Multiple Histology Phase II Trials.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Leblanc
Michael
M
Fred Hutchinson Cancer Research Center, Seattle, Washington and Cancer Research and Biostatistics, Seattle, Washington, USA. mleblanc@fhcrc.org
Rankin
Cathryn
C
Crowley
John
J
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic / Q000379:methods* / Q000706:statistics & numerical data; D003198:Computer Simulation; D006801:Humans; D009367:Neoplasm Staging; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use; D012107:Research Design; D012509:Sarcoma / Q000188:drug therapy / Q000473:pathology; D000077157:Sorafenib; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib