Vo, Kieuhoa T.

Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.

PURPOSE The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. METHODS As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). RESULTS Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. CONCLUSION Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

3009 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm J evaluated the ERK1/2 inhibitor ulixertinib (BVD-523FB) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAPK1, MAP2K1, GNA11, GNAQ hotspot mutations; NF1inactivating mutations; BRAF fusions). Methods: As there were no prior pediatric data, ulixertinib was initially tested in a dose escalation cohort using a rolling 6 design to establish the recommended phase 2 dose (RP2D) before proceeding with enrollment to the phase 2 cohort. Ulixertinib was administered at 260 mg/m2/dose PO BID (dose level 1, DL1, n = 15) or 350 mg/m2/dose PO BID (dose level 2, DL2, n = 5). Patients were treated on continuous 28-day cycles for up to 2 years, until disease progression or intolerable toxicity; response assessment occurred every 2-3 cycles. The primary endpoint was objective response rate; secondary endpoints included safety/tolerability and progression-free survival (PFS). Results: Twenty patients (median age 12 years; range 5-20) were enrolled between November 2018 and March 2021. All patients were evaluable for response. High-grade glioma (HGG, n = 7) was most common, with CNS tumors comprising 55% (11/20) of diagnoses; all CNS tumors except one (HGG with KRAS and NF1 mutations) harbored BRAF fusions or V600 mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis, with NRAS mutations detected in 4 tumors. DL1 was declared the RP2D after first-cycle dose limiting toxicities (DLTs) occurred in 1/6 DLT-evaluable patients at DL1 and 2/5 patients at DL2 in the dose escalation cohort. Any-cycle DLTs in 8 patients in the dose escalation and primary cohorts included fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, increased creatinine, hypoalbuminemia, hypernatremia, and hip fracture. No objective responses were observed. Six-month PFS was 37% (95% CI: 17%, 58%). Three patients with CNS tumors achieved stable disease > 6 months (HGG with BRAF fusion, 15 cycles; glioneuronal tumor with BRAF V600E, 9 cycles; low-grade glioma with BRAF fusion, 7 cycles). Analyses of correlative studies, including pharmacokinetics and circulating tumor DNA, are ongoing. Conclusions: The pediatric RP2D of ulixertinib was established as 260 mg/m2/dose PO BID. There were no objective responses in this cohort of children and young adults with treatment-refractory tumors with activating MAPK alterations. Clinical benefit of prolonged disease control was observed in 3 patients with BRAF-altered gliomas and glioneuronal tumors. Clinical trial information: NCT03698994.

10526 Background: Pro-angiogenic factors may represent therapeutic targets in sarcoma. Preclinical studies have demonstrated a potential additive or synergistic interaction between anti-angiogenic agents and chemotherapy. The purpose of this study was to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetic (PK) and pharmacodynamics (PD) effects of PAZIT in patients with advanced sarcoma. Methods: Patients 6-30 years of age with relapsed/refractory sarcomas were eligible. In the initial dose escalation plan (A), patients received pazopanib PO (225-450 mg/m2/dose) on Days 1-21 of 21-day cycles. Pazopanib was combined with fixed doses of irinotecan (IV 50 or PO 90 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Due to DLTs, an amendment was made to the dose escalation plan (B) and patients received fixed doses of pazopanib PO (225 mg/m2/dose) on Days 1-21 of 21-day cycles and reduced irinotecan doses (IV 25-37.5 or PO 45-67.5 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Oral cephalosporin diarrhea prophylaxis was required. Dose escalation followed a 3+3 design. Correlative studies included PK (pazopanib, irinotecan) and PD (angiogenic factors, ctDNA) effects. Results: Sixteen patients were treated (median age 16 years, range 7-21). The dose levels in the table were evaluated. First cycle DLTs occurred at all dose levels (Table) and included diarrhea, pancreatitis, colitis, neutropenia, hypertension, deep vein thrombosis, and ALT increase. Due to excessive toxicity, an MTD could not be established. One patient with osteosarcoma had a partial response. Four patients had prolonged stable disease > 4 cycles, including 2 patients with Ewing sarcoma (5 and 6 cycles), rhabdomyosarcoma (9 cycles), and desmoplastic small round cell tumor (6 cycles). Mean±SD plasma exposures to pazopanib, irinotecan, and SN-38 in patients treated on dose level 1B (n = 4) on Day 4 were 601±83, 1.4±0.2 and 0.1±0.04 ug/mL*hr, respectively. Analyses of correlative studies are ongoing. Conclusions: Combination PAZIT therapy is not tolerable as evaluated at these doses/schedules. This study provides important toxicity data to inform future clinical trials using combination anti-angiogenic strategies in sarcoma. Clinical trial information: NCT03139331. [Table: see text]