title: Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors.
  
  
  METHODS
  Sorafenib dose was escalated from 90 to 110 mg/m(2) twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m(2) daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course.
  
  
  RESULTS
  Nineteen patients (11 males; median age, 9.2 years) received a median of four courses (range, 1-23). DLTs during course 1 included grade 3 rash (two), increased lipase (one), anorexia (one), and thrombus (one). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (nine), lymphopenia (nine), and rashes (four). Five of 17 evaluable patients had partial tumor responses, and five had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m(2). Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m(2) at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGF receptor 2 (VEGFR2) was inversely correlated with sorafenib steady-state concentrations (P = 0.019).
  
  
  CONCLUSIONS
  The recommended phase II doses are sorafenib, 90 mg/m(2) twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m(2) once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.
authors.affiliation: Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. fariba.navid@stjude.org
authors.forename: Fariba
authors.initials: F
authors.lastname: Navid
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: M Beth
authors.initials: MB
authors.lastname: McCarville
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Spunt
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Furman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McGregor
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: David
authors.initials: D
authors.lastname: Turner
authors.forename: Demba
authors.initials: D
authors.lastname: Fofana
authors.forename: Wilburn E
authors.initials: WE
authors.lastname: Reddick
authors.forename: Wing
authors.initials: W
authors.lastname: Leung
authors.forename: Victor M
authors.initials: VM
authors.lastname: Santana
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D012008:Recurrence; D000077157:Sorafenib; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D010671:Phenylurea Compounds; D009536:Niacinamide; D000068258:Bevacizumab; D003520:Cyclophosphamide; D000077157:Sorafenib