title: A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.
abstract: BACKGROUND
  This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC).
  
  
  METHODS
  Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured.
  
  
  RESULTS
  Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival.
  
  
  CONCLUSIONS
  The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.
authors.affiliation: Department of Medicine, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, Box 1700, San Francisco, CA 94143, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Kelley
authors.forename: J
authors.initials: J
authors.lastname: Hwang
authors.forename: M J M
authors.initials: MJ
authors.lastname: Magbanua
authors.forename: L
authors.initials: L
authors.lastname: Watt
authors.forename: J H
authors.initials: JH
authors.lastname: Beumer
authors.forename: S M
authors.initials: SM
authors.lastname: Christner
authors.forename: S
authors.initials: S
authors.lastname: Baruchel
authors.forename: B
authors.initials: B
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Fong
authors.forename: B M
authors.initials: BM
authors.lastname: Yeh
authors.forename: A P
authors.initials: AP
authors.lastname: Moore
authors.forename: A H
authors.initials: AH
authors.lastname: Ko
authors.forename: W M
authors.initials: WM
authors.lastname: Korn
authors.forename: S
authors.initials: S
authors.lastname: Rajpal
authors.forename: J W
authors.initials: JW
authors.lastname: Park
authors.forename: M A
authors.initials: MA
authors.lastname: Tempero
authors.forename: A P
authors.initials: AP
authors.lastname: Venook
authors.forename: E K
authors.initials: EK
authors.lastname: Bergsland
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068258:Bevacizumab; D000068877:Imatinib Mesylate; D003520:Cyclophosphamide
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