title: One-stage and two-stage designs for phase II clinical trials with survival endpoints.
abstract: This work is motivated by trials in rapidly lethal cancers or cancers for which measuring shrinkage of tumours is infeasible. In either case, traditional phase II designs focussing on tumour response are unsuitable. Usually, tumour response is considered as a substitute for the more relevant but longer-term endpoint of death. In rapidly lethal cancers such as pancreatic cancer, there is no need to use a surrogate, as the definitive endpoint is (sadly) available so soon. In uveal cancer, there is no counterpart to tumour response, and so, mortality is the only realistic response available. Cytostatic cancer treatments do not seek to kill tumours, but to mitigate their effects. Trials of such therapy might also be based on survival times to death or progression, rather than on tumour shrinkage. Phase II oncology trials are often conducted with all study patients receiving the experimental therapy, and this approach is considered here. Simple extensions of one-stage and two-stage designs based on binary responses are presented. Outcomes based on survival past a small number of landmark times are considered: here, the case of three such times is explored in examples. This approach allows exact calculations to be made for both design and analysis purposes. Simulations presented here show that calculations based on normal approximations can lead to loss of power when sample sizes are small. Two-stage versions of the procedure are also suggested.
authors.affiliation: Medical and Pharmaceutical Statistics Research Unit, Lancaster University, Lancaster, U.K.
authors.forename: John
authors.initials: J
authors.lastname: Whitehead
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D023381:Endpoint Determination; D006801:Humans; D015233:Models, Statistical; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D012107:Research Design; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents
keywords: cancer trial; phase II trial; sample size calculation; survival data; two-stage designs