title: A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer.
abstract: BACKGROUND
  Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a "5-drug" oral regimen in children with recurrent or progressive cancer.
  
  
  METHODS
  Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed.
  
  
  RESULTS
  One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days-21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009).
  
  
  CONCLUSIONS
  The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Division of Pediatric Hematology-Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Robison
authors.forename: Federico
authors.initials: F
authors.lastname: Campigotto
authors.forename: Susan N
authors.initials: SN
authors.lastname: Chi
authors.forename: Peter E
authors.initials: PE
authors.lastname: Manley
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Turner
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Zimmerman
authors.forename: Christine A
authors.initials: CA
authors.lastname: Chordas
authors.forename: Annette M
authors.initials: AM
authors.lastname: Werger
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Allen
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
authors.forename: Michael S
authors.initials: MS
authors.lastname: Isakoff
authors.forename: Wilbur J
authors.initials: WJ
authors.lastname: Pan
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Khatib
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Comito
authors.forename: Anne E
authors.initials: AE
authors.lastname: Bendel
authors.forename: Jay B
authors.initials: JB
authors.lastname: Pietrantonio
authors.forename: Laura
authors.initials: L
authors.lastname: Kondrat
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Hubbs
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
mesh_terms: D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068579:Celecoxib; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011379:Prognosis; D011446:Prospective Studies; D011720:Pyrazoles / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D013792:Thalidomide; D005047:Etoposide; D003520:Cyclophosphamide; D000068579:Celecoxib; D011345:Fenofibrate
keywords: angiogenesis; drug resistance; pediatric oncology; phase II clinical trials