Safety and Efficacy of Nivolumab in Treating Oral Proliferative Verrucous Leukoplakia

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

The purpose of this study is to evaluate effectiveness (how well the drug works) of nivolumab
in treating OPVL and or prolonging the onset of possible malignancy.

Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own
immune system to attack cancer cells. Nivolumab has been demonstrated to activate the immune
system to attack cancer cells in participants with different types of cancers. OPVL has a
high risk for turning into cancer and the investigators are testing if nivolumab may help to
shrink the white lesions in the participant's mouth and reduce cancer risk.

In November 2016, the Food and Drug Administration (FDA) approved nivolumab for the treatment
of participants with recurrent or metastatic squamous cell carcinoma of the head and neck
(SCCHN). Squamous cell carcinoma is the kind of cancer that OPVL can transform into.

Inclusion Criteria:

- Subject must have histologically confirmed oral proliferative verrucous leukoplakia
(OPVL), as defined by: multifocal lesions (≥ 2) or contiguous lesions ≥ 3 cm or a
single lesion ≥ 4 cm in largest diameter (at least one lesion with any degree of
dysplasia). (Note: no restriction on the length of time that patients have had one or
more existing lesions)

- Willing to provide blood and tissue from diagnostic biopsies

- Any smoking history is permitted. A history of prior or current tobacco use is not an
exclusion criteria. While discouraged, patients are permitted to continue tobacco use
while on the study.

- Age 18 years or older

- ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A)

- Participant must have normal organ and marrow function as defined below within 21 days
prior to study registration:

- leukocytes ≥3,000/mcL

- absolute neutrophil count ≥1,000/mcL

- platelets ≥100,000/mcL

- total bilirubin ≤2.0 g/dL

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- creatinine within normal institutional limits OR

- creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal

- 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. WOCBP should plan to use an adequate method to avoid pregnancy for 5
months (30 days plus the time required for nivolumab to undergo five half-lives) after
the last dose of investigational drug

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 iu/l or equivalent units of hcg) at screening. Pregnancy test
will be repeated on the day of the first dose of study drug (before administration),
although results of this test are not required for registration.

- "Women of childbearing potential (WOCBP)" is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes. In addition, women under the age of 55 must have a documented
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL

- Men who are sexually active with WOCBP must agree to use any contraceptive method with
a failure rate of less than 1% per year. Men who are sexually active with WOCBP will
be instructed to adhere to contraception for a period of 7 months 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

Exclusion Criteria:

- Known carcinoma in situ (CIS) or invasive squamous cell carcinoma of the oral cavity.
A history of a prior stage III (T1-2N1, T3N0) or IV (T1-3N2, T4N0) invasive head &
neck squamous cell carcinoma treated with surgery and radiation with or without
chemotherapy. Patients with prior locoregionally advanced tumors treated with surgery
alone are eligible.

- Existing significant autoimmune conditions. Patients with a history of Hashimoto
thyroiditis who are stable on replacement hormone therapy are not excluded. Patients
cannot be on long-term (> 4 weeks) corticosteroids at doses exceeding prednisone 20 mg
(or its equivalent) prior to enrollment. Short-term corticosteroid dosing is permitted
as long as steroids are discontinued within 2 weeks of study registration.

- Subject who has had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Subject who has been treated with immunotherapy. This includes prior treatment with
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways.

- 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.

- Known human immunodeficiency virus carrier or a diagnosis of immunodeficiency.

- Any positive test result for hepatitis B virus or hepatitis C virus indicating
presence of virus, e.g., Hepatitis B surface antigen (HBsAg, Australia antigen)
positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA is negative).

- A personal history of hematopoietic stem cell or solid organ transplant.

- Known non-infectious pneumonitis or any history of interstitial lung disease.

- A personal history of other active malignancies, with the exception of
non-melanomatous skin cancers, low-risk prostate adenocarcinoma on active
surveillance, or treated cancers in remission for the last 5 years