| Background:The optimal dose chosen by the dose finding methods in early phase trials for oncology drug development directly affects the success of subsequent confirmatory trials.Therefore,it is crucial for early clinical trials to increase the percentage of correct selection.The traditional paradigm has many flaws.Due to limited sample size and using the surrogates not associated with long survival to evaluate drug efficacy in the early phase trials,the probability of selecting the suboptimal dose increases.Although construction of appropriate early dose finding model according to the drug characteristics can increase the accuracy to identify the true optimal dose,there are still nearly 50%of clinical trial failures.Therefore,this study aims to propose a clinical trial design that increases the percentage of correct selection,and then improve the power.Objectives:This study attempts to construct a hybrid Ⅰ-Ⅱ/Ⅱ-Ⅲ clinical trial for oncology clinical trials that can control Type Ⅰ errors and guarantee the power,besides it can increase the accuracy to identify the true optimal dose through early dose exploration and dose re-optimization.Further,our study constructs a hybrid Ⅰ-Ⅱ/Ⅱ-Ⅲ clinical trial suitable for immunotherapy.Methods:In order to increase the percentage of correct selection,this study uses an appropriate early dose finding model and then re-optimizes the dose based on mean survival time.Considering that the optimal dose chosen by the dose finding method and the dose selected by re-optimizing may be different,this study first proposes a mixedⅠ-Ⅱ/Ⅱ-Ⅲ clinical trial design in order to guarantee the randomization.The design is mainly divided into two parts:(1)Constructing early dose finding model based on toxicity and efficacy,and selecting three promising doses to enter Phase Ⅱ-Ⅲ;(2)At the end of phase Ⅱ In Phase Ⅱ-Ⅲ,constructing the dose re-optimization and sample size re-estimation based on the toxicity,efficacy and survival time continuously collected in Phase Ⅰ-Ⅱ and part of Phase Ⅱ-Ⅲ.In this study,according to the characteristics of immunotherapy,immune response was added to the early dose exploration and dose reoptimization to build a hybrid Ⅰ-Ⅱ/Ⅱ-Ⅲ clinical trial suitable for immunotherapy.Finally,the performance of the clinical trial design proposed in this study and the validity of dose selection were evaluated through multiple simulations.Results:The simulation results show that the hybrid Ⅰ-Ⅱ/Ⅱ-Ⅲ clinical trial(1)In the case of the null hypothesis H0,the new clinical trial design can keep the Type Ⅰerrors without inflation in all simulation scenarios,(2)What’s more,the new clinical trial design can improve the validity of dose selection,(3)The new clinical trial design is able to improve the power.The hybrid Ⅰ-Ⅱ/Ⅱ-Ⅲ clinical trial for immunotherapy can significantly improve the validity of dose selection under the premise of controlling Type Ⅰ errors and maintaining the power.Conclusion:The hybrid Ⅰ-Ⅱ/Ⅱ-Ⅲ clinical trial design proposed in this study divides the dose selection into two steps:early dose exploration and dose re-optimization.The newly proposed clinical trial design re-estimates sample size and corrects the problem of multiplicity issues after the dose re-optimization step.For immunotherapy,a hybrid Ⅰ-Ⅱ/Ⅱ-Ⅲ clinical trial design was constructed by adding immune response in dose re-optimization.The clinical trial design proposed in this study can improve the percentage of correct selection,control Type Ⅰ errors,and maintaining the power. |
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