Window Study of Nivolumab With or Without Ipilimumab in Squamous Cell Carcinoma of the Oral Cavity

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied.

The purpose of this study is to evaluate effectiveness (how well the drug/s work) of
Nivolumab or Nivolumab combined with Ipilimumab prior to standard of care surgery.

Nivolumab and Ipilimumab are types of immunotherapy. Immunotherapy works by encouraging the
body's own immune system to attack cancer cells. Both nivolumab and Ipilimumab have been
demonstrated to activate the immune system to attack cancer cells in laboratory studies and
in patients with different types of cancers.

Nivolumab (Opdivo ™) has been approved by the US Food and Drug Administration (FDA) for the
treatment of metastatic melanoma (a type of skin cancer), and specific types of previously
treated advanced lung and kidney cancers. Ipilimumab (Yervoy™) is approved by the FDA for the
treatment of metastatic melanoma.

Because Nivolumab and Ipilimumab help the immune system work in different ways, the
combination of Nivolumab and Ipilimumab was tested in laboratory studies. The data from these
studies suggested that giving the two drugs together could be of benefit to patients, and
this was indeed found to be the case in patients with melanoma. The combination of Nivolumab
and Ipilimumab is now FDA approved as treatment for patients with metastatic melanoma.
However, the use of Nivolumab as well as Ipilimumab alone or in combination for the treatment
of patients with head and neck cancer is not approved. Results from clinical trials
investigating the safety and efficacy of Nivolumab and Ipilimumab in patients with head and
neck cancer are not available at this time.

In the proposed study, either Nivolumab or the combination of Nivolumab and Ipilimumab is
being tested is being tested prior to surgery to remove cancers of the oral cavity. By
stimulating the immune system to attack cancer cells, these drugs may cause the cancer to
decrease in size prior to surgery and prevent the cancer from coming back.

Inclusion Criteria:

- Pathologically confirmed squamous cell carcinoma of the oral cavity. Clinical stage
>=T2 (primary tumor greater than 2 cm in size) and/or evidence of regional nodal
involvement by clinical exam or imaging

- Only patients 18 years and older are eligible. There is no upper age limit but the
patients must be able to medically tolerate the regimen. Adverse event data are
currently unavailable on the use immune checkpoint blockade for participants < 18
years of age, and thus children are excluded from this study

- ECOG performance status <=1

- Patients much be a surgical candidate (e.g. their disease must be considered
resectable before any treatment and must have no serious medical contraindications
that definitively preclude undergoing general anesthesia) Ability to understand and
the willingness to sign a written informed consent document

- Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of
contraception (see Appendix B). WOCBP should use an adequate method to avoid pregnancy
for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives)
after the last dose of investigational drug. WOCBP is defined as any woman or
adolescent who has begun menstruation and is not post- menopausal. A post-menopausal
woman is defined as a woman who is over the age of 45 and has not had a menstrual
period for at least 12 months

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the
start of nivolumab

- Men who are sexually active with WOCBP must agree to use any contraceptive method (see
Appendix B) with a failure rate of less than 1% per year. Men receiving nivolumab and
who are sexually active with WOCBP will be instructed to adhere to contraception for a
period of 31 weeks after the last dose of investigational product Women who are not of
childbearing potential (ie, who are postmenopausal or surgically sterile as well as
azoospermic men do not require contraception)

- Participants must have normal organ and marrow function as defined below:

Laboratory parameters: WBC ≥ 2000/uL, Absolute neutrophil count (ANC) ≥ 1500/mm3; Platelets
≥ 100,000/mm3; Hemoglobin (Hgb) ≥ 9 g/dL; Hgb-A1C ≤ 7.5%; Aspartate aminotransferase (AST)
and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); Bilirubin ≤ 2.5 × ULN
(≤ 4 × ULN for subjects with Gilbert's disease); Alkaline phosphatase ≤ 2.5 × ULN;
Creatinine ≤ 1.5 × ULN

Exclusion Criteria:

- Pathologically proven, radiologic or clinical evidence of distant metastatic disease
(this includes all disease below the clavicles, as well as disease metastatic to the
bone, brain, or in the spinal canal)

- Any prior immunologic cancer therapy with systemic inhibitors of the PD-1 or CTLA-4
pathway

- Uncontrolled intercurrent illness including but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances: if they have been disease-free for at least 2 years and are
deemed by the investigator to be at low risk for recurrence of that malignancy; or if
diagnosed and treated within the past 2 years for cervical cancer in situ or basal
cell or squamous cell carcinoma of the skin

- Prior radiation to the head and neck region

- Prior chemotherapy within the last 2 years

- History of pneumonitis or interstitial lung disease

- Has evidence of active, noninfectious pneumonitis that required treatment with
steroids.

- Active, suspected or prior documented autoimmune disease that has required systemic
treatment in the last 2 years with immune modifying agents (e.g. replacement therapy
such as thyroxine, insulin or physiologic corticosteroids is not an exclusion
criteria). This does not include patients with vitiligo or type 1 diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger

- The subject is known to be positive for the human immunodeficiency virus (HIV),
HepBsAg, or HCV RNA

- Lack of availability for follow up assessments

- Concurrent administration of other cancer specific therapy during the course of this
study is not allowed

- Patients who require systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days of study
drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg
daily prednisone equivalents are permitted in the absence of active autoimmune disease

- History of allergy to study drug components

- History of severe hypersensitivity reaction to any monoclonal antibody

- The investigator's belief that the subject is medically unfit to receive nivolumab,
and/or ipilimumab or unsuitable for any other reason

- Has received a live vaccine within 28 days of planned start of study therapy