New combo attack on stubborn head and neck cancers enters early human testing

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * Pathologically confirmed either persistent and/ or locoregionally recurrent HNSCC of oral cavity, pharynx, larynx, unknown primary head and neck (H\&N) squamous cell carcinoma * Resectable disease as determined by the surgeon and team * Eastern Cooperative Oncology Group (ECOG) performance status (PS) \< 2 * At least 18 years of age * Adequate hematologic, renal, and hepatic function * Must have at least 2 week washout period from prior therapy * Willingness and ability to provide informed consent * Negative pregnancy test for females of reproductive potential * Patients who have undergone therapy for their cancer, such as surgery and/or chemotherapy and/or radiotherapy and recurred * Disease measurable by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria. * Prior definitive and palliative chemotherapy will be allowed * Prior radiation therapy will be allowed * Tumor tissue from resected site of disease must be provided for biomarker analyses, in addition to urine and blood sample as scheduled per protocol * White blood cell (WBC) \>= 2000/uL (obtained within 14 days of randomization) * Neutrophils \>= 1500/uL (obtained within 14 days of randomization) * Platelets \>= 100 x10\^3/uL (obtained within 14 days of randomization) * Hemoglobin \> 9.0 g/dL (obtained within 14 days of randomization) * Serum creatinine =\< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) \>= 40 mL/min (Cockcroft and Gault or Wright formula may be used according to local practice) (obtained within 14 days of randomization) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3 x institutional ULN * Total Bilirubin =\< 1.5 x institutional ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) * Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for four months after the last dose of pembrolizumab. * Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) * Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of four months after the last dose of investigational product Exclusion Criteria: * Requirement of immunosuppressive therapy within 14 days of randomization * Salivary gland carcinomas, lip carcinoma, adenocarcinoma of the skin * Prior use of immune checkpoint blockade agent * History of human immunodeficiency virus (HIV), hepatitis B, C: Participants who test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection, those who test positive for human immunodeficiency virus (HIV) or have known acquired immunodeficiency syndrome (AIDS) * Unresectable disease, as determined by the surgeon and team * Subjects with history of grade 3 toxicity with prior immunotherapy * Patients with distant metastases * Subjects with active autoimmune disease * Breastfeeding women * Additional prior malignancy within the previous 3 years (treated or untreated, except for skin carcinomas treated with excision alone and carcinoma in situ of the cervix) * Palliative radiotherapy less than 14 days prior to first dose of study drug * Any history of hypersensitivity to any of the trial medications * Poorly controlled or serious medical or psychiatric illness likely to interfere with participation and/or compliance in this clinical trial * Prisoners or subjects who are involuntarily incarcerated * Patients not available for follow-up/future contact as defined in the ICF * Note: Patients on this protocol are not excluded from participation in other clinical trials