Menggang Yu

The exploratory nature of phase II trials makes it quite common to include heterogeneous patient subgroups with different prognoses in the same trial. Incorporating such patient heterogeneity or stratification into statistical calculation for sample size can improve efficiency and reduce sample sizes in single-arm phase II trials with binary outcomes. However, such consideration is lacking in randomized phase II trials. In this paper, we propose methods that can utilize some natural order constraints that may exist in stratified population to gain statistical efficiency for randomized phase II designs. For thoroughness and simplicity, we focus on the randomized phase II selection designs in this paper, although our method can be easily generalized to the randomized phase II screening designs. We consider both binary and time-to-event outcomes in our development. Compared with methods that do not use order constraints, our method is shown to improve the probabilities of correct selection or reduce sample size in our simulation and real examples.

Background The tyrosine kinase receptors Axl and MerTK are highly overexpressed in head and neck cancer (HNC) cells, where they are critical drivers of survival, proliferation, metastasis, and therapeutic resistance. Methods We investigated the role of Axl and MerTK in creating an immunologically “cold” tumor immune microenvironment (TIME) by targeting both receptors simultaneously with a small molecule inhibitor of Axl and MerTK (INCB081776). Effects of INCB081776 and/or anti‐PDL1 on mouse oral cancer (MOC) cell growth and on the TIME were evaluated. Results Targeting Axl and MerTK can reduce M 2 and induce M 1 macrophage polarization. In vivo, INCB081776 treatment alone or with anti‐PDL1 appears to slow MOC tumor growth, increase proinflammatory immune infiltration, and decrease anti‐inflammatory immune infiltration. Conclusions This data indicates that simultaneous targeting of Axl and MerTK with INCB081776, either alone or in combination with anti‐PDL1, slows tumor growth and creates a proinflammatory TIME in mouse models of HNC.