Ch14.18 is a chimeric human/murine anti-GD2 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. A Phase I study enrolled 25 patients. The MTD of ch14.18 was determined to be 25 mg/m2/d for 4 days given concurrently with 4.5 x 106 U/m2/d of IL-2 for 4 days. IL-2 was also given at a dose of 3 x 106 U/m2/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. This was followed by a phase III trial. A recent randomized phase 3 clinical trial (ANBL0032, ClinicalTrials.gov identifier: NCT00026312) in children with high-risk neuroblastoma following autologous stem cell transplant conducted by the Children's Oncology Group (COG) found that the primary study endpoint [event-free survival (EFS) from randomization] to be significantly prolonged for patients on the ch14.18-based experimental immunotherapy regimen (a combination of isotretinoin plus immunotherapy with ch14.18, IL-2, and GM-CSF) compared to the standard maintenance therapy post-transplantation (isotretinoin). This conclusion is based on results of a planned study interim analysis performed by the COG Data Safety and Monitoring Committee (DSMC). As a result of the ANBL0032 study findings, COG and DCTD now consider the ch14.18-based immunotherapy administered as per ANBL0032 to be an appropriate standard treatment for children with neuroblastoma following autologous stem cell transplantation. Overall survival was also better for children randomized to the experimental immunotherapy arm of ANBL0032, although further follow-up will be needed to confirm this survival advantage. The ANBL0032 study is now open as a single arm study in which all patients receive Ch14.18-based immunotherapy and isotretinoin.
Pediatric oncologists treat most of their patients on protocol and the COG (Children Oncology Group) has a major role is deciding when a treatment is standard of care. COG now considers this to be standard of care and not experimental based on the resutls discussed above.
GILMAN Andrew L. ; FEVZI OZKAYNAK M. ; MATTHAY Katherine K. ; KRAILO Mark ; YU Alice L. ; GAN Jacek ; STERNBERG Adam ; HANK Jacquelyn A. ; SEEGER Robert ; REAMAN Gregory H. ; SONDEL Paul MPhase I Study of ch 14.18 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 Journal of clinical oncology 2009, vol. 27, no1, pp. 85-91 [7 page(s) (article)] (23 ref.)