• Patients must have clinically suspected SCCHN that is amenable to surgical resection with therapeutic intent

• Be willing and able to provide written informed consent/assent for the trial

• Be \>=18 years of age on day of signing informed consent.

• Agree to research analysis of an existing pre-treatment biopsy available that was obtained within 90 days prior to the day of consent or agree to a new biopsy for research (or clinical diagnosis) within the screening window. Needle biopsies must be at least 20 Gauge in diameter

• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale

• Demonstrate adequate organ function as defined below. All screening labs should be performed within 14 days of treatment initiation

‣ Absolute neutrophil count (ANC) \>=1,500 /microliter (mcL)

⁃ Platelets \>=100,000 / mcL

⁃ Hemoglobin \>= 9 g/dL

⁃ Lymphocyte count \>= 500/mcL

⁃ White blood count \>=3,000/mcL or \<=14,000/mcL

⁃ Serum creatinine =\< 1.5 x upper limit of normal (ULN) OR ≥50 mL/min creatinine clearance by Cockcroft-Gault formula for participants in whom, in the Investigator's judgment, serum creatinine levels do not adequately reflect renal function. \* Creatinine clearance should be calculated per institutional standard

⁃ Serum total bilirubin =\< 1.5 x ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 ULN

‣ \* Excluding Gilbert's syndrome. Participants with Gilbert's syndrome will be eligible for the study. The diagnosis of Gilbert's syndrome is suspected in people who have persistent, slightly elevated levels of unconjugated bilirubin (\<= 3.0 x ULN) without any other apparent cause. A diagnosis of Gilbert's syndrome will be based on the exclusion of other diseases on the basis of the following criteria: i. Unconjugated hyperbilirubinemia noted on several occasions ii. No evidence of hemolysis (normal hemoglobin, normal haptoglobin levels, reticulocyte count), and lactate dehydrogenase iii. Normal liver function tests iv. Absence of other diseases associated with unconjugated hyperbilirubinemia

⁃ Aspartate aminotransferase (AST) \[serum glutamic-oxaloacetic transaminase (SGOT)\] and alanine aminotransferase (ALT) \[serum glutamate pyruvate transaminase (SGPT)\] =\< 3 x ULN

⁃ Albumin \>= 2.5 mg/dL

⁃ International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants

⁃ Activated partial thromboplastin rime (aPTT) =\< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 5 months after the last dose of study medication.

• Male subjects must agree to use an adequate method of contraception and refrain from donating sperm, starting with the first dose of study therapy through 5 months after the last dose of study therapy

‣ Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.