title: Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children's Oncology Group (ANBL0621).
abstract: BACKGROUND
  ABT-751, an orally bioavailable sulfonamide binds the colchicine site of beta-tubulin and inhibits microtubule polymerization. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m(2) PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT-751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population.
  
  
  METHODS
  Children and adolescents (n = 91) with a median (range) age 7.7 (2.3-21.5) years and progressive neuroblastoma were enrolled and stratified by disease status into disease measureable by CT/MRI (n = 47) or disease assessable by (123) I-metaiodobenzylguanine scintigraphy (MIBG, n = 44). Response was evaluated using RECIST for measureable disease and the Curie score for MIBG-avid disease.
  
  
  RESULTS
  ABT-751 was well tolerated. The objective response rate was 7%. The median TTP was 42 days (95% CI: 36, 56) in the measureable disease stratum and 45 days (95% CI: 42, 85) in the MIBG-avid disease stratum. TTP was similar to the historical control group (n = 136, median TTP 42 days). For the combined strata (n = 91), 1-year progression free survival (PFS) was 13 ± 4% and overall survival (OS) was 48 ± 5%.
  
  
  CONCLUSIONS
  The low objective response rate and failure to prolong TTP indicate that ABT-751 is not sufficiently active to warrant further development for neuroblastoma. However, this trial demonstrates the utility of TTP as the primary endpoint in phase 2 trials in children and adolescents with neuroblastoma.
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mosse'
authors.forename: Holly M
authors.initials: HM
authors.lastname: Meany
authors.forename: James G
authors.initials: JG
authors.lastname: Gurney
authors.forename: Geetika
authors.initials: G
authors.lastname: Khanna
authors.forename: Hollie A
authors.initials: HA
authors.lastname: Jackson
authors.forename: Gary
authors.initials: G
authors.lastname: Gordon
authors.forename: Suzanne
authors.initials: S
authors.lastname: Shusterman
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers; D002214:Capsules; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced; D009447:Neuroblastoma / Q000188:drug therapy* / Q000628:therapy; D011788:Quality of Life; D012008:Recurrence; D016879:Salvage Therapy; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013535:Suspensions; D017211:Treatment Failure; D050257:Tubulin Modulators / Q000627:therapeutic use*
chemical_list: C490492:ABT751; D000970:Antineoplastic Agents; D015415:Biomarkers; D002214:Capsules; D013449:Sulfonamides; D013535:Suspensions; D050257:Tubulin Modulators
keywords: childhood cancer; clinical trial; microtubule inhibitor; neuroblastoma; time to progression