeutic index and AUC[C(IAR)(t)] remained favorable over a broad range of administered doses (0.48–1.40mg or 881–2592MBq). While anti-tumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%. CONCLUSION: The 2-compartmental pharmacokinetic model when applied to intra-Ommaya (131)I-omburtamab yielded both intuitive and non-intuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00089245

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.

Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.

Optimizing the conduct of clinical trials for diffuse intrinsic pontine glioma (DIPG) involves use of consistent, objective disease assessments and standardized response criteria. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, an international panel of pediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address unique challenges in assessing response in children with CNS tumors. A subcommittee of RAPNO was formed to specifically address response assessment in children and young adults with DIPG and to develop a consensus on recommendations for response assessment. Distinct issues related to the response assessment of DIPG include its definition and recent molecular classifications, dearth of imaging response data, the phenomena of pseudoprogression, and measuring response in the era of focal drug delivery. The committee has recommended response be assessed using magnetic resonance imaging (MRI) of brain and spine, neurologic examination, and use of supportive medication, i.e. steroids and anti-angiogenic agents. Clinical imaging standards and imaging quality control are defined. Unique recommendations for DIPG response include an eight-week response duration, a twenty-five percent decrease for partial response, and the distinction of pontine and extra-pontine response for trials that use focal drug delivery. The recommendations presented here represent an initial effort to uniformly collect and evaluate response assessment criteria; these recommendations can now be incorporated into clinical trials to assess feasibility and corroboration with patient outcomes.

Background Programmable ventriculoperitoneal shunts (pVP shunts) are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of thecal space drug concentrations with minimization in the peritoneum. Drug delivery quantification using several types of pVP shunts has not been reported. Methods We performed a retrospective analysis on patients with CNS tumors and pVP shunts at Memorial Sloan Kettering Cancer Center from 2003–2020, noting shunt model. CSF flow through the pVP shunt was evaluated using In-111-DTPA scintigraphy at approximately 4 and 24 hours after injection. pVP shunts were calibrated pre-injection to minimize peritoneal flow and re-calibrated to baseline setting 4–5 hours following injection. Scintigraphy studies quantified ventricular-thecal and peritoneal drug activity at these 2 time points. Results Twenty-one CSF flow studies were administered to 15 patients, ages 1–27 years. Diagnoses included medulloblastoma (N=10), metastatic neuroblastoma (N=3), pineoblastoma (N=1), and choroid plexus carcinoma (N=1). Models of pVP shunts included Aesculap Miethke proGAV (N=3), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 5), and Sophysa Polaris (N= 1). All 21 studies (100%) demonstrated ventriculo-thecal drug activity. 29% (6 of 21) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 21) of the studies had minimal peritoneal uptake ( Conclusions pVP shunts successfully deliver drugs to the ventriculo-thecal space with 80% of studies having minimal (

Purpose Pediatric central nervous system tumors remain a leading cause of cancer-related death in children and adolescents. Safe sampling of tumor tissue for diagnostic purposes may be challenging. Subclinical detection of disease prior to clinical or imaging progression may provide opportunity for earlier intervention and ultimately improve overall survival. Additionally, our understanding of molecular evolution in response to therapy remains limited, given the rarity of serial sampling of tumor tissue. Methods We report our experience with minimally invasive molecular diagnostics using a validated next generation sequencing assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA) obtained at the time of surgery, by intraventricular catheter or lumbar puncture. All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. Results We analyzed 64 CSF samples from 45 pediatric and adolescent and young adult (AYA) patients (pediatric=25; AYA=20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n=10), medulloblastoma (n=10), pineoblastoma (n=5), low grade glioma (n=4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n=4), metastatic retinoblastoma (n=4), ependymoma (n=3), and other (n=5). Somatic alterations were detected in 28/64 samples (44.4%) and in at least one sample per unique patient in 22/45 patients (48.8%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (86.3%). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient’s disease course. Conclusion We identified four general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: 1) diagnosis; 2) identification of actionable alterations; 3) track response to therapy; and 4) monitoring tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population that may improve care.

Background Programmable ventriculoperitoneal (pVP) shunts are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of thecal space drug concentrations with minimization in the peritoneum. Drug delivery quantification using several types of pVP shunts has not been reported. Methods We performed a retrospective analysis on patients with CNS tumors and pVP shunts at Memorial Sloan Kettering Cancer Center from 2003–2020, noting shunt model. CSF flow through the pVP shunt was evaluated using In-111-DTPA scintigraphy at approximately 4 hours and 24 hours after injection. pVP shunts were calibrated pre-injection to minimize peritoneal flow and re-calibrated to baseline setting 4–5 hours following injection. Scintigraphy studies quantified ventricular-thecal and peritoneal drug activity at these 2 time points. Results Twenty-one CSF flow studies were administered to 15 patients, ages 1–27 years. Diagnoses included medulloblastoma (N=10), metastatic neuroblastoma (N=3), pineoblastoma (N=1), and choroid plexus carcinoma (N=1). pVP shunt models included Aesculap Miethke proGAV (N=3), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 5), and Sophysa Polaris (N= 1). All 21 studies (100%) demonstrated ventriculo-thecal drug activity. 29% (6 of 21) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 21) of the studies had minimal peritoneal uptake ( Conclusions Successful drug delivery to the ventriculo-thecal space can be accomplished using pVP shunts: 80% of studies have minimal (

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.

Pediatric CNS tumors remain the leading cause of cancer-related death in children and adolescents. Safe sampling of tumor tissue for diagnostic purposes may be difficult if not impossible. Detection of minimal residual or recurrent disease prior to definitive clinical or radiographic progression may allow earlier initiation of novel therapies and ultimately improve overall survival. Given the rarity of serial sampling of tumor tissue, our understanding of molecular evolution in response to therapy remains limited. Recent technological advances have led to the development of “liquid biopsy” assays, which detect cell-free DNA (cfDNA) in blood, cerebrospinal fluid (CSF) or other bodily fluids. Here, we report our initial clinical experience with the recently established MSK Kids pediatric neuro-oncology liquid-biopsy program at Memorial Sloan Kettering Cancer Center (MSKCC) using MSK-IMPACT, which is clinically validated by the New York State Department of Health for CSF cell-free DNA (cfDNA)vprofiling. All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. Samples from 29 unique patients were sequenced. Histopathology included high-grade glioma (5); low-grade glioma (2); medulloblastoma (8); pineoblastoma (3); retinoblastoma (4); other (7). CSF cfDNA could be detected in 18/42 samples (43%) and 12/29 patients (34%). CSF cfDNA was more commonly detected in higher-grade, disseminated tumors such as high-grade glioma (60%), medulloblastoma (38%), and pineoblastoma (100%). Low-grade lesions without leptomeningeal involvement did not result in detectable CSF cfDNA shedding (86% were negative). In a subset of patients, MSK-IMPACT identified previously unrecognized molecular actionable targets (e.g. BRAF-KIAA1549 fusion); or the detection of “minimal residual disease” prior to the detection of tumor recurrence by conventional diagnostics, impacting clinical care decisions. Future directions include integration of CSF cfDNA into prospective clinical trials as a correlative biomarker.

BACKGROUND The incidence of abnormal CSF flow dynamics in the pediatric population with CNS tumors prior to intraventricular therapy has not been described. METHODS We performed a single-institution, retrospective review of patients with primary or metastatic CNS tumors treated between 2003–2018 (15 years).. Patients underwent 111-indium diethylene triamine pentaacetic acid injection into the CSF intraventricular space followed by nuclear medicine imaging at 90 minutes, 4, 24, and 48 hours (if required). CSF flow was classified as normal, delayed, asymmetric or obstructed. RESULTS 278 CSF flow studies were performed in 224 patients, 202(90%) CONCLUSIONS Abnormal CSF flow and necessity of neurosurgical intervention must be considered when attempting to ensure appropriate intraventricular therapy in the pediatric population.

BACKGROUND: Patients with primary or metastatic central nervous system (CNS) tumors may be treated with adjuvant intraventricular chemotherapy or radioimmunotherapy. Effectiveness of the drug may in part depend on adequate drug distribution throughout the thecal space. The incidence of normal, delayed, asymmetric or obstructed cerebrospinal fluid (CSF) flow in the pediatric population with CNS tumors prior to intraventricular therapy has not been described. METHODS: We performed a retrospective review of patients with primary or metastatic CNS tumors treated at MSK over a 15-year period (2003–2018). Patients underwent 111-indium diethylene triamine pentaacetic acid (DTPA) injection into the CSF with nuclear medicine imaging at 90 min-4 hours, 24 hours and 48 hours (if required). CSF flow studies were classified as normal, delayed, asymmetric or obstructed. RESULTS: 278 CSF flow studies were performed in 224 patients, 202 (90%) < 18 years of age. 116 (52%) of patients had metastatic CNS neuroblastoma, 57 (25%) had medulloblastoma and 51 (23%) had other CNS histologies. Of the 278 flow studies, 237 (85%) were normal, 9 (3%) were obstructed requiring neurosurgical intervention, 25 (9%) were delayed and 7(3%) were asymmetric. CONCLUSIONS: Abnormal CSF flow studies are noted in 15% of pediatric patients with CNS tumors; 3% of patients will require a procedure to improve adequate flow prior to receiving intraventricular therapy. These results have implications for successful delivery of intraventricular therapies.

2010 Background: The prognosis of diffuse intrinsic pontine glioma (DIPG) is dire with a median overall survival less than one-year. 124I-omburtamab is a radiolabeled monoclonal antibody that targets B7-H3 epitope. We evaluated the safety of administering escalating doses and volumes of 124I-omburtamab via convection-enhanced delivery (CED) in children with DIPG. Methods: MSKCC 11-011 trial is a standard 3+3 phase 1, open-label, dose escalation study in patients with non-progressive DIPG. CED of 124I-omburtamab was performed between 4-14 weeks post-external radiation therapy. Nine dose levels of a single injection of 124I-omburtamab (Y-mAbs Therapeutics, USA) (range 0.25 to 8.0 mCi; and volume of infusion (Vi) from 250 to 8,000 µl) have been evaluated so far. Patients were assessed weekly for 30 days. Results: 46 children were evaluable for primary and secondary endpoints. The median age at enrolment was 6.5 years (range 2-17). Two patients have experienced AEs CTCAE grade 3 that were categorized as dose limiting toxicities (DLTs), which led to inclusion of three more patients at both the 4 and 6 mCi dose levels. Eight patients have reported transient AEs of grade 3 considered related to 124I-omburtamab. The acute grade 3 AEs were generally indicative of nervous system effects due to volume intolerance or radiation injury, and included hemiparesis (n = 3), dysarthria (n = 3), ataxia (n = 3), dysphagia (n = 2), muscular weakness (n = 2) and gait disturbance (n = 1). There were no related AEs CTCAE grade 4 or 5. Estimations of distribution volumes based on T2-weighted imaging were linearly related to volume with a mean volume of distribution/volume of infusion ratio (Vd/Vi) between 3 and 3.5. The mean ratio of lesion-to-whole body absorbed dose was ̃1000. Median overall survival from diagnosis across all cohorts was 14.8 months (n = 46, 95% CI 11.5, 16.8) and the survival rate estimates (with 95% confidence intervals) at 1, 2, 3 and 5 years were 0.63 (0.46;0.76); 0.13 (0.05;0.26); 0.08 (0.02;0.19); and 0.04 (0.00;0.16), respectively. Four patients have survived > 3 years; two remain alive at 46 and 96 months and two have died at 43 and 53 months, both with CNS disease outside of the treatment field and one with extra-CNS metastases. Conclusions: 124I-omburtamab via CED into the brain stem of children with DIPG and previously irradiated provides a possibility for improved treatment of DIPG. A dose of 8mCi and an infusion volume of 8,000 µl is considered safe and may provide a distribution volume large enough to cover tumor volumes up to 20 cm3. The median overall survival of all patients included in the trial appears to be increased with 3-4 months compared to historical control data from consortia trials. A phase 2 trial aiming at investigating the efficacy of radiolabeled omburtamab administered via CED is being planned. Clinical trial information: NCT01502917.

A correction to this paper has been published: https://doi.org/10.1007/s00262-021-02942-3

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.

Arsenic trioxide has in vitro and in vivo radiosensitizing properties. We hypothesized that arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG) and tested the combination in a phase II clinical trial. Methods: Patients with recurrent or refractory stage 4 neuroblastoma or metastatic paraganglioma/pheochromocytoma (MP) were treated using an institutional review board–approved protocol (Clinicaltrials.gov identifier NCT00107289). The planned treatment was 131I-MIBG (444 or 666 MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25 mg/m2) intravenously on days 6–10 and 13–17. Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria, version 3.0. Response was assessed by International Neuroblastoma Response Criteria or (for MP) by changes in 123I-MIBG or PET scans. Results: Twenty-one patients were treated: 19 with neuroblastoma and 2 with MP. Fourteen patients received 131I-MIBG and arsenic trioxide, both at maximal dosages; 2 patients received a 444 MBq/kg dose of 131I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide; and 3 patients received a 666 MBq/kg dose of 131I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide. One did not receive arsenic trioxide because of transient central line–induced cardiac arrhythmia, and another received only 6 of 10 planned doses of arsenic trioxide because of grade 3 diarrhea and vomiting with concurrent grade 3 hypokalemia and hyponatremia. Nineteen patients experienced myelosuppression higher than grade 2, most frequently thrombocytopenia (n = 18), though none required autologous stem cell rescue. Twelve of 13 evaluable patients experienced hyperamylasemia higher than grade 2 from transient sialoadenitis. By International Neuroblastoma Response Criteria, 12 neuroblastoma patients had no response and 7 had progressive disease, including 6 of 8 entering the study with progressive disease. Objective improvements in semiquantitative 131I-MIBG scores were observed in 6 patients. No response was seen in MP. Seventeen of 19 neuroblastoma patients continued on further chemotherapy or immunotherapy. Mean 5-year overall survival (±SD) for neuroblastoma was 37% ± 11%. Mean absorbed dose of 131I-MIBG to blood was 0.134 cGy/MBq, well below myeloablative levels in all patients. Conclusion:131I-MIBG plus arsenic trioxide was well tolerated, with an adverse event profile similar to that of 131I-MIBG therapy alone. The addition of arsenic trioxide to 131I-MIBG did not significantly improve response rates when compared with historical data with 131I-MIBG alone.

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.

PURPOSE: Embryonal Tumor/Multilayered Rosettes (ETMR) is an aggressive CNS tumor in young children; median survival is 12 months. We explored the use of intraventricular (131)I-8H9 targeting B7-H3 in patients with ETMR on a trial at MSK. METHODS: Patients received 2 mCi (131)I-8H9 as a tracer followed by 1 or 2 therapeutic (131)I-8H9 injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after (131)I-8H9, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3+ ETMR. Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received (131)I-8H9 (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to (131)I-8H9 treated with surgery, craniospinal radiation, chemotherapy, then (131)I-8H9 (36 mCi). (131)I-8H9 was well-tolerated; patient 2 had grade 4 thrombocytopenia 1 month after injection. Mean dose delivered by (131)I-8H9 was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 5.5 and 1.2 years after diagnosis, respectively. Patient 3 suffered a third local recurrence 22 months after diagnosis and remains alive with disease. CONCLUSIONS: (131)I-8H9 appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, (131)I-8H9 may have therapeutic benefit for patients with ETMR.

PURPOSE: Novel treatment strategies are needed for children with recurrent ependymoma. We explored the use of intraventricular targeted immunotherapy with monoclonal antibodies (cRIT-mAb) using (131)I-8H9 and (131)I-3F8 targeting B7-H3 or G(D2), respectively. METHODS: Patients received 2 mCi cRIT- (131)I- mAb for dosimetry with serial CSF sampling and region of interest (ROI) on nuclear scans. Therapy injections were 40 -100 mCi (131)I-8H9 or up to 40 mCi (131)I-3F8. Brain and spine MRIs, CSF cytology were routinely assessed. Acute toxicities and survival were noted. RESULTS: 11 patients with anaplastic ependymoma (median age 8.5 years, 1–32) suffered 1- 7 recurrences (median 2.9); median age at cRIT was 12.3 years (3–35). 39 injections were delivered (13 (131)I-3F8; 26 (131)I-8H9). Transient headache, nausea and vomiting was observed following (131)I-3F8; (131)I-8H9 was well-tolerated. Mean CSF cGy/mCi by sampling was 37.6 (131)I-8H9 and 40.1 (131)I-3F8. Mean ventricular ROI dose was 75.3 cGy/mCi (131)I-8H9 and 111 cGy/mCi (131)I-3F8 and to spine 20.2 cGy/mCi (131)I-8H9 and 18.9 cGy/mCi (131)I-3F8. 4/5 patients with radiographic evidence of disease progressed; 1 had spinal disease improvement. Of 5 patients treated in radiographic remission, 2 remain in remission 2.5 and 8 years since cRIT, 1 is alive with disease 2.5 years post; 2 patients died of disease 7 and 13 years post cRIT. CONCLUSIONS: cRIT mAb appear safe with a favorable dosimetry therapeutic index and may be considered as a viable therapeutic option for patients with recurrent ependymoma.

INTRODUCTION: Patients with DIPG sometime present with mild symptoms and/or atypical MRI findings. Since palliative radiation therapy(RT) is the only effective treatment, a decision to treat with RT or wait for progressive symptoms and/or MRI changes arise. Progression free survival(PFS) and overall survival(OS) after delay in RT (>30 days from diagnosis) was compared against patients treated without delay. METHODS: An IRB retrospective waiver for patients with DIPG treated within Pediatrics at MSKCC from 2000–2016 was obtained. Univariate analysis of days to RT from diagnosis, gender, age, symptom duration, MRI (typical versus atypical) and association with PFS and OS via the Cox proportional hazard model was performed. Patients treated with radio-labeled antibody delivered via convection enhanced delivery were excluded (n=26). RESULTS: Thirty-nine patients with complete records were analyzed, median age: 6.8 years (range: 2–36.5), gender: 19 girls, atypical MRIs: 18. Six patients had delayed RT (days: 32, 33, 42, 74, 77 and 2793). The patient delayed 2793 days had a biopsy at progression demonstrating K27M staining. Patients had varying treatment courses: concomitant chemotherapy with RT, chemotherapy after RT and re-irradiation. Non-delayed versus delayed RT, PFS (6.7mo versus 10.4mo, p=0.184) and OS (12.7mo versus 12.9mo, p=0.485) were not associated with any significant difference. Univariate analysis found no associations. DISCUSSION: We found no association between delayed initiation of RT and PFS or OS in this retrospective analysis. Our data suggest that in a small subset of patients with DIPG presenting with atypical MRI findings and/or mild symptoms, it may be reasonable to delay initiation of RT.

BACKGROUND: The success of programmable ventriculoperitoneal shunts (pVP-shunts) in fully diverting therapeutics into cerebrospinal fluid (CSF) has not been reported. METHODS: Patients with CNS tumors under consideration for intraventricular radioimmunotherapy were assessed with pre-treatment CSF flow studies. pVP-shunts were adjusted pre-administration, and readjusted to baseline approximately 4-5 hours post. 111-In-DTPA was injected into the pVP-shunts; nuclear images obtained immediately, 4-5 and 24 hours post-injection. Patients receiving radioimmunotherapy underwent the same procedure, with serial PET or SPECT imaging 2 to 48 hours using 124I/131I radiolabeled antibody. Imaging assessed CSF flow and adequacy of drug administration. RESULTS: 21 patients (ages 1 - 51 years) had medulloblastoma (N=9), choroid plexus carcinoma (N=2), rhabdoid tumor (N=2), ependymoma (N=1), metastatic neuroblastoma (N=4), retinoblastoma (N=2), or melanoma (N=1). On CSF flow studies, 5 patients (24%) had normal flow, 10 (48%) had delayed thecal sac ascent or descent. Of these, 4 had shunt revision or contralateral Ommaya placement; 3 then achieved normal flow. Six patients (29%) had adequate CSF flow down the thecal space with some activity in the peritoneum (6-23%). Similar drug localization was observed on nuclear scans after radioimmunotherapy, with PET and SPECT having greater sensitivity in detecting activity in the peritoneum. CONCLUSIONS: While pVP-shunts are effective intraventricular devices, normal CSF flow is seen in 24% of patients. Drug accumulation (up to 23%) in the peritoneum is still observed in 29% of patients. Shunt revision and/or contralateral Ommaya catheter placement may still be required to address drug delivery.

Radionecrosis is a potentially devastating complication of external beam radiotherapy (XRT). Intraventricular compartmental radioimmunotherapy (cRIT) using (131)I-3F8 or (131)I-8H9 can eradicate malignant cells in the CSF. The incidence of radionecrosis using cRIT (131)I based intraventricular radioimmunotherapy, when used alone or in combination with conventional craniospinal CSI-XRT is unknown. We retrospectively analyzed the incidence of radionecrosis in two cohorts of pediatric patients treated with both CSI-XRT and cRIT at MSKCC since 2003: patients with metastatic CNS neuroblastoma (NB) and medulloblastoma (MB). 94 patients received both CSI-XRT and cRIT, two received cRIT alone, median follow up 41.5 months (6.5-124.8 months). Mean CSI-XRT dose was 28 Gy (boost to the primary tumor site up to 54 Gy) in the MB cohort, and CSI XRT dose 18-21 Gy (boost to 30 Gy for focal parenchymal mass) in the NB cohort. For MB patients, 20 % had focal re-irradiation for a second or more subsequent relapse, mean repeat-XRT dose was 27.5 Gy; seven patients with NB had additional focal XRT. Median CSF cRIT dose was 18.6 Gy in the MB cohort and 32.1 in the NB cohort. One asymptomatic patient underwent resection of 0.6-cm hemorrhagic periventricular white-matter lesion confirmed to be necrosis and granulation tissue, 2.5 years after XRT. The risk of radionecrosis in children treated with XRT and cRIT appears minimal (~1 %). No neurologic deficits secondary to radionecrosis have been observed in long-term survivors treated with both modalities, including patients who underwent re-XRT. Administration of cRIT may safely proceed in patients treated with conventional radiotherapy without appearing to increase the risk of radionecrosis.

BACKGROUND: High-risk and recurrent medulloblastoma is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on medulloblastoma. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131Ilabeled 3F8 in patients with medulloblastoma on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent medulloblastoma were eligible for cRIT. After determining adequate cerebral spinal fluid (CSF) flow, patients received 2 mCi 124I-3F8 or 131I-3F8 with nuclear imaging for dosimetry, followed by a maximum of 4 therapeutic (10 mCi /dose)131I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hours plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and post-therapy brain/spine MRI approximately every 3 months for the first year after treatment, and every 6–12 months thereafter. RESULTS: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities included acute bradycardia with somnolence, headache, fatigue and CSF pleocytosis consistent with chemical meningitis, and dystonic reaction. Total CSF absorbed dose was 1453 (350.0–2784) cGy. Median OS from first dose of cRIT was 24.9 months (95% CI: 16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (HR: 0.40, 95%CI: 0.18–0.88, p=0.024). CONCLUSIONS: cRIT with 131I-3F8 is safe, has favorable dosimetry to CSF and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent medulloblastoma.

Rapidly evolving advances in the understanding of theorized unique driver mutations within individual patient’s cancers, as well as dramatic reduction in the cost of genomic profiling, have stimulated major interest in the role of such testing in routine clinical practice. The aim of this study was to report our initial experience with genomic testing in heavily pretreated breast cancer patients. Patients with primary or recurrent breast cancer managed at any of our five hospitals and whose malignancy had failed to respond to therapy or had progressed on all recognized standard-of-care options were offered the opportunity to have their cancer undergo next-generation sequencing genomic profiling. Of a total of 101 patients, 98 (97 %) had at least one specific genomic alteration identified. A total of 465 different somatic genetic abnormalities were revealed in this group of patients. Although 52 % of patients were found to have an abnormality for which an U.S. Food and Drug Administration (FDA)-approved drug was available, 69 % of patients had an FDA-approved agent for an indication other than breast cancer. The most common genomic alterations of potential clinical consequence were PIK3 (25 %), FGFR1 (16 %), AKT (11 %), PTEN (10 %), ERBB2 (8 %), JAK2 (6 %), and RAF1 (5 %). Almost all advanced breast cancers possess at least one well-characterized genomic alteration that might be actionable at the clinical level. Further, in most cases, a plausible argument can be advanced for the potential biological and clinical relevance of an FDA-approved antineoplastic agent not currently indicated in the treatment of breast cancer.

Anti-G(D2) murine antibody 3F8 plus subcutaneously (sc) administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. Large study size and long follow-up allowed assessment of prognostic factors in a multivariate analysis not reported with other anti-G(D2) antibodies. In a phase II trial, 79 patients without prior progressive disease were treated for persistent osteomedullary neuroblastoma documented by histology and/or metaiodobenzyl-guanidine (MIBG) scan. In the absence of human antimouse antibody, 3F8 + scGM-CSF cycles were repeated up to 24 months. Minimal residual disease (MRD) in bone marrow was measured by quantitative reverse transcription-polymerase chain reaction pre-enrollment and post-cycle #2, before initiation of 13-cis-retinoic acid. Study endpoints were: (i) progression-free survival (PFS) compared with the predecessor trial of 3F8 plus intravenously administered (iv) GM-CSF (26 patients) and (ii) impact of MRD on PFS. Using all 105 patients from the two consecutive 3F8 + GM-CSF trials, prognostic factors were analyzed by multivariate Cox regression model. Complete response rates to 3F8 + scGM-CSF were 87% by histology and 38% by MIBG. Five-year PFS was 24 ± 6%, which was significantly superior to 11 ± 7% with 3F8 + ivGM-CSF (p = 0.002). In the multivariate analysis, significantly better PFS was associated with R/R or H/R FCGR2A polymorphism, sc route of GM-CSF and early MRD response. MYCN amplification was not prognostic. Complement consumption was similar with either route of GM-CSF. Toxicities were manageable, allowing outpatient treatment. 3F8 + scGM-CSF is highly active against chemoresistant osteomedullary neuroblastoma. MRD response may be an indicator of tumor sensitivity to anti-G(D2) immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors.

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

Purpose: To report on a phase I trial designed to find the maximally tolerated dose in children of the immunologic adjuvant OPT-821 in a vaccine containing neuroblastoma-associated antigens (GD2 and GD3; Clinicaltrials.gov NCT00911560). Secondary objectives were to obtain preliminary data on immune response and activity against minimal residual disease (MRD). Treatment also included the immunostimulant β-glucan. Experimental Design: Patients with neuroblastoma in ≥2nd complete/very good partial remission received vaccine subcutaneously (weeks 1–2–3–8–20–32–52). Vaccine contained 30 μg each of GD2 and GD3 stabilized as lactones and conjugated to the immunologic carrier protein keyhole limpet hemocyanin; and OPT-821, which was dose escalated as 50, 75, 100, and 150 μg/m2 per injection. Oral β-glucan (40 mg/kg/day, 14 days on/14 days off) started week 6. Results: The study was completed with 15 patients because there was no dose-limiting toxicity at 150 μg/m2 of OPT-821 (the dosing used in adults). Thirteen of fifteen patients received the entire protocol treatment, including 12 who remain relapse-free at 24+ to 39+ (median 32+) months and 1 who relapsed (single node) at 21 months. Relapse-free survival was 80% ± 10% at 24 months. Vaccine and β-glucan were well tolerated. Twelve of fifteen patients had antibody responses against GD2 and/or GD3. Disappearance of MRD was documented in 6 of 10 patients assessable for response. Conclusions: This immunotherapy program lacks major toxicity and is transportable to any outpatient clinic. Patient outcome is encouraging but the efficacy is uncertain because of the complexity and heterogeneity of prior therapies. A larger phase II trial is underway. Clin Cancer Res; 20(5); 1375–82. ©2014 AACR.