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We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase <jats:bold>(<\/jats:bold>ADI\u2010PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose\u2010expansion study of patients with argininosuccinate synthetase (ASS1)\u2010deficient metastatic UM. Eligible patients received up to six cycles of Pem (500\u2009mg\/m<jats:sup>2<\/jats:sup>) and Cis (75\u2009mg\/m<jats:sup>2<\/jats:sup>) every 3\u2009weeks plus weekly intramuscular ADI (36\u2009mg\/m<jats:sup>2<\/jats:sup>), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1\u2010deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one \u2265 grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression\u2010free survival of 3.0\u00a0months (range, 1.3\u20138.1) and a median overall survival of 11.5\u00a0months (range, 3.2\u201336.9). Despite anti\u2010ADI\u2010PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18\u2009weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re\u2010expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional anti\u2010metabolite strategies.<\/jats:p>","DOI":"10.1111\/pcmr.13042","type":"journal-article","created":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T08:44:23Z","timestamp":1650876263000},"page":"461-470","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["A Phase 1 study of <scp>ADI\u2010PEG20<\/scp> (pegargiminase) combined with cisplatin and pemetrexed in <scp>ASS1\u2010negative<\/scp> metastatic uveal melanoma"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7804-4482","authenticated-orcid":false,"given":"Pui Ying","family":"Chan","sequence":"first","affiliation":[{"name":"Department of Medical Oncology St Bartholomew's Hospital, Barts Health NHS Trust  London UK"},{"name":"Wellcome Sanger Institute, Hinxton  Cambridgeshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa M.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology St Bartholomew's Hospital, Barts Health NHS Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Ellis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology St Bartholomew's Hospital, Barts Health NHS Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Johnston","sequence":"additional","affiliation":[{"name":"Polaris Pharmaceuticals Inc  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxing","family":"Feng","sequence":"additional","affiliation":[{"name":"Polaris Pharmaceuticals Inc  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Arora","sequence":"additional","affiliation":[{"name":"Department of Ocular Oncology, Moorfields Eye Hospital Moorfields Eye Hospital NHS Foundation Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon","family":"Hay","sequence":"additional","affiliation":[{"name":"Department of Ocular Oncology, Moorfields Eye Hospital Moorfields Eye Hospital NHS Foundation Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria M. L.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Ocular Oncology, Moorfields Eye Hospital Moorfields Eye Hospital NHS Foundation Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandeep S.","family":"Sagoo","sequence":"additional","affiliation":[{"name":"Department of Ocular Oncology, Moorfields Eye Hospital Moorfields Eye Hospital NHS Foundation Trust  London UK"},{"name":"NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London Institute of Ophthalmology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Bomalaski","sequence":"additional","affiliation":[{"name":"Polaris Pharmaceuticals Inc  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Sheaff","sequence":"additional","affiliation":[{"name":"Department of Histopathology, Royal London Hospital Barts Health NHS Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W.","family":"Szlosarek","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology St Bartholomew's Hospital, Barts Health NHS Trust  London UK"},{"name":"Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30258"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1702"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cnr2.1183"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.0933"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-007-0655-9"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-20-0317"},{"key":"e_1_2_9_8_1","volume-title":"International Mesothelioma Interest Group Meeting","author":"Barnett S.","year":"2021"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.71.3230"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0048787"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19564"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/pcmr.12607"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2021.1943253"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-018-0612-6"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.123.12.1639"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.20057"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.106"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019004500"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.7765"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3729"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-148X.2012.00979.x"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1194472"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2641"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.34.15_suppl.9541"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1143997"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.5114\/ceji.2020.103339"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0054-z"},{"issue":"15","key":"e_1_2_9_28_1","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1158\/1538-7445.AM2015-1156","article-title":"Widespread deficiency of ASS1 in uveal melanoma and sensitivity to pegylated arginine deiminase","volume":"75","author":"Khadeir R. 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