title: Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers.
abstract: Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2and cisplatin 75 mg/m2which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2plus three-weekly cisplatin 75 mg/m2and pemetrexed 500 mg/m2.
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Emma
authors.initials: E
authors.lastname: Beddowes
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: James
authors.initials: J
authors.lastname: Spicer
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Pui Ying
authors.initials: PY
authors.lastname: Chan
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Ramsay
authors.initials: R
authors.lastname: Khadeir
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Javier Garcia
authors.initials: JG
authors.lastname: Corbacho
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Repana
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Steele
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Szyszko
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Gary
authors.initials: G
authors.lastname: Cook
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Monica
authors.initials: M
authors.lastname: Diaz
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Feng
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Johnston
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Jim
authors.initials: J
authors.lastname: Thomson
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sheaff
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Bor-Wen
authors.initials: BW
authors.lastname: Wu
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: John
authors.initials: J
authors.lastname: Bomalaski
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Simon
authors.initials: S
authors.lastname: Pacey
authors.affiliation: Emma Beddowes, Javier Garcia Corbacho, and Simon Pacey, University of Cambridge, Cambridge; James Spicer, Dimitra Repana, Teresa Szyszko, and Gary Cook, King's College London; Pui Ying Chan, Jeremy P. Steele, Peter Schmid, Michael Sheaff, and Peter W. Szlosarek, St Bartholomew's Hospital; Ramsay Khadeir, Peter Schmid, and Peter W. Szlosarek, Queen Mary University of London, London, United Kindgom; and Monica Diaz, Xiaoxing Feng, Amanda Johnston, Jim Thomson, Bor-Wen Wu, and John Bomalaski, Polaris Pharmaceuticals, San Diego, CA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Szlosarek
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001124:Argininosuccinate Synthase / Q000172:deficiency*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage / Q000009:adverse effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000201:enzymology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage / Q000009:adverse effects; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000068437:Pemetrexed; D011092:Polyethylene Glycols; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase; D002945:Cisplatin