Cemiplimab in Treating Participants With Recurrent Stage III-IV Head and Neck Squamous Cell Cancer Before Surgery

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR) using Response Evaluation Criteria in Solid
Tumors (RECIST) version (v)1.1 criteria to neoadjuvant cemiplimab (REGN2810) (anti-PD-1
inhibitor) in patients with advanced-stage cutaneous squamous cell carcinoma (cSCC) of the
head and neck who are planned for definitive local surgery and radiation.

SECONDARY OBJECTIVES:

I. To determine the pathologic response rate to neoadjuvant REGN2810 in patients with
advanced-stage cSCC of the head and neck.

II. To determine the safety and tolerability of neoadjuvant REGN2810 in patients with
advanced-stage cSCC of the head and neck who are planned for definitive local surgery and
radiation.

III. To estimate the 2-year disease-specific (DSS), disease-free (DFS) and overall survival
(OS) compared to historical controls.

IV. To determine the time to recurrence and patterns of failure. V. To evaluate the effects
of neoadjuvant REGN2810 on the expression of PD-1 and potential related immune regulating
targets in cSCC of the head and neck.

OUTLINE:

Participants receive cemiplimab intravenously (IV) over 30 minutes every 3 weeks. Courses
repeat every 3 weeks for up to 6 weeks in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, participants are followed up for 30 days and then
periodically for up to 5 years.

Inclusion Criteria:

- Biopsy-proven, primary or recurrent advanced-stage (III/IV) cutaneous squamous cell
carcinoma of the head and neck.

- Surgical resection must be planned as primary therapy with expected adjuvant radiation
therapy. Patients are eligible with previous surgical intervention if they have
residual or recurrent disease, and it is greater than 4 weeks since surgery and they
have fully recovered from surgery.

- Signed informed consent form (ICF).

- Ability and willingness to comply with the requirements of the study protocol.

- Absolute neutrophil count (ANC) >= 1500 cells/uL (obtained within 4 weeks [+/-3 days]
prior to study entry).

- White blood cell (WBC) counts >= 2500/uL (obtained within 4 weeks [+/-3 days] prior to
study entry).

- Lymphocyte count >= 300/uL (obtained within 4 weeks [+/-3 days] prior to study entry).

- Platelet count >= 100,000uL for patients with hematologic malignancies, platelet count
>= 75,000/uL (obtained within 4 weeks [+/-3 days] prior to study entry).

- Hemoglobin >= 9.0 g/dL (obtained within 4 weeks [+/-3 days] prior to study entry).

- Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception:
patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be
enrolled (obtained within 4 weeks [+/-3 days] prior to study entry).

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN
(obtained within 4 weeks [+/-3 days] prior to study entry).

- Alkaline phosphatase =< 2.5 x ULN with the following exception: patients with
documented bone metastases: alkaline phosphatase =< 5 x ULN (obtained within 4 weeks
[+/-3 days] prior to study entry).

- Serum creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min on the basis of the
Cockcroft-Gault glomerular filtration rate estimation (obtained within 4 weeks [+/-3
days] prior to study entry).

- Measurable disease per RECIST v1.1 and/or per direct clinical measurements for primary
tumors upon a variance between clinical and radiographic evaluation.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
=< 1.5 x ULN (This applies only to patients who do not receive therapeutic
anticoagulation; patients receiving therapeutic anticoagulation [such as
low-molecular-weight heparin or warfarin] should be on a stable dose.)

- No evidence of distant metastases and measurable disease (> 1.5 cm).

Exclusion Criteria:

- Any approved anticancer therapy, including chemotherapy, hormonal therapy, or
radiotherapy, within 3 weeks prior to initiation of study treatment; however, the
following are allowed: Hormone-replacement therapy; palliative radiotherapy for bone
metastases > 2 weeks prior to cycle 1, day 1.

- Adverse events (AEs) from prior anticancer therapy that have not resolved to grade =<
1 except for alopecia.

- Bisphosphonate therapy for symptomatic hypercalcemia (use of bisphosphonate therapy
for other reasons [e.g., osteoporosis] is allowed.)

- Patients with acute leukemias, accelerated/blast phase chronic myelogenous leukemia,
chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory
myeloma.

- Pregnancy, lactation, or breastfeeding.

- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies.

- Inability to comply with study and follow-up procedures.

- History or risk of autoimmune disease, including but not limited to systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis. Patients with a history of
autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be
eligible. Patients with controlled type 1 diabetes mellitus on a stable insulin
regimen may be eligible.

- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be
excluded) are permitted provided that they meet the following conditions: Patients
with psoriasis must have a baseline ophthalmologic exam to rule out ocular
manifestations; Rash must cover less than 10% of body surface area (BSA); Disease is
well controlled at baseline and only requiring low potency topical steroids (e.g.,
hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%,
alclometasone dipropionate 0.05%); No acute exacerbations of underlying condition
within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA],
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids).

- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan. (History of radiation pneumonitis in the radiation field
[fibrosis] is permitted.)

- Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications.

- History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic
or acute) or hepatitis C infection. (Patients with past or resolved hepatitis B
infection; defined as having a negative hepatitis B surface antigen [HBsAg] test and a
positive anti-HBc [antibody to hepatitis B core antigen] antibody test, are eligible.
Patients positive for hepatitis C virus [HCV] antibody are eligible only if polymerase
chain reaction [PCR] is negative for HCV ribonucleic acid [RNA].)

- Active tuberculosis.

- Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia.

- Signs or symptoms of infection as determined by the treating team within 2 weeks prior
to cycle 1, day 1.

- Received oral or IV antibiotics within 2 weeks prior to cycle 1, day 1 (Patients
receiving prophylactic antibiotics [e.g., for prevention of a urinary tract infection
or chronic obstructive pulmonary disease] are eligible.)

- Major surgical procedure within 28 days prior to cycle 1, day 1.

- Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
anticipation that such a live, attenuated vaccine will be required during the study.
(Influenza vaccination should be given during influenza season only [approximately
October to March]. Patients must not receive live, attenuated influenza vaccine [e.g.,
FluMist] within 4 weeks prior to cycle 1, day 1 or at any time during the study.)

- Malignancies other than the disease under study within 5 years prior to cycle 1, day
1, with the exception of those with a negligible risk of metastasis or death and with
expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, localized prostate cancer treated surgically with
curative intent, or ductal carcinoma in situ treated surgically with curative intent)
or undergoing active surveillance per standard-of-care management (e.g., chronic
lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score =< 6, and
prostate-specific antigen [PSA] =< 10 mg/mL, etc.)

- Continued sexual activity in men** or women of childbearing potential*** who are
unwilling to practice highly effective contraception during the study and until 6
months after the last dose of study drug (highly effective contraceptive measures
include stable use of oral contraceptives such as combined estrogen and progestogen
and progestogen only hormonal contraception or other prescription pharmaceutical
contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device
[IUD]; intrauterine hormone-releasing system [IUS]; bilateral tubal ligation;
vasectomy, and sexual abstinence). (**Contraception is not required for men with
documented vasectomy ***Postmenopausal women must be amenorrheic for at least 12
months in order not to be considered of childbearing potential. Pregnancy testing and
contraception are not required for women with documented hysterectomy or tubal
ligation.)

- Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway
targeting agents. Patients who have received prior treatment with anti-CTLA-4 may be
enrolled, provided the following requirements are met: Minimum of 12 weeks from the
first dose of anti-CTLA-4 and > 6 weeks from the last dose. No history of severe
immune-related adverse effects from anti-CTLA 4 (National Cancer Institute [NCI]
Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4).

- Treatment with systemic immunostimulatory agents (including but not limited to
interferon [IFN] or interleukin [IL]-2) within 6 weeks or five half-lives of the drug
(whichever is shorter) prior to cycle 1, day 1.

- Treatment with investigational agent within 4 weeks prior to cycle 1, day 1 (or within
five half lives of the investigational product, whichever is longer).

- Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1. (Patients
who have received acute, low dose, systemic immunosuppressant medications [e.g., a
one-time dose of dexamethasone for nausea] may be enrolled. The use of inhaled
corticosteroids and mineralocorticoids [e.g., fludrocortisone] for patients with
orthostatic hypotension or adrenocortical insufficiency is allowed.)

- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins.

- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation.

- Patients with prior treatment with idelalisib.