Comparison of Various Phase I Combination Therapy Designs in Oncology for Evaluation of Early Tumor Shrinkage Using Simulations.

There is still a lack of efficient designs for identifying the dose response in oncology combination therapies in early clinical trials. The concentration response relationship can be identified using the early tumor shrinkage time course, which has been shown to be a good early response marker of clinical efficacy. The performance of various designs using an exposure-tumor growth inhibition model was explored using simulations. Different combination effects of new drug M and cetuximab (reference therapy) were explored first assuming no effect of M on cetuximab (to investigate the type I error (α)), and subsequently assuming additivity or synergy between cetuximab and M. One-arm, two-arm, and four-arm designs were evaluated. In the one-arm design, 60 patients received cetuximab + M. In the two-arm design, 30 patients received cetuximab and 30 received cetuximab + M. In the four-arm design, in addition to cetuximab and cetuximab + M as standard doses, combination arms with lower doses of cetuximab were evaluated (15 patients/arm). Model-based predictions or "simulated observations" of early tumor shrinkage at week 8 (ETS8) were compared between the different arms. With the same number of individuals, the one-arm design showed better statistical power than other designs but led to strong inflation of α in case of misestimated reference for ETS8 value. The two-arm design protected against this misestimation and, with the same total number of subjects, would provide higher statistical power than a four-arm design. However, a four-arm design would be helpful for exploring more doses of cetuximab in combination with M to better understand the interaction.