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We propose PROComb, a practical and robust design with randomization to optimize dose combinations, to address these challenges with minimal assumptions and to facilitate practical implementation. In the first stage, the complex dose\u2010combination space is efficiently explored through the integration of multi\u2010source data and the inherent relationships among different dose\u2010outcomes. Patients are adaptively assigned to dose combinations to establish a therapeutic dose space (TDS), defined as the set of doses with acceptable toxicity and promising efficacy. A recommended Stage II dose set (RS2D) is constructed at the end of Stage I. In the second stage, patients are randomized to RS2D combinations for further monitoring, screening and identification of the optimal biologic dose combination (OBDC). Three PROComb versions are developed to mitigate potential between\u2010stage drift. Simulation studies demonstrate that PROComb achieves favorable operating characteristics compared with conventional model\u2010based and model\u2010assisted designs.<\/jats:p>","DOI":"10.1002\/sim.70743","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:13:43Z","timestamp":1790147623000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PROComb: A Practical and Robust Design With Randomization to Optimize Dose Combinations in Drug Combination Trials"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9429-2131","authenticated-orcid":false,"given":"Yingjie","family":"Qiu","sequence":"first","affiliation":[{"name":"Peter O'Donnell Jr. School of Public Health University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Harold C. Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyue","family":"Li","sequence":"additional","affiliation":[{"name":"Peter O'Donnell Jr. School of Public Health University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01856-7"},{"key":"e_1_2_9_3_1","unstructured":"National Cancer Institute ComboMATCH \u201cA Precision Medicine Cancer Initiative \u201d 2023 https:\/\/www.cancer.gov\/news\u2010events\/press\u2010releases\/2023\/combomatch\u2010precision\u2010medicine\u2010cancer\u2010initiative."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0006-341X.2004.00215.x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1541-0420.2008.01119.x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-9876.2009.00649.x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1541-0420.2011.01560.x"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/19466315.2013.767213"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.1621"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.6434"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7095"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280215594494"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280220919450"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0389-8"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2008.26.15_suppl.2509"},{"key":"e_1_2_9_16_1","unstructured":"U. 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