title: Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study.
abstract: BACKGROUND
  Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma.
  
  
  METHODS
  In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989.
  
  
  RESULTS
  Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0·94 [95% CI 0·61-1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related.
  
  
  CONCLUSIONS
  Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma.
  
  
  BACKGROUND
  Astellas.
authors: Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany; Central Laboratory, Research Unit, University Hospital Würzburg, Würzburg, Germany.
authors: Martin
authors: M
authors: Fassnacht
authors: Department of Medic Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.
authors: Alfredo
authors: A
authors: Berruti
authors: Department of Nuclear Medicine and Endocrine Tumors, Institut Gustave Roussy, Villejuif, France.
authors: Eric
authors: E
authors: Baudin
authors: Translational Genomics Research Institute, Phoenix, AZ, USA.
authors: Michael J
authors: MJ
authors: Demeure
authors: Vanderbilt School of Medicine, Nashville, TN, USA.
authors: Jill
authors: J
authors: Gilbert
authors: Department of Internal Medicine, Máxima Medical Centre, Eindhoven, Netherlands; Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; Maastricht University, Department of Health Services Research, and CAPHRI School for Public Health and Primary Care, Maastricht, Netherlands.
authors: Harm
authors: H
authors: Haak
authors: Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors: Matthias
authors: M
authors: Kroiss
authors: Univeristy of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: David I
authors: DI
authors: Quinn
authors: Endocrine Oncology Program-Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI, USA.
authors: Elizabeth
authors: E
authors: Hesseltine
authors: Central Laboratory, Research Unit, University Hospital Würzburg, Würzburg, Germany.
authors: Cristina L
authors: CL
authors: Ronchi
authors: Univerita degli Studi di Torino, Orbassano, Turin, Italy.
authors: Massimo
authors: M
authors: Terzolo
authors: Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Toni K
authors: TK
authors: Choueiri
authors: Astellas Pharma Global Development, Northbrook, IL, USA.
authors: Srinivasu
authors: S
authors: Poondru
authors: Astellas Pharma Global Development, Northbrook, IL, USA.
authors: Tanya
authors: T
authors: Fleege
authors: Astellas Pharma Global Development, Northbrook, IL, USA.
authors: Ramona
authors: R
authors: Rorig
authors: Astellas Pharma Global Development, Northbrook, IL, USA.
authors: Jihong
authors: J
authors: Chen
authors: Piramal Imaging, Berlin, Germany.
authors: Andrew W
authors: AW
authors: Stephens
authors: Endocrine Oncology Program-Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI, USA.
authors: Francis
authors: F
authors: Worden
authors: Endocrine Oncology Program-Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI, USA. Electronic address: ghammer@umich.edu.
authors: Gary D
authors: GD
authors: Hammer
mesh_terms: D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D010919:Placebos; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D007093:Imidazoles; D010919:Placebos; D047428:Protein Kinase Inhibitors; D011719:Pyrazines