This open-label research study will evaluate two investigational therapies, TransCon TLR7/8 Agonist and TransCon IL-2 β/γ, which are not approved by the U.S. Food and Drug Administration (FDA). Pembrolizumab, an FDA approved medication, also a study drug on this trial is given as standard of care for this type of cancer. This study begins with two study treatment groups, Groups A:TransCon TLR7/8 Agonist injected directed into the tumor once every 21 days and Group B: TransCon IL-2 β/γ which is given through a IV over 30 minutes once every 21 days. The surgery may occur after Cycle 2 of the medications at a scheduled time that the study doctor feels appropriate. Once 12 participants have completed study treatment, 6 in each group (A and B), an analysis will determine the continuation of the study. If it passes the criteria, the study will continue, and another study treatment group, Group C: Pembrolizumad alone given through an IV over 30 minutes once every 21 days, will open. Participants will be randomly assigned to one of the three groups. At the present time, limited information is available on the adverse side effects potentially related to TransCon IL-2 β/γ and TransCon TLR7/8. Very common side effects observed with TransCon IL-2 β/γ include changes with your immune system being stimulated, blood pressure, and heartbeat. Also flu-like symptoms (nausea, fever, and chills), changes in lung/liver/kidney function, and brain related symptoms including dizziness, weakness, confusion, difficulty speaking, and/or decreased brain function, which may become life-threatening. TransCon TLR7/8 Agonist requires more data collection to determine the extent of side effects in humans. At this time, there are no proven benefits in humans however, the animal studies have shown promising results. The national accrual goal for this study is 92 participants and MUSC projects to accrual approximately 5 participants per year over a span of 2 years.

This phase III study is for participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that is negative for a type of virus called human papilloma virus (HPV). If decided to participate in this study, participants will be receive either ficlatuzumab in combination with cetuximab, or placebo in combination with cetuximab. There are 3 Arms participants will be randomly assigned to: Arm 1 will receive ficlatuzumab (10mg/kg by intravenous (IV) infusion) and cetuximab (by IV infusion), Arm 2 will be given ficlatuzumab (20mg/kg by IV infusion) and cetuximab, and Arm 3 will receive placebo and cetuximab. The effectiveness of the 2 different ficlatuzumab groups (Arm 1 and Arm 2) will be compared at the first on-study scan, and the more successful Arm will began enroll more participants. This study is estimated to last approximately 5 years. Study drugs will be administered until disease progression or unacceptable toxicity, withdrawal of consent, death, or until the Sponsor terminates the study (whichever comes first). The main risk associate with the trial are swelling of your lower legs or arms, fatigue, shortness of breath, vomiting, diarrhea or constipation, bone pain, decreased appetite, anemia, high level of liver enzymes in your blood, dizziness, infusion reactions, cardiopulmonary arrest, pulmonary (lung) toxicity, skin reactions, inflammation of the mouth, low blood counts, liver problems, infection, headache, allergic reactions, and there may be unknown risks. This treatment can not guarantee the cancer will get better, since it may stay the same or get worse. What is discovered from this study may help other people in the future. The alternative to this study is not participating in this study and receiving HNSCC in patients who have previously received immunotherapy including chemotherapy with other treatment drugs or another clinical trial.

This study is designed to learn more about how nivolumab and ipilimumab, with or without cabozantinib effects the growth and spreading of head and neck cancer. If decided to take part in this study, participants will go through a screening period, treatment period, and follow-up period. During the screening period following signing of consent form participants will be evaluated for screening criteria and determined if they qualify for the study. During treatment period participants will be randomly assigned to either receive the combination of two immunotherapy drugs, nivolumab and ipilimumab for up to 2 years, or the two immunotherapy drugs with an additional targeted drug, cabozantinib, for up to 2 years unless your cancer gets worse or the side effects of the treatment become too severe. In the follow up period the side effects will be observed by the study team every 3 to 4 months for 2 years after treatment. The most common risks and discomforts expected in this study are diarrhea, nausea, vomiting, tiredness, weight loss, loss of appetite, changes in taste or voice, redness, pain or peeling of palms and soles, and high blood pressure which may cause blurred vision. There may not a benefit from joining the study. The head and neck cancer may improve while on this study but it may not, and it may even get worse. It will also help inform how well this combination treatment works at curing this type of cancer. The study results may be used to help others in the future.