title: Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study.
abstract: BACKGROUND
  To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (PC), the authors conducted a phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.
  
  
  METHODS
  In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m(2)  every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m(2)  every 21 days. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied.
  
  
  RESULTS
  Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3-4 toxicity. Drug-drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26 of 46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone marker assessments, 33 of 38 (87%) and 26 of 34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months.
  
  
  CONCLUSIONS
  The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC. Parallel declines in levels of PSA and bone markers are consistent with cotargeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study. Cancer 2012;. © 2011 American Cancer Society.
authors: The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. johna@mdanderson.org
authors: John C
authors: JC
authors: Araujo
authors: Paul
authors: P
authors: Mathew
authors: Andrew J
authors: AJ
authors: Armstrong
authors: Edward L
authors: EL
authors: Braud
authors: Edwin
authors: E
authors: Posadas
authors: Mathew
authors: M
authors: Lonberg
authors: Gary E
authors: GE
authors: Gallick
authors: Géralyn C
authors: GC
authors: Trudel
authors: Prashni
authors: P
authors: Paliwal
authors: Shruti
authors: S
authors: Agrawal
authors: Christopher J
authors: CJ
authors: Logothetis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D002369:Castration; D000069439:Dasatinib; D000077143:Docetaxel; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D011743:Pyrimidines; D043823:Taxoids; D013844:Thiazoles; D000077143:Docetaxel; D017430:Prostate-Specific Antigen; D000069439:Dasatinib