title: Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies.
abstract: BACKGROUND
  A previous phase II trial in patients with chemorefractory metastatic colorectal cancer demonstrated a 63 % disease control rate with a combination of bevacizumab and sorafenib. This phase I trial sought to determine the maximum tolerable dose (MTD) of bevacizumab and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers.
  
  
  METHODS
  A standard 3 + 3 trial design utilized 3 escalating sorafenib dose levels: (1) 200 mg daily, days 3-7, 10-14; (2) 200 mg twice daily, days 3-6, 10-13; and (3) 200 mg twice daily, days 3-7, 10-14 combined with standard dose FOLFIRI (5-fluouracil, leucovorin, and irinotecan) and bevacizumab (5 mg/kg), repeated every 14 days.
  
  
  RESULTS
  Fifteen patients were evaluable for safety and response assessment. There were no dose limiting toxicities (DLTs) at dose level 1 or 2. At dose level 3, two patients experienced DLTs (asymptomatic grade 3 hypophosphatemia, grade 3 dehydration and diarrhea). The MTD was determined to be dose level 2: sorafenib 200 mg twice daily, days 3-6, 10-13 combined with FOLFIRI and bevacizumab at standard doses. Four patients had a partial response and 8 had stable disease as best response (disease control rate of 80 %). Three patients with CRC had disease control >12 months.
  
  
  CONCLUSIONS
  The MTD of this regimen is sorafenib 200 mg twice daily, days 3-6, 10-13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies.
authors.affiliation: Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA. hubbard.joleen@mayo.edu.
authors.forename: Joleen M
authors.initials: JM
authors.lastname: Hubbard
authors.affiliation: University of Florida Health Oncology, Jacksonville, FL, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kim
authors.affiliation: Mayo Clinic Scottsdale, Scottsdale, AZ, USA.
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.affiliation: Mayo Clinic Jacksonville, Jacksonville, FL, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Johnson
authors.affiliation: Regeneron Pharmaceuticals, Basking Ridge, NJ, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.affiliation: Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Lensing
authors.affiliation: Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA.
authors.forename: Suneetha
authors.initials: S
authors.lastname: Puttabasavaiah
authors.affiliation: Investigational Drug Branch of the Cancer Therapy Evaluation Program, Bethesda, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.affiliation: Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.affiliation: Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: Antiangiogenesis; Colorectal cancer; Systemic therapy