Phase II Trial of Immunotherapeutic HPV Vaccine PRGN-2009 With Pembrolizumab Before Standard Treatment in Subjects With Newly Diagnosed HPV-Associated Oropharyngeal Cancer

Oropharyngeal Squamous Cell Carcinoma (SCC)

HPV16/18, PD-1 inhibitor, Monoclonal Antibody

Background: Cancers in and around the mouth associated with human papilloma virus (HPV) are common. Two treatments (the drug pembrolizumab and the HPV vaccine PRGN-2009) have been shown to work well when used individually against these cancers. Researchers want to find out if they might work better when used together. Objective: To test pembrolizumab combined with PRGN-2009 in people with HPV-positive cancers in and around the mouth. Eligibility: Adults aged 18 and older newly diagnosed with HPV-positive cancers in and around the mouth. Design: Participants will be screened. They will have a physical exam with blood tests. They will have imaging scans. They may need to have a biopsy: A sample of tissue will be taken from the tumor. PRGN-2009 is given as an injection under the skin. Pembrolizumab is given through a tube attached to a needle inserted into a vein in the arm. Participants will have at least 3 clinic visits: At the first, they will receive both the drug and the vaccine; 15 days later, they will receive a second shot of the vaccine. At the third visit, about 1 week after the second, they will have follow-up tests. During these visits, participants will give samples of blood, urine, and saliva. Imaging scans and biopsies will be repeated. They will have tests of their heart function. Participants may opt to return for another follow-up visit about 1 month after their second dose of the vaccine. Participants will have follow-up contacts by phone 3 and 6 months after starting the study. The calls will continue once a year for 5 years.

Background -Human papilloma virus-associated oropharyngeal cancer (HPV-OPC) is the most common HPV-associated malignancy in the United States, with an increasing incidence. Although the prognosis for stage I HPV-OPC is favorable, about 20 percent of patients with stage II disease and 35 percent of patients with stage III disease will die within four years. * The standard-of-care primary treatment for HPV-OPC without distant metastasis is definitive concurrent chemoradiotherapy (primarily) or surgery (which may be followed by adjuvant chemoradiotherapy). * Neoadjuvant/induction immunotherapy is in clinical trials aiming to induce antigen-specific immunity prior to primary treatment and to reduce the risk of disease relapse. Pembrolizumab, an anti-PD-1 monoclonal antibody that is Food and Drug Administration (FDA)-approved for first-line treatment of recurrent/metastatic head and neck squamous cell cancer (HNSCC) has been used in these trials and shown to be safe and active. * PRGN-2009 is an anti-HPV immunotherapeutic vaccine. It has demonstrated induction of HPV antigen-specific responses and tumor growth inhibition in pre-clinical models of HPV-associated malignancy, with improved anti-tumor efficacy upon addition of T-cell immune checkpoint blockade. In a Phase I/II trial at the National Cancer Institute (NCI) it has demonstrated excellent safety and tolerability as monotherapy or in combination with checkpoint blockade in recurrent/metastatic disease but also as monotherapy in neoadjuvant/induction context for HPV-OPC. Objective: -To determine if the use of PRGN-2009 with pembrolizumab in participants with p16-positive OPC can result in a \>= 2-fold increase in cluster of differentiation 3 (CD3+) tumor infiltrating T cells post treatment compared with pre-treatment. Eligibility: * Age \>= 18 years. * Pathologically confirmed newly diagnosed Stage I (T1, T2; N1), II or III p16-positive OPC. Design: * This is a Phase II study to evaluate the effect of PRGN-2009 and pembrolizumab before definitive treatment in subjects with p16-positive OPC. * Participants will receive PRGN-2009 and pembrolizumab prior to definitive treatment. * Participants will receive two doses of PRGN-2009 5x10\^11 viral particles (VP) subcutaneously (SC) approximately two weeks apart, and one dose of pembrolizumab 200 mg intravenously (IV) concurrently with the first vaccine dose. * Up to 20 evaluable participants will be enrolled.

United States