title: Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors.
abstract: OBJECTIVE
  Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol.
  
  
  METHODS
  This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity.
  
  
  RESULTS
  Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma).
  
  
  CONCLUSIONS
  Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. mackallc@mail.nih.gov.
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Merchant
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wright
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Kristin
authors.initials: K
authors.lastname: Baird
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY and Weill-Cornell Medical College, New York, NY.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Wexler
authors.affiliation: Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Donna
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Cindy
authors.initials: C
authors.lastname: Delbrook
authors.affiliation: National Institute of Child Health and Human Development, NIH, Bethesda, MD.
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.affiliation: National Eye Institute, NIH, Bethesda, MD.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bishop
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Weill-Cornell Medical College, New York, NY.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Investigational Drug Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Howard
authors.initials: H
authors.lastname: Streicher
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D056747:Immunomodulation; D000074324:Ipilimumab; D008279:Magnetic Resonance Imaging; D008297:Male; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D019233:Retreatment; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab