title: Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer.
  
  
  OBJECTIVE
  To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma.
  
  
  METHODS
  A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma.
  
  
  METHODS
  Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone.
  
  
  METHODS
  The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography.
  
  
  RESULTS
  Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS.
  
  
  CONCLUSIONS
  In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01279967.
authors: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England2Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Peter W
authors: PW
authors: Szlosarek
authors: Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Jeremy P
authors: JP
authors: Steele
authors: Southampton University Hospital NHS Foundation Trust, Southampton, England.
authors: Luke
authors: L
authors: Nolan
authors: Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, England.
authors: David
authors: D
authors: Gilligan
authors: University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, England.
authors: Paul
authors: P
authors: Taylor
authors: Division of Cancer Studies, King's College London, Guy's Hospital, London, England.
authors: James
authors: J
authors: Spicer
authors: University of Hull, Castle Hill Hospital, Cottingham, England.
authors: Michael
authors: M
authors: Lind
authors: Brighton and Sussex University Hospitals, Brighton, England.
authors: Sankhasuvra
authors: S
authors: Mitra
authors: Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Jonathan
authors: J
authors: Shamash
authors: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England2Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Melissa M
authors: MM
authors: Phillips
authors: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England.
authors: Phuong
authors: P
authors: Luong
authors: Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Sarah
authors: S
authors: Payne
authors: Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Paul
authors: P
authors: Hillman
authors: Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Stephen
authors: S
authors: Ellis
authors: King's College London, St Thomas' Hospital, London, England.
authors: Teresa
authors: T
authors: Szyszko
authors: Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea, England.
authors: Gairin
authors: G
authors: Dancey
authors: University College London Cancer Institute, University College London, London, England.
authors: Lee
authors: L
authors: Butcher
authors: University College London Cancer Institute, University College London, London, England.
authors: Stephan
authors: S
authors: Beck
authors: Cleveland Clinic, Cleveland, Ohio.
authors: Norbert E
authors: NE
authors: Avril
authors: Polaris Pharmaceuticals Inc, San Diego, California.
authors: Jim
authors: J
authors: Thomson
authors: Polaris Pharmaceuticals Inc, San Diego, California.
authors: Amanda
authors: A
authors: Johnston
authors: Center for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England.
authors: Marianne
authors: M
authors: Tomsa
authors: Center for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England.
authors: Cheryl
authors: C
authors: Lawrence
authors: Barts Health NHS Trust, St Bartholomew's Hospital, London, England14Center for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England.
authors: Peter
authors: P
authors: Schmid
authors: Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea, England.
authors: Timothy
authors: T
authors: Crook
authors: Polaris Pharmaceuticals Inc, San Diego, California.
authors: Bor-Wen
authors: BW
authors: Wu
authors: Polaris Pharmaceuticals Inc, San Diego, California.
authors: John S
authors: JS
authors: Bomalaski
authors: Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England.
authors: Nicholas
authors: N
authors: Lemoine
authors: Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Michael T
authors: MT
authors: Sheaff
authors: Barts Health NHS Trust, St Bartholomew's Hospital, London, England.
authors: Robin M
authors: RM
authors: Rudd
authors: University of Leicester, Leicester Royal Infirmary, Leicester, England.
authors: Dean
authors: D
authors: Fennell
authors: Cancer Research UK and UCL Cancer Trials Center, University College London, London, England.
authors: Allan
authors: A
authors: Hackshaw
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D020159:Citrullinemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D018572:Disease-Free Survival; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase