title: Phase 2 trial of the topoisomerase II inhibitor, amrubicin, as second-line therapy in patients with metastatic urothelial carcinoma.
abstract: OBJECTIVE
  The purpose of this investigator-initiated multicenter phase II study was to determine the activity of the third-generation synthetic anthracycline, amrubicin, administered as second-line therapy in patients with advanced urothelial carcinoma.
  
  
  METHODS
  Patients with progressive metastatic urothelial cancer despite first-line chemotherapy were eligible for enrollment. Amrubicin was initially administered at a dose of 40 mg/m(2)/day daily × 3 every 21 days, and the dose was subsequently reduced to 35 mg/m(2)/day daily × 3 every 21 days. Prophylactic granulocyte colony-stimulating factor was administered to all patients, and prophylactic antibiotics were administered to patients at high risk of febrile neutropenia. Treatment was administered for up to six cycles in the absence of intolerable toxicity or disease progression. The primary endpoint was the objective response rate.
  
  
  RESULTS
  A total of 22 patients were enrolled. Among the first three patients enrolled, all developed grade 4 neutropenia and one patient died of neutropenic sepsis. The starting dose of amrubicin was subsequently reduced, there were no further episodes of febrile neutropenia, and only one patient required a subsequent dose reduction. The most common adverse events were hematologic; grade ≥3 neutropenia occurred in 27 %, and other grade ≥3 adverse events were uncommon. Partial responses were achieved in three patients [13.6, 95 % confidence interval (CI) 0-28 %), while stable disease was the best response in 12 patients (54.5, 95 % CI 33.7-75.3 %). The trial was closed prematurely due to a development decision by the funder.
  
  
  CONCLUSIONS
  Amrubicin as second-line therapy in advanced urothelial carcinoma is associated with modest single-agent activity. While there remains a role for the introduction of novel cytotoxic agents in the management of metastatic urothelial cancer, optimal development of such therapies will likely require patient selection biomarkers.
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. matthew.galsky@mssm.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Noah M
authors.initials: NM
authors.lastname: Hahn
authors.affiliation: Banner MD Anderson Cancer Center, Gilbert, AZ, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Wong
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Argiriadi
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Costantine
authors.initials: C
authors.lastname: Albany
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Kiev
authors.initials: K
authors.lastname: Gimpel-Tetra
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Lowe
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Shahin
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Patel
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Che-Kai
authors.initials: CK
authors.lastname: Tsao
authors.affiliation: Genitourinary Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
mesh_terms: D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D018943:Anthracyclines / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D059005:Topoisomerase II Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; C055866:amrubicin
keywords: Amrubicin; Anthracyclines; Bladder cancer; Chemotherapy; Metastatic; Urothelial cancer