Antitumor Activity and Tolerability of hu14.18-IL2 with GMCSF and Isotretinoin in Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Phase II Study

Purpose: Combining anti-GD2 (disialoganglioside) mAb with GM-CSF, IL2, and isotretinoin is now FDA-approved for high-risk neuroblastoma minimal residual disease (MRD) therapy. The humanized anti-GD2 antibody conjugated to IL2 (hu14.18-IL2) has clinical activity in neuroblastoma and is more effective in neuroblastoma-bearing mice than antibody and cytokine given separately. We therefore evaluated the safety, tolerability, and antitumor activity of hu14.18-IL2 given with GM-CSF and isotretinoin in a schedule similar to standard MRD therapy. Patients and Methods: Hu14.18-IL2 was given at the recommended phase II dose of 12 mg/m(2)/day on days 4-6 of a 28-day cycle with GM-CSF (250 mg/m(2)/dose, days 1-2 and 8-14) and isotretinoin (160 mg/m(2)/day, days 11-25). Tolerability was determined on the basis of the number of unacceptable toxicities observed. Response was evaluated separately for patients with disease measurable by standard radiologic criteria (stratum 1), and for patients with disease evaluable only by I-123-metaiodobenzylguanidine (I-123-MIBG) scan and/or bone marrow histology (stratum 2). Results: Fifty-two patients with recurrent or refractory neuroblastoma were enrolled; 51 were evaluable for toxicity and 45 were evaluable for response. Four patients had unacceptable toxicities, well below the protocol-defined rule for tolerability. Other grade 3 and 4 nonhematologic toxicities were expected and reversible. No responses were seen in stratum 1 (n = 14). In stratum 2 (n = 31), 5 objective responses were confirmed by central review (3 complete, 2 partial). Conclusions: Hu14.18-IL2 given in combination with GMCSF and isotretinoin is safe and tolerable. Patients with MIBG and/or bone marrow-only disease had a 16.1% response rate, confirming activity of the combination.