Comparison of power between randomized discontinuation design and upfront randomization design on progression-free survival.
OBJECTIVE
Enrichment based on molecular characteristics has emerged as an important inclusion criterion in phase II trials of targeted anticancer agents. In this study, we evaluate a well-described method of population enrichment by tumor growth characteristics in the early development stage of targeted cytostatic agents.


METHODS
For some solid tumors, such as pancreatic carcinoma, using a time-to-event end point (eg, time to disease progression) to evaluate the efficacy of a cytostatic agent in a phase II trial is more relevant than clinical response by Response Evaluation Criteria in Solid Tumors. In this setting, we compared the power of the randomized discontinuation and upfront randomization designs under two previously proposed tumor growth models for treatment effect when the end point is time-to-event.


RESULTS
By selecting patients with more homogeneous tumor growth characteristics, the randomized discontinuation design is more efficient than the upfront randomization design when treatment benefit is restricted to slow-growing tumors. Under a model where only a subset of patients expressing the molecular target are sensitive to the agent, the randomized discontinuation design is more powerful than the upfront randomization design when the treatment effect is small; and vice versa when the treatment effect is moderate to large.


CONCLUSIONS
For selected targeted agents where a bioassay to select patients expressing the specific molecular target is not available, the randomized discontinuation design is a feasible alternative patient enrichment strategy in certain disease settings and provides a reasonable platform to evaluate drugs before phase III testing.
Fu
Pingfu
P
Department of Epidemiology and Biostatistics, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USA. pxf@bfox.cwru.edu
Dowlati
Afshin
A
Schluchter
Mark
M
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D018572:Disease-Free Survival; D005240:Feasibility Studies; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents