Phase I Trial of Lenalidomide in Pediatric Patients With Recurrent, Refractory, or Progressive Primary CNS Tumors: Pediatric Brain Tumor Consortium Study PBTC-018.

WARREN KE; GOLDMAN S; POLLACK IF; FANGUSARO J; SCHAIQUEVICH P; STEWART CF; WALLACE D; BLANEY SM; PACKER R; MACDONALD T; JAKACKI R,; BOYETT JM; KUN LE

JOURNAL OF CLINICAL ONCOLOGY

AMER SOC CLINICAL ONCOLOGY

Año: 2011 vol. 20 p. 324 - 329

0732-183X

Purpose 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).Patients and MethodsCohorts of children with solid tumors received lenalidomide once daily for 21 days, every 28 days at dose levels of 15 to 70 mg/m2 /dose. Children with MDS received a fixed dose of 5 mg/m2 /dose. Specimens for PK and immune modulation were obtained in the first cycle.ResultsForty-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/m2; hypophosphatemia/hypokalemia, neutropenia, and somnolence at 40 mg/m2; and urticaria at 55 mg/m2  .At the highest dose level evaluated (70 mg/m2 ), 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. ConclusionLenalidomide is well-tolerated at doses up to 70 mg/m2 /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.