Addressing heterogeneity in the design of phase II clinical trials in geriatric oncology

Abstract

Introduction: Cancer in the elderly is a major public issue. However, older patients have long been debarred from clinical trials. There is a high unmet medical need for specific trials addressing oncology strategies adapted to older patients' conditions. While randomised phase III trials remain the gold standard, they usually require large numbers of patients. In this perspective, late single-arm phase II trials assessing treatment feasibility might prove a good alternative. However, it is essential to take into account the heterogeneity in an ageing population characterised by frailty. Standard parallel phase II studies in defined frail and non-frail populations also require a high number of patients. Used in molecular subtyping and treatment effect heterogeneity, stratified adaptive designs can improve statistical performance, but they have never been used in geriatric oncology. This report describes their potential benefits and useful applications as compared with standard designs.

Methods: In a heterogeneous population, stratified adaptive designs allowed us to select subgroups of interest in two stages. Operational characteristics were evaluated through simulations of clinical trials under different scenarios.

Results: Simulations showed that the use of stratified adaptive designs can efficiently minimise both the number of patients to be included and accrual duration with competitive statistical power and high heterogeneity detection rate at interim analysis.

Conclusion: Compared with classical phase II designs, stratified adaptive phase II trial methodology offers a promising approach to improve clinical research in geriatric oncology. These designs may also be efficient in other populations such as children or adolescents and young adults.

Keywords: Elderly; Frailty; Geriatric oncology; Heterogeneity; Phase II clinical trial; Stratified adaptive design.