title: A phase I open-label study of the safety, tolerability, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab for relapsed or refractory metastatic colorectal cancer.
abstract: BACKGROUND
  Pazopanib is a multi-targeted tyrosine kinase inhibitor shown to be clinically active in the treatment of various cancer types. This study aimed to evaluate the maximum tolerated regimen (MTR), safety, and pharmacokinetics of pazopanib in combination with irinotecan and cetuximab in adult patients with relapsed or refractory metastatic colorectal cancer (mCRC).
  
  
  METHODS
  This was a Phase I, 3 + 3 design, open-label, dose-escalation study (NCT0050943; VEG108925) conducted in sequential cohorts to determine the MTR of pazopanib and irinotecan administered with cetuximab. Twenty-five patients received treatment in three dosing cohorts and were evaluated for safety and tolerability of the combination and pharmacokinetics of individual drugs.
  
  
  RESULTS
  The MTR was determined to be 400 mg pazopanib per day orally in combination with 150 mg/m(2) irinotecan biweekly and 250 mg/m(2) cetuximab weekly by infusion. Neutropenia was the main dose-limiting toxicity. Pharmacokinetic results suggested that the overall systemic exposure to SN-38, the active metabolite of irinotecan, was affected by pazopanib to a greater extent than was the systemic exposure to irinotecan itself.
  
  
  CONCLUSIONS
  This study provided evidence for the manageable safety profile and feasibility of using the novel triplet combination of pazopanib, irinotecan, and cetuximab in patients with refractory mCRC. Further large-scale Phase II studies are warranted.
authors.affiliation: Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.forename: Marion
authors.initials: M
authors.lastname: Deslandres
authors.forename: Helene
authors.initials: H
authors.lastname: Senellart
authors.forename: Cecile
authors.initials: C
authors.lastname: de Labareyre
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Ruiz-Soto
authors.forename: Claire
authors.initials: C
authors.lastname: Wixon
authors.forename: Jeff
authors.initials: J
authors.lastname: Botbyl
authors.forename: A Benjamin
authors.initials: AB
authors.lastname: Suttle
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007191:Indazoles; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012008:Recurrence; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; C516667:pazopanib; D000068818:Cetuximab; D002166:Camptothecin