Anti-neuroblastoma activity of hu14.18-IL2 against minimal residual disease in a Children’s Oncology Group (COG) phase II study

Abstract

3002 Background: The hu14.18-IL2 fusion protein consists of IL2 linked to a humanized mAb that recognizes the GD2 disialoganglioside expressed on neuroblastoma (NB) cells. Hu14.18-IL2 has preclinical activity in mouse models of NB and melanoma, particularly when given to mice with a smaller tumor burden. Using the dosing and schedule developed in our phase I study, we determined the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory NB. Methods: Hu14.18-IL2 was given intravenously at a dose of 12 mg/m2/day over 4 hours for three consecutive days every 28 days. Responses were evaluated every 2 cycles for patients with disease measurable by standard radiographical criteria (stratum 1) and for patients with disease evaluable only by MIBG and/or bone marrow histology (stratum 2). In each stratum, a one-stage design was powered to conclude efficacy with 4 or more responders (CR or PR) out of 20. Response was established by independent radiology review as well as bone marrow histology and immuno-cytochemistry, and durability assessed by repeat evaluation after >3 weeks. Results: 39 patients were enrolled (37 evaluable). No responses were seen in stratum 1 (n=13). In stratum 2, response rate was 21% (5/24 overall; 95% CI: 5%,37%), all 5 in first 20. All 5 responders had CR (3/5 bone marrow disease only at study entry, 1/5 MIBG-avid disease only and 1/5 marrow and MIBG-avid disease) of 12, 8, 8+, 7+ and 3+ mo duration. Two additional stratum 2 patients had partial improvement, but did not meet criteria for a PR. Two patients required dopamine for hypotension; 1 patient required ventillatory support for capillary leak and hypoxia. Other grade 3 and 4 non- hematologic toxicities included pain, rash, allergic reaction, fever and transaminitis. Most toxicities were reversible within 1–2 days of completing a treatment course and were expected based on phase 1 results. Correlative lab studies are being analyzed. Conclusions: Patients with MIBG and/or bone marrow only disease had a 21% CR rate to hu14.8-IL2 while patients with bulky disease did not respond. These results warrant further study of hu14.8-IL2 in recurrent or refractory NB patients with minimal residual disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration EMD-Lexigen Research Center EMD-Lexigen EMD-Lexigen EMD-Lexigen