title: A phase 1 study of gemcitabine combined with dasatinib in patients with advanced solid tumors.
abstract: OBJECTIVE
  Dasatinib has been shown preclinically to overcome resistance to gemcitabine. We evaluated the safety and biological activity of the combination of dasatinib and gemcitabine in patients with advanced solid tumors.
  
  
  METHODS
  In a phase 1 study (3 + 3 design), patients received daily dasatinib with weekly gemcitabine on days 1, 8 and 15 of a 28-day cycle (except cycle 1 which was 8 weeks). Dose escalation began with dasatinib 70 mg orally (PO) daily and gemcitabine 800 mg/m(2) intravenously (IV) weekly.
  
  
  RESULTS
  Forty-seven patients (15 men; median age = 55 years; median number of prior systemic treatments = 4) were enrolled. Dose-limiting toxicities were grade 3 fatigue and dehydration, with the maximum tolerated dose being dasatinib 100 mg PO qd and gemcitabine 600 mg/m(2) IV weekly. The most common grade 3-4 toxicities were anemia (21.5 %), thrombocytopenia (26.2 %), leukopenia (26.2 %), and pleural effusion (10.7 %). Six of 47 patients attained stable disease (SD) ≥ 6 months or partial response including 2 of 8 patients with pancreatic cancer (SD ≥ 6 months; both gemcitabine-refractory), 2 of 3 patients with thymoma (SD for 9.8 and 15 months), 1 of 1 patient with anal squamous cancer (SD 15 months) and 1 of 5 patients with inflammatory breast cancer. No significant changes in circulating tumor cells or interleukin-8 levels were observed.
  
  
  CONCLUSIONS
  The combination was well tolerated at doses of dasatinib 100 mg PO daily and gemcitabine 600 mg/m(2) IV weekly. SD ≥ 6 months/ PR was observed in gemcitabine-refractory pancreatic cancer, thymoma, anal cancer and inflammatory breast cancer.
authors.affiliation: Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. dshong@mdanderson.org
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Jennifer Hsing
authors.initials: JH
authors.lastname: Choe
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: Goldy C
authors.initials: GC
authors.lastname: George
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Choe
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Strauss
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count; D000069439:Dasatinib; D003710:Demography; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D016209:Interleukin-8; D011743:Pyrimidines; D013844:Thiazoles; D003841:Deoxycytidine; D000069439:Dasatinib; D000093542:Gemcitabine