A Study of Cemiplimab With Chemotherapy and Immunotherapy in People With Head and Neck Cancer

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of squamous cellcarcinoma of the head and neck that has arisen from the oral cavity, oropharynx,nasal cavity, paranasal sinuses, larynx, or hypopharynx

• Clinical stage T1, N2-3; T2, N1-3, T3/T4a, Any N (AJCC, 8th ed.) without evidence ofdistant metastasis (M0) based on PET/CT or CT chest, abdomen, and pelvis, for whichstandard-of-care treatment would entail surgical resection with adjuvant radiation +/- chemotherapy.

° Patients with recurrent and multiple primary head and neck cancers that aresurgically resectable are eligible if the patient did not receive prior radiation orsystemic therapy.

• Disease must be amenable to surgical resection.

• The patient must be a surgical candidate.

1. Hemoglobin > 9.0 g/dL

2. Absolute neutrophil count (ANC) >1.5 x 10^9/L

3. Platelet count >100 x 10^9/L

4. Serum creatinine <1.5 upper limit of normal (ULN) or estimated creatinineclearance (CrCl) >30 mL/min

5. Adequate hepatic function:

• Total bilirubin <1.5 x upper limit of normal ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both < 3 x ULN

• Alkaline phosphatase (ALP) <2.5 x ULN Note: For patients with Gilbert syndrome,total bilirubin <3x ULN. Upper central must be documented appropriately as pastmedical history.

• Men and woman >18 years old

• Eastern cooperative oncology group performance status < 1

Exclusion Criteria:

• Prior radiation and systemic therapy for a head and neck cancer.

• Oral cavity cancer that is not amenable to surgical resection or the patient is nota surgical candidate.

• Active or prior documented autoimmune or inflammatory disorders that have beentreated with steroids or immunomodulator therapy in the past 5 years.

Exceptions: Patients with vitiligo, type 1 diabetes mellitus, and endocrinopathies (including hypothyroidism due to autoimmune thyroiditis) only requiring hormone replacement, childhood asthma that is resolved, or psoriasis it does not require systemic treatment are permitted.

• Conditions requiring systemic treatment with either corticosteroids (> 10 mg dailyprednisone equivalents) or other immunosuppressant medications within 14 days oftreatment on study.

• Receipt of live attenuated vaccine within 30 days prior initiating treatment onstudy.

• Prior allogeneic stem cell transplantation, or autologous stem cell transplantation.

• Any infection requiring hospitalization and/or intravenous antibiotic therapy within 2 weeks of the start of treatment.

• Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B orhepatitis C virus (HBV or HCV) infection; or diagnosis of immunodeficiency.

1. Patients with known HIV infection who have controlled infection (undetectableviral load (HIV RNA PCR) and CD4 count above 350, either spontaneously or on astable antiviral regimen) are permitted. For patients with controlled HIVinfection monitoring will be performed per local standards

2. Patients with HBV (hepatitis B surface antigen positive; HBsAg+) who havecontrolled infection (serum HBV DNA PCR that is below the limit of detectionand receiving anti-viral therapy for HBV) are permitted. Patients withcontrolled infections must undergo periodic monitoring of HBV DNA. Patientsmust remain on anti-viral therapy for at least 6 months be on the last dose ofCemiplimab.

3. Patients were HCV antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR, either spontaneously or in response to successfulprior course of anti-HCV therapy) are permitted.

• History of immune-related pneumonitis with the last 5 years.

• History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis,organizing pneumonia) or active, noninfectious pneumonitis that requiredimmune-suppressive doses of leuko-corticoids to assist with management.

• Known hypersensitivity or allergy to any of the excipients in the cemiplimab drugproduct.

• Patients with a history of solid organ transplant (exception: corneal transplant)

• Any medical comorbidity, physical examination finding, or metabolic dysfunction, orclinical laboratory abnormality that in the opinion of the investigator renders thepatient unsuitable for participation in a clinical trial due to high safety risks.

• Women with a positive serum or urine beta-hCG pregnancy test at screening/baselinevisit. If positive, pregnancy must be ruled out by ultrasound for patient to beeligible.

• Breast-feeding women

• Women of childbearing potential who are sexually active and aren't willing topractice highly effective contraception prior to the first dose of Cemiplimab,during the study, and for at least 180 days after the last dose. Highly effectivecontraceptive measures include:

1. Stable use of combined estrogen and progesterone containing hormonalcontraception or progesterone and-only hormonal contraception associated withinhibition of ovulation initiated 2 or more menstrual cycles prior to screening

2. Intrauterine device; intrauterine hormone-releasing system

3. Bilateral tubal ligation

4. Vasectomized partner and/or

5. Sexual abstinence