title: Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors.
abstract: BACKGROUND
  Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors.
  
  
  METHODS
  Satraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60 mg/m(2) /dose), and DL2 (80 mg/m(2) /dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated.
  
  
  RESULTS
  Nine patients received 1-15 cycles (median = 2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (---6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed.
  
  
  CONCLUSIONS
  The MTD of oral satraplatin in children with solid tumors was 60 mg/m(2) /dose daily ×5 days every 28 days, which is lower than the adult recommended dose of 80-120 mg/m(2) /dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Srivandana
authors.initials: S
authors.lastname: Akshintala
authors.forename: Leigh
authors.initials: L
authors.lastname: Marcus
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Warren
authors.forename: Robert F
authors.initials: RF
authors.lastname: Murphy
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.forename: Anjali
authors.initials: A
authors.lastname: Srivastava
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Goodspeed
authors.forename: Anne
authors.initials: A
authors.lastname: Goodwin
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Brewer
authors.forename: Christopher
authors.initials: C
authors.lastname: Zalewski
authors.forename: Kelly A
authors.initials: KA
authors.lastname: King
authors.forename: AeRang
authors.initials: A
authors.lastname: Kim
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C081294:satraplatin
keywords: pediatric; phase 1 trial; satraplatin; solid tumors