Cemiplimab and Cetuximab Prior Salvage Surgery in Patients With Recurrent Oral Cavity and HPV-negative Oropharyngeal Squamous Cell Carcinoma

Primary Objective:

• Primary Objectives To evaluate the clinical efficacy, defined as overall response rate, of cemiplimab combined with cetuximab in patients with recurrent oral cavity and HPV-negative oropharynx squamous cell carcinoma.

Secondary Objective:

-To evaluate other markers of clinical efficacy (pathological response rates, objective response rate per RECIST, overall survival) and safety.

Exploratory Endpoints

• To explore patient-reported outcomes (PRO) during CC and following salvage surgical resection
• Assess impact of cemiplimab and cetuximab on surgery and adjuvant therapy
• To explore biomarkers that may predict response to therapy

Inclusion criteria

• Subjects .18 years with histology-proven locoregionally recurrent oral cavity squamous cell carcinoma or HPV-negative OPSCC
• HPV testing is required only in oropharyngeal sites and must be negative
• Amenable to salvage surgery
• Disease recurrence at least 3 months after completion of curative-intent therapy, which must include at least surgery and post operatory radiation. Previous systemic therapy is the curative-setting is not required but allowed (e.g., neoadjuvant chemotherapy, concurrent chemotherapy).
• Measurable disease per RECIST 1.1
• Performance status ECOG of 0 or 1
• Willing to undergo baseline (if archival tumor specimen is not available) and on-treatment biopsy for correlative studies
• Laboratory measurements, blood counts:

• Hemoglobin ≥ 9 g/dL. Red blood cell transfusions are permitted to meet the hemoglobin inclusion criteria
• Absolute neutrophil count ≥ 1 x 109/mL
• Platelets ≥ 80 x 109/mL
• Laboratory measurements, renal function:

a) Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation

• Laboratory measurements, hepatic function:

• AST and ALT ≤ 3 x ULN
• Total bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN and primarily unconjugated if subject has a documented history of Gilbert's syndrome or genetic equivalent.
• Female subjects with reproductive potential must practice two effective contraceptive measures for the duration of study drug therapy and for at least 120 days after completion of study therapy. The two birth control methods can be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The following are considered adequate barrier methods of contraception: diaphragm, condom, copper intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents).
• Male participants who are sexually active with women with reproductive potential must agree to use contraception for the duration of treatment and for at least 90 days after completion of study therapy.

Exclusion criteria

• Disease recurrence within 3 months after completion of definitive treatment (including surgery, post operatory, systemic therapy)
• Distant metastatic disease (M1), visceral and/or distant nodal
• Prior treatment with an t immune checkpoint inhibitor agent in the curative setting is allowed if over 1 year from the date of completion (last dose)
• Subjects with a condition requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) within 14 days of the first dose of study drug.

Exceptions: Physiologic replacement doses are allowed even if they are >10 mg of prednisone/day or equivalent, as long as they are not being administered for immunosuppressive intent. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder.

• Subjects with active, known, or suspected autoimmune disease that has required systemic therapy within 5 years of the projected enrollment date. Exceptions: Subjects with vitiligo, type I diabetes mellitus, and endocrinopathies (including hypothyroidism due to autoimmune thyroiditis) only requiring hormone replacement, childhood asthma that has resolved, or psoriasis that does not require systemic treatment are permitted.
• History of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management.
• Recipient of a solid organ transplant (other than corneal transplants)
• Prior allogeneic stem cell transplantation, or autologous stem cell transplantation
• History of previous malignancy other than malignancy treated with curative intent within less than 5 years. Participants with the following diagnoses represents an exception and may enroll if ≥ 1 year with no evidence of active disease before the first dose of the study drug:

• Locally advanced non-melanoma skin cancers with no current evidence of disease
• Melanoma in situ with no current evidence of disease
• Localized cancer of the prostate with prostate-specific antigen of <1 ng/mL
• Treated or localized well-differentiated thyroid cancer
• Treated cervical carcinoma in situ
• Treated ductal/lobular carcinoma in situ of the breast
• Evidence of uncontrolled, active infection, requiring systemic anti-bacterial, anti-viral or anti-fungal therapy ≤ 10 days prior to administration of cemiplimab and cetuximab. Subjects with known hepatitis B, hepatitis C (HCV), or HIV infection could go on study if the viral load is undetectable at screening.
• Disease or medical conditions that would substantially increase the risk-benefit ratio of participating in the study that include acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV
• Female participants who are pregnant or breast-feeding
• Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient