title: A phase I trial of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer.
abstract: OBJECTIVE
  Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities.
  
  
  METHODS
  Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6-bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily.
  
  
  RESULTS
  Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib.
  
  
  CONCLUSIONS
  MTD was imatinib 400 mg plus full dose mFOLFOX-bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.
authors.affiliation: Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Victoria 8006, Australia. michael.michael@petermac.org
authors.forename: M
authors.initials: M
authors.lastname: Michael
authors.forename: J
authors.initials: J
authors.lastname: Zalcberg
authors.forename: P
authors.initials: P
authors.lastname: Gibbs
authors.forename: L
authors.initials: L
authors.lastname: Lipton
authors.forename: M
authors.initials: M
authors.lastname: Gouillou
authors.forename: M
authors.initials: M
authors.lastname: Jefford
authors.forename: G
authors.initials: G
authors.lastname: McArthur
authors.forename: M
authors.initials: M
authors.lastname: Copeman
authors.forename: K
authors.initials: K
authors.lastname: Lynch
authors.forename: N C
authors.initials: NC
authors.lastname: Tebbutt
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D000068877:Imatinib Mesylate; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D009944:Organoplatinum Compounds; D010879:Piperazines; D011743:Pyrimidines; D000068258:Bevacizumab; D000068877:Imatinib Mesylate; D002955:Leucovorin; D005472:Fluorouracil