Background: 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 toxicities, and 40% of patients relapse. LEN has immunomodulatory effects in pediatric solid-tumor patients and is well tolerated. The combination of LEN with ch14.18, was supported by preclinical data that demonstrate the activity in NB. We conducted a phase I trial to determine the tolerability of LEN with ch14.1 and RA in patients with RR-NB. Methods: LEN dose escalation followed a 3+3 design (25, 50, 75 and 100mg /m2/day). The administration schedule is: LEN days 1-21, ch14.18 (17.5mg/m2/day) days 8-11, and RA (160mg/m2/day) days 15-28 (Dose level 2-5). Results: 27 patients enrolled with a median age of 8 years (range: 3-20), of whom 23 were evaluable for dose escalation. The median number of courses was 4 (range 1–12). No MTD was identified. There were 7 patients with dose limiting toxicities (course): grade 3 diarrhea(C1), grade 3 diarrhea/delayed neutrophils(C1), delayed neutrophils(C2), grade 4 ALT(C8), anaphylaxis(C5), delayed platelets(C5), delayed neutrophils(C4), delayed neutrophils/grade 4 sinus bradycardia(C6). Overall regimen was tolerable with no grade 3 capillary leak, 7% grade 3 hypotension and 4% grade 3 fever. there was 1 complete response, 3 partial responses, 3 minor responses, 8 stable diseases and 6 progressive diseases in 21 patients evaluable for response. Immunomodulation was seen with statistically significant increases in frequency of circulating effector NK cells, an increase in the frequency of CD4+ (T-helper) effector memory T lymphocytes and increased antibody dependent cytotoxicity (ADCC) in patients. Plasma protein concentrations demonstrated statistically significant therapy-associated increases in granzyme B, IL-15, IFNg, CXCL9, CXCL10, CXCL11, sIL-2R, and GM-CSF as well as IL-6, IL-8, IL-10, MCP-1, and M-CSF. Conclusions: LEN 100 mg/m2 QD for 21 days per cycle is tolerable with ch14.18 and RA, and is associated with antitumor response and immunomodulatory effects. Further studies are warranted in studying this combination. Clinical trial information: NCT01711554