Originally published as JCO Early Release 10.1200/JCO.2006.10.3564 on December 1 2008

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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

Andrew L. Gilman, M. Fevzi Ozkaynak, Katherine K. Matthay, Mark Krailo, Alice L. Yu, Jacek Gan, Adam Sternberg, Jacquelyn A. Hank, Robert Seeger, Gregory H. Reaman, Paul M. Sondel

From the Levine Children's Hospital, Charlotte, NC; New York Medical College, Valhalla, NY; University of California San Francisco Children's Hospital, San Francisco; Department of Preventive Medicine, Keck School of Medicine, University of Southern California; Children's Hospital Los Angeles, Los Angeles; Children's Hospital San Diego, San Diego, CA; University of Wisconsin Comprehensive Cancer Center and University of Wisconsin Children's Hospital, Madison; and the Children's Oncology Group, Bethesda, MD

Corresponding author: Andrew Gilman, MD, Levine Children's Hospital, PO Box 32861, Charlotte, NC 28232; e-mail: andrew.gilman{at}carolinashealthcare.org

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/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.

published online ahead of print at www.jco.org on December 1, 2008.

Supported by COG Grant No. CA 98543. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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