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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.

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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:In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.Patients and Methods:We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.Results:Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS.Conclusions:This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

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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.

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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.

Monoclonal antibodies (mAbs) targeting disialoganglioside 2 (GD2) are an important treatment advance for high-risk neuroblastoma, including in patients with refractory or relapsed disease. Dinutuximab and dinutuximab beta are administered for ≥8 hours (and up to 10 days for dinutuximab beta), whereas naxitamab is administered over 0.5 to 2 hours as tolerated. As acute pain is a class effect of anti-GD2 mAbs, effective pain management is crucial to successful treatment. Here, we provide an overview of current pain-management strategies for anti-GD2 mAb infusions, including discussion of opioid analgesics, ketamine, gabapentin, and other similar agents, and non-pharmacologic approaches. Potential future pain management options are also discussed, in addition to the use of sedatives to reduce the anxiety that may be associated with infusion-related pain. Specific guidance for pain management during naxitamab infusions is provided, as these infusions are administered over 0.5 to 2 hours and may not need overnight hospitalization based on the physician’s assessment, and require rapid-onset analgesia options suitable for potential outpatient administration.

NANT2011-11 evaluatedThe cohort included 99 patients who had at least one biomarker available for analysis. Significant modulation in most biomarkers between baseline, 72 hours, and 96 hours followingPeripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after 131I-MIBG and concomitant radiation sensitizers impact extent of modulation. Biomarkers related to hematopoietic damage and apoptosis were associated with hematologic toxicity.

Pelvic neuroblastomas are rare and often present in children as massive tumors whose surgical resection can be associated with significant morbidity, given sacral nerve root involvement and close proximity to pelvic vascular structures. We sought to examine the characteristics of patients with pelvic neuroblastoma and the effect of extent of surgical resection on survival and surgical outcomes.After institutional review board approval, a retrospective chart review was performed at Children's Hospital Los Angeles from 2000 to 2018. Collected data included tumor location, size, image-defined risk factors histology, stage and risk classification, amplification of the oncogene MYCN or N-myc, use of preoperative chemotherapy, and extent of surgical resection. Outcome variables included postoperative complications and survival.Ten patients with primary pelvic neuroblastoma tumors were identified. The median age at diagnosis was 4.2 y (3 mo to 11 y). Four patients presented with a localized pelvic tumor (stage I or stage II) and underwent upfront tumor resection. Six patients presented with advanced disease (stage III or stage IV) and underwent neoadjuvant chemotherapy, followed by partial resection (30%-90% debulked). One patient experienced a complication: lower extremity hypotonia after tumor resection. One patient died from extensive metastatic disease for which no resection was attempted. The mean postoperative follow-up was 3.9 y with 90% overall survival.Our data show that patients who undergo gross total resection for localized pelvic neuroblastoma or neoadjuvant chemotherapy, followed by partial resection for advanced disease have excellent survival. We recommend that small localized pelvic neuroblastoma undergo gross total resection and large unresectable tumors undergo neoadjuvant chemotherapy, followed by partial debulking resection to avoid neurovascular morbidity.

(131)I-metaiodobenzylguanidine ((131)I-mIBG) is a targeted radiation therapy developed for the treatment of advanced neuroblastoma. We have previously shown that this patient cohort can be used to predict absorbed dose associated with early (131)I exposure, 72 h after treatment. We now expand these studies to identify gene expression differences associated with (131)I-mIBG exposure 15 days after treatment. Total RNA from peripheral blood lymphocytes was isolated from 288 whole blood samples representing 59 relapsed or refractory neuroblastoma patients before and after (131)I-mIBG treatment. We found that several transcripts predictive of early exposure returned to baseline levels by day 15, however, selected transcripts did not return to baseline. At 72 h, all 17 selected pathway-specific transcripts were differentially expressed. Transcripts CDKN1A (P < 0.000001), FDXR (P < 0.000001), DDB2 (P < 0.000001), and BBC3 (P < 0.000001) showed the highest up-regulation at 72 h after (131)I-mIBG exposure, with mean log(2) fold changes of 2.55, 2.93, 1.86 and 1.85, respectively. At day 15 after (131)I-mIBG, 11 of the 17 selected transcripts were differentially expressed, with XPC, STAT5B, PRKDC, MDM2, POLH, IGF1R, and SGK1 displaying significant up-regulation at 72 h and significant down-regulation at day 15. Interestingly, transcripts FDXR (P = 0.01), DDB2 (P = 0.03), BCL2 (P = 0.003), and SESN1 (P < 0.0003) maintained differential expression 15 days after (131)I-mIBG treatment. These results suggest that transcript levels for DNA repair, apoptosis, and ionizing radiation-induced cellular stress are still changing by 15 days after (131)I-mIBG treatment. Our studies showcase the use of biodosimetry gene expression panels as predictive biomarkers following early (72 h) and late (15 days) internal (131)I exposure. Our findings also demonstrate the utility of our transcript panel to differentiate exposed from non-exposed individuals up to 15 days after exposure from internal (131)I.

PURPOSE The primary objective of the Children’s Oncology Group study ANBL0531 (ClinicalTrials.gov identifier: NCT00499616 ) was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma using a biology- and response-based algorithm to assign treatment duration while maintaining a 3-year overall survival (OS) of 95% or more for the entire cohort. PATIENTS AND METHODS Children younger than age 12 years with intermediate-risk stage 2A/2B or stage 3 tumors with favorable histology; infants younger than age 365 days with stage 3, 4 or 4S disease; and toddlers from 365 to younger than 547 days with favorable histology, hyperdiploid stage 4, or unfavorable histology stage 3 tumors were eligible. Patients with MYCN-amplified tumors were excluded. Patients were assigned to initially receive two (group 2), four (group 3), or eight (group 4) cycles of chemotherapy with or without surgery on the basis of prognostic markers, including allelic status of chromosomes 1p and 11q; ultimate duration of therapy was determined by overall response. RESULTS Between 2007 and 2011, 404 evaluable patients were enrolled. Compared with legacy Children’s Oncology Group studies, subsets of patients had a reduction in treatment. The 3-year event-free survival and OS rates were 83.2% (95% CI, 79.4% to 87.0%) and 94.9% (95% CI, 92.7% to 97.2%), respectively. Infants with stage 4 tumors with favorable biology (n = 61) had superior 3-year event-free survival compared with patients with one or more unfavorable biologic features (n = 47; 86.9% [95% CI, 78.3% to 95.4%] v 66.8% [95% CI, 53.1% to 80.6%]; P = .02), with a trend toward OS advantage (95.0% [95% CI, 89.5% to 100%] v 86.7% [95% CI, 76.6% to 96.7%], respectively; P = .08). OS for patients with localized disease was 100%. CONCLUSION Excellent survival was achieved with this treatment algorithm, with reduction of therapy for subsets of patients. More-effective treatment strategies still are needed for infants with unfavorable biology stage 4 disease.

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.

10003 Background: The addition of dinutuximab (DIN) in the post-consolidation setting led to improved event-free survival rates for patients with high-risk neuroblastoma. Chemoimmunotherapy including irinotecan, temozolomide, DIN and sargramostim (GM-CSF) in patients with recurrent or refractory neuroblastoma results in robust objective clinical responses. Evaluation of chemoimmunotherapy in the induction setting for patients with newly-diagnosed high-risk neuroblastoma (HR-NBL) warrants investigation. Methods: Children’s Oncology Group (COG) ANBL17P1 is a prospective, single arm, limited institution pilot study to assess the tolerability and feasibility of administering DIN (17.5mg/m2/dose, IV Days 2-5) and GM-CSF (250mcg/m2/dose, subcutaneous Days 6-count recovery) with COG Induction chemotherapy Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma. The primary endpoint of tolerability included the number of toxic deaths and number of patients experiencing predefined unacceptable toxicities during Induction Cycles 3-5. Unacceptable toxicities included: hypotension requiring pressors > 24 hours, respiratory toxicity requiring ventilatory support > 24 hours, Grade 4 neuropathy that did not resolve prior to the next cycle, and failure to recover the ANC to > 750 mm3 by day 35. Feasibility was assessed as being able to receive > 75% of planned DIN doses administered during Induction Cycles 3-5. Revised International Neuroblastoma Response Criteria (INRC) were used to assess end of Induction (EOI) response. Results: Forty-two eligible and evaluable patients with newly-diagnosed high-risk neuroblastoma enrolled at 8 sites (22 [52.4%] males; median age 3.3 years at diagnosis) from January 14, 2019 to June 4, 2020. The most common DIN related Grade >3 toxicities observed during Induction Cycles 3-5 included fever (31.0%) and pain (9.5%). None of the patients experienced a toxic death or unacceptable toxicity during Induction Cycles 3-5. Thus, the regimen was deemed tolerable. Patients received 97.4% - 101.8% of the total DIN dose expected to be administered during Induction Cycles 3-5. Therefore, the regimen was deemed feasible. Thirty-eight of 42 patients completed the EOI evaluations, including 11 with complete response, 22 with partial response, 0 with minor response, 3 with stable disease and 2 with progressive disease. The overall EOI objective response rate (CR+PR+MR) was 86.8%. Conclusions: The administration of DIN and GM-CSF to COG Induction Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma was tolerable and feasible. The objective response rate at EOI appears encouraging. This therapeutic regimen will be studied in a randomized phase 3 trial to further evaluate the efficacy of Induction phase chemoimmunotherapy for high-risk neuroblastoma. Clinical trial information: NCT03786783.

10026 Background: 131I-metaiodobenzylguanidine (131I-MIBG) has demonstrated efficacy as a single agent for patients with neuroblastoma. Recent trials have focused on 131I-MIBG combination strategies, though little is known about the impact of combination agents on markers of radiation exposure. Methods: NANT11-01 (NCT02035137) was a multicenter, open label, randomized phase II clinical trial that evaluated 131I-MIBG therapy alone (Arm A) or in combination with vincristine/irinotecan (Arm B) or vorinostat (Arm C) for patients with resistant/relapsed neuroblastoma. We collected blood samples at baseline, 72 hours, 96 hours, and 15 days after 131I-MIBG infusion and determined levels of plasma FLT3 ligand, serum amylase, and gene expression for selected RNA transcripts (apoptosis, DNA damage response and cell cycle related). We evaluated marker association with treatment arm, clinical response using NANT response criteria, toxicity, and whole-body radiation dose. Results: The cohort included 99 patients who had at least one biomarker available for analysis (32 Arm A; 35 Arm B; 32 Arm C). We observed both positive and negative significant modulation in most biomarkers between baseline, 72 hours, and 96 hours following 131I-MIBG. Patients in Arm C had the lowest degree of modulation in FLT3 ligand. Elevated baseline levels of FLT3 ligand were significantly associated with improved Curie response but not overall response. Lower baseline BCL2 levels were associated with higher overall and Curie response. Patients with increased FLT3 ligand at 96 hours after 131I-MIBG therapy were significantly more likely to have grade 4 thrombocytopenia.Peripheral blood gene expression of the BCL2 family of apoptotic markers (BCL2/L1 and BAX) was significantly associated with grade 4 hematological toxicity. Whole-body radiation dose and PRKDC fold change at 72 hours were significantly correlated. No other individual biomarkers were correlated with whole body radiation dose at 72 or 96 hours post 131I-MIBG. Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation over time after 131I-MIBG treatment. Biomarkers related to hematopoietic damage and apoptosis were associated with hematological toxicity. Patients treated with vorinostat and 31I-MIBG had differential modulation of FLT3-ligand Further use of these biomarkers may improve our ability to care for patients treated with 131I-MIBG.

10041 Background: Lorlatinib, a macrocyclic ATP-competitive ALK inhibitor, exerts potent activity against neuroblastoma (NB) xenograftsharboring the most common ALK mutations. We performed a first-in-child phase 1 study of lorlatinib for patients with refractory/relapsed (R/R) ALK aberrant high-risk NB. We previously reported on Part A of the study, where safety of single agent lorlatinib was determined, showing complete responses (CR) to lorlatinib at the recommended phase 2 dose (RP2D) of 115 mg/m2 in pts < 18 years and 150 mg in pts > 18 yrs. Part B of the study aimed to determine the safety, pharmacokinetics (PK), RP2D, and explore the anti-tumor activity of lorlatinib in combination with topotecan and cyclophosphamide in pts with R/R ALK-driven NB. Methods: Patients with R/R NB ages 1-17 years with ALK mutations or amplification were eligible; prior ALK inhibitor (ALKi) treatment was allowed. Lorlatinib was orally administered once daily on days 1-28 with topotecan (0.75 mg/m2/day) and cyclophosphamide (250 mg/m2/day) administered intravenously days 1-5 and GCSF starting day 6. Two lorlatinib dose levels (DL) of 95 mg/m2/day (DL4B) and 115 mg/m2/day (DL5B) were assessed using a 3+3 dose escalation design with the primary endpoint of dose limiting toxicity (DLT) in Course 1. We report lorlatinib safety, PK, and objective response rate (ORR) for patients enrolled on Part B. Results: Between 10FEB2020 and 03DEC2021,9 eligible pts enrolled on Part B with a median age of 6.7 years (3.7-12.7). Three pts were enrolled onto DL4B and six onto DL5B (2/3 pts on DL4B and 4/6 pts on DL5B had received prior ALKi therapy) with no DLT’s observed in course 1. One patient on DL5B experienced a neuropsychological DLT in Course 3. Most common treatment-related adverse events were hematological, febrile neutropenia, high cholesterol, hypertriglyceridemia, and neuropsychological effects. The median number of courses received was 6 with a range of 1-8 on DL4B and 1-7 on DL5B. Of the 8 patients evaluable for response, ORR was 50%: 2/3 pts on DL4B and 2/5 pts on DL5B. Preliminary PK data demonstrate comparable dose level-associated lorlatinib steady state exposure between Part B chemotherapy combination and Part A monotherapy cohorts, supporting that chemotherapy had no effect on lorlatinib exposure that there are no overlapping toxicities. Conclusions: Lorlatinib in combination with topotecan and cyclophosphamide is well tolerated, and early data suggest encouraging objective anti-tumor activity. These data support the current integration of lorlatinib into up-front high risk neuroblastoma therapy for patients with ALK-driven neuroblastoma. Clinical trial information: NCT03107988.

10038 Background: 131I-metaiodobenzylguanidine (MIBG) is one of the most active salvage therapies for patients with relapsed or refractory (R/R) high-risk neuroblastoma (HRNB). Preclinical neuroblastoma studies show cooperative effects when radiation is combined with anti-GD2 monoclonal antibody (mAb). We hypothesized that MIBG would synergize with the anti-GD2 mAb dinutuximab to provide improved anti-tumor responses. The primary aims of Part A of this study were to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of MIBG administered with dinutuximab in children with R/R HRNB and to define and describe the toxicities. Methods: Patients 1-29 years of age with R/R HRNB who had MIBG uptake in ≥ 1 site were eligible. Prior anti-GD2 mAb therapy was allowed provided it was not administered with MIBG and not permanently discontinued due to toxicity. One prior MIBG therapy was allowed. MIBG was administered on day 1 at one of three dose levels (DLs): 12, 15, and 18 mCi/kg (DL1-DL3, respectively) with an expansion cohort at the RP2D. Doses were escalated using a rolling six design starting at DL1. The primary endpoint was dose-limiting toxicity (DLT) during course 1. Dinutuximab (17.5 mg/m2/dose) was administered intravenously on days 8-11 and 29-32 and GM-CSF (250 mcg/m2/dose) subcutaneously on days 8-17 and 29-38. Autologous peripheral blood stem cells were infused to all patients on day 15 (+/- 2 days). A maximum of 2 courses per patient were allowed. Response rate was defined as the proportion of patients with a complete or partial response. Results: Thirty-one patients were enrolled. Fourteen were evaluable for dose escalation (4 on DL1, 4 on DL2, and 6 on DL3); 5 evaluable patients were treated in the DL3 expansion. The median age was 7.4 years (range: 3.1 – 22.0) and 20 (65%) were male. Twenty-seven (87%) patients had previously received a median of 8.5 cycles of chemoimmunotherapy (range: 2 – 21). Eight patients previously progressed while receiving anti-GD2 mAb including 7 in DL3. Five (16%) patients had previously received MIBG. No patient at any dose level experienced DLT. Common grade 3/4 treatment-related toxicities were expected hematologic toxicities attributable to MIBG and non-hematologic toxicities attributable to dinutuximab or GM-CSF. Among 26 response-evaluable patients, the centrally-confirmed response rate was 31% across all dose levels: 2/6 (33%) in DL1, 3/5 (60%) in DL2, and 3/15 (20%) in DL3. There were 3 minor responses, 1 in DL2 and 2 in DL3. Conclusions: The RP2D of MIBG in combination with standard doses of dinutuximab and GM-CSF is 18 mCi/kg. This radioimmunotherapy regimen is well-tolerated without additive toxicity. Preliminary efficacy data are encouraging in this heavily pre-treated patient population. A phase 2 trial of this regimen is planned in patients with R/R HRNB. Clinical trial information: NCT03332667.

e22003 Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. The clinical and biologic predictors of response to MIBG therapy have not been systematically characterized in a recent era trial. Methods: Patients 1-30 years were enrolled on the randomized phase 2 trial of MIBG vs. MIBG/vincristine/irinotecan vs. MIBG/vorinostat for relapsed/refractory neuroblastoma (NANT2011-01, NCT02035137) between 2014-2019. Data were compared between those who had an objective response (partial response or better using NANT response criteria) to MIBG after the first cycle and those who did not according to clinical features (age at study enrollment; sex; response to prior therapy; prior receipt of MIBG therapy; bone marrow involvement at study enrollment; and measurable disease status at study enrollment) and MYCN status. Univariate analyses were performed using odds ratio and Fisher exact tests. Multivariate logistic regression analysis was used to identify predictors of response to MIBG therapy while controlling for key confounders. Results: 105 response-evaluable patients were included in the analytic cohort. Across the 3 study arms, 20% (21/105) had an objective response to the treatment. Only measurable disease status was statistically significantly associated with response to therapy, with higher rates of response among patients without measurable disease at study enrollment (30% vs. 13%, p = 0.049). Response to prior therapy, sex, MYCN status, and measurable disease status showed univariate odds ratios of 2 or greater (Table). Only measurable disease status remained statistically significant in the multivariate analysis (p = 0.043, Table). Conclusions: Patients without measurable disease have a higher rate of objective responses to MIBG therapy. Understanding these differences based upon predictors of response may help to inform stratification methods for future MIBG clinical trials.[Table: see text]

Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

CONTEXT. Racial and ethnic disparities in end-of-life care are well documented among adults with advanced cancer. OBJECTIVES. To examine the extent to which communication and care differ by race and ethnicity among children with advanced cancer. METHODS. We conducted a prospective cohort study at nine pediatric cancer centers enrolling 95 parents (42% racial/ethnic minorities) of children with poor prognosis cancer (relapsed/refractory high-risk neuroblastoma). Parents were surveyed about whether prognosis was discussed; likelihood of cure; intent of current treatment; and primary goal of care. Medical records were used to identify high-intensity medical care since the most recent recurrence. Logistic regression evaluated differences between white non-Hispanic and minority (black, Hispanic, and Asian/other race) parents. RESULTS. About 26% of parents recognized the child’s low likelihood of cure. Minority parents were less likely to recognize the poor prognosis (odds ratio [OR] = 0.19; 95% CI = 0.06−0.63; P = 0.006) and the fact that current treatment was unlikely to offer cure (OR = 0.07; 95% CI = 0.02−0.27; P

Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited “large cell neuroblastoma” histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with “aberrant” desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.

Neuroblastoma, an embryonic cancer of the sympathetic nervous system, is the most common extracranial solid tumor in childhood. Dinutuximab (formerly called ch14.18), a monoclonal antibody targeting the disialoganglioside GD2, has been shown to significantly improve survival rates in patients with high-risk neuroblastoma. However, the safe and effective use of dinutuximab therapy in these high-risk patients requires medical expertise in patient selection, treatment administration, and the monitoring and management of adverse events. Findings of the randomized phase III study (ANBL0032) led to the approval of dinutuximab for the treatment of children with high-risk neuroblastoma. Multi-institutional nursing approaches to implementing standard protocols ensure the effective management of high-risk neuroblastoma patients receiving dinutuximab immunotherapy. Understanding and implementing recommendations for the management of the clinically important and most common adverse events are essential to ensuring patient continuation of therapy and improving patient outcomes.

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: Many parents of children with advanced cancer pursue curative goals when cure is no longer possible. To the authors’ knowledge, no pediatric studies to date have prospectively evaluated prognosis communication or influences on decision making in poor-prognosis childhood cancer. METHODS: The authors conducted a prospective cohort study at 9 pediatric cancer centers that enrolled 95 parents of children with recurrent or refractory, high-risk neuroblastoma (63% of those who were approached), a condition for which cure rarely is achieved. Parents were surveyed regarding the child’s likelihood of cure; their primary goal of care; the child’s symptoms, suffering, and quality of life; and regret concerning the last treatment decision. Medical records identified care and treatment decisions. RESULTS: Only 26% of parents recognized that the chance of cure was

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]

IMPACT: Preliminary results will inform the formal evaluation of the reliability of point-of-care ultrasound (POCUS) done by the gastroenterologist compared to standard of care methods such as MR-Enterography. OBJECTIVES/GOALS: Evaluation of mucosal healing is standard for pediatric patients with inflammatory bowel disease (IBD). Point-of-care ultrasound is a non-invasive, cost-efficient tool for assessing intestinal inflammation. We aim to evaluate the agreement between POCUS and typical cross-sectional imaging, such as MR-Enterography (MRE). METHODS/STUDY POPULATION: In this cross-sectional study, we recruited consecutive patients newly diagnosed with IBD, presenting to the specialty outpatient clinic or hospitalized in a pediatric tertiary care center between August to November 2020. They underwent POCUS performed by a single gastroenterologist, in addition to MRE. The sonographer was blinded to MRE results. Bowel wall thickness (BWT) was measured across different bowel segments and recorded twice in longitudinal view and twice in axial view. An average segmental BWT of the four measurements of more than 3 mm was considered inflamed. Agreement between sections of the bowel measured as inflamed were compared to inflamed bowel segments seen by MRE, using Cohen’s kappa. RESULTS/ANTICIPATED RESULTS: Eight of 12 patients completed both MRE and POCUS.A total of 40 bowel segments were assessed, namely the terminal ileum, ascending, transverse, descending and sigmoid colon. There were 4 girls with a median age of 15 years (IQR 14.25-16 years), and 6 patients were diagnosed with Crohn’s disease. Median PCDAI was 32.5 (IQR 30.6-40), and median PUCAI was 75 (72.5-77.5). Agreement between MRE and point-of-care ultrasound was substantial to perfect for the terminal ileum *(κ= 0.75, 95%CI 0.31-1), transverse colon (κ= 1, 95%CI 1-1) and sigmoid colon (κ= 1, 95%CI 1-1). The agreement was poor for the ascending (κ= 0, 95%CI 0-0) and moderate for the descending colon. (κ= 0.6, 95%CI -0.07-1) DISCUSSION/SIGNIFICANCE OF FINDINGS: In pediatric patients with IBD, we found a high agreement between POCUS and MRE for imaging of the terminal ileum, transverse and sigmoid colon, areas commonly involved in IBD. This reinforces adult data, outlining the potential of POCUS as an evaluation tool of disease activity in clinical practice.

Background Pelvic neuroblastomas are rare and often present in children as massive tumors whose surgical resection can be associated with significant morbidity, given sacral nerve root involvement and close proximity to pelvic vascular structures. We sought to examine the characteristics of patients with pelvic neuroblastoma and the effect of extent of surgical resection on survival and surgical outcomes. Materials and methods After institutional review board approval, a retrospective chart review was performed at Children's Hospital Los Angeles from 2000 to 2018. Collected data included tumor location, size, image-defined risk factors histology, stage and risk classification, amplification of the oncogene MYCN or N-myc, use of preoperative chemotherapy, and extent of surgical resection. Outcome variables included postoperative complications and survival. Results Ten patients with primary pelvic neuroblastoma tumors were identified. The median age at diagnosis was 4.2 y (3 mo to 11 y). Four patients presented with a localized pelvic tumor (stage I or stage II) and underwent upfront tumor resection. Six patients presented with advanced disease (stage III or stage IV) and underwent neoadjuvant chemotherapy, followed by partial resection (30%-90% debulked). One patient experienced a complication: lower extremity hypotonia after tumor resection. One patient died from extensive metastatic disease for which no resection was attempted. The mean postoperative follow-up was 3.9 y with 90% overall survival. Conclusions Our data show that patients who undergo gross total resection for localized pelvic neuroblastoma or neoadjuvant chemotherapy, followed by partial resection for advanced disease have excellent survival. We recommend that small localized pelvic neuroblastoma undergo gross total resection and large unresectable tumors undergo neoadjuvant chemotherapy, followed by partial debulking resection to avoid neurovascular morbidity.

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.

Purpose Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products. Methods In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m2/day (ch14.18-UTC) and 25 mg/m2/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3–5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM® version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (Cmax). All comparisons were based on a standardized single-dose regimen (17.5 mg/m2 over 10 h). Results Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products’ systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88–1.04) and Cmax (1.04; 90 % CI 0.98–1.11) within standard bioequivalence bounds (90 % CI 0.80–1.25). Products’ adverse events were similar and consistent with those previously reported. Conclusions Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences. Electronic supplementary material The online version of this article (doi:10.1007/s00280-015-2955-9) contains supplementary material, which is available to authorized users.

Objectives: Circulating tumor DNA (ctDNA) has been shown to be detectible in children with neuroblastoma, yet little is known about the dynamics of how ctDNA levels change during treatment. 131I-MIBG is a targeted radiopharmaceutical selectively taken up by 90% of neuroblastomas. We evaluated changes in ctDNA levels and identified somatic events from ctDNA in a cohort of patients treated with 131I-MIBG. Methods: NANT 11-01 is a randomized phase 2 study for patients with relapsed or refractory neuroblastoma designed to evaluate the benefit of radiosensitizing agents in combination with 131I-MIBG (MIBG vs. MIBG + vincristine/irinotecan vs. MIBG + vorinostat). Patients had samples collected beginning prior to therapy (c1d1), 72 hours after 131I-MIBG (c1h72), cycle 1 day 15 (c1d15) and for patients who met criteria for a second cycle, cycle 2 day 1 (c2d1). Ultra-low-pass whole-genome sequencing (ULP-WGS) was used to quantify ctDNA in each plasma sample by identifying somatic segmental copy number changes. The correlation between baseline %ctDNA and disease burden using Curie score from the patient’s pretreatment MIBG scan was assessed with linear regression. ctDNA levels and copy number changes were analyzed descriptively. Results: 112 samples from 49 patients were evaluated. The number of patients with detectable ctDNA changed throughout therapy as follows: c1d1 40.4% (19/47); c1h72 42.5% (17/40); c1d15 18% (2/11); and c2d1 0% (0/14) detectable. Among patients with detectable ctDNA, median ctDNA levels at these timepoints were as follows: 17% (range 3.9-91%) at c1d1; 22% (range 2.9-86%) at c1hr72; and 18% (range 3.5-33%) at c1d15. There was a nonsignificant positive correlation between baseline ctDNA levels and baseline Curie score (n=47; R2 = 0.07; p=0.081). MYCN amplification was detected in ctDNA in 4 out of 5 patients with detectable ctDNA known to have MYCN amplified tumors, but never in patients without known MYCN amplification. Conclusions: ctDNA is detectable using ULP-WGS at multiple time points for patients with neuroblastoma treated with 131I-MIBG. ctDNA levels declined during therapy and were rarely detectable at cycle 1 day 15 or by the start of cycle 2. MYCN amplification was identified in the plasma from the majority of patients with MYCN amplified disease if ctDNA levels were detectable. After enrollment is completed for this study, we plan to determine whether baseline ctDNA and changes in ctDNA levels are associated with treatment response. Citation Format: David S. Shulman, Kelly Klega, Araz Marachelian, Katherine K. Matthay, Julie R. Park, M. Meaghan Granger, Steven G. DuBois, Brian D. Crompton. Evaluation of ctDNA in children with relapsed or refractory neuroblastoma treated with 131I-MIBG [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A61.

TPS10561 Background: Aurora kinase A (AurA) has been implicated in high-risk neuroblastoma, including roles stabilizing and increasing expression of MYCN protein. AurA impacts the function of MYCN in mediating transcription in a cell cycle dependent manner, suggesting that neuroblastoma and other MYC/MYCN-driven tumors may be sensitive to AurA inhibition. LY3295668 is a selective AurA inhibitor. The lack of AurB inhibitory activity is hypothesized to minimize on-target hematologic toxicity associated with AurB inhibition. The molecule’s selectivity is intended to allow for continuous dosing at exposures associated with > 90% target inhibition at trough. In an analysis of LY3295668 antiproliferative effects in 560 cancer cell lines, neuroblastoma was among the most sensitive histologies tested. This screen also separately evaluated genomic predictors of response to LY3295668, with MYC/ MYCN amplification identified as among the strongest predictors of sensitivity to this agent. LY3295668 is currently being evaluated in early phase adult trials. The current trial (J10-MC-JZHD) was uniquely designed to hasten time to first-in-child oncology development for a rare unmet need of relapsed/refractory neuroblastoma patients. Methods: Study J1O-MC-JZHD (NCT04106219) is a multicenter, dual collaboration (NANT and ITCC), randomized, open-label, Phase 1 study of oral LY3295668 in children with relapsed/refractory neuroblastoma. A rolling 6 design will be followed for dose escalation in both a monotherapy cohort and a combination cohort testing LY3295668 together with cyclophosphamide and topotecan. The starting monotherapy dose will be equivalent to 80% of the adult maximum tolerated dose. Key eligibility criteria include recurrent/refractory neuroblastoma not amenable to curative treatment, age 2-21 years, mandatory archival tissue submission, ability to swallow capsules, and adequate hematologic and organ function. LY3295668 is administered in capsule form orally BID continuously. Primary objectives include assessments of safety and tolerability of study drug to identify RP2D as monotherapy and combination, and assess antitumor activity. Secondary objectives include assessment of the pharmacokinetic profile as monotherapy and in combination, and assessment of the relationship between study drug exposure and efficacy. Following determination of the RP2Ds, an expansion phase will randomize patients to monotherapy or to the combination arm. Enrollment began 16 Dec 2019 and is ongoing. Clinical trial information: NCT04106219.

10504 Background: Lorlatinib, a potent ALK inhibitor, exerts unprecedented activity against neuroblastoma (NB) derived xenografts harboring common crizotinib-resistant ALK mutations, leading to a first in child phase I study. Methods: R/R NB patients (pts) > 12 months, with ALK mutations/amplification and prior ALK inhibitor (ALKi) treatment were eligible. Lorlatinib was administered in 28-day courses (C). For pts < 18 years, 5 dose levels (DL) (45, 60, 75, 95, 115 mg/m2/day) were assessed. DL5 (115 mg/m2/day) expansion is enrolling (cohort A1). For patients > 18 years, two DL (DL3a the adult RP2D of 100 mg/day and DL4a at 150mg/day) were assessed (cohort A2). Primary endpoint was dose-limiting toxicity (DLT) during C1 and neurocognitive toxicity through C2. Blood samples for circulating tumor DNA (ctDNA) were matched to radiologic restaging. Results: From 9/2017 to 1/2019, 33 eligible patients enrolled (13 with prior ALKi therapy), with median age (range) 5.5 years (2-17) on A1, 21.5 years (15-50) on A2. In A1, 3 pts each enrolled onto DL1-3, with no DLT’s. 5/10 pts enrolled on DL4, with no DLT’s. 1/3 on DL5 had a DLT of grade 3 diarrhea, with expansion ongoing. In cohort A2, 5 patients enrolled at 100 mg/day with no DLT’s; 6 enrolled at 150 mg/day, with one DLT (grade 4 reversible psychosis). Most common treatment-related adverse events were weight gain (90%, grade 1-3), hyperlipidemia (90%, grade 1-3), concentration/memory impairment (23%, grade 1-2), peripheral neuropathy (13%; grade 1-2, A2 only), and peripheral edema (10%; grade 1, A2 only). Lorlatinib steady state exposure at DL3 and DL4 was in the range of exposures seen in adult lung cancer patients at the 100 mg and 200 mg DLs. In A1, 1/18 had partial response (PR), 3/18 had minor responses (MR), and 4/18 had stable disease (SD). Of pts with MR, 2/3 had PR of soft tissue and 1/3 had complete response (CR) by MIBG. In A2 pts, 1/10 had CR, 3/10 PR, and 3/10 MR; Notably, 2/3 with PR had CR by MIBG. Of the pts with MR, one had PR and one CR by MIBG. Responses occurred across dose levels, ALK mutations, and in ALKi pre-treated pts with median courses of 2 (1-24) on A1 and 10.5 (2-28) on A2. Serial ctDNA results showed mutant ALK variant allele frequency trajectories that correlated with clinical response and emergence of novel ALK mutations in cis that corresponded with disease progression. Conclusions: Inhibition of ALK-driven NB with lorlatinib occurs with manageable toxicity and objective anti-tumor activity. Prospective ctDNA allows for monitoring of disease and evolution of resistance. Clinical trial information: NCT03107988.

10500 Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. It is not clear if putative radiation sensitizers improve upon this activity. The primary aim of this trial was to identify the MIBG treatment regimen with highest response rate among: MIBG monotherapy (Arm A); MIBG/Vincristine/Irinotecan (Arm B); MIBG/Vorinostat (Arm C). The secondary aim was to compare toxicity across arms. Methods: We conducted a multicenter, randomized phase II trial. Patients 1-30 years with relapsed/refractory high-risk neuroblastoma were eligible with at least one MIBG-avid site and adequate autologous stem cells (ASCs). All patients received MIBG 18 mCi/kg on Day 1 and ASC on day 15. Patients on Arm A received only MIBG; patients on Arm B also received vincristine (2 mg/m2) IV on Day 0 and irinotecan (50 mg/m2) IV daily on Days 0-4; patients on Arm C also received vorinostat (180 mg/m2) orally once daily on days -1 to 12. The primary endpoint was response after one course according to NANT response criteria. The trial was designed as a pick-the-winner study with a maximum of 105 eligible and evaluable patients to ensure an 80% chance that the arm with highest response rate is selected, if that response rate is at least 15% higher than the other arms. Results: 114 patients enrolled. Three patients were ineligible and 6 eligible patients never received MIBG, leaving 105 eligible and evaluable patients (36 Arm A; 35 Arm B; and 34 Arm C; 55 boys; median age 6.5 years). 9 patients had received prior MIBG monotherapy, 65 prior irinotecan, and 7 prior vorinostat. After one course, the response rates (Partial Response or better) on Arms A, B, and C were 17% (95% CI 7-33%), 14% (5-31%), and 32% (18-51%). An additional 4, 4, and 7 patients met NANT Minor Response criteria [partial response in one disease category (e.g., bone marrow) and stable disease in other categories] on Arms A, B, and C, respectively. On Arms A, B, and C, rates of any grade 3+ non-hematologic toxicity were 19%, 49% and 32%; rates of grade 3+ diarrhea were 0%, 11%, 0%; and rates of grade 3+ febrile neutropenia were 6%, 11%, and 0%. Conclusions: The combination of vorinostat/MIBG had the highest response rate, with manageable toxicity. Vincristine and irinotecan do not improve the response rate to MIBG and are associated with increased toxicity. These data provide response rates for MIBG monotherapy in a contemporary patient population assessed with current response criteria. Clinical trial information: NCT02035137.

Background Vorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD. Methods Isotretinoin (cis-13-retinoic acid) 80 mg/m2 /dose was administered by mouth twice daily on days 1-14 in combination with escalating doses of daily vorinostat up to 430 mg/m2 /dose (days 1-4; 8-11) in each 28-day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed. Results Twenty-nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1-15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose-limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2 /day, days 1-4; 8-11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen. Conclusions Increased dose vorinostat (430 mg/m2 /day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation.

Background (131) I-metaiodobenzylguanidine ((131) I-MIBG) is a targeted radiopharmaceutical for patients with neuroblastoma. Despite its tumor-specific uptake, the treatment with (131) I-MIBG results in whole-body radiation exposure. Our aim was to correlate whole-body radiation dose (WBD) from (131) I-MIBG with tumor response, toxicities, and other clinical factors. Methods This retrospective cohort analysis included 213 patients with high-risk neuroblastoma treated with (131) I-MIBG at UCSF Benioff Children's Hospital between 1996 and 2015. WBD was determined from radiation exposure rate measurements. The relationship between WBD ordered tertiles and variables were analyzed using Cochran-Mantel-Haenszel test of trend, Kruskal-Wallis test, and one-way analysis of variance. Correlation between WBD and continuous variables was analyzed using Pearson correlation and Spearman rank correlation. Results WBD correlated with (131) I-MIBG administered activity, particularly with (131) I-MIBG per kilogram (P 1 hypothyroidism). Conclusions This study showed that (131) I-MIBG activity per kilogram correlates with WBD and suggests that activity per kilogram will predict WBD in most patients. Within the range of activities prescribed, there was no correlation between WBD and either response or toxicity. Future studies should evaluate tumor dosimetry, rather than just WBD, as a tool for predicting response following therapy with (131) I-MIBG.

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.