Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting.

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.

Pediatric Phase I Trial and Pharmacokinetic Study of Trebananib in Relapsed Solid Tumors, Including Primary Tumors of the Central Nervous System ADVL1115: A Children's Oncology Group Phase I Consortium Report.

Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide-Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK).Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI.Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI.Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062-9. ©2017 AACR.

¹³¹I-Metaiodobenzylguanidine Theranostics in Neuroblastoma: Historical Perspectives; Practical Applications.

Much efficacy is gained in clinical practice if a single agent can be used for both diagnosis and therapy, a practice termed theranostics. Metaiodobenzylguanidine (mIBG), a norepinephrine analogue with high sensitivity and specificity for neuroblastoma, is an exemplar of theranostics. The physiologic biodistribution of mIBG, with absence of uptake in bone and bone marrow, allows ready detection not only of primary soft tissue tumors but also of disease in bone and marrow, the two most common sites of metastases in those with neuroblastoma. Owing to its increased sensitivity and specificity in disease detection compared to the Technetium-99m methylene diphosphonate bone scan, (123)I-mIBG has become the cornerstone of staging and therapeutic response monitoring in patients with neuroblastoma. More recently, semiquantitative scoring systems have been developed to evaluate disease burden and response to treatment based on (123)I-mIBG scans. Initial data suggest that the use of these semiquantitative scoring methods has prognostic value in assessing outcomes for patients with high-risk neuroblastoma. When labeled with (131)I, mIBG can be used as a systemic therapeutic agent to treat high-risk disease, and to date, over 1000 patients with neuroblastoma have been treated worldwide with this agent. This article reviews the evolution of (131)I-mIBG therapy from its initial use as a single therapeutic agent to modern applications involving high-dose chemotherapy and autologous stem-cell transplant as well as its use as a front-line agent in high-risk neuroblastoma.