Immunotherapy with anti-GD2 monoclonal antibody in infants with high-risk neuroblastoma.

Anti-GD2 monoclonal antibodies (mAb) improve the prognosis of high-risk neuroblastoma (HR-NB). Worldwide experience almost exclusively involves toddlers and older patients treated after multimodality or second-line therapies, that is, many months postdiagnosis. In contrast, at our center, infants received anti-GD2 mAbs because this immunotherapy started during or immediately after induction chemotherapy. We now report on the feasibility, safety, and long-term survival in this vulnerable age group. Thirty-three HR-NB patients were <19 months old when started on 3F8 (murine mAb; n = 21) or naxitamab (humanized-3F8; n = 12), with 30″ to 90″ intravenous infusions. Patients received analgesics and antihistamines. Common toxicities (pain, urticaria, cough) were manageable, allowing outpatient treatment. Capillary leak, posterior reversible encephalopathy syndrome, and mAb-related long-term toxicities did not occur. Two 3F8 cycles were aborted due to bradycardia (a preexisting condition) and asthmatic symptoms, respectively. One patient received ½ dose of Day 1 naxitamab because of hypotension; full doses were subsequently administered. Post-mAb treatments included chemotherapy, radiotherapy, and anti-NB vaccine. Among 3F8 patients, 17/21 are in complete remission off all treatment at 5.6+ to 24.1+ (median 13.4+) years from diagnosis. Among naxitamab patients, 10/12 remain relapse-free post-mAb at 1.7+ to 4.3+ (median 3.1+) years from diagnosis. Toxicity was similar with short outpatient infusions and matched that observed with these and other anti-GD2 mAbs in older patients. These findings were reassuring given that naxitamab is dosed >2.5× higher (~270 mg/m2 /cycle) than 3F8, dinutuximab, and dinutuximab beta (70-100 mg/m2 /cycle). HR-NB in infants proved to be highly curable.

Stage 4N neuroblastoma before and during the era of anti-GD2 immunotherapy.

Patients with stage 4N neuroblastoma (distant metastases limited to lymph nodes) stand out as virtually the only survivors of high-risk neuroblastoma (HR-NB) before myeloablative therapy (MAT) and immunotherapy with anti-GD2 monoclonal antibodies (mAbs) became standard. Because no report presents more recent results with 4N, we analyzed our large 4N experience. All 51 pediatric 4N patients (<18 years old) diagnosed 1985 to 2021 were reviewed. HR-NB included MYCN-nonamplified 4N diagnosed at age ≥18 months and MYCN-amplified 4N. Among 34 MYCN-nonamplified high-risk patients, 20 are relapse-free 1.5+ to 37.5+ (median 12.5+) years post-diagnosis, including 13 without prior MAT and 5 treated with little (1 cycle; n = 2) or no mAb (n = 3), while 14 patients (7 post-MAT, 8 post-mAbs) relapsed (all soft tissue). Of 15 MYCN-amplified 4N patients, 7 are relapse-free 2.1+ to 26.4+ (median 11.6+) years from the start of chemotherapy (all received mAbs; 3 underwent MAT) and 4 are in second remission 4.2+ to 21.8+ years postrelapse (all soft tissue). Statistical analyses showed no significant association of survival with either MAT or mAbs for MYCN-nonamplified HR-NB; small numbers prevented these analyses for MYCN-amplified patients. The two patients with intermediate-risk 4N (14-months-old) are relapse-free 7+ years postresection of primary tumors; distant disease spontaneously regressed. The natural history of 4N is marked by NB confined to soft tissue without early relapse in bones or bone marrow, where mAbs have proven efficacy. These findings plus curability without MAT, as seen elsewhere and at our center, support consideration of treatment reduction for MYCN-nonamplified 4N.

Outcomes of intraventricular 131-I-omburtamab and external beam radiotherapy in patients with recurrent medulloblastoma and ependymoma.

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.

Clinical outcomes of pediatric patients receiving multimodality treatment of second central nervous system relapse of neuroblastoma.

BACKGROUND: 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. PROCEDURE: 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] with 131 I-monoclonal antibodies targeting GD2 or B7H3) and management of post-CSI CNS relapse ("second CNS relapse") were characterized. Cox proportional hazards models to evaluate factors associated with third CNS relapse and overall survival (OS) were used. RESULTS: Of 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). CONCLUSIONS: 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.

Quantifying intraventricular drug delivery utilizing programmable ventriculoperitoneal shunts as the intraventricular access device.

PURPOSE: Programmable ventriculoperitoneal shunts (pVP shunts) are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of drug concentrations in the thecal space with minimization in the peritoneum. This report assesses the success of the pVP shunt as an access device for intraventricular therapies. Quantifying intrathecal drug delivery using scintigraphy by pVP shunt model has not been previously reported. METHODS: We performed a single-institution, retrospective analysis on patients with CNS tumors and pVP shunts from 2003 to 2020, noting shunt model. pVP flow was evaluated for consideration of compartmental radioimmunotherapy (cRIT) using In-111-DTPA scintigraphy. Scintigraphy studies at 2-4 h and at 24 h quantified ventricular-thecal and peritoneal drug activity. RESULTS: Twenty-two CSF flow studies were administered to 15 patients (N = 15) with diagnoses including medulloblastoma, metastatic neuroblastoma, pineoblastoma, and choroid plexus carcinoma. Six different types of pVP models were noted. 100% of the studies demonstrated ventriculo-thecal drug activity. 27% (6 of 22) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 22) of the studies had minimal relative peritoneal uptake (< 12%). 27% (6 of 22) of the studies demonstrated moderate relative peritoneal uptake (12-37%). No studies demonstrated peritoneal uptake above 37%. CONCLUSIONS: All patients had successful drug delivery of In-111-DTPA to the ventriculo-thecal space. 73% of the patients had minimal relative (< 12%) peritoneal drug uptake. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies assesses drug distribution of In-111-DTPA, informing CSF flow for delivery of intraventricular therapies.

Mast cell proliferation in the cerebrospinal fluid after intraventricular administration of anti-B7H3 immunotherapy.

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.

IntraOmmaya compartmental radioimmunotherapy using 131I-omburtamab-pharmacokinetic modeling to optimize therapeutic index.

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 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. METHODS: 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)]. RESULTS: 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%. CONCLUSION: 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. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT00089245.

Response assessment in diffuse intrinsic pontine glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

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.

Reduced-dose craniospinal irradiation for central nervous system relapsed neuroblastoma.

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.

Targeted radioimmunotherapy for embryonal tumor with multilayered rosettes.

PURPOSE: We explored the use of intraventricular 131I-Omburtamab 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 three 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 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-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 131I-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 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-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 months after therapy (2 years after diagnosis). CONCLUSIONS: 131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.

Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial.

BACKGROUND: Diffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma. METHODS: We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0-59·4 Gy at 1·8 Gy per fraction over 30-33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3 + 3 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort. FINDINGS: From April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200. INTERPRETATION: Convection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma. FUNDING: National Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, The Lyla Nsouli Foundation, Cookies for Kids' Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

Treatment and outcome of adult-onset neuroblastoma.

Adult-onset neuroblastoma is rare and little is known about its biology and clinical course. There is no established therapy for adult-onset neuroblastoma. Anti-GD2 immunotherapy is now standard therapy in children with high-risk neuroblastoma; however, its use has not been reported in adults. Forty-four adults (18-71 years old) diagnosed with neuroblastoma between 1979 and 2015 were treated at Memorial Sloan Kettering Cancer Center. Five, 1, 5 and 33 patients had INSS stage 1, 2, 3 and 4 diseases, respectively. Genetic abnormalities included somatic ATRX (58%) and ALK mutations (42%) but not MYCN-amplification. In the 11 patients with locoregional disease, 10-year progression-free (PFS) and overall survival (OS) was 35.4 ± 16.1% and 61.4 ± 15.3%, respectively. Among 33 adults with stage 4 neuroblastoma, 7 (21%) achieved complete response (CR) after induction chemotherapy and/or surgery. Seven patients with primary refractory neuroblastoma (all with osteomedullary but no soft tissue disease) received anti-GD2 antibodies, mouse or humanized 3F8. Antibody-related adverse events were similar to those in children, response rate being 71.4%. In patients with stage 4 disease at diagnosis, 5-year PFS was 9.7± 5.3% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years, 10-year OS being only 19.0 ± 8.2%. Patients who achieved CR after induction had superior PFS and OS (p = 0.006, p = 0.031, respectively). Adult-onset neuroblastoma appeared to have different biology from pediatric or adolescent NB, and poorer outcome. Complete disease control appeared to improve long-term survival. Anti-GD2 immunotherapy was well tolerated and might be beneficial.

Central nervous system relapse of rhabdomyosarcoma.

PURPOSE: The optimal management of central nervous system (CNS) relapse of rhabdomyosarcoma (RMS) is unclear. We examined diagnosis, management, and outcomes of patients with RMS developing CNS relapse. METHODS: Records of 23 patients diagnosed with CNS relapse between 1999 and 2016 were reviewed. Median age at presentation of CNS relapse was 15 years (range, 1-34 years). High-risk features at initial presentation were as follows: 16 alveolar patients, 13 Stage IV, and 13 with primary tumor in parameningeal locations. RESULTS: CNS relapse occurred at a median 12 months (range, 1-23 months) from diagnosis and most common presenting symptoms were headache (n = 9), nausea/vomiting (n = 8), visual difficulty (n = 5), and none (n = 5). Leptomeningeal metastases were detected in 21 patients while only 2 developed parenchymal metastases without leptomeningeal involvement. Fifteen patients received CNS-directed radiation therapy (RT), including craniospinal irradiation to a median 36 Gy (range, 18-36 Gy) and/or whole brain radiotherapy to a median 30 Gy (range, 6-41.4 Gy). Three patients received concurrent chemotherapy. Follow-up magnetic resonance imaging was conducted in 13 patients after RT initiation with 8 demonstrating improvement, 2 with stable disease, and 3 with progression. Twelve patients were tested for reactivity to I-131-labeled monoclonal antibody 8H9, and three tested positive and received at least one intra-Ommaya dose; all three lived >12 months post-CNS relapse. Twenty­two patients died of CNS disease and one of treatment complications, with metastatic disease at other sites. Median survival post-CNS relapse was 5 months (range, 0.1-49 months). CONCLUSIONS: The prognosis for patients with RMS developing CNS relapse remains poor. Treatment including CNS-directed RT should be considered and investigation into preventative therapies is warranted.

A phase II study of radioimmunotherapy with intraventricular 131 I-3F8 for medulloblastoma.

BACKGROUND: High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131 I-labeled 3F8 in patients with MB on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) 124 I-3F8 or 131 I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) 131 I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging 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 related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0-2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [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 (hazard ratio: 0.40, 95% CI: 0.18-0.88, P = 0.024). CONCLUSIONS: cRIT with 131 I-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 MB.

A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma.

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 50-75 mg m-2  day-1 after a loading dose of 100-200 mg m-2 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 123 I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings (i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; (ii) 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 (iii) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable.

A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors.

BACKGROUND: The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination. PROCEDURE: We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/m2 /day) and temsirolimus (25-75 mg/m2 IV weekly) were investigated. RESULTS: Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved. CONCLUSIONS: The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.

Evaluating the Utility of a 'N-of-1' Precision Cancer Medicine Strategy: The Case for 'Time-to-Subsequent-Disease Progression'.

It is increasingly recognized that cancer is a highly heterogeneous group of illnesses even within a particular organ site (e.g., breast, lung, colon, etc.). This observation presents a serious challenge to the traditional concept of phase 3 randomized trials designed to define therapeutic efficacy of a novel treatment strategy. For while 10% of the patients with a common malignancy (e.g., non-small-cell lung cancer) may be sufficient to consider such an effort, enrolling a sufficient number of patients into a clinical trial in a timely manner to define clinical utility would be extremely difficult if the population in question represented only 1% of this population, and essentially impossible if one wished to explore the benefits of treatment in a rarer neoplasm (e.g. ovarian cancer). Therefore, in the new era of precision cancer medicine, alternative research designs are imperative. One option would be to compare the time-to-disease progression of an individual cancer patient following treatment with a novel therapeutic to the time-to-disease progression for that specific patient on her/his immediately preceding treatment. The rationale for this strategy and early experience with this innovative approach to evaluating the efficacy of anticancer therapy is highlighted in this report.

Osteochondroma in long-term survivors of high-risk neuroblastoma.

BACKGROUND: 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. METHODS: The authors examined osteochondromas in 362 patients who were aged <10 years when diagnosed with neuroblastoma, had received a MoAb plus isotretinoin since 2000, and had survived >24 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. RESULTS: 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). CONCLUSIONS: 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.

Low incidence of radionecrosis in children treated with conventional radiation therapy and intrathecal radioimmunotherapy.

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.