title: TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis.
abstract: OBJECTIVE
  Osteoclast-mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase II dose (RP2D) and clinical efficacy of the src kinase inhibitor dasatinib combined with zoledronic acid in bone predominant, HER2-negative breast cancer metastases.
  
  
  METHODS
  A 3+3 lead in phase I design confirmed the RP2D allowing activation of the single-arm, phase II trial. Zoledronic acid was administered intravenously on day 1, and dasatinib was given orally once daily for 28 days each cycle as twice daily administration caused dose-limiting toxicity (DLT). Response was assessed every three cycles. N-telopeptide (NTx) was serially measured.
  
  
  RESULTS
  A total of 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib = 100 mg/d. Common adverse events were grade 1-2: rash (9/25, 36%), fatigue (9/25, 36%), pain (9/25, 36%), nausea (6/25, 20%). The objective response rate in bone was 5/22 (23%), all partial responses (PR). The clinical benefit rate [PRs + stable disease (SD) ≥ 6 months] in bone was 8/22 (36%). Median time to treatment failure was 2.70 months [95% confidence interval (CI), 1.84-5.72] in the general cohort, 3.65 months (95% CI, 1.97-7.33) in patients with hormone receptor (HR)-positive breast cancer and 0.70 months (95% CI, 0.30-NA) in those with HR-negative disease. Factors associated with response in bone included lower tumor grade, HR-positive status, and pretreatment high NTx levels.
  
  
  CONCLUSIONS
  Combination therapy was well tolerated and produced responses in bone in patients with HR-positive tumors. Clin Cancer Res; 22(23); 5706-12. ©2016 AACR.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zahi
authors.initials: Z
authors.lastname: Mitri
authors.affiliation: The University of Chicago, Chicago, Illinois.
authors.forename: Rita
authors.initials: R
authors.lastname: Nanda
authors.affiliation: Duke Cancer Institute, Durham, North Carolina.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Blackwell
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Costelloe
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ilona
authors.initials: I
authors.lastname: Hood
authors.affiliation: Pfizer, Groton, Connecticut.
authors.forename: Caimiao
authors.initials: C
authors.lastname: Wei
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Abenaa M
authors.initials: AM
authors.lastname: Brewster
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nuhad K
authors.initials: NK
authors.lastname: Ibrahim
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Koenig
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Catherine
authors.initials: C
authors.lastname: Van Poznak
authors.affiliation: Baylor University College of Medicine, Houston, Texas.
authors.forename: Mothaffar F
authors.initials: MF
authors.lastname: Rimawi
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas. smoulder@mdanderson.org.
authors.forename: Stacy
authors.initials: S
authors.lastname: Moulder-Thompson
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D001940:Breast / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000069439:Dasatinib / Q000627:therapeutic use*; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000077211:Zoledronic Acid; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D000069439:Dasatinib; D004164:Diphosphonates; D007093:Imidazoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077211:Zoledronic Acid; D019061:src-Family Kinases