title: Safety, pharmacokinetics, and efficacy of CPX-1 liposome injection in patients with advanced solid tumors.
abstract: OBJECTIVE
  CPX-1 is a novel, liposome-encapsulated formulation of irinotecan and floxuridine designed to prolong in vitro optimized synergistic molar ratios of both drugs postinfusion. This open-label, single-arm, dose-escalating phase I study was designed to determine the maximum tolerated dose and pharmacokinetics of CPX-1 in patients with advanced solid tumors.
  
  
  METHODS
  Patients received CPX-1 at 30, 60, 100, 150, 210, or 270 units/m(2) (1 unit = 1 mg irinotecan + 0.36 mg floxuridine) infused over 90 minutes every 14 days in 28-day cycles. Pharmacokinetic samples were collected on days 1 and 15 of cycle 1.
  
  
  RESULTS
  Thirty-three patients were enrolled, treated, and evaluated for safety; 30 patients were evaluated for response. A 1:1 plasma irinotecan to floxuridine molar ratio was maintained for 8 to 12 hours. Grade 3/4 toxicities included diarrhea (24.2%), neutropenia (12.1%), and hypokalemia (12.1%); 1 patient (270 units/m(2)) died of persistent diarrhea, which led to dehydration and renal failure (grade 5). Partial response occurred in 3 (12%) of the 25 subjects evaluated through Response Evaluation Criteria in Solid Tumors. Progression-free survival lasting >6 months occurred in 9 patients, 6 with colorectal cancer. Among 15 colorectal cancer patients (10 with prior irinotecan), the calculated median progression-free survival was 5.4 months; 11 patients (72.7%) achieved disease control and 2 patients (13%) had partial response.
  
  
  CONCLUSIONS
  Outpatient CPX-1 was well tolerated and antitumor activity was shown in patients with advanced solid tumors. The recommended dose for future studies is 210 units/m(2). This is the first clinical evaluation of fixed drug ratio dosing designed to maintain synergistic molar ratios for enhanced therapeutic benefit.
authors.affiliation: Segal Cancer Center, Sir Mortimer B. Davis Jewish General Hospital, Department of Oncology, McGill University, Montreal, Quebec, Canada. gerald.batist@mcgill.ca
authors.forename: Gerald
authors.initials: G
authors.lastname: Batist
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gelmon
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.forename: Stephen K L
authors.initials: SK
authors.lastname: Chia
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Mayer
authors.forename: Christine E
authors.initials: CE
authors.lastname: Swenson
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Janoff
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Louie
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D005467:Floxuridine; D000077146:Irinotecan; D002166:Camptothecin