Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group

Abstract

Purpose: Recurrence of high-risk neuroblastoma is common despite multimodality therapy. ch14.18, a chimeric human/murine anti-G(D2) antibody, lyses neuroblastoma cells. This study determined the maximum tolerable dose (MTD) and toxicity of ch14.18 given in combination with interleukin-2 (IL-2) after high-dose chemotherapy (HDC)/stem-cell rescue (SCR). Biologic correlates including ch14.18 levels, soluble IL-2 receptor levels, and human antichimeric antibody (HACA) activity were evaluated.

Patients and methods: Patients were given ch14.18 for 4 days at 28-day intervals. Patients received IL-2 during the second and fourth courses of ch14.18 and granulocyte-macrophage colony-stimulating factor (GM-CSF) during the first, third, and fifth courses. The MTD was determined based on toxicities occurring with the second course. After the determination of the MTD, additional patients were treated to confirm the MTD and to clarify appropriate supportive care.

Results: Twenty-five patients were enrolled. The MTD of ch14.18 was determined to be 25 mg/m(2)/d for 4 days given concurrently with 4.5 x 10(6) U/m(2)/d of IL-2 for 4 days. IL-2 was also given at a dose of 3 x 10(6) U/m(2)/d for 4 days starting 1 week before ch14.18. Two patients experienced dose-limiting toxicity due to ch14.18 and IL-2. Common toxicities included pain, fever, nausea, emesis, diarrhea, urticaria, mild elevation of hepatic transaminases, capillary leak syndrome, and hypotension. No death attributable to toxicity of therapy occurred. No additional toxicity was seen when cis-retinoic acid (cis-RA) was given between courses of ch14.18. No patient treated at the MTD developed HACA.

Conclusion: ch14.18 in combination with IL-2 was tolerable in the early post-HDC/SCR period. cis-RA can be administered safely between courses of ch14.18 and cytokines.

Figures

Fig A1.

Serum ch14.18 level (gold bars) and human antichimeric antibody (HACA) reactivity (blue open circles, and sometimes referred to as “anti-idiotypic” antibody [aID]) detected in specimens collected from patient who received six courses of treatment (regimen 1). This was the only patient showing strong HACA reactivity starting after fourth infusion of ch14.18 antibody. GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-2 interleukin 2; OD, optical density.

Fig A2.

Soluble interleukin 2 receptor alpha subunit (sIL-2Rα; blue circles) and ch14.18 (gold circles) level in serum in two representative patients who received five courses of treatment (on regimen 3). GM-CSF, granulocyte-macrophage colony-stimulating factor.

Fig 1.

Treatment schema of Children's Oncology Group study A0935A. The schema reflects the final treatment regimen (regimen 3 in Table 1). GM-CSF, granulocyte-macrophage colony-stimulating factor; Cis-RA, cis-retinoic acid; IL-2, interleukin 2.