{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:58:53Z","timestamp":1760234333222,"version":"build-2065373602"},"reference-count":21,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Biomarkers play a key role in the development of personalized medicine. Cancer clinical trials with biomarker should be appropriately designed and analyzed reflecting the various factors, such as the phase of trials, the type of biomarker, the study objectives, and whether the used biomarker is already validated or not. In this paper, we demonstrate design and analysis of two phase II cancer clinical trials, one with a predictive biomarker and the other with a prognostic biomarker. A statistical testing method and its sample size calculation method are presented for each of the trials. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint with associated testing methods. The test statistics and their sample size formulas are derived using the large sample approximation based on the martingale central limit theorem. Using simulations, we find that the test statistics control the type I error rate accurately and the sample sizes calculated using the formulas maintain the statistical power specified at the design stage.<\/jats:p>","DOI":"10.3390\/jpm11050376","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T11:06:01Z","timestamp":1620212761000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design and Analysis of Cancer Clinical Trials for Personalized Medicine"],"prefix":"10.3390","volume":"11","author":[{"given":"Sin-Ho","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1093\/jnci\/djp477","article-title":"Randomized Clinical Trials with Biomarkers: Design Issues","volume":"102","author":"Freidlin","year":"2010","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3304","DOI":"10.1200\/JCO.2012.43.3946","article-title":"Randomized Phase II Trial Designs with Biomarkers","volume":"30","author":"Freidlin","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4027","DOI":"10.1200\/JCO.2009.22.3701","article-title":"Clinical Trial Designs for Predictive Biomarker Validation: Theoretical Considerations and Practical Challenges","volume":"27","author":"Mandrekar","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1080\/10543406.2017.1372777","article-title":"Phase II Cancer Clinical Trials for Biomarker-Guided Treatments","volume":"28","author":"Jung","year":"2018","journal-title":"J. Biopharm. Stat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1349-7006.2009.01358.x","article-title":"Significance of Thymidylate Synthase for Resistance to Pemetrexed in Lung Cancer","volume":"101","author":"Ozasa","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1200\/JCO.2014.59.9324","article-title":"Pemetrexed plus Cisplatin versus Gemcitabine plus Cisplatin according to Thymidylate Synthase Expression in Nonsquamous Non\u2013Small-Cell Lung Cancer: A Biomarker-Stratified Randomized Phase II Trial","volume":"33","author":"Sun","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.2517-6161.1972.tb00899.x","article-title":"Regression Models and Life Tables (with discussion)","volume":"34","author":"Cox","year":"1972","journal-title":"J. R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"ref_8","unstructured":"Fleming, T.R., and Harrington, D.P. (1991). Counting Processes and Survival Analysis, Wiley."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1097\/JTO.0b013e3182208ea8","article-title":"Significance of Thymidylate Synthase and Thyroid Transcription Factor 1 Expression in Patients with Nonsquamous Non\u2013Small Cell Lung Cancer Treated with Pemetrexed-Based Chemotherapy","volume":"6","author":"Sun","year":"2011","journal-title":"J. Thorac. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1002\/sim.4780110812","article-title":"Sample Size for Proportional Hazards Survival Studies with Arbitrary Patient Entry and Loss to Follow-up Distributions","volume":"11","author":"Yateman","year":"1992","journal-title":"Stat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1002\/sim.1975","article-title":"On the Efficiency of Targeted Clinical Trials","volume":"24","author":"Maitournam","year":"2005","journal-title":"Stat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1214\/aos\/1176344247","article-title":"Nonparametric Inference for a Family of Counting Processes","volume":"6","author":"Aalen","year":"1978","journal-title":"Ann. Stat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1080\/00224065.1969.11980344","article-title":"Hazard Plotting for Incomplete Failure Data","volume":"1","author":"Nelson","year":"1969","journal-title":"J. Qual. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1080\/10543400500265736","article-title":"Sample Size Computation for Noninferiority Log-Rank Test","volume":"15","author":"Jung","year":"2005","journal-title":"J. Biopharm. Stat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"185","DOI":"10.2307\/2344317","article-title":"Asymptotically Efficient Rank Invariant Test Procedures (with discussion)","volume":"135","author":"Peto","year":"1972","journal-title":"J. R. Stat. Soc. Ser. A Stat. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/10543406.2010.550701","article-title":"On Sample Size Calculation for Comparing Survival Curves under General Hypotheses Testing","volume":"22","author":"Jung","year":"2012","journal-title":"J. Biopharm. Stat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1182\/blood-2018-01-827246","article-title":"CALBG 50604: Risk-Adapted Treatment of Non-Bulky Early Stage Hodgkin Lymphoma based on Interim PET","volume":"132","author":"Straus","year":"2018","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jung, S.H. (2013). Randomized Phase II Cancer Clinical Trials, Chapman & Hall\/CRC.","DOI":"10.1201\/b14751"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0197-2456(89)90015-9","article-title":"Optimal Two-Stage Designs for Phase II Clinical Trials","volume":"10","author":"Simon","year":"1989","journal-title":"Control. Clin. Trials"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1080\/10543406.2014.901343","article-title":"Randomized Phase II Clinical Trials","volume":"24","author":"Jung","year":"2014","journal-title":"J. Biopharm. Stat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6759","DOI":"10.1158\/1078-0432.CCR-04-0496","article-title":"Evaluating the Efficiency of Targeted Designs for Randomized Clinical Trials","volume":"10","author":"Simon","year":"2004","journal-title":"Clin. Cancer Res."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/5\/376\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:57:04Z","timestamp":1760162224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/5\/376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":21,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["jpm11050376"],"URL":"https:\/\/doi.org\/10.3390\/jpm11050376","relation":{},"ISSN":["2075-4426"],"issn-type":[{"type":"electronic","value":"2075-4426"}],"subject":[],"published":{"date-parts":[[2021,5,4]]}}}