title: Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation.
abstract: OBJECTIVE
  To evaluate the safety and tolerability of LiPlaCis, a liposomal formulated platinum compound, in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous (i.v.) LiPlaCis. and to assess plasma and urine pharmacokinetics and plasma biomarkers.
  
  
  METHODS
  Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3weeks until RECIST progression or unacceptable toxicity. Cohorts of 3-6 patients were treated at each dose level until MTD was reached.
  
  
  RESULTS
  Eighteen patients were enrolled and 64 cycles were delivered. At the first dose level 3 patients experienced an infusion reaction. Despite prophylactic pre-medication and prolongation of the infusion to 2 h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients. Peak plasma concentrations and AUC were dose proportional. The interpatient variability in the clearance of total LiPlaCis-derived platinum was 41%. Platinum was excreted via the urine mainly during the first 24 h after administration. Investigated plasma biomarkers sPLA(2) and SC5b-9 were related to, but not predictive for, acute infusion reactions.
  
  
  CONCLUSIONS
  The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development.
authors.affiliation: Erasmus University Medical Center Daniel Den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands. m.dejonge@erasmusmc.nl
authors.forename: Maja J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: Marije
authors.initials: M
authors.lastname: Slingerland
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kroep
authors.forename: Margret A G
authors.initials: MA
authors.lastname: den Hollander
authors.forename: Diane
authors.initials: D
authors.lastname: van der Biessen
authors.forename: Mei-Ho
authors.initials: MH
authors.lastname: Lam
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D002945:Cisplatin