title: A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours.
abstract: BACKGROUND
  This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours.
  
  
  METHODS
  Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1-5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m(-2)) were administered 2-3 h after the end of the belinostat infusion.
  
  
  RESULTS
  In all 23 patients received 600-1000 mg m(-2) per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m(-2) per day for days 1-5, with paclitaxel (175 mg m(-2)) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting > or =6 months.
  
  
  CONCLUSIONS
  The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.
authors.affiliation: Department of Oncology, University Hospital, Rigshospitalet, Copenhagen 2100, Denmark. ulrik.lassen@rh.regionh.dk
authors.forename: U
authors.initials: U
authors.lastname: Lassen
authors.forename: L R
authors.initials: LR
authors.lastname: Molife
authors.forename: M
authors.initials: M
authors.lastname: Sorensen
authors.forename: S-A
authors.initials: SA
authors.lastname: Engelholm
authors.forename: L
authors.initials: L
authors.lastname: Vidal
authors.forename: R
authors.initials: R
authors.lastname: Sinha
authors.forename: R T
authors.initials: RT
authors.lastname: Penson
authors.forename: P
authors.initials: P
authors.lastname: Buhl-Jensen
authors.forename: E
authors.initials: E
authors.lastname: Crowley
authors.forename: J
authors.initials: J
authors.lastname: Tjornelund
authors.forename: P
authors.initials: P
authors.lastname: Knoblauch
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D013449:Sulfonamides
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D016190:Carboplatin; C487081:belinostat; D017239:Paclitaxel