title: An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer.
abstract: BACKGROUND
  Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A.
  
  
  METHODS
  A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5%, H1 ≥ 20%, α = 10% and β = 20%). Eligibility included failure of at least one platinum-based regimen.
  
  
  RESULTS
  From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4%) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4%) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1%), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6% (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1%, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9% mucositis, 36.4% fatigue, 18.2% neutropenia (13.6% febrile neutropenia). There were 2 treatment-related deaths.
  
  
  CONCLUSIONS
  The study did not meet the primary EP, yet sustained disease control was obtained in about 14% of patients. The incidence of AE and the issue of patient selection are two major concerns.
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy. andrea.necchi@istitutotumori.mi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Necchi
authors.affiliation: Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lo Vullo
authors.affiliation: Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Raggi
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giannatempo
authors.affiliation: Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Calareso
authors.affiliation: Pharmacy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Togliardi
authors.affiliation: Nuclear Medicine and PET Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Crippa
authors.affiliation: Clinical Trials Center, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Di Genova
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Colecchia
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: Paolini
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.|Università degli Studi di Milano, Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Nicolai
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Procopio
authors.affiliation: Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvioni
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy.|Università degli Studi di Milano, Milano, Italy.
authors.forename: Filippo G
authors.initials: FG
authors.lastname: De Braud
mesh_terms: D000368:Aged; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D019459:Urothelium / Q000187:drug effects / Q000473:pathology*
chemical_list: D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064096:Aurora Kinase A
keywords: Alisertib; Aurora A kinase; Bladder cancer; Salvage therapy; Urothelial carcinoma