Novel Clinical Trial Designs with Dose Optimization to Improve Long-term Outcomes

Abstract

Conventional designs for choosing a dose for a new therapy may select doses that are unsafe or ineffective, and fail to optimize progression free survival time, overall survival time, or remission duration. We explain and illustrate limitations of conventional dose finding designs, and make four recommendations to address these problems. When feasible, a dose-finding design should account for long-term outcomes, include screening rules that drop unsafe or ineffective doses, enroll an adequate sample size, and randomize patients among doses. As illustrations, we review three designs that include one or more of these features. The first illustration is a trial that randomized patients among two cell therapy doses and standard of care in a setting where it was assumed on biological grounds that dose-toxicity and dose-response curves did not necessarily increase with cell dose. The second design generalizes phase 1-2 by first identifying a set of candidate doses, rather than one dose, randomizing additional patients among the candidates, and selecting an optimal dose to maximize progression free survival over a longer follow up period. The third design combines a phase 1-2 trial and a group sequential randomized phase 3 trial by using survival time data available after the first stage of phase 3 to re-optimize the dose selected in phase 1-2. By incorporating one or more of the recommended features, these designs improve the likelihood that a selected dose or schedule will be optimal, and thus will benefit future patients and obtain regulatory approval.

A phase I trial of autologous RAK cell immunotherapy in metastatic renal cell carcinoma

“…The infusion dose of 1.5 × 10 10 RAK cells is not recommended because its efficacy was not superior to those of either 5 × 10 9 or 1.0 × 10 10 dose and might increase risk of cardiovascular events. Patients in low-dose RAK cells cohort (5 × 10 9 ) seemed to show higher activity than higher-dose cohorts (1 × 10 10 and 1.5 × 10 10 ), which may be consistent with the point recently made by Thall et al [ 31 ] that some cellular therapies in oncology (e.g., NK cell therapies) show higher efficacy at lower doses. In this case, designs other than conventional 3 + 3 dose escalation, such as a randomized controlled design, should be used for optimal dose-finding of autologous RAK cell immunotherapy in the future.…”