We are doing this study to find the most effective, safe dose of an experimental drug called zanzalintinib (the study drug). We want to know how well it works in combination with pembrolizumab when it is given to people who have recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)

Adults ages 18+ who:

• Are diagnosed with recurrent or metastatic HNSCC that cannot be cured with standard treatments
• Have not been treated with any anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy
• Have never taken zanzalintinib

For more information about who can join this study, please contact the study team at annmarie.peters@duke.edu or 919-681-4768.

If you decide to participate in this study, you will have a Screening visit to see if you meet the criteria to be included in this study. If you meet the criteria, you will get a random assignment to 1 of 2 groups:

• Group 1: Participants in this group will get pembrolizumab (200 mg) given by a needle into a vein in the arm (also called an intravenous [IV] infusion) every 3 weeks and take the study drug once daily by mouth.
• Group 2: Participants in this group will get pembrolizumab (200 mg) every 3 weeks take a placebo (a pill that looks like the study drug but contains no medication) once daily by mouth.

You will have study visits every 3 weeks while you are taking the study regimen. Your visits will be more frequent during the first 2 months of the study. On days when your infusion is given at the study center, some tests will need to be done before you get your dose of the study drug, and some will be done after.
You may continue to receive the study drug as long as the study doctor thinks it is suitable for you based on your clinical condition and possible continued benefit. Once you stop the study regimen, you will return to the study center after about 30 days for a safety follow-up visit. The following tests and procedures will be performed throughout the study:

• A physical exam and vital signs
• Electrocardiogram (ECG), a recording of the electrical activity of your heart
• Blood and urine samples collected
• Tumor tissue biopsy
• Imaging assessments (CT/MRI)
• Questionnaires

It is estimated that you will be in the study for about 3-5 months. However, it is possible that you could take part in this study for 2 years or longer. Study procedures with pembrolizumab will last no longer than 2 years. You will be asked to take part in follow-up activities to see how you are doing after you stop taking the study drug. Your total time in the study will depend on how long those follow-up activities are needed.