title: Phase I trial of oxaliplatin, infusional 5-fluorouracil, and leucovorin (FOLFOX4) with erlotinib and bevacizumab in colorectal cancer.
abstract: BACKGROUND
  This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.
  
  
  METHODS
  Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously. Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval. Correlative studies included pharmacokinetics, pharmacodynamics was assessed in paired skin biopsies, and fluorodeoxyglucose positron emission tomography scans.
  
  
  RESULTS
  Fifteen patients received 60 cycles (120 FOLFOX treatments). Two dose-limiting toxicities (DLTs) were seen at DL 3: intolerable grade 2 rash (Common Terminology Criteria for Adverse Events version 2) lasting > 1 week, and grade 4 neutropenia. Dose level 2 was expanded to 6 more patients, this time adding bevacizumab, and 1 DLT of grade 3 mucositis occurred. As expected, the primary toxicities were cytopenias, diarrhea, rash, and fatigue. There were 2 occurrences of pneumatosis. One patient experienced an unrelated grade 4 myocardial infarction before starting chemotherapy. No pharmacokinetic drug interactions were observed. The Response Evaluation Criteria in Solid Tumors response rate was 11 of 14 (78%), median progression-free survival was 9.5 months, and median overall survival was 30 months. Three patients are currently alive > 3 years, with 1 having no evidence of disease.
  
  
  CONCLUSIONS
  The MTD of erlotinib with FOLFOX4 with or without bevacizumab is 100 mg daily. The regimen appeared to increase toxicity but showed activity in patients with CRC.
authors.affiliation: University of Colorado Cancer Center, Aurora, CO 80045, USA. wells.messersmith@ucdenver.edu
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Heather
authors.initials: H
authors.lastname: Jacene
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Piotr
authors.initials: P
authors.lastname: Kulesza
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Laheru
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Kahn
authors.forename: Alexander
authors.initials: A
authors.lastname: Spira
authors.forename: Janet
authors.initials: J
authors.lastname: Dancey
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000069347:Erlotinib Hydrochloride; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D011799:Quinazolines; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; D002955:Leucovorin; D005472:Fluorouracil