Information borrowing in phase II randomized dose-ranging clinical trials in oncology

Abstract Introduction Over the past decades, the advent of new therapeutics such as immunotherapies and targeted therapies has challenged conventional clinical trial designs, such as single-arm studies. Selecting a single dose in phase I trials with short follow-up, typically based solely on toxicity endpoints, has been shown to lead to suboptimal dosing decisions. Consequently, dose optimization is now increasingly encouraged in oncology. This study was motivated by the case of ibrutinib in chronic lymphocytic leukemia, for which the initially approved dose of 420 mg/day, determined using conventional phase I designs based on the maximum tolerated dose, was later shown to achieve comparable response rates at lower doses. This example highlights the potential value of dose-ranging phase II studies in oncology. Assuming that borrowing information across doses can improve statistical power, our objective was to compare several strategies for information borrowing in phase II randomized trials involving multiple doses of the same drug. Methods The backbone design considered was the Bayesian Optimal Phase II (BOP2) design, adapted to a multi-arm setting and allowing for co-primary binary endpoints as well as interim analyses. This design relies on a multinomial conjugate model to describe the endpoints within a Bayesian framework, with decision rules for early stopping due to futility and/or toxicity based on posterior probabilities. We adapted and compared several information-borrowing approaches to estimate efficacy and toxicity: (i) power prior, (ii) Bayesian hierarchical modeling, (iii) Bayesian calibrated hierarchical modeling, and (iv) Bayesian logistic regression. These approaches were applied alongside BOP2 decision rules. In addition, a Simon’s two-stage design with added toxicity monitoring was used as a comparator. A simulation study was conducted to evaluate the operating characteristics of the designs, using a hypothetical randomized dose-ranging trial with efficacy and toxicity as co-primary endpoints against reference values. Results Our results indicate that the power prior, without dynamic adaptation of the borrowing strength, is unsuitable in this context as it substantially increases the false positive rate. Bayesian hierarchical modeling shrinks estimates toward a common mean, reducing variance but also leading to inflated false positive rates. In contrast, Bayesian logistic regression provides a more balanced trade-off, achieving moderate gains in power while increasing the false positive rates. Conclusion In multi-arm trials, the BOP2 design without information borrowing offers stricter control of the false positive rate than borrowing-based approaches when only toxic or futile doses are considered. Nevertheless, Bayesian logistic regression modeling of the dose–toxicity and dose–efficacy relationships, combined with BOP2 decision rules, could be considered as a possible approach for borrowing information in dose-ranging studies with a limited number of doses.