An Open‐Label Phase II Trial of Pembrolizumab, an Immune Checkpoint Inhibitor Alone or in Combination With Oral Azacitidine as Second‐Line Therapy for Advanced Head and Neck Squamous Cell Cancers

ABSTRACT Background and Aims Sensitivity to immune checkpoint inhibitor (ICI) therapy depends in part on the genetic and epigenetic makeup of cancer cells, and CD8 T‐lymphocytes that mediate immune responses. Epigenetics are heritable reversible changes in gene expression that occur without any changes in the nuclear DNA sequence or DNA copy number. Primary Objective i. To determine if non‐cytotoxic oral azacytidine when combined with pembrolizumab can improve ORRs of ICI treatment in patients with recurrent/metastatic tumors of head and neck region. Secondary Objectives i. To evaluate the clinical effectiveness endpoints and toxicity of oral azacytidine when combined with pembrolizumab. ii. To assess the induction of a T‐cell response among the study subjects. iii. To examine the hypotheses on the predictive biomarkers of response to pembrolizumab, and the mechanisms of resistance. Methods Our trial is a Phase 2 randomized study of immunotherapy drug pembrolizumab given in combination with azacitidine (HMA). The intervention model includes “Parallel assignment,” with the primary purpose of the trial being treatment. The primary effectiveness endpoint is overall RECIST‐defined response. To accomplish this goal, 232 patients will be randomized 1:1 (116 in each arm), respectively, to azacitidine plus pembrolizumab or pembrolizumab only groups. Results In this trial, molecular profiling of tumor and peripheral blood samples will be conducted which will enable in gaining biological insights for survival benefit. The expected primary outcome assessed at a time frame of 2 years includes the objective response rate of patients measured as per RECIST 1.1 criteria. The secondary outcomes assessed at 2 years include progression‐free survival, time to progression, overall survival, and incidence of treatment‐emergent adverse events. Conclusion The findings of this trial will have translational implications, in terms of immune reprogramming induced by epigenetic therapy among a subset of advanced H & N cancer patients in a clinical setting.