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Phase I Study of Chimeric Human/Murine Anti–Ganglioside G_D2 Monoclonal Antibody (ch14.18) With Granulocyte-Macrophage Colony-Stimulating Factor in Children With Neuroblastoma Immediately After Hematopoietic Stem-Cell Transplantation: A Children’s Cancer Group Study

From the Department of Pediatrics, Section of Hematology/Oncology, New York Medical College, Valhalla, NY; Departments of Pediatrics and Human Oncology, University of Wisconsin Medical Center, Madison, WI; Children’s Cancer Group, Operations Office, Arcadia; The Scripps Research Institute, La Jolla; Department of Pediatrics, University of California School of Medicine, San Francisco; Department of Pediatrics, Division of Hematology/Oncology, Childrens Hospital of Los Angeles, University of Southern California School of Medicine, Los Angeles, CA; and Department of Pediatrics, Hematology/Oncology, Childrens National Medical Center, Washington DC.

Address reprint requests to M. Fevzi Ozkaynak, MD, Children’s Cancer Group, PO Box 60012, Arcadia, CA 91066-6012; email mehmet_ozkaynak{at}nymc.edu

PURPOSE: Ganglioside G_D2 is strongly expressed on the surface of human neuroblastoma cells. It has been shown that the chimeric human/murine anti-G_D2 monoclonal antibody (ch14.18) can induce lysis of neuroblastoma cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The purposes of the study were (1) to determine the maximum-tolerated dose (MTD) of ch14.18 in combination with standard dose granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with neuroblastoma who recently completed hematopoietic stem-cell transplantation (HSCT), and (2) to determine the toxicities of ch14.18 with GM-CSF in this setting.

PATIENTS AND METHODS: Patients became eligible when the total absolute phagocyte count (APC) was greater than 1,000/µL after HSCT. ch14.18 was infused intravenously over 5 hours daily for 4 consecutive days. Patients received GM-CSF 250 µg/m²/d starting at least 3 days before ch14.18 and continued for 3 days after the completion of ch14.18. The ch14.18 dose levels were 20, 30, 40, and 50 mg/m²/d. In the absence of progressive disease, patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF. Nineteen patients with neuroblastoma were treated.

RESULTS: A total of 79 courses were administered. No toxic deaths occurred. The main toxicities were severe neuropathic pain, fever, nausea/vomiting, urticaria, hypotension, mild to moderate capillary leak syndrome, and neurotoxicity. Three dose-limiting toxicities were observed among six patients at 50 mg/m²/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting. Human antichimeric antibody developed in 28% of patients.

CONCLUSION: ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities. The MTD is 40 mg/m²/d for 4 days when given in this schedule with GM-CSF.

Laboratory analyses were performed at the GCRC at Childrens Hospital of Los Angeles, Los Angeles, CA (R.C.S.), and the Children’s Cancer Group Immunotherapy Resource Laboratory in Madison, WI (P.M.S. and J.G.).

© 2000 by American Society of Clinical Oncology. 0732-183X/00/1824-4077

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