Abstract
Several designs, such as designs to find the optimal biological dose, the Eff-Tox design and seamless Phase I/II designs, have been proposed to evaluate both drug toxicity and efficacy as alternatives to the traditional paradigm of a stepwise drug development approach. Here, we first examine the effect of sample and cohort size on the accuracy of dose selection in early phase oncology designs and then propose a design that is large enough to allow accurate dose selection for toxicity and that incorporates Bayesian decision rules at the end to select an optimal dose for toxicity and efficacy. We propose the Accelerated Titration Large Cohort Early Phase (ATLCEP) design, a moderately large, simple rule-based integrated Phase I/II trial design that evaluates both safety and efficacy. This design incorporates stopping rules within dose levels to allow more flexible decision-making. Finally, we compare the operating characteristics of this design with other Phase I/II strategies, via simulations. Our simulations of the ATLCEP design yield a mean sample size of approximately 42 patients for the true DLT and response rates and stopping rules considered and show that with this sample size the design can robustly pick a dose that is optimal for efficacy and safety. In our simulations, it performs as well as or better than the Eff-Tox or the Optimal Biological Dose (OBD) Isotonic design. It also performs better than a 3+3 Phase I design followed by a standard Phase II design.
Highlights
In a Phase I oncology clinical trial, the safety of the investigational drug is studied and the Maximum Tolerated Dose (MTD) to be used in a Phase II trial is determined (Huang et al, 2016; Yang et al, 2015)
We evaluated other scenarios for the Continual Reassessment Method (CRM) design than those shown in Table 2, as well as many scenarios for the Eff-Tox design
In these examples that we studied, we found that the accuracy of MTD or dose selection improved dramatically with an increase in sample size for all the cases and designs considered
Summary
In a Phase I oncology clinical trial, the safety of the investigational drug is studied and the Maximum Tolerated Dose (MTD) to be used in a Phase II trial is determined (Huang et al, 2016; Yang et al, 2015). Phase I trials may not target the optimal dose taking into consideration both toxicity and response. Assessment of both Dose Limiting Toxicities (DLTs) and efficacy responses in a larger trial has the potential for a more accurate determination of a suitable dose, compared to a Phase I followed by a Phase II trial
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