title: Dasatinib plus capecitabine for advanced breast cancer: safety and efficacy in phase I study CA180004.
abstract: OBJECTIVE
  Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis.
  
  
  METHODS
  Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m(2) twice daily (DL1 and DL2) or 1,000 mg/m(2) twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis.
  
  
  RESULTS
  Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor-positive. Most common adverse events (AE) were any grade nausea (58%), hand-foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand-foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m(2) twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed.
  
  
  CONCLUSIONS
  Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m(2) twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect.
authors: City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. GSomlo@coh.org
authors: George
authors: G
authors: Somlo
authors: Francesco
authors: F
authors: Atzori
authors: Lewis C
authors: LC
authors: Strauss
authors: William J
authors: WJ
authors: Geese
authors: Jennifer M
authors: JM
authors: Specht
authors: William J
authors: WJ
authors: Gradishar
authors: Alissa
authors: A
authors: Rybicki
authors: Oumar
authors: O
authors: Sy
authors: Linda T
authors: LT
authors: Vahdat
authors: Javier
authors: J
authors: Cortes
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D000069287:Capecitabine; D000069439:Dasatinib; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011743:Pyrimidines / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D011743:Pyrimidines; D013844:Thiazoles; D003841:Deoxycytidine; D000069287:Capecitabine; D000069439:Dasatinib; D005472:Fluorouracil