title: Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma.
abstract: OBJECTIVE
  To assess, in a multicentre phase II trial, the safety and efficacy of BEZ235, an oral pan-class I phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) complex1/2 inhibitor, in locally advanced or metastatic transitional cell carcinoma (TCC) after failure of platinum-based therapy.
  
  
  METHODS
  Patients with locally advanced or metastatic TCC progressing after platinum therapy were prospectively stratified by PI3K/Akt/mTOR pathway alterations, defined as PTEN loss and PIK3CA mutation. All patients received BEZ235 until progressive disease or unacceptable toxicity. The primary endpoint was the progression-free survival (PFS) rate at 16 weeks. This study was, however, closed prematurely because BEZ235 was withdrawn from further development.
  
  
  RESULTS
  A total of 20 patients (18 without and two with PI3K/Akt/mTOR alterations) were enrolled and received BEZ235. One partial response (5%) and two cases of stable disease (10%) were observed, all in patients without PI3K/mTOR pathway alterations. The PFS rate at 8 and 16 weeks was 15 and 10%, respectively; the median (range) PFS was 62 (38-588) days (95% confidence interval [CI] 53-110); and the median (range) overall survival was 127 (41-734) days (95% CI 58-309). Among the 90% of patients who experienced drug-related adverse events of any grade, 50% experienced grade 3-4 adverse events, including stomatitis (15%), fatigue (5%), nausea (5%), diarrhoea (5%), renal failure (5%), cutaneous rash (5%), hepatotoxicity (5%) and hypertension (5%).
  
  
  CONCLUSIONS
  BEZ235 showed modest clinical activity and an unfavourable toxicity profile in patients with advanced and pretreated TCC; however, a minority of patients experienced a clinical benefit, suggesting that a complete blockade of the PI3K/mTOR axis could improve outcome in some specific patients. Furthermore, this study showed that molecular stratification of patients for personalized medicine before treatment is feasible.
authors.affiliation: Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.|Department of Medical Oncology, Centre Hospitalier de Jolimont, Haine Saint-Paul, Belgium.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Seront
authors.affiliation: Department of Medical Oncology, Ghent University Hospital and Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rottey
authors.affiliation: Department of Medical Oncology, Centre Hospitalier de Jolimont, Haine Saint-Paul, Belgium.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Filleul
authors.affiliation: Department of Medical Oncology, Cliniques du Sud-Luxembourg-Vivalia, Arlon, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Glorieux
authors.affiliation: Department of Medical Oncology, Centre de Maternité Sainte Elisabeth, Namur, Belgium.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Goeminne
authors.affiliation: Department of Medical Oncology, Grand Hopital de Charleroi, Charleroi, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Verschaeve
authors.affiliation: Department of Medical Oncology, Réseau Hospitalier de Médecine Sociale, Tournai, Belgium.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Vandenbulcke
authors.affiliation: Department of Medical Oncology, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium.
authors.forename: Brieuc
authors.initials: B
authors.lastname: Sautois
authors.affiliation: Department of Medical Oncology, Centre Hospitalier Epicura, Baudour, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Boegner
authors.affiliation: Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Aline
authors.initials: A
authors.lastname: Gillain
authors.affiliation: Statistical Support Unit, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Aline
authors.initials: A
authors.lastname: van Maanen
authors.affiliation: Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011446:Prospective Studies; D011804:Quinolines / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: BEZ235; PI3K inhibitor; mTOR inhibitor; transitional cell carcinoma