Rapid enrollment design for finding the optimal dose in immunotherapy trials with ordered groups

ABSTRACT

In immunotherapy dose-finding trials, the optimal dose is usually defined based on both toxicity and response because the relationship between toxicity and response is different than that seen with cytotoxic anti-neoplastic therapies. In immunotherapy trials, toxicity and response often require a longer follow-up time compared to trials with cytotoxic agents. The rapid enrollment design has been proposed for dose-finding trials to find the maximum-tolerated dose where the follow-up for toxicity is long and it is desirable to assign a patient to a dose of a new therapy as soon as the patient is enrolled. We extend the rapid enrollment design to immunotherapy trials to find the optimal dose. We further describe how to use the design in immunotherapy trials with ordered groups where efficacy and safety considerations dictate running dose-finding trials in each group separately as efficacy and toxicity at the same dose can vary across groups. The estimation of the optimal dose in each of the groups can be improved in many, but not all, cases by using the monotonicity of toxicity and response among groups.

KEYWORDS:

• Bayesian isotonic transformation
• rapid enrollment design
• RED
• optimal safe dose
• ordered groups
• phase 1/2 trials

Acknowlegments

The authors thank the two guest editors for overseeing the review process for this special issue and anonymous reviewers for tremendously helpful comments.

Additional information

Funding

This work was supported by the NIH [P01 CA142538].