Purpose: Testing agents in cancers with multiple disease subtypes, in which the activity of a new treatment may vary between subtypes, presents statistical and logistical challenges. We propose a flexible phase II strategy which includes both analyses for each histology or stratum and a combined analysis which borrows information from all the patients in the study. Sequential futility analyses are conducted once each subgroup or the overall group reaches a specified minimum accrual.
Experimental design: Examples based on a soft tissue sarcoma phase II trial, which includes multiple histologies and simulation studies, are used to assess the statistical properties of the proposed strategy.
Results: The combined analyses in one phase II trial lead to smaller expected sample sizes when the drug is broadly inactive, and to greater statistical power if there is modest activity across multiple strata as compared with conducting several smaller phase II studies. In addition, by retaining the stratum-specific tests, the design allows the identification of subgroups for which the agents are most active.
Conclusion: To consider phase II testing with multiple biological subtypes, a strategy which combines both the individual subgroup tests and overall combined tests has promising statistical properties. Our results support the appropriate use of statistical borrowing of information in phase II studies in this setting. More broadly, this work fits the paradigm that phase II studies should include as broad a group of patients as scientifically reasonable, but incorporate design considerations for subsets of patients with potentially differing responses to therapy.