Performance of multinomial designs in comparison with response-based designs in non-randomized phase II trials of targeted cancer agents

Background: In phase II trials of cytotoxic agents, a multinomial phase II design incorporating early progression and response end points was shown to perform more efficiently than designs based only on response. We undertook a study to evaluate the performance of these designs in trials of targeted agents using the actual phase II data. Patients and methods: Using best response data from sequentially enrolled patients in 15 NCIC Clinical Trials Group and 7 European Organization for Research and Treatment of Cancer trials of targeted agents, we determined that trials would have been stopped at the end of stage I of accrual by applying rules generated by the multinomial and Fleming designs. Two variants of the multinomial design were studied: to stop accrual after stage I of enrolment, Variant A required either response or progression criteria to be met, whereas Variant B required that both response and progression criteria to be met. Results: Using early progression, null/alternate hypotheses of 60% and 40% (60/40), the multinomial A variant recommended early stopping more often than the Fleming design. In most of the cases, this recommendation was correct given the final trial outcome. In contrast, the multinomial B variant never led to recommendations for early stopping and changing progression hypotheses did not improve the performance of this design. Conclusions: The multinomial A design using 60/40 hypotheses carried out better than the Fleming design in appropriately stopping trials of inactive targeted agents early. The multinomial B design was not useful for early stopping decisions. The multinomial A design may be favored over response-based designs in phase II trials of targeted