{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:18:38Z","timestamp":1790007518420,"version":"4.0.1"},"reference-count":22,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,10,4]],"date-time":"2017-10-04T00:00:00Z","timestamp":1507075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004339","name":"Sanofi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2018,1,15]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Phosphoinositide 3\u2010kinase (PI3K) \u03b2 is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)\u2010deficient tumor models. This was a first\u2010in\u2010human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3K\u03b2\u2010selective inhibitor (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">clinicaltrials.gov<\/jats:ext-link> identifier NCT01673737).<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose\u2010control process based on the occurrence of dose\u2010limiting toxicity in the first 28\u2010day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically\u2010based PK modeling was used for exposure predictions.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Twenty\u2010one patients received treatment at doses ranging from 100 mg once daily to 440 mg\/m<jats:sup>2<\/jats:sup> twice daily. Dose\u2010limiting toxicities included 1 episode of grade 3 pneumonitis (400 mg twice daily) and 1 grade 3 \u03b3\u2010glutamyltransferase increase (600 mg twice daily). The maximum tolerated dose was not reached. The most frequently occurring treatment\u2010related adverse events were nausea, vomiting, and diarrhea (14% each). Pharmacologically active concentrations were reached, but SAR260301 was rapidly cleared, and exposures associated with antitumor activity in preclinical models were not maintained at the highest dose tested. Food further decreased SAR260301 exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. <jats:bold><jats:italic>Cancer<\/jats:italic> 2018;124:315\u201024<\/jats:bold>. \u00a9 <jats:italic>2017 American Cancer Society<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.31044","type":"journal-article","created":{"date-parts":[[2017,10,4]],"date-time":"2017-10-04T11:16:38Z","timestamp":1507115798000},"page":"315-324","source":"Crossref","is-referenced-by-count":34,"title":["First\u2010in\u2010human trial of the PI3K\u03b2\u2010selective inhibitor SAR260301 in patients with advanced solid tumors"],"prefix":"10.1002","volume":"124","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6771-2999","authenticated-orcid":false,"given":"Philippe L.","family":"B\u00e9dard","sequence":"first","affiliation":[{"name":"Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre University Health Network and Department of Medicine, University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Davies","sequence":"additional","affiliation":[{"name":"Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Kopetz","sequence":"additional","affiliation":[{"name":"Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejan","family":"Juric","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey I.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana\u2010Farber Cancer Institute Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason J.","family":"Luke","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Chicago Cancer Center Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Spreafico","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre University Health Network and Department of Medicine, University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sanofi Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christelle","family":"Castell","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Sanofi Vitry sur Seine France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Gomez","sequence":"additional","affiliation":[{"name":"Department of Drug Disposition, Sanofi Alfortville France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvaine","family":"Cartot\u2010Cotton","sequence":"additional","affiliation":[{"name":"Department of Drug Disposition, Sanofi Alfortville France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Mazuir","sequence":"additional","affiliation":[{"name":"Department of Drug Disposition, Sanofi Alfortville France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Dubar","sequence":"additional","affiliation":[{"name":"Department of Translational Informatics, Sanofi Chilly\u2010Mazarin France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Micallef","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Oncology Sanofi R&amp;D, Vitry sur Seine France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Demers","sequence":"additional","affiliation":[{"name":"Department of Oncology \u2010 Early Development, Sanofi Vitry sur Seine France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith T.","family":"Flaherty","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,10,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2926"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-1777"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.3641"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3037"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802655105"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07091"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm401642q"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1323004111"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-15-0496"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.advenzreg.2010.09.011"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-06-0746"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_2_8_14_1","volume-title":"Common 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