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Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45–115 mg/m2/dose in children and 100–150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for NCT03107988.

Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination.Experimental Design: Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.Results: Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14.Conclusions: Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing. Clin Cancer Res; 21(12); 2715–21. ©2015 AACR.

Supplementary Figure Legends for A1-A3

Supplemental Figure 1. PCR cycle count for NET mRNA expression in peripheral blood mononuclear cells from 7 patients obtained on Day 1 and/or 3 of protocol therapy.

Table A1. Therapies received for samples submitted on this study; Table A2. Genes and Primer and Probe Sets for NB5 assay; Table A3. Clinical Evaluations and NB5 TLDA Assays Performed; Table A4. Contribution of Individual Gene to NB5 Signature and AUC.

Comparison of 1 year EFS in two groups defined by a range of ∆CT cut points (left column) and corresponding ROC analysis of the ability of ∆CT values above the cutpoint to predict 1 year EFS (right column), for assays based on different combinations of genes. NB5 assay (A, B), Phox2B/TH/DDC (C, D), Phox2B/TH (E, F), Phox2B/TH/Dcx (G, H), Th/Dcx (I, J). These analyses show that the NB5 assay is at least as or more predictive then the other gene combinations.

Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma.Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, ΔCt, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, 123I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between ΔCt and progression-free survival (PFS).Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their ΔCt values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow Ct was 7.9 ± 0.5 Ct stronger than blood Ct. When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity (P < 0.0001 and P = 0.007). Bone marrow and blood ΔCt values correlated with PFS (P < 0.001; P = 0.001) even when bone marrow was morphologically negative (P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood ΔCt values were associated with PFS independently of clinical disease and MYCN gene status (P < 0.001; P = 0.055).Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374–83. ©2017 AACR.

Consensus criteria; Early phase; Neuroblastoma Criteris de consens; Fase inicial; Neuroblastoma Criterios de consenso; Fase inicial; Neuroblastoma Background International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. Methods A National Cancer Institute–sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. Results Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. Conclusions The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma. National Cancer Institute Pediatric and Adolescent Solid Tumor Steering Committee; Alex's Lemonade Stand Foundation for Childhood Cancer; Ben Towne Foundation; EVAN Foundation; Cancer Research UK Institute of Cancer Research, Grant/Award Number C347/A15403; National Institute for Health Research Research Methods Programme/Institute of Cancer Research Biomedical Research Centre.

PURPOSE 131I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate. PATIENTS AND METHODS Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m2/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected. RESULTS One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%. CONCLUSION Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.

INTRODUCTION: (131)I-metaiodobenzylguanidine ((131)I-MIBG) is effective in relapsed neuroblastoma. The Children’s Oncology Group (COG) conducted a pilot study (NCT01175356) to assess tolerability and feasibility of induction chemotherapy followed by (131)I(-)MIBG therapy and myeloablative busulfan/melphalan (Bu/Mel) in patients with newly diagnosed high-risk neuroblastoma. METHODS: Patients with MIBG-avid high-risk neuroblastoma were eligible. After the first two patients to receive protocol therapy developed severe sinusoidal obstruction syndrome (SOS), the trial was re-designed to include an (131)I-MIBG dose escalation (12, 15, 18 mCi/kg), with a required 10-week gap before Bu/Mel administration. Patients who completed induction chemotherapy were evaluable for assessment of (131)I-MIBG feasibility; those who completed (131)I-MIBG therapy were evaluable for assessment of (131)I-MIBG+Bu/Mel feasibility. RESULTS: Fifty-nine of 68 patients (86.8%) who completed induction chemotherapy received (131)I-MIBG. Thirty-seven of 45 patients (82.2%) evaluable for (131)I-MIBG+Bu/Mel received this combination. Among those who received (131)I-MIBG after revision of the study design, one patient per dose level developed severe SOS. Rates of moderate to severe SOS at 12, 15 and 18 mCi/kg were 33.3%, 23.5%, and 25.0%, respectively. There was 1 toxic death. The (131)I-MIBG and (131)I-MIBG+Bu/Mel feasibility rates at the 15 mCi/kg dose level designated for further study were 96.7% [95% CI: (83.3%, 99.4%)] and 81.0% [95% CI: (60.0%, 92.3%)]. CONCLUSION: This pilot trial demonstrated feasibility and tolerability of administering (131)I-MIBG followed by myeloablative therapy with Bu/Mel to newly diagnosed children with high-risk neuroblastoma in a cooperative group setting, laying the groundwork for a cooperative randomized trial (NCT03126916) testing the addition of (131)I-MIBG during induction therapy.

Background: Metaiodobenzylguanidine (MIBG; iobenguane), a guanethidine derivative, is a substrate for norepinephrine reuptake transporter which is highly expressed on the surface of neuroblastoma cells. AZEDRA® (HSA I-131 MIBG) has been approved by the FDA for the treatment of pheochromocytoma and paraganglioma, in pts 12 years and older with MIBG avid, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. The aim of this study was to establish the maximum tolerated dose in children with neuroblastoma, with secondary aims of assessing overall response and tumor and organ dosimetry. Here we report current long-term survival and toxicity data. Methods: Eligible pts were 1-30 years old with resistant neuroblastoma. A diagnostic dose of HSA I-131 MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. To prevent prolonged myelosuppression, autologous hematopoietic stem cells were infused 14 days after therapy. Response and toxicity were evaluated on day 60. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/µL within 28 days, or platelets to greater than 20,000/µL within 56 days, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: First pt was enrolled in June 2008. 15 pts total were evaluable at 12 (n=5), 15 (n=3), and 18 (n=7) mCi/kg. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight pts had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. MYC-N amplification was present in two of 11 pts with available results. Of the 15 treated pts, 1 had a complete response, 3 had a partial response, 1 had a mixed response and 6 had stable disease. The remaining 4 had progressive disease. Twelve of the 15 evaluable pts received non-protocol therapy after HSA I-131 MIBG, the remaining 3 died due to tumor without further therapy. At 3.6 years of follow-up the overall survival was 26.7% (95% CI, 8.3%-49.6%). As of March 2018, one remaining pt is in long term follow up with an overall survival of 8.4 years. This pt was previously reported to have a secondary malignancy of myelodysplastic syndrome which has been in remission since receiving an allogenic bone marrow transplant in March 2014. Conclusions: HSA I-131 MIBG contributed to long term median survival of two years and was well tolerated. Treatment showed promising activity in the absence of significant nonhematologic toxicity.

Background Vitamin A-derived retinoids have been reported to cause skeletal abnormalities ranging from hypercalcemia to premature epiphyseal closure. Isotretinoin is a retinoid used as standard therapy for high-risk neuroblastoma and has been reported to cause premature epiphyseal growth plate arrest. Procedure We identified patients from the Children's Hospital Los Angeles (CHLA) database with high-risk neuroblastoma diagnosed from 1991 to 2018 who experienced premature epiphyseal growth plate arrest and compared their characteristics to other patients with high-risk neuroblastoma. We then performed a literature review of this complication. Data collection included diagnosis age of neuroblastoma, presentation age, agent of exposure, dose, exposure range, and skeletal deformity. Results Among 216 patients, high-risk neuroblastoma was diagnosed before age of five years (n = 165), between ages of 5 and 10 years (n = 41), and after 10 years of age (n = 13). Three out of 216 patients developed premature epiphyseal growth arrest after isotretinoin exposure (overall incidence = 1.38%). The incidence of bony abnormalities was significantly higher in patients diagnosed in 5- to 10-year age group than in other two groups (P = 0.014). Literature review identified eight additional patients with neuroblastoma who presented with retinoid associated skeletal abnormalities. The median range of isotretinoin exposure for these 11 patients was between 6.5 and 7.625 years (range, 2-14) with no cases of isotretinoin therapy completion before age 5 years. Conclusion Bone toxicity associated with isotretinoin exposure is a concern. Growth plate arrest is a serious adverse effect that is attributable to isotretinoin therapy. Our findings suggest the prepubescent growth plate may be most at risk, and we recommend special attention to this population.

Background Eyes with Group D intraocular retinoblastoma have low salvage rates. A pilot study showed safety and efficacy of sub-Tenon's fascia carboplatin with systemic chemotherapy supporting further study. Methods Children with newly diagnosed bilateral intraocular retinoblastoma with at least one remaining Group C or D eye were treated with six courses of carboplatin/etoposide/vincristine (CEV) with sub-Tenon's fascia carboplatin for Group C/D eyes during courses 2-4. Local ophthalmic therapy started at course 3. The primary study objective was to determine the 1-year failure rate of Group D eyes. Results The study closed prematurely due to poor accrual and 22 of 30 patients were evaluable for failure rate, contributing 25 Group D and four Group C eyes. Among the 25 Group D eyes, there were 13 failures within the first year of study enrollment including eight needing external beam radiotherapy (EBR) and five needing enucleation, resulting in 1-year failure rate of 52%. The failure rate was significantly lower than the historical rate of 70% (P = .039). The 1-year eye preservation rate for Group D eyes was 80% (20/25). One-year failure rate for Group C eyes was 25% (1/4); 1-year preservation rate was 100% without need for EBR. Systemic toxicity included Grade 3 hearing loss in two subjects, infections, neutropenia, and thrombocytopenia. Ocular toxicities included periorbital fat atrophy (13/29 = 45% eyes), optic nerve atrophy (1/29 = 3% eyes), and restrictive fibrosis (1/29 = 3% eyes). Conclusions Sub-Tenon's fascia carboplatin plus CEV was partially effective in Group D intraocular retinoblastoma but had unacceptable ocular toxicities.

10012 Background: Circulating tumor DNA (ctDNA) is detectable in children with neuroblastoma. Less is known about how levels change during treatment and the implications of these changes. We evaluated ctDNA pre- and post- 131I-metaiodobenzylguanidine (MIBG) therapy. Methods: We utilized plasma samples from NANT11-01 (NCT02035137), a multi-center, open label, randomized phase II clinical trial evaluating MIBG with or without radiation sensitizers for patients with relapsed or refractory neuroblastoma. Plasma was collected at Baseline prior to MIBG, 72 hours (Hr72), 96 hours (Hr96), 15 days after MIBG (D15), and prior to a second course among patients without progression who received a second course (C2). Samples were analyzed for percent ctDNA levels using ultra-low passage whole genome sequencing. We evaluated associations between ctDNA findings with baseline disease measures of percent involvement in bone marrow, Curie score, and RECIST disease sum of diameters as well as overall response by NANT Response Criteria v1.2 (complete response or partial response coded as responders). Results: Eighty-four patients had a baseline sample and were included in this analysis. Of the 37 patients (44%) with detectable ctDNA at baseline, the median ctDNA level was 32% (range 3.9-91%). Baseline ctDNA levels showed a significant positive correlation with percent involvement in bone marrow (r=0.37; p=0.0004) and Curie score (r=0.26; p = 0.018), but not RECIST sum of diameters for soft tissue sites (r=0.065; p=0.56). Following therapy, the proportions of patients with detectable ctDNA were: Hr72 47% (34/73; median level 28%); Hr96 50% (26/52; median 28%); D15 33% (7/21; median 4%); and C2 14% (3/21; median 50%). Rate of ctDNA detection was similar between responders and non-responders at baseline, Hr72, and Hr96, but lower among responders at D15 and C2 (Table). Among the 21 patients with C2 data, ctDNA levels were either undetectable (n=18) or lower than Cycle 1 Baseline (n=3). Among patients with detectable baseline ctDNA, the median relative ctDNA level at Hr72 (Hr72 ctDNA/baseline ctDNA) for non-responders was 0.87 (n=24) vs. 1.16 for responders (n=7). In contrast, the median relative ctDNA level at C2 for non-responders was 0.56 (n=4) vs. 0 for responders (n=4). Conclusions: ctDNA is detectable in a substantial proportion of patients with relapsed / refractory neuroblastoma, with levels correlated with conventional measures of disease burden. Following MIBG therapy, early timepoints (Hr72 and Hr96) are less informative, whereas ctDNA becomes undetectable at D15 and C2 more commonly in patients with clinical response.[Table: see text]

Background Myeloablative therapy for high-risk neuroblastoma commonly includes melphalan. Increased cellular glutathione (GSH) can mediate melphalan resistance. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor, enhances melphalan activity against neuroblastoma cell lines, providing the rationale for a Phase 1 trial of BSO-melphalan. Procedures Patients with recurrent/resistant high-risk neuroblastoma received BSO (3 gram/m2 bolus, then 24 grams/m2/day infusion days −4 to −2), with escalating doses of intravenous melphalan (20–125 mg/m2) days −3 and −2, and autologous stem cells day 0 using 3 + 3 dose escalation. Results Among 28 patients evaluable for dose escalation, one dose-limiting toxicity occurred at 20 mg/m2 melphalan (grade 3 aspartate aminotransferase/alanine aminotransferase) and one at 80 mg/m2 (streptococcal bacteremia, grade 4 hypotension/pulmonary/hypocalcemia) without sequelae. Among 25 patients evaluable for response, there was one partial response (PR) and two mixed responses (MRs) among eight patients with prior melphalan exposure; one PR and three MRs among 16 patients without prior melphalan; one stable disease with unknown melphalan history. Melphalan pharmacokinetics with BSO were similar to reports for melphalan alone. Melphalan Cmax for most patients was below the 10 μM concentration that showed neuroblastoma preclinical activity with BSO. Conclusions BSO (75 gram/m2) with melphalan (125 mg/m2) is tolerable with stem cell support and active in recurrent/refractory neuroblastoma. Further dose escalation is feasible and may increase responses.

PurposeNeuroblastoma is the most common extracranial solid pediatric malignancy, with poor outcomes in high-risk disease. Standard treatment approaches employ an increasing array of aggressive multimodal therapies, of which local control with surgery and radiotherapy remains a backbone; however, the benefit of broad regional nodal irradiation remains controversial. We analyzed centrally reviewed radiation therapy data from patients enrolled on COG A3973 to evaluate the impact of primary site irradiation and the extent of regional nodal coverage stratified by extent of surgical resection.MethodsThree hundred thirty high-risk neuroblastoma patients with centrally reviewed radiotherapy plans were analyzed. Outcome was evaluated by the extent of nodal irradiation. For the 171 patients who also underwent surgery (centrally reviewed), outcome was likewise analyzed according to the extent of resection. Overall survival (OS), event-free survival (EFS), and cumulative incidence of local progression (CILP) were examined by Kaplan-Meier, log-rank test (EFS, OS), and Grey test (CILP).ResultsThe five-year CILP, EFS, and OS for all 330 patients receiving radiotherapy on A3973 were 8.5% ± 1.5%, 47.2% ± 3.0%, and 59.7% ± 3.0%, respectively. There were no significant differences in outcomes based on the extent of lymph node irradiation regardless of the degree of surgical resection (

Background 131 I-metaiodobenzylguanidine ( 131 I-MIBG) is a targeted radiopharmaceutical with significant activity in high-risk relapsed and chemotherapy-refractory neuroblastoma. Our primary aim was to determine if there are differences in response rates to 131 I-MIBG between patients with relapsed and treatment-refractory neuroblastoma. Methods This was a retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with 131 I-MIBG at UCSF between 1996 and 2014. Results were obtained by chart review and database abstraction. Baseline characteristics and response rates between relapsed patients and refractory patients were compared using Fisher exact and Wilcoxon rank sum tests, and differences in overall survival (OS) were compared using the log-rank test. Results The response rate (complete and partial response) to 131 I-MIBG-based therapies for all patients was 27%. There was no difference in response rates between relapsed and refractory patients. However, after 131 I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients ( p =0.02). Among all patients, the 24-month OS was 47.0% (95% confidence interval (CI) 39.9–53.9%). The 24-month OS for refractory patients was significantly higher at 65.3% (95% CI 51.8–75.9%), compared to 38.7% (95% CI 30.4–46.8%) for relapsed patients ( p Conclusions Although there was no significant difference in overall response rates to 131 I-MIBG between patients with relapsed versusrefractory neuroblastoma, patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after 131 I-MIBG compared to patients with refractory disease.

Purpose To evaluate BSO-mediated glutathione (GSH) depletion in combination with L-PAM for children with recurrent or refractory high-risk neuroblastoma (NB) as a means to enhance alkylator sensitivity. Procedure This pilot study (NCI #T95-0092) administered L-S,R-buthionine sulfoximine (BSO) as a bolus followed by 72 hr continuous infusion of either 0.75 g/m2/hr (level 1) or 1.0 g/m2/hr (level 2) and melphalan (L-PAM) (15 mg/m2 bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC. Results Thirty two patients received 58 courses of therapy (median 1, range 1–4 courses). Blood mononuclear cell GSH decreased (48 hr) to 47% ± 15.7%. Level 2 mean steady-state concentration (Css) for BSO = 524 ± 207 μM and peak L-PAM concentration = 3.32 ± 1.2 μM. Grade 3–4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm3) of a pelvic mass, and three/five patients with >3 log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/105). Conclusions BSO/L-PAM has activity against recurrent high-risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity. Pediatr Blood Cancer 2015;62:1739–1746. © 2015 Wiley Periodicals, Inc.

Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination. Experimental Design: Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design. Results: Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14. Conclusions: Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing. Clin Cancer Res; 21(12); 2715–21. ©2015 AACR.

Purpose More than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not previously widely available. The National Cancer Institute sponsored a clinical trials planning meeting in 2012 to update and refine response criteria for patients with neuroblastoma. Methods Multidisciplinary investigators from 13 countries reviewed data from published trials performed through cooperative groups, consortia, and single institutions. Data from both prospective and retrospective trials were used to refine the INRC. Monthly international conference calls were held from 2011 to 2015, and consensus was reached through review by working group leadership and the National Cancer Institute Clinical Trials Planning Meeting leadership council. Results Overall response in the revised INRC will integrate tumor response in the primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine-123 (123I) –metaiodobenzylguanidine (MIBG) scans or [18F]fluorodeoxyglucose–positron emission tomography scans if the tumor is MIBG nonavid. 123I-MIBG scans, or [18F]fluorodeoxyglucose–positron emission tomography scans for MIBG-nonavid disease, replace technetium-99m diphosphonate bone scintigraphy for osteomedullary metastasis assessment. Bone marrow will be assessed by histology or immunohistochemistry and cytology or immunocytology. Bone marrow with ≤ 5% tumor involvement will be classified as minimal disease. Urinary catecholamine levels will not be included in response assessment. Overall response will be defined as complete response, partial response, minor response, stable disease, or progressive disease. Conclusion These revised criteria will provide a uniform assessment of disease response, improve the interpretability of clinical trial results, and facilitate collaborative trial designs.

SummaryBackgroundMyeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma.MethodsBetween March 16, 2001, and Feb 24, 2006, children and young adults (

UnlabelledRadiolabeled metaiodobenzylguanidine (mIBG) is a highly sensitive and specific marker for detecting neuroblastoma. A semiquantitative mIBG score (Curie score [CS]) was assessed for utility as a prognostic indicator for a cohort of patients with high-risk metastatic disease.MethodsmIBG scans from 280 patients with mIBG-avid, stage 4 neuroblastoma enrolled on the Children's Oncology Group (COG) protocol A3973 were evaluated at diagnosis (n = 280), after induction chemotherapy (n = 237), and after an autologous stem cell transplantation (n = 178). Individual mIBG scans were evaluated at 10 different anatomic regions, with the scoring of each site (0-3) based on the extent of disease at that anatomic region.ResultsThere was no correlation between CS at diagnosis and subsequent treatment outcome. Patients with a CS > 2 after induction therapy had a significantly worse event-free survival (EFS) than those with scores ≤ 2 (3-y EFS: 15.4% ± 5.3% vs. 44.9% ± 3.9%, respectively; P < 0.001). A postinduction CS > 2 identified a cohort of patients at greater risk for an event, independent of other known neuroblastoma factors, including age, MYCN status, ploidy, mitosis-karyorrhexis index, and histologic grade. For MYCN-amplified tumors, the presence (CS > 0) versus absence (CS = 0) of residual mIBG avidity after induction was associated with a significantly worse outcome (3-y EFS: 11.8% ± 7.8% vs. 49.6% ± 7.7%, respectively; P = 0.003). After transplantation, patients with a CS > 0 had an EFS inferior to that of patients with a CS of 0 (3-y EFS: 28.9% ± 6.8% vs. 49.3% ± 4.9%, respectively [n = 133]; P = 0.009).ConclusionCurie scoring carries prognostic significance in the management of patients with high-risk neuroblastoma. In particular, patients with CSs > 2 after induction have extremely poor outcomes and should be considered for alternative therapeutic strategies.

Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma. Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, ΔCt, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, 123I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between ΔCt and progression-free survival (PFS). Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their ΔCt values were correlated (Spearman r = 0.67, P < 0.0001), although bone marrow Ct was 7.9 ± 0.5 Ct stronger than blood Ct. When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity (P < 0.0001 and P = 0.007). Bone marrow and blood ΔCt values correlated with PFS (P < 0.001; P = 0.001) even when bone marrow was morphologically negative (P = 0.001; P = 0.014). Multivariate analysis showed that bone marrow and blood ΔCt values were associated with PFS independently of clinical disease and MYCN gene status (P < 0.001; P = 0.055). Conclusions: This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. Clin Cancer Res; 23(18); 5374–83. ©2017 AACR.

Purpose:131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical with activity in patients with relapsed or refractory neuroblastoma. Irinotecan is a known radiosensitizer with activity in neuroblastoma. This phase I study aimed to determine the recommended phase 2 dose of MIBG together with fixed doses of vincristine and irinotecan. Experimental Design: Patients 1 to 30 years old with relapsed or refractory neuroblastoma and MIBG-avid tumors were eligible. All patients had autologous hematopoietic stem cells (PBSC) available and met standard phase I organ function requirements. Irinotecan (20 mg/m2/dose IV) was given on days 0 to 4 and 7 to 11, with vincristine (1.5 mg/m2 IV) on days 0 and 7. MIBG was given on day 1 following a 3 + 3 phase I dose escalation design starting at 8 mCi/kg MIBG. PBSCs were administered at dose level 8 mCi/kg for prolonged myelosuppression and for all patients at 12 mCi/kg or more. Results: Twenty-four patients evaluable for dose escalation (median age, 6.7 years; range, 1.9–26.8 years) received 1 (n = 17), 2 (n = 5), or 3 (n = 2) cycles of therapy. Myelosuppression and diarrhea were the most common toxicities. Two of 6 patients at the 18 mCi/kg dose level had dose-limiting toxicity (DLT), including one with protocol-defined DLT with prolonged mild aspartate aminotransferase elevation. Eighteen mCi/kg was the recommended phase 2 dose. Six additional patients were treated at 18 mCi/kg, with one additional DLT. Responses (2 complete and 4 partial responses) occurred in 6 of 24 (25%) evaluable patients. Conclusions: MIBG is tolerable and active at 18 mCi/kg with standard doses of vincristine and irinotecan. Clin Cancer Res; 18(9); 2679–86. ©2012 AACR.

Purpose: To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma. Experimental Design: Patients received 7 days of fenretinide: 2,475 mg/m2/d divided TID ( Results: Sixty-two eligible patients, median age 5 years (range 0.6–19.9), were treated in stratum 1 (n = 38) and stratum 2 (n = 24). One partial response (PR) was seen in stratum 2 (n = 24 evaluable). No responses were seen in stratum 1 (n = 35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in stratum 1 and 6 patients in stratum 2 for 4 to 45+ (median 15) courses. Median time to progression was 40 days (range 17–506) for stratum 1 and 48 days (range 17–892) for stratum 2. Mean 4-HPR steady-state trough plasma concentrations were 7.25 μmol/L (coefficient of variation 40–56%) at day 7 course 1. Toxicities were mild and reversible. Conclusions: Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric phase I studies. Clin Cancer Res; 17(21); 6858–66. ©2011 AACR.

Background Choroid plexus tumors (CPT) are rare, and predominate in early childhood. An association with the Li–Fraumeni syndrome (LFS) has been reported, but the biological and clinical implications of this association remain poorly defined. We have investigated the clinical features and overall survival of all CPT patients treated at Children's Hospital Los Angeles (CHLA) over a 20-year period, with particular attention to the association of CPT with LFS. Methods A retrospective evaluation of the course of therapy and clinical outcome was undertaken on the 42 patients diagnosed with and treated for CPT at CHLA from January 1991 to December 2010. Any association with multiple primary tumors and family histories consistent with LFS was investigated in all patients. Results Six of the 42 patients (16.7%), demonstrated either phenotypic and/or genotypic characteristics consistent with LFS, with either a distinct family history of cancer, a synchronous diagnosis of a different type of cancer, or the subsequent development of metachronous cancers. Of 11 patients with choroid plexus carcinoma tested for TP53 germline mutations, four (36.4%) were positive. A single patient with a choroid plexus papilloma had phenotypic characteristics of LFS but tested negative for TP53. Conclusions Children with CPC appear to have a high frequency of TP53 germline mutations in association with LFS. This raises the question whether all children with CPC should be tested for TP53 germline mutations in order to institute screening to enhance early detection and treatment of subsequent cancers. Pediatr Blood Cancer 2012; 58: 905–909. © 2011 Wiley Periodicals, Inc.

Background To describe the serial histopathology of intermediate risk stage 3 neuroblastoma after chemotherapy, and correlate with residual mass at therapy completion and outcome. Procedure A retrospective review of intermediate risk stage 3 neuroblastoma patients treated 1989–2005 at Children's Hospital Los Angeles according to CCG 3881 or CCG 3961 protocols was performed, with central review of histopathology, radiology, and surgery. Results Eighteen patients treated per CCG 3881 (n = 9) or CCG 3961 (n = 9), with including 1 (n = 5), 2 (n = 9), ≥3 (n = 3), or unknown number (n = 1) of surgical procedures were included. At therapy completion, 10 patients had residual tumor: 10% original size (n = 6) (5 MIBG avid; 4 with elevated catecholamines), and CT non-measurable MIBG avid tumor (n = 1). Post-chemotherapy histology showed tumor regression (n = 4); or maturation with (n = 6) or without (n = 2) Schwannian development. Histologic changes correlated with median tumor shrinkage of 80% (regressing tumors) and

TrkB acts as an oncogenic kinase in a subset of human neuroblastomas. Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated activity in preclinical models of neuroblastoma.Patients with refractory high-risk neuroblastoma received lestaurtinib twice daily for 5 days out of seven in 28-day cycles, starting at 70% of the adult recommended Phase 2 dose. Lestaurtinib dose was escalated using a 3 + 3 design. Pharmacokinetics and plasma phospho-TrkB inhibitory activity were evaluated in the first cycle.Forty-seven subjects were enrolled, and 10 dose levels explored starting at 25 mg/M(2)/dose BID. Forty-six subjects were evaluable for response, and 42 subjects were fully evaluable for determination of dose escalation. Asymptomatic and reversible grade 3-4 transaminase elevation was dose limiting in 4 subjects. Reversible pancreatitis (grade 2) was observed in 3 subjects after prolonged treatment at higher dose levels. Other toxicities were mild and reversible. Pharmacokinetic analyses revealed rapid drug absorption, however inter-patient variability was large. Plasma inhibition of phospho-TrkB activity was observed 1 h post-dosing at 85 mg/M(2) with uniform inhibition at 120 mg/M(2). There were two partial responses and nine subjects had prolonged stable disease at dose levels ≥ 5, (median: 6 cycles). A biologically effective and recommended phase 2 dose of 120 mg/M(2)/dose BID was established.Lestaurtinib was well tolerated in patients with refractory neuroblastoma, and a dose level sufficient to inhibit TrkB activity was established. Safety and signs of activity at the higher dose levels warrant further evaluation in neuroblastoma.

Background Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials.

(131) I-Metaiodobenzylguanidine ((131) I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and (131) I-MIBG is concentrated in the liver after (131) I-MIBG therapy. The aim of our study was to analyze the effects of (131) I-MIBG therapy on thyroid and liver function.Pre- and post-therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with (131) I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined.In patients who presented with Grade 0 or 1 thyroid toxicity at baseline, 12 ± 4% experienced onset of or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by 2 years after (131) I-MIBG therapy. At 2 years post-(131) I-MIBG therapy, 76 ± 4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23 ± 5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity was usually transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies.The prophylactic regimen of potassium iodide and potassium perchlorate with (131) I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following (131) I-MIBG therapy were primarily reversible and did not result in late toxicity. (131) I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction.

10522Background: Ch14.18 (dinutuximab) increases event free and overall survival in patients with high-risk NB when given in a regimen with GM-CSF/IL-2. However, this therapy has significant toxici...

PURPOSE: The New Approaches to Neuroblastoma Therapy Response Criteria (NANTRC) were developed to optimize response assessment in patients with recurrent/refractory neuroblastoma. Response predictors and associations of the NANTRC version 1.0 (NANTRCv1.0) and prognostic factors with outcome were analyzed. METHODS: A retrospective analysis was performed of patients with recurrent/refractory neuroblastoma enrolled from 2000 to 2009 on 13 NANT Phase 1/2 trials. NANTRC overall response integrated CT/MRI (Response Evaluation Criteria in Solid Tumors [RECIST]), metaiodobenzylguani-dine (MIBG; Curie scoring), and percent bone marrow (BM) tumor (morphology). RESULTS: Fourteen (6.9%) complete response (CR) and 14 (6.9%) partial response (PR) occurred among 203 patients evaluable for response. Five-year progression-free survival (PFS) was 16 ± 3%; overall survival (OS) was 27 ± 3%. Disease sites at enrollment included MIBG-avid lesions (100% MIBG trials; 84% non-MIBG trials), measurable CT/MRI lesions (48%), and BM (49%). By multivariable analysis, Curie score of 0 (P < 0.001), lower Curie score (P = 0.003), no measurable CT/MRI lesions (P = 0.044), and treatment on peripheral blood stem cell (PBSC) supported trials (P = 0.005) were associated with achieving CR/PR. Overall response of stable disease (SD) or better was associated with better OS (P < 0.001). In multivariable analysis, MYCN amplification (P = 0.037) was associated with worse PFS; measurable CT/MRI lesions (P = 0.041) were associated with worse OS; prior progressive disease (PD; P < 0.001/P < 0.001), Curie score > 1 (P < 0.001; P = 0.001), higher Curie score (P = 0.048/0.037), and treatment on non-PBSC trials (P = < 0.001/0.003) were associated with worse PFS and OS. CONCLUSIONS: NANTRCv1.0 response of at least SD is associated with better OS in patients with recurrent/refractory neuroblastoma. Patient and tumor characteristics may predict response and outcome. Identifying these variables can optimize Phase 1/2 trial design to select novel agents for further testing.

Background Poor outcome in Stage 4 neuroblastoma may be improved with increased dose intensity of therapy. We investigated the feasibility of sequential collection and infusion of peripheral blood stem cells (PBSCs) as hematopoietic support for non-myeloablative dose intensive induction chemotherapy given every 21–28 days. Methods Twenty-two children with Stage 4 neuroblastoma (≥1 year of age) received two cycles of high-dose cyclophosphamide (4 g/m2), doxorubicin (75 mg/m2), and vincristine (2 mg/m2) followed by three cycles of interpatient dose escalating carboplatin (Dose Level 0 = 800 mg/m2; Dose Level 1 = 1,000 mg/m2), high-dose cyclophosphamide (4 g/m2), and etoposide (600 mg/m2). PBSC were harvested following cycle 2, 3, and 4 in Cohort 1 and infused after each subsequent cycle. In Cohort 2, PBSC were harvested after cycle 2 and split into three aliquots for infusion. Dose limiting toxicity (DLT) and ability to administer cycles within 28 days was assessed. Results Sufficient PBSC (≥2 × 106 CD34 cells/kg per infusion) were collected from 17/21 eligible patients with minimal toxicity and no detectable neuroblastoma cells by immunocytology. Carboplatin at 1000 mg/m2 resulted in DLT of delayed platelet recovery >28 days in 4/8 patients. Despite de-escalation to 800 mg/m2, platelet DLT occurred in 4/7 Cohort 1 and 3/7 Cohort 2 patients. Conclusion As defined in this protocol, doses of carboplatin were not tolerable with the PBSC dose administered. However, it was feasible to collect sufficient PBSC from small neuroblastoma patients to use as hematopoietic support with minimal risk of tumor contamination and toxicity. Pediatr Blood Cancer 2010;54:596–602. © 2009 Wiley-Liss, Inc.

Purpose Iodine-131—metaiodobenzylguanidine (131I-MIBG) provides targeted radiotherapy with more than 30% response rate in refractory neuroblastoma, but activity infused is limited by radiation safety and hematologic toxicity. The goal was to determine the maximum-tolerated dose of 131I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem-cell rescue (ASCR) 2 weeks after the second dose. Patients and Methods The 131I-MIBG dose was escalated using a 3 + 3 phase I trial design, with levels calculated by cumulative red marrow radiation index (RMI) from both infusions. Using dosimetry, the second infusion was adjusted to achieve the target RMI, except at level 4, where the second infusion was capped at 21 mCi/kg. Results Twenty-one patients were enrolled onto the study at levels 1 to 4, with 18 patients assessable for toxicity and 20 patients assessable for response. Cumulative 131I-MIBG given to achieve the target RMI ranged from 22 to 50 mCi/kg, with cumulative RMI of 3.2 to 8.92 Gy. No patient had a dose-limiting toxicity. Reversible grade 3 nonhematologic toxicity occurred in six patients at level 4, establishing the recommended cumulative dose as 36 mCi/kg. The median time to absolute neutrophil count more than 500/μL after ASCR was 13 days (4 to 27 days) and to platelet independence was 17 days (6 to 47 days). Responses included two partial responses, eight mixed responses, three stable disease, and seven progressive disease. Responses by semiquantitative MIBG score occurred in eight patients, soft tissue responses occurred in five of 11 patients, but bone marrow responses occurred in only two of 13 patients. Conclusion The lack of toxicity with this approach allowed dramatic dose intensification of 131I-MIBG, with minimal toxicity and promising activity.

Background The components of therapy required for patients with INSS Stage 3 neuroblastoma and high-risk features remain controversial. Procedure A retrospective cohort design was used to determine if intensive chemoradiotherapy with purged autologous bone marrow rescue (ABMT) and/or 13-cis-retinoic acid (13-cis-RA) improved outcome for patients with high-risk neuroblastoma that was not metastatic to distant sites. We identified 72 patients with INSS Stage 3 neuroblastoma enrolled between 1991 and 1996 on the Phase 3 CCG-3891 randomized trial. Patients were analyzed on an intent-to-treat basis using a log-rank test. Results The 5-year event-free survival (EFS) and overall survival (OS) rates for patients with Stage 3 neuroblastoma were 55 ± 6% and 59 ± 6%, respectively (n = 72). Patients randomized to ABMT (n = 20) had 5-year EFS of 65 ± 11% and OS of 65 ± 11% compared to 41 ± 11 (P = 0.21) and 46 ± 11% (P = 0.23) for patients randomized to CC (n = 23), respectively. Patients randomized to 13-cis-RA (n = 23) had 5-year EFS of 70 ± 10% and OS of 78 ± 9% compared to 63 ± 12% (P = 0.67) and 67 ± 12% (P = 0.55) for those receiving no further therapy (n = 16), respectively. Patients randomized to both ABMT and 13-cis-RA (n = 6) had a 5-year EFS of 80 ± 11% and OS of 100%. Conclusion Patients with high-risk Stage 3 neuroblastoma have an overall poor prognosis despite aggressive chemoradiotherapy. Further studies are warranted to determine if myeloablative consolidation followed by 13-cis-RA maintenance therapy statistically significantly improves outcome. Pediatr Blood Cancer 2009;52:44–50. © 2008 Wiley-Liss, Inc.

PurposeTo determine the maximal tolerated dosage (MTD) of oral fenretinide given as intact capsules for 7 days, repeated every 21 days, in children with high-risk solid tumors.MethodsChildren 21 years of age or younger received daily doses from 350 mg/m2to 3,300 mg/m2(divided into two or three doses), with pharmacokinetics during course one. The MTD was defined as zero to one of six patients with dose-limiting toxicity (DLT), with at least two of three or two of six DLT at next higher dose.ResultsFifty-four patients, age 2 years to 20 years (median, 9 years), were treated: neuroblastoma (n = 39), Ewing sarcoma (n = 5), and other (n = 10). Prior therapy included autologous stem cell transplantation (n = 42), 13-cis-RA (n = 35), and 9-cis-RA (n = 1). One of four patients at 1,050 mg/m2with prior liver transplant had grade 3 ALT/abdominal pain/nausea/dehydration and grade 4 AST/emesis. At 1,860 mg/m2, one of seven patients had grade 3 hypoalbuminemia/hypophosphatemia. At 2,475 mg/m2, one of eight patients had grade 3 alkaline phosphatase; three of five patients had DLT at 3,300 mg/m2: grade 3 AST/ALT (n = 1), grade 4 bilirubin/grade 3 AST/ALT (n = 1), pseudotumor cerebri (n = 1). Pseudotumor cerebri also occurred at 600 mg/m2and 800 mg/m2. There was one complete response and 13 patients with stable disease (SD) for 8 or more courses in 30 assessable neuroblastoma patients. SD for 8 or more courses was seen in one of five Ewing sarcoma patients and one melanoma patient. Mean N-4-hydroxyphenyl retinamide plasma level (day 7, steady-state concentration) was 9.9 μmol/L at MTD.ConclusionThe pediatric MTD of oral capsular fenretinide was 2,475 mg/m2per day, which achieved levels active against neuroblastoma in vitro with minimal toxicity. Response data support a phase II trial in neuroblastoma.

Purpose To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131–metaiodobenzylguanidine (131I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma. Patients and Methods Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. 131I-MIBG was administered on day −21, CEM was administered on days −7 to −4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. 131I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR). Results The MTD for patients with normal GFR (≥ 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils ≥ 500/μL of 10 days and median time for platelets ≥ 20,000/μL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 ± 0.10 and 0.58 ± 0.10, respectively. Conclusion 131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.

BACKGROUND Ninety percent of children with diffuse, intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit to these children, and a potential way to improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing; however, its delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The objective of this Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy to children with newly diagnosed, diffuse, intrinsic brainstem gliomas. METHODS RMP-7 was given prior to the end of carboplatin infusion. Local radiotherapy, in dose fractions of 180 centigrays (cGy) per day (to a total dose of 5940 cGy), was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion in cohorts of 3 patients, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, and their median age was 7 years (age range, 3–12 yrs). RESULTS One child died early during treatment of progressive disease and was not assessable for toxicity. Treatment for 3 weeks, 4 weeks, and 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. One of 3 children treated at the full duration of therapy (33 doses over 7 weeks) developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival was 328 days, and 1 patient remained free of disease progression for > 400 days after the initiation of treatment. CONCLUSIONS The results of this study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy to children with brainstem tumors. Cancer 2005. © 2005 American Cancer Society.

Juvenile granulosa cell tumor (JGCT) of the ovary, a rare pediatric cancer, carries a very poor prognosis in advanced and recurrent cases. A 10-year-old girl with stage IA JGCT, initially treated with resection only, presented with extensive unresectable multifocal pelvic recurrence. She underwent surgery, chemotherapy (cisplatin/paclitaxel alternating with cisplatin/cyclophosphamide/etoposide/bleomycin), myeloablative chemotherapy (carboplatin/etoposide/melphalan) with autologous bone marrow transplant, and pelvic radiation. She tolerated therapy well and is in complete remission 69 months after her recurrence.

Background and purpose: Isotretinoin (13-cis-retinoic acid; 13-cisRA), a differentiation inducer, improves outcome for high-risk neuroblastoma when given after myeloablative therapy. Published pharmacokinetic (PK) studies suggested that many patients achieve 13-cisRA levels lower than 5 μM (effective against neuroblastoma in vitro) and that 4-oxo-13-cisRA is an active metabolite of 13-cisRA. We assessed the pharmacokinetics (PK) of 13-cisRA and 4-oxo-13-cisRA and their relation to treatment outcome in Children’s Oncology Group (COG) phase III studies that treated high-risk neuroblastoma patients with 13-cisRA and immunotherapy. Methods: Blood samples from COG high-risk neuroblastoma phase III clinical trials (A3973, ANBL0532, ANBL0032, and ANBL0931) were obtained for PK analyses. Plasma levels of 13-cisRA and 4-oxo-13-cisRA were measured using high-performance liquid chromatography for all patients treated with 13-cisRA. The relationship of PK to outcome was analyzed for the patient subgroup treated with 13-cisRA and ch14.18 anti-GD2 antibody + cytokines. PK variables analyzed included plasma levels of 13-cisRA, 4-oxo-13-cisRA, and the sum of both. Results: Of 617 patients, 370 (60%) achieved median plasma concentrations of 13-cisRA + 4-oxo-13-cisRA (combined) >5 μM. Plasma levels were higher in patients taking intact capsules relative to open-capsule takers (13-cisRA: 1.74 vs. 1.03, 4-oxo-13-cisRA: 7.2 vs. 3.3 μM, P < 0.001). Both 13-cisRA and 4-oxo-13-cisRA concentrations positively correlated with older age (P < 0.001). The relationship of PK to overall survival (OS) was analyzed for 524 patients treated with 13-cisRA and immunotherapy on ANBL0032 or ANBL0931. In patients ≥18 months old at diagnosis (n=445/524) the 5-year OS was significantly higher for patients with upper quartile 13-cisRA levels (2.5 μM, 73%) relative to lower quartile (0.6 μM, 60%, P = 0.039) although event-free survival was not significantly different (P = 0.44). Higher active metabolite concentrations (4-oxo-13-cisRA >5 µM, 76%) was also associated with significantly higher OS relative to lower levels ( Conclusions: Age and route of administration influenced plasma levels of 13-cisRA and 4-oxo-13-cisRA. Combined levels of 13-cisRA and the active metabolite (4-oxo-13-cisRA) were >5 µM in 85% of patients. In patients ≥18 months old, low plasma levels of 13-cisRA and 4-oxo-13-cisRA were associated with a lower overall survival. Citation Format: Hwangeui Cho, Arlene Naranjo, Collin Van Ryn, Shengping Yang, Poonam Sonawane, Judith G. Villablanca, Alice L. You, Julie R. Park, Susan Kreissman, C Patrick Reynolds, Min H. Kang. Low plasma levels of 13-cis-retinoic acid (isotretinoin) and its active metabolite 4-oxo-13-cis-retinoic acid are associated with lower overall survival of high-risk neuroblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-049. doi:10.1158/1538-7445.AM2017-LB-049

To evaluate BSO-mediated glutathione (GSH) depletion in combination with L-PAM for children with recurrent or refractory high-risk neuroblastoma (NB) as a means to enhance alkylator sensitivity.This pilot study (NCI #T95-0092) administered L-S,R-buthionine sulfoximine (BSO) as a bolus followed by 72 hr continuous infusion of either 0.75 g/m(2)/hr (level 1) or 1.0 g/m(2)/hr (level 2) and melphalan (L-PAM) (15 mg/m(2) bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC.Thirty two patients received 58 courses of therapy (median 1, range 1-4 courses). Blood mononuclear cell GSH decreased (48 hr) to 47% ± 15.7%. Level 2 mean steady-state concentration (Css) for BSO = 524 ± 207 μM and peak L-PAM concentration = 3.32 ± 1.2 μM. Grade 3-4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm(3)) of a pelvic mass, and three/five patients with3 log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/10(5)).BSO/L-PAM has activity against recurrent high-risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity.

For the past 30 years, retinoblastoma, a tumor that occurs in only 3 % of children with cancer, has been the subject of extensive molecular biologic research. However, apart from a short period in the 1970s, retinoblastoma has not been studied by any of the pediatric cooperative groups. The past decade has witnessed significant multidisciplinary prospective clinical and biologic studies of this rare pediatric neoplasm. The Children’s Oncology Group (COG) has successfully opened four clinical trials with a fifth recently approved. This chapter will review these ongoing prospective multicenter trials.

Background: Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study. Case presentation: On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity. Conclusions: After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.

We evaluated the toxicity and maximum tolerated dose of topotecan in a novel myeloablative regimen as treatment for high-risk pediatric tumors. Patients received an assigned topotecan dosage in combination with fixed doses of carboplatin and thiotepa, followed by autologous hematopoietic stem cells infusion. Topotecan dose was escalated in cohorts of four patients until the maximum tolerated dose of topotecan was defined or until accrual of 30 patients. Pharmacokinetics of topotecan were examined, and event-free survival was estimated. We describe preliminary results following treatment of 25 pediatric patients with high-risk solid tumors. Med. Pediatr. Oncol. 35: 719–723, 2000. © 2000 Wiley-Liss, Inc.

Background Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival. Methods All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months. Results The mean (±SE) event-free survival rate three years after the first randomization was si...

A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma.4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design.Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), (125/131) I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m(2) /day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m(2) /day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1,700 mg/m(2) /day. Of 29 response-evaluable patients, six had stable disease (SD) (4-26 courses); four with marrow- or bone disease-only had complete responses (CR) (10-46 courses). 4-HPR plasma levels were several folds higher (P 0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1,700 mg/m(2) /day was 21 µM. An MTD was not reached.4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1,500 mg/m(2) /day, TID, on Days 0-6, of a 21-day course.

A phase I clinical trial of 13-cis-retinoic acid (cis-RA) was undertaken to determine the maximally tolerated dose (MTD) and pharmacokinetics (PK) of cis-RA following bone marrow transplantation (BMT) in children with high-risk neuroblastoma. Mean peak serum levels of cis-RA in 31 pediatric patients ranged from 4.9 to 8.9 microM following doses of 100-200 mg/m2 per day, divided into two doses every 12 h administered orally. The PK of cis-RA obeyed a single-compartment model following first-order absorption in the majority of patients. A linear increase in the mean peak serum levels and area under the time-concentration curve (AUC) with increasing dose was observed. The average half-lives of absorption and elimination were 1.0 and 5.8 h, respectively. At the MTD of 160 mg/m2 per day, the mean cis-RA peak serum concentration was 7.2 +/- 5.3 microM. AUC values were not altered significantly during a 2-week course of treatment or over a long period of multiple courses. Levels of trans-retinoic acid, a metabolite of cis-RA, remained low but were similar on days 1 and 14, whereas the 4-oxo-13-cis-RA metabolite had increased in 64% of patients by day 14. Peak serum cis-RA concentrations correlated with clinical toxicity as grade 3 to 4 toxicity was seen in 44% of patient-courses (8/18) with peak serum levels10 microM, but only 13% (12/96) with peak serum levels10 microM. These results show that cis-RA given at 160 mg/m2 to children achieved serum concentrations known to be effective against neuroblastoma in vitro, and the PK for cis-RA differs from that reported for trans-retinoic acid in children.

PURPOSE Radiation therapy for CNS germ cell tumors (GCT) is commonly associated with neurologic sequelae. We designed a therapeutic trial to determine whether irradiation could be avoided. PATIENTS AND METHODS Patients received four cycles of carboplatin, etoposide, and bleomycin. Those with a complete response (CR) received two further cycles; others received two cycles intensified by cyclophosphamide. RESULTS Seventy-one patients were enrolled (45 with germinoma and 26 with nongerminomatous GCT [NGGCT]). Sixty-eight were assessable for response. Thirty-nine of 68 (57%) achieved a CR within four cycles. Of 29 patients with less than a CR, 16 achieved CR with intensified chemotherapy or second surgery. Overall, 55 of 71 (78%) achieved a CR without irradiation. The CR rate was 84% for germinomas and 78% for NGGCT. With a median follow-up duration of 31 months, 28 of 71 patients were alive without relapse or progression. Thirty-five showed tumor recurrence (n = 28) or progression (n = 7) at a median of 13 months. Twenty-six of 28 patients (93%) who recurred following remission underwent successful salvage therapy. Pathology was the only variable predictive of survival. The probability of surviving 2 years was .84 for germinoma patients and .62 for NGGCT. Seven of 71 patients died of toxicity associated with study chemotherapy. CONCLUSION Forty-one percent of surviving patients and 50% of all patients were treated successfully with chemotherapy only without irradiation. Chemotherapy-only regimens for CNS GCT, although encouraging, should continue to be used only in the setting of formal clinical trials.

Esthesioneuroblastoma, a malignant neoplasm arising from olfactory epithelium, is unusual in the pediatric age-group. Management has traditionally involved surgery and radiotherapy, alone or in combination, with chemotherapy reserved for recurrent or high grade disease. We report a single institution experience utilizing chemotherapy and radiotherapy as the initial treatment and successful control of the primary tumor in two patients. In one patient, neck dissection and high dose chemotherapy combined with autologous bone marrow transplantation were used as successful salvage therapy of neck metastasis. Both patients are alive and disease free with a mean follow-up of 56 months. These results support the role of chemotherapy in the treatment of esthesioneuroblastoma and suggest that chemotherapy be used as part of the initial combined modality treatment plan.

PURPOSE Treatment of neuroblastoma cell lines with 13-cis-retinoic acid (cis-RA) can cause sustained inhibition of proliferation. Since cis-RA has demonstrated clinical responses in neuroblastoma patients, it may be effective in preventing relapse after cytotoxic therapy. This phase I trial was designed to determine the maximal-tolerated dosage (MTD), toxicities, and pharmacokinetics of cis-RA administered on an intermittent schedule in children with neuroblastoma following bone marrow transplantation (BMT). PATIENTS AND METHODS Fifty-one assessable patients, 2 to 12 years of age, were treated with oral cis-RA administered in two equally divided doses daily for 2 weeks, followed by a 2-week rest period, for up to 12 courses. The dose was escalated from 100 to 200 mg/m2/d until dose-limiting toxicity (DLT) was observed. A single intrapatient dose escalation was permitted. RESULTS The MTD of cis-RA was 160 mg/m2/d. Dose-limiting toxicities in six of nine patients at 200 mg/m2/d included hypercalcemia (n = 3), rash (n = 2), and anemia/thrombocytopenia/emesis/rash (n = 1). All toxicities resolved after cis-RA was discontinued. Three complete responses were observed in marrow metastases. Serum levels of 7.4 +/- 3.0 mumol/L (peak) and 4.0 +/- 2.8 mumol/L (trough) at the MTD were maintained during 14 days of therapy. The DLT correlated with serum levels > or = 10 mumol/L. CONCLUSION The MTD of cis-RA given on this intermittent schedule was 160 mg/m2/d. Serum levels known to be effective against neuroblastoma in vitro were achieved at this dose. The DLT included hypercalcemia, and may be predicted by serum cis-RA levels. Monitoring of serum calcium and cis-RA levels is indicated in future trials.