{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T23:23:25Z","timestamp":1785799405236,"version":"3.56.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:p>Copanlisib is an intravenously administered phosphatidylinositol 3\u2010kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefit\u2013risk profile of the class PI3K inhibitors were scrutinized for use in hematological malignancies. Specifically, their unique toxicities may contribute to the high incidences in reported serious and high\u2010grade treatment emergent adverse events (TEAEs), thereby reducing their overall tolerability and potentially limiting their successful use. These tolerability concerns may be contributed by or compounded by inadequate dose optimization. The recommended dosing regimen of copanlisib 60\u2009mg administered on days 1, 8, and 15 of a 28\u2010day\u2009cycle was selected as the maximal tolerated dose (MTD) during phase I. Thus, this analysis sought to justify the copanlisib dose regimen selection. Copanlisib exposure\u2010efficacy relationships were considered from its large phase III trial, CHRONOS\u20103, whereas copanlisib safety was investigated by pooling data across its two large clinical trials to comprehensively assess its exposure\u2010safety relationships. Results demonstrated a statistically significant positive linear exposure\u2010efficacy relationship at the MTD. Exposure\u2010safety analyses revealed a borderline significant linear relationship for grade\u2009\u22653 TEAEs and no significant exposure\u2010safety relationships for other investigated safety end points. The model\u2010based benefit\/risk framework considered the established exposure\u2010response models and defined clinical utility function which confirmed the appropriateness of the copanlisib dosing regimen across the range of its achieved exposures.<\/jats:p>","DOI":"10.1002\/cpt.3173","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T04:52:30Z","timestamp":1705380750000},"page":"1092-1104","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Model\u2010Based Benefit\/Risk Analysis for the Copanlisib Intermittent Dosing Regimen"],"prefix":"10.1002","volume":"115","author":[{"given":"Peter N.","family":"Morcos","sequence":"first","affiliation":[{"name":"Bayer HealthCare Pharmaceuticals, Inc.  Whippany New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Moss","sequence":"additional","affiliation":[{"name":"BAST Inc Limited  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4216-3446","authenticated-orcid":false,"given":"Josh","family":"Veasy","sequence":"additional","affiliation":[{"name":"BAST Inc Limited  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Hiemeyer","sequence":"additional","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barrett H.","family":"Childs","sequence":"additional","affiliation":[{"name":"Bayer HealthCare Pharmaceuticals, Inc.  Whippany New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Garmann","sequence":"additional","affiliation":[{"name":"Bayer AG  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"e_1_2_9_1_1","unstructured":"Haike K.et al.Molecular mechanisms supporting inhibition of PI3K isoforms by copanlisib in blocking B\u2010cell signaling and tumor cell growth in diffuse large B\u2010cell lymphoma. In: 1st American Society of Hematology Meeting on Lymphoma Biology Colorado Springs CO USA August 10\u201313 2014."},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-05-850461"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022018546"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813904"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.01460"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0993-T"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0611"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.12.003"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw282"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx289"},{"issue":"1","key":"e_1_2_9_11_1","first-page":"S5","article-title":"Use of a population pharmacokinetic approach and time\u2010to\u2010event analysis to support the clinical recommendation of a flat dosing of copanlisib in cancer patients","volume":"99","author":"Reif S.","year":"2016","journal-title":"Clin. Pharmacol. Ther."},{"key":"e_1_2_9_12_1","unstructured":"US Food and Drug Administration ALIQOPA (copanlisib) highlights of prescribing information<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/209936s004lbl.pdf> (2020). Accessed May 5 2023."},{"key":"e_1_2_9_13_1","unstructured":"Taiwan Food and Drug Administration ALIQOPA (copanlisib) Assessment Report<https:\/\/www.fda.gov.tw\/tc\/includes\/GetFile.ashx?id=f637085445784753113> (2022). Accessed May 5 2023."},{"key":"e_1_2_9_14_1","unstructured":"The Israeli Drug Registry ALIQOPA (copanlisib)<https:\/\/israeldrugs.health.gov.il\/#!\/medDetails\/165%2045%2035773%2000> (2022). 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