title: Phase I and pharmacokinetic study of pegylated liposomal CKD-602 in patients with advanced malignancies.
abstract: OBJECTIVE
  S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors.
  
  
  METHODS
  S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over 2 weeks and total (lactone+hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated+released) CKD602 measured by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  Forty-five patients (21 males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m2, grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in two patients with refractory ovarian cancer (1.7 and 2.1 mg/m2). High interpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602.
  
  
  CONCLUSIONS
  S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Molecular Therapeutics, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599-7360, USA. zamboni@email.unc.edu
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: Suresh
authors.initials: S
authors.lastname: Ramalingam
authors.forename: David M
authors.initials: DM
authors.lastname: Friedland
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Stoller
authors.forename: Sandra
authors.initials: S
authors.lastname: Strychor
authors.forename: Lauren
authors.initials: L
authors.lastname: Maruca
authors.forename: Beth A
authors.initials: BA
authors.lastname: Zamboni
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
mesh_terms: D000328:Adult; D000368:Aged; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage
chemical_list: D008081:Liposomes; C116963:belotecan; D011092:Polyethylene Glycols; D002166:Camptothecin