title: Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors.
abstract: BACKGROUND
  EZN-2208 is a water-soluble PEGylated conjugate of the topoisomerase inhibitor SN38, the active metabolite of irinotecan. Compared to irinotecan, EZN-2208 has a prolonged half-life permitting extended exposure to SN38. EZN-2208 has demonstrated clinical tolerability and antitumor activity in adults with advanced solid tumors. This Phase 1 study evaluated the safety, pharmacokinetics, and preliminary antitumor activity of EZN-2208 in children with relapsed or refractory solid tumors.
  
  
  METHODS
  EZN-2208 was administered as a 1-hour intravenous infusion once every 21 days at five dose levels (12-30 mg/m(2) ). Filgrastim or pegfilgrastim was administered 24-48 hours after treatment with EZN-2208. The rolling-six design was used for dose determination.
  
  
  RESULTS
  Thirty eligible patients (15 females; median [range] age 11.5 years [2-21 years]) were treated with EZN-2208. Dose-limiting diarrhea occurred in one patient receiving 16 mg/m(2) and dose-limiting dehydration was seen in one patient receiving 24 mg/m(2) . At dose levels above 16 mg/m(2) , Grade ≥3 myelosuppression was demonstrated in the majority of patients. Additional adverse events included nausea, vomiting, and fatigue. The maximum tolerated dose was identified as 24 mg/m(2) due to dose-limiting thrombocytopenia in two patients receiving 30 mg/m(2) . Two of nine patients with neuroblastoma who were evaluable for response had partial responses. Five patients (four with neuroblastoma) remained on study for ≥8 cycles.
  
  
  CONCLUSIONS
  EZN-2208 was generally well-tolerated and was associated with clinical benefit in patients with neuroblastoma.
authors: Division of Pediatric Hematology/Oncology, University Hospitals Case Medical Center Rainbow Babies & Children's Hospital, Cleveland, Ohio.
authors: Robin E
authors: RE
authors: Norris
authors: Suzanne
authors: S
authors: Shusterman
authors: Lia
authors: L
authors: Gore
authors: Jodi A
authors: JA
authors: Muscal
authors: Margaret E
authors: ME
authors: Macy
authors: Elizabeth
authors: E
authors: Fox
authors: Noah
authors: N
authors: Berkowitz
authors: Aby
authors: A
authors: Buchbinder
authors: Rochelle
authors: R
authors: Bagatell
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C528970:EZN-2208; D011092:Polyethylene Glycols; D002166:Camptothecin
keywords: EZN-2208; Phase 1 trial; pediatric cancer; pharmacokinetic