title: Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer.
abstract: BACKGROUND
  The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib.
  
  
  METHODS
  Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI.
  
  
  RESULTS
  Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated.
  
  
  CONCLUSIONS
  Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified.
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, P Vall d'Hebron 119-129, Barcelona 08035, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Macarulla
authors.affiliation: Department of Haematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Avda Blasco Ibáñez 17, Valencia 46010, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, P Vall d'Hebron 119-129, Barcelona 08035, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Haematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Avda Blasco Ibáñez 17, Valencia 46010, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Roselló
authors.affiliation: Department of Gastroenterology, University Hospitals Gasthuisberg and KU Leuven, Herestraat 49, Leuven 3000, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Department of Gastroenterology, University Hospitals Gasthuisberg and KU Leuven, Herestraat 49, Leuven 3000, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Department of Gastroenterology, University Hospitals Gasthuisberg and KU Leuven, Herestraat 49, Leuven 3000, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Prenen
authors.affiliation: Department of Experimental and Clinical Medicine, Second University of Naples, Via S Pansini 5, Naples 80131, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Martinelli
authors.affiliation: Department of Experimental and Clinical Medicine, Second University of Naples, Via S Pansini 5, Naples 80131, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Troiani
authors.affiliation: Merck Serono SA, 9 Chemin des Mines, Geneva 1202, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Laffranchi
authors.affiliation: Merck Serono SA, 9 Chemin des Mines, Geneva 1202, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Jego
authors.affiliation: Merck KGaA, Frankfurter Strasse 250, F131/102, Darmstadt 64293, Germany.
authors.forename: O
authors.initials: O
authors.lastname: von Richter
authors.affiliation: Department of Experimental and Clinical Medicine, Second University of Naples, Via S Pansini 5, Naples 80131, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D011905:Genes, ras; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D011518:Proto-Oncogene Proteins; D009536:Niacinamide; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin