  In recent years new cancer treatments improved survival in multiple
histologies. Some of these therapeutics, and in particular treatment
combinations, are often associated with severe treatment-related adverse events
(AEs). It is therefore important to identify alternative de-intensified
therapies, for example dose-reduced therapies, with reduced AEs and similar
efficacy. We introduce a sequential design for multi-arm de-intensification
studies. The design evaluates multiple de-intensified therapies at different
dose levels, one at the time, based on modeling of toxicity and efficacy
endpoints. We study the utility of the design in oropharynx cancer
de-intensification studies. We use a Bayesian nonparametric model for efficacy
and toxicity outcomes to define decision rules at interim and final analysis.
Interim decisions include early termination of the study due to inferior
survival of experimental arms compared to the standard of care (SOC), and
transitions from one de-intensified treatment arm to another with a further
reduced dose when there is sufficient evidence of non-inferior survival. We
evaluate the operating characteristics of the design using simulations and data
from recent de-intensification studies in human papillomavirus (HPV)-associated
oropharynx cancer.
