Azacitidine and Pembrolizumab in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of any major malignancy in the United States and, unlike other common cancers, annual deaths from PDA are rising. Despite recent advances, cytotoxic chemotherapy for PDA has been disappointing. Even among the small subset of patients who are suitable for surgical resection at the time of diagnosis, complete resection is followed by recurrence in majority of patients without further systemic therapy. Thus all PDA patients require systemic chemotherapy and more effective regimens are urgently needed. Combination chemotherapy is effective in controlling disease and prolonging survival in patients with advanced pancreatic cancer. Despite recent successful phase 3 studies in the first-line setting, there is no defined second-line treatment for patients who experience disease progression following first-line therapy. Consensus guidelines (such as the National Comprehensive Cancer Network (NCCN) guidelines) recommend clinical trial participation in this setting. The investigators' pre-clinical data suggests that decitabine treatment in the KPC model of pancreatic cancer leads to a significant up-regulation of interferon-related genes and a polarization of the infiltrating immune cells. Based on these results, the investigators have evaluated the effect of single agent decitabine or anti-PD1H (a homologue of PD1 with very similar function and expression pattern) compared to combination therapy (treatment with decitabine followed by PD1H blockade). The investigators' preliminary results showed minimal effect of either agent alone on tumor growth but marked decrease in tumor progression in the combination arm. These results form the foundation of this phase II study. This study will treat patients with the combination of azacitidine and pembrolizumab. A direct comparison between azacitidine and decitabine in terms of efficacy within a controlled clinical trial has not been performed thus far. In randomized myelodysplastic syndrome (MDS) trials, the remission rates were similar for azacitidine and decitabine but the overall survival in the experimental arm was significantly shorter in the decitabine trial compared to the azacitidine trial. A primary reason to utilize azacitidine in this setting is our desire to amply reduced dose therapy with the goal of maintaining subjects on therapy Low-dose azacitidine is being tested in phase I/II clinical trials for advanced solid tumors-mainly colorectal cancer, small-cell lung carcinomas, ovarian cancer, and breast cancer.