title: Phase I study of cetuximab, erlotinib, and bevacizumab in patients with advanced solid tumors.
abstract: BACKGROUND
  Complex interrelationships exist between the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor pathways. EGFR activation elicits cell proliferation and increased VEGF expression. To maximally inhibit EGFR and then downstream VEGF activity, this phase I study was initiated to determine the maximum tolerated dose (MTD) of erlotinib with fixed-dose cetuximab, and then combine with bevacizumab in patients with advanced malignancies.
  
  
  METHODS
  Patients with advanced malignancies likely to express EGFR were treated with a full dose of cetuximab intravenous weekly, combined with various doses of oral erlotinib daily (Part 1). Once the MTD was determined in Part 1, escalating doses of bevacizumab were administered intravenously biweekly (Part 2).
  
  
  RESULTS
  Forty patients were enrolled and received 155 courses over four dose levels. In Part 1, dose-limiting grade 3 rash occurred in two patients administered with erlotinib at 100 mg daily, and the MTD of erlotinib for this combination was 50 mg daily with standard-dose cetuximab (11 patients treated). Other adverse events included rash, diarrhea, fatigue, and hypomagnesemia. In Part 2, bevacizumab at 10 mg/kg intravenous every 2 weeks was safely added, with additional nondose-limiting headache, proteinuria, and hypertension. There was one partial response in a patient with renal cell carcinoma. Durable stable disease was observed in five patients for 6-11 months.
  
  
  CONCLUSIONS
  The MTD for Part 1 was 50 mg daily of erlotinib combined with standard cetuximab. Bevacizumab at 10 mg/kg biweekly can be safely administered with the MTD for erlotinib and cetuximab combination.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Glenn G
authors.initials: GG
authors.lastname: Preston
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mita
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Theresa
authors.initials: T
authors.lastname: Mays
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Pat
authors.initials: P
authors.lastname: O'Rourke
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Janet E
authors.initials: JE
authors.lastname: Dancey
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D000068818:Cetuximab; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab