title: A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO).
abstract: BACKGROUND
  The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan.
  
  
  METHODS
  Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation.
  
  
  RESULTS
  The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference.
  
  
  CONCLUSIONS
  The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC.
  
  
  BACKGROUND
  The trial was funded by Cancer Research UK and supported by Amgen Pharma.
authors: School of Cancer Sciences, University of Birmingham, Edgbaston, UK. Electronic address: g.middleton@bham.ac.uk.
authors: Gary
authors: G
authors: Middleton
authors: Sarah
authors: S
authors: Brown
authors: Catherine
authors: C
authors: Lowe
authors: Timothy
authors: T
authors: Maughan
authors: Stephen
authors: S
authors: Gwyther
authors: Alfred
authors: A
authors: Oliver
authors: Susan
authors: S
authors: Richman
authors: Denise
authors: D
authors: Blake
authors: Vicky
authors: V
authors: Napp
authors: Helen
authors: H
authors: Marshall
authors: Jonathan
authors: J
authors: Wadsley
authors: Nick
authors: N
authors: Maisey
authors: Ian
authors: I
authors: Chau
authors: Mark
authors: M
authors: Hill
authors: Simon
authors: S
authors: Gollins
authors: Sun
authors: S
authors: Myint
authors: Sarah
authors: S
authors: Slater
authors: John
authors: J
authors: Wagstaff
authors: John
authors: J
authors: Bridgewater
authors: Matthew
authors: M
authors: Seymour
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016572:Cyclosporine / Q000008:administration & dosage; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016017:Odds Ratio; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D002166:Camptothecin; D016572:Cyclosporine; D000077146:Irinotecan; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C545242:panitunumab
keywords: Colorectal; PICCOLO; Phase III