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Demonstrate proof-of-principle: target engagement and activity, synergistic or additive effect at tolerable and achievable doses.
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Characterize PK and PD profile of individual drugs and the combination.
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Identify optimal concentrations of each drug to inform clinical dose selection.
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Explore potential biomarkers which can later be refined clinically.
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Set pre-determined benchmarks defining success prior to considering clinical testing.
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Develop validated immuno-competent animal models.
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Develop models of putative mechanisms of resistance.
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Use multiple models where practicable.
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| Early phase trials: combination selection and overall goals |
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Focus on populations with unmet need, e.g. PD-1 blockade-refractory patients.
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Sound biological rationale is a prerequisite for starting clinical development.
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Combination therapy should offer significant therapeutic advantage over monotherapy with manageable toxicity.
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Set clearly-defined clinical development plan from the outset and pre-determined decision rules with criteria to define success or failure.
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Combine best-in-class agents.
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Industry and academic collaboration vital to minimize duplication of investigational studies and resources.
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| Early phase clinical trial design |
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Trial design features including method of dose escalation and endpoints, should be carefully considered based on nonclinical or single agent clinical data, tumor and patient characteristics, and objectives.
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Novel trial designs, including model-based designs, should be strongly considered.
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Parallel biomarker development studies encouraged to assess mechanisms of resistance and response, PK/PD endpoints and to identify predictive biomarkers.
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Trial designs aimed at accelerating the development process such as seamless designs with expansion cohorts in phase I may be appropriate for highly efficacious agents and ideally should be implemented in concert with FDA expedited programs to protect patient safety and purpose-fit efforts (112,113).
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