title: Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study.
abstract: BACKGROUND
  Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective).
  
  
  METHODS
  Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h, folinic acid 400 mg/m(2), and either oxaliplatin 85 mg/m(2) or irinotecan 180 mg/m(2). On days 4-10, patients received regorafenib 160 mg orally once daily.
  
  
  RESULTS
  The median duration of treatment was 108 (range 2-345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥ 3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand-foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42-281 days).
  
  
  CONCLUSIONS
  Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.
authors.affiliation: Department of Hematology and Medical Oncology, University of Bochum, Herne, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schultheis
authors.forename: G
authors.initials: G
authors.lastname: Folprecht
authors.forename: J
authors.initials: J
authors.lastname: Kuhlmann
authors.forename: R
authors.initials: R
authors.lastname: Ehrenberg
authors.forename: U T
authors.initials: UT
authors.lastname: Hacker
authors.forename: C H
authors.initials: CH
authors.lastname: Köhne
authors.forename: M
authors.initials: M
authors.lastname: Kornacker
authors.forename: O
authors.initials: O
authors.lastname: Boix
authors.forename: J
authors.initials: J
authors.lastname: Lettieri
authors.forename: J
authors.initials: J
authors.lastname: Krauss
authors.forename: R
authors.initials: R
authors.lastname: Fischer
authors.forename: S
authors.initials: S
authors.lastname: Hamann
authors.forename: D
authors.initials: D
authors.lastname: Strumberg
authors.forename: K B
authors.initials: KB
authors.lastname: Mross
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: chemotherapy; colorectal cancer; combination therapy; regorafenib; tyrosine kinase inhibition