title: Safety, pharmacokinetics, and immunomodulatory effects of lenalidomide in children and adolescents with relapsed/refractory solid tumors or myelodysplastic syndrome: a Children's Oncology Group Phase I Consortium report.
abstract: OBJECTIVE
  To determine the maximum-tolerated or recommended phase II dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and immunomodulatory effects of lenalidomide in children with recurrent or refractory solid tumors or myelodysplastic syndrome (MDS).
  
  
  METHODS
  Cohorts of children with solid tumors received lenalidomide once daily for 21 days, every 28 days at dose levels of 15 to 70 mg/m(2)/dose. Children with MDS received a fixed dose of 5 mg/m(2)/dose. Specimens for PK and immune modulation were obtained in the first cycle.
  
  
  RESULTS
  Forty-nine patients (46 solid tumor, three MDS), median age 16 years (range, 1 to 21 years), were enrolled, and 42 were fully assessable for toxicity. One patient had a cerebrovascular ischemic event of uncertain relationship to lenalidomide. DLTs included hypercalcemia at 15 mg/m(2); hypophosphatemia/hypokalemia, neutropenia, and somnolence at 40 mg/m(2); and urticaria at 55 mg/m(2). At the highest dose level evaluated (70 mg/m(2)), zero of six patients had DLT. A maximum-tolerated dose was not reached. No objective responses were observed. PK studies (n = 29) showed that clearance is faster in children younger than 12 years of age. Immunomodulatory studies (n = 26) showed a significant increase in serum interleukin (IL) -2, IL-15, granulocyte-macrophage colony-stimulating factor, natural killer (NK) cells, NK cytotoxicity, and lymphokine activated killer (LAK) cytoxicity, and a significant decrease in CD4(+)/CD25(+) regulatory T cells.
  
  
  CONCLUSIONS
  Lenalidomide is well-tolerated at doses up to 70 mg/m(2)/d for 21 days in children with solid tumors. Drug clearance in children younger than 12 years is faster than in adolescents and young adults. Lenalidomide significantly upregulates cellular immunity, including NK and LAK activity.
authors.affiliation: Texas Children's Cancer Center, 6621 Fannin St, MC3-3320, Houston, TX 77030, USA. sberg@txccc.org
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Berg
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Cairo
authors.forename: Heidi
authors.initials: H
authors.lastname: Russell
authors.forename: Janet
authors.initials: J
authors.lastname: Ayello
authors.forename: Ashish Mark
authors.initials: AM
authors.lastname: Ingle
authors.forename: Henry
authors.initials: H
authors.lastname: Lau
authors.forename: Nianhang
authors.initials: N
authors.lastname: Chen
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007223:Infant; D000077269:Lenalidomide; D020714:Maximum Tolerated Dose; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D012008:Recurrence; D016879:Salvage Therapy; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide