title: Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors.
abstract: BACKGROUND
  Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT.
  
  
  METHODS
  In a two-stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non-ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST.
  
  
  RESULTS
  Of 54 patients: 40 ACC, 14 non-ACC (1, ineligible excluded); M:F = 28 : 26, median age 56 years (range 20-82 years), ECOG performance status 0 : 1 : 2 = 24 : 28 : 2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3-14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non-ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1-7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2.
  
  
  CONCLUSIONS
  Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT.
authors.affiliation: Division of Hematology Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee swong@mcw.edu.
authors.forename: S J
authors.initials: SJ
authors.lastname: Wong
authors.affiliation: The University of Chicago, Chicago.
authors.forename: T
authors.initials: T
authors.lastname: Karrison
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill.
authors.forename: D N
authors.initials: DN
authors.lastname: Hayes
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: M S
authors.initials: MS
authors.lastname: Kies
authors.affiliation: University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore.
authors.forename: K J
authors.initials: KJ
authors.lastname: Cullen
authors.affiliation: H. Lee Moffitt Cancer Center & Research Institute, Tampa, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tanvetyanon
authors.affiliation: Department of Medical Oncology, Hygeia Hospital, Athens, Greece University of Texas Health Science Center at San Antonio, San Antonio.
authors.forename: A
authors.initials: A
authors.lastname: Argiris
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, Rockville.
authors.forename: N
authors.initials: N
authors.lastname: Takebe
authors.affiliation: Department of Medicine, City of Hope, Duarte.
authors.forename: D
authors.initials: D
authors.lastname: Lim
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta.
authors.forename: N F
authors.initials: NF
authors.lastname: Saba
authors.affiliation: Department of Medicine, University of Michigan Cancer Center, Ann Arbor.
authors.forename: F P
authors.initials: FP
authors.lastname: Worden
authors.affiliation: Department of Hematology Oncology, Vanderbilt University, Nashville.
authors.forename: J
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: USC Norris Comprehensive Cancer Center, Los Angeles.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto.
authors.forename: A R A
authors.initials: AR
authors.lastname: Razak
authors.affiliation: Massey Cancer Center, Richmond.
authors.forename: J D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: The University of Chicago, Chicago.
authors.forename: E E
authors.initials: EE
authors.lastname: Vokes
authors.affiliation: University of California San Diego, Moores Cancer Center, San Diego, USA.
authors.forename: E E W
authors.initials: EE
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy* / Q000473:pathology; D000069439:Dasatinib / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib
keywords: adenoid cystic carcinoma; cKIT; dasatinib; malignant salivary gland cancer; phase II