title: 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: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Levine Children's Hospital, Charlotte, NC 28232, USA. andrew.gilman@carolinashealthcare.org
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gilman
authors.forename: M Fevzi
authors.initials: MF
authors.lastname: Ozkaynak
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
authors.forename: Jacek
authors.initials: J
authors.lastname: Gan
authors.forename: Adam
authors.initials: A
authors.lastname: Sternberg
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Hank
authors.forename: Robert
authors.initials: R
authors.lastname: Seeger
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009447:Neuroblastoma / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; C112746:dinutuximab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor