title: Mixed response and time-to-event endpoints for multistage single-arm phase II design.
abstract: BACKGROUND
  The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development.
  
  
  METHODS
  We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula.
  
  
  RESULTS
  Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint.
  
  
  CONCLUSIONS
  The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.
authors.affiliation: Division of Biostatistics, Jockey Club School of Public Health and Primary Care, Room 501, JC School of Public Health and Primary Care, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. Laixin@cuhk.edu.hk.|Clinical Trials and Biostatistics Lab, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. Laixin@cuhk.edu.hk.
authors.forename: Xin
authors.initials: X
authors.lastname: Lai
authors.affiliation: Division of Biostatistics, Jockey Club School of Public Health and Primary Care, Room 501, JC School of Public Health and Primary Care, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. bzee@cuhk.edu.hk.|Clinical Trials and Biostatistics Lab, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. bzee@cuhk.edu.hk.
authors.forename: Benny Chung-Ying
authors.initials: BC
authors.lastname: Zee
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods* / Q000706:statistics & numerical data; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D018450:Disease Progression; D018572:Disease-Free Survival; D023381:Endpoint Determination / Q000706:statistics & numerical data; D006801:Humans; D053208:Kaplan-Meier Estimate; D015233:Models, Statistical; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D012107:Research Design / Q000706:statistics & numerical data; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents