title: A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours.
abstract: BACKGROUND
  This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436).
  
  
  METHODS
  In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1.
  
  
  RESULTS
  As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%).
  
  
  CONCLUSIONS
  BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.
authors: European Institute of Oncology, Milan, Italy nicola.fazio@ieo.it.
authors: Nicola
authors: N
authors: Fazio
authors: IRCCS National Tumor Institute, Milan, Italy.
authors: Roberto
authors: R
authors: Buzzoni
authors: Institut Gustave Roussy, Villejuif, France.
authors: Eric
authors: E
authors: Baudin
authors: Careggi University Hospital, Florence, Italy.
authors: Lorenzo
authors: L
authors: Antonuzzo
authors: The Christie NHS Foundation Trust, Manchester, U.K.
authors: Richard A
authors: RA
authors: Hubner
authors: University of Duisburg-Essen, Essen, Germany.
authors: Harald
authors: H
authors: Lahner
authors: Erasmus MC, Rotterdam, the Netherlands.
authors: Wouter W
authors: WW
authors: DE Herder
authors: University Hospital of Vienna, Vienna, Austria.
authors: Markus
authors: M
authors: Raderer
authors: Alexandre
authors: A
authors: Teulé
authors: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors: Jaume
authors: J
authors: Capdevila
authors: Montefiore Medical Center and Albert Einstein College of Medicine, New York, NY, U.S.A.
authors: Steven K
authors: SK
authors: Libutti
authors: Dana-Farber Cancer Institute, Boston, MA, U.S.A.
authors: Matthew H
authors: MH
authors: Kulke
authors: The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, U.S.A.
authors: Manisha
authors: M
authors: Shah
authors: Novartis Healthcare Private Limited, Hyderabad, India.
authors: Debarshi
authors: D
authors: Dey
authors: Novartis Pharma AG, Basel, Switzerland.
authors: Sabine
authors: S
authors: Turri
authors: Novartis Pharma AG, Basel, Switzerland.
authors: Paola
authors: P
authors: Aimone
authors: Novartis Oncology, Paris, France.
authors: Cristian
authors: C
authors: Massacesi
authors: University Hospitals Leuven, Leuven, Belgium.
authors: Chris
authors: C
authors: Verslype
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D000068338:Everolimus; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: BEZ235; PI3K; everolimus; mTOR; pNETs