title: Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.
abstract: OBJECTIVE
  Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC).
  
  
  METHODS
  Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28).
  
  
  RESULTS
  Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007).
  
  
  CONCLUSIONS
  The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.
authors.affiliation: Duke University Medical Center, Seeley G. Mudd Bldg, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Strickler
authors.forename: Shannon
authors.initials: S
authors.lastname: McCall
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
authors.forename: John C
authors.initials: JC
authors.lastname: Brady
authors.forename: Herbert
authors.initials: H
authors.lastname: Pang
authors.forename: Christel
authors.initials: C
authors.lastname: Rushing
authors.forename: Allen
authors.initials: A
authors.lastname: Cohn
authors.forename: Alexander
authors.initials: A
authors.lastname: Starodub
authors.forename: Christy
authors.initials: C
authors.lastname: Arrowood
authors.forename: Sherri
authors.initials: S
authors.lastname: Haley
authors.forename: Kellen L
authors.initials: KL
authors.lastname: Meadows
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Hope E
authors.initials: HE
authors.lastname: Uronis
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
authors.forename: S David
authors.initials: SD
authors.lastname: Hsu
authors.forename: S Yousuf
authors.initials: SY
authors.lastname: Zafar
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000097:blood; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000069439:Dasatinib; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D019061:src-Family Kinases; D000069439:Dasatinib; D005472:Fluorouracil