ABSTRACT
Operating Characteristics .............................................. 100 6.3 Methodology .............................................................................................. 102
6.3.1 Base Model ...................................................................................... 102 6.3.2 Metrics for Dosing Recommendations ....................................... 104
6.3.2.1 Posterior Distributions ................................................... 104 6.3.2.2 Predictive Distributions ................................................. 106 6.3.2.3 Formal Decision Analysis .............................................. 106
6.3.3 Prior Distributions ......................................................................... 106 6.3.3.1 Weakly Informative Priors............................................. 107 6.3.3.2 Prior Effective Sample Size ............................................ 107 6.3.3.3 Meta-Analytic-Predictive (MAP) Priors ...................... 108 6.3.3.4 Mixture Priors ................................................................. 109
6.3.4 Combination Models ..................................................................... 111 6.3.4.1 Combination of Two Agents .......................................... 112 6.3.4.2 Combination of Three Agents ....................................... 114
6.4 Applications ................................................................................................ 115 6.4.1 Dual-Combination Trial ................................................................ 115
6.4.1.1 Study Design .................................................................... 115 6.4.1.2 Model and Prior Distributions ...................................... 115 6.4.1.3 Trial Conduct: Dose Escalations and
MTD Declaration ............................................................. 117 6.4.2 Triple-Combination Trial .............................................................. 120
6.4.2.1 Study Design .................................................................... 120
Phase I trials are still perceived by many as simple. Although this is controversial in the single-agent setting, it is certainly mistaken for combinations of two or more compounds. In oncology, the challenges are many: while keeping patient safety within acceptable limits, the trials should be small, adaptive, and enable a quick declaration of the maximum tolerable dose (MTD) and/or recommended phase II dose (RP2D).
