title: Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity.
abstract: OBJECTIVE
  Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).
  
  
  METHODS
  A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.
  
  
  RESULTS
  The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had<pT2 disease. Analysis of pre- and posttreatment tumors demonstrated significantly decreased pSFK (P = 0.003) but no overall significant changes in Ki-67 or Cas3. In total, 4 cases demonstrated a nonsignificant decrease in Ki-67, of which 3 cases also demonstrated a decrease in pSFK and 2 cases had marginal increase in Cas3.
  
  
  CONCLUSIONS
  Neo-D in miUCB patients was feasible and safe. Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients. These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with miUCB is unlikely.
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
authors.forename: Noah M
authors.initials: NM
authors.lastname: Hahn
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Beatrice S
authors.initials: BS
authors.lastname: Knudsen
authors.affiliation: Oregon Health and Science University, Portland, OR; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA.
authors.forename: Siamak
authors.initials: S
authors.lastname: Daneshmand
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Koch
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
authors.forename: Richard
authors.initials: R
authors.lastname: Bihrle
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Foster
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gardner
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
authors.forename: Timothy
authors.initials: T
authors.lastname: Breen
authors.affiliation: Virginia Oncology Associates, Eastern Virginia Medical School, Norfolk, VA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Fleming
authors.affiliation: Urology of Virginia, Eastern Virginia Medical School, Norfolk, VA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lance
authors.affiliation: Oregon Health and Science University, Portland, OR.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
authors.forename: Ajjai S
authors.initials: AS
authors.lastname: Alva
authors.affiliation: The Methodist Hospital Research Institute, Houston, TX.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Shen
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Fangjin
authors.initials: F
authors.lastname: Huang
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Gertych
authors.affiliation: MD Anderson Cancer Center, Houston, TX.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Jayati
authors.initials: J
authors.lastname: Mallick
authors.affiliation: Oregon Health and Science University, Portland, OR.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ryan
authors.affiliation: Mount Sinai School of Medicine Tisch Cancer Institute, New York, NY.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.affiliation: Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX.
authors.forename: Seth P
authors.initials: SP
authors.lastname: Lerner
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Posadas
authors.affiliation: University of Alabama Birmingham Comprehensive Cancer Center, Birmingham, AL. Electronic address: gsonpavde@uabmc.edu.
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000069439:Dasatinib / Q000627:therapeutic use*; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000069439:Dasatinib
keywords: Bladder; Dasatinib; Neoadjuvant therapy; Protein kinase inhibitors; Src-family kinases; Translational medical research; Urothelial carcinoma