{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:54:59Z","timestamp":1791554099546,"version":"4.3.4"},"reference-count":32,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"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"],"abstract":"<jats:p>The emergence of targeted therapies and immunotherapies has challenged the traditional \u201cmore is better\u201d paradigm underlying maximum tolerated dose (MTD)\u2010based trials, as dose escalation beyond receptor saturation often yields limited additional efficacy while substantially increasing toxicity. In response, the U.S. Food and Drug Administration's Project Optimus emphasizes dose optimization (DO) prior to confirmatory studies to ensure a favorable benefit\u2013risk profile. Motivated by this shift, we systematically evaluate strategies for incorporating DO at different stages of oncology drug development. We compare three approaches: (1) DO combined with proof\u2010of\u2010concept in a seamless Phase Ib\/II study prior to a registrational trial; (2) DO conducted in an operational seamless Phase II\/III design; and (3) DO embedded within an inferential seamless Phase II\/III design. Simulation studies were performed across a range of efficacy\u2013toxicity scenarios to assess dose\u2010selection accuracy, statistical operating characteristics, expected sample size, and overall study duration. Under the simulated settings, both the Phase Ib\/II DO strategy and the inferential seamless Phase II\/III design reduced total development time compared with the operational seamless approach. The inferential seamless design achieved the lowest expected sample size and the shortest average trial duration while maintaining high power under the primary simulated scenarios. The comparative performance of the three strategies also depended on how well the short\u2010term dose\u2010selection endpoints predicted long\u2010term survival. Overall, DO can be effectively implemented at multiple stages of clinical development. The optimal strategy should balance statistical rigor, development speed, practical feasibility, and the suitability of the endpoints used for dose selection.<\/jats:p>","DOI":"10.1002\/cpt.70522","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:43:36Z","timestamp":1791553416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Phase Ib\/\n                    <scp>II<\/scp>\n                    to Seamless Phase\n                    <scp>II<\/scp>\n                    \/\n                    <scp>III<\/scp>\n                    : A Simulation\u2010Based Discussion of Design Strategies for Dose Optimization and Confirmatory Phase"],"prefix":"10.1002","author":[{"given":"Annan","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Population Health New York University Grossman School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9499-6464","authenticated-orcid":false,"given":"Xiaochen","family":"Zhu","sequence":"additional","affiliation":[{"name":"Data &amp; Quantitative Sciences Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyang","family":"Sheng","sequence":"additional","affiliation":[{"name":"Data &amp; Quantitative Sciences Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Li","sequence":"additional","affiliation":[{"name":"Data &amp; Quantitative Sciences Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Chen","sequence":"additional","affiliation":[{"name":"Oncology Biometrics AstraZeneca  Gaithersburg Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu\u2010Pang","family":"Huang","sequence":"additional","affiliation":[{"name":"Data &amp; Quantitative Sciences Bristol Myers Squibb  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2109826"},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.15.1281"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1295"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00371"},{"key":"e_1_2_11_5_1","volume-title":"Project Optimus: Reforming the dose optimization and dose selection paradigm in oncology","author":"US Food and Drug Administration","year":"2022"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-009-0108-y"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djad103"},{"key":"e_1_2_11_8_1","unstructured":"US Food and Drug Administration.Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases(2024) <https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/optimizing\u2010dosage\u2010human\u2010prescription\u2010drugs\u2010and\u2010biological\u2010products\u2010treatment\u2010oncologic\u2010diseases>. Accessed 27\/10\/2025."},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djac232"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.8361"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.20.00257"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1541-0420.2009.01302.x"},{"key":"e_1_2_11_13_1","unstructured":"Sun H.&Li J.A comparative evaluation of Bayesian model\u2010assisted two\u2010stage designs for phase I\/II clinical trials(2025) arXiv preprint arXiv:2501.08410."},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7338"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.2030"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543406.2024.2429481"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/19466315.2023.2292816"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.10129"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2023.107300"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543406.2011.551335"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280210379035"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/19466315.2024.2308856"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13079"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3658"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/17407745231207085"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1201\/9780367805326"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0006-341X.1999.01286.x"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504627"},{"key":"e_1_2_11_29_1","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1001\/jamaoncol.2018.3039","article-title":"Effect of anlotinib as a third\u2010line or further treatment on overall survival of patients with advanced non\u2013small cell lung cancer: the ALTER 0303 phase 3 randomized clinical trial","volume":"4","author":"Han B.","year":"2018","journal-title":"JAMA Oncol."},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280215594494"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0592"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0168"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70522","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70522","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70522","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:43:37Z","timestamp":1791553417000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70522"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":32,"alternative-id":["10.1002\/cpt.70522"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70522","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"assertion":[{"value":"2026-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cpt.70522"}}