Oncology Combination Dose-Finding Study Design for Targeted and Immuno-Oncology Therapies.

Combination therapies are often evaluated during the clinical development of oncology investigational agents. A new investigational agent may be combined with one or more approved agent(s) or investigational agent(s). As the initial step to test combination therapies, combination dose escalation of an investigational agent and an approved drug is generally conducted using one of the following designs: sequential design, parallel (staggered) design, healthy participant first-in-human prior to first-in-patient combination escalation, monotherapy lead-in (intra-patient "crossover"), and potentially combination escalation (no monotherapy component). Dose-finding studies for the combinations of two investigational agents may follow similar principles and considerations, and a more conservative approach may be required. A comparison of the characteristics of these designs indicates an efficient design should consider factors including the predicted difference in dose/exposure-response relationships between monotherapy and combination therapy, any potential for PK and PD interactions between the combinatory agents, and the benefit/risk to study participants, etc. In this report, we propose application scenarios for each trial design based on the above considerations and a review of internal database and published external studies. Generation of robust exposure-response data via an appropriate design will assist the selection of appropriate doses for further assessment to support optimal dose selection as encouraged by the FDA based on Project Optimus.