Study of Pembrolizumab (MK-3475) for High Risk Oral Intra-Epithelial Neoplasias

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as
in the flip of a coin) to 1 of 2 study groups. If you are assigned to Arm A (the control
group), you will not receive treatment and will only be observed. If you are in Arm B, you
will receive pembrolizumab. This is called randomization.

Both you and the study doctor will know to which group you have been assigned. If you are in
Arm A, you will not be able to crossover into Arm B and you will not have any study visits
until the end-of-treatment/follow-up visits (described below).

Study Drug Administration:

Each cycle is 3 weeks (21 days).

If you are in Arm B, you will receive pembrolizumab by vein over 30 minutes on Day 1 (+/- 7
days) of Cycles 1-4.

Study Visits (Arm B Only):

On Day 1 of Cycles 2-4:

- You will have a physical exam.

- Blood (about 3-4 teaspoons) will be drawn for routine tests.

- During Cycle 2, blood (about 4 tablespoons) will be drawn for biomarker testing.

- During Cycle 2, you will have 2 oral swabs for biomarker testing.

Any blood, tissue, and oral swabs left over after study testing (including the follow-up
visits described below) will be stored at MD Anderson for use in future biomarker testing,
including genetic biomarkers, as described in this consent form.

If at anytime during the study or during follow-up you are diagnosed with oral cancer, or if
you previously had oral cancer and it returns:

- Blood (about 4 tablespoons) will be drawn for biomarker testing.

- You will have oral swabs for biomarker testing.

Length of Study Participation:

If you are in Arm B, you may receive pembrolizumab for up to 4 cycles. You will no longer be
able to take the study drug if the disease gets worse, if intolerable side effects occur, or
if you are unable to follow study directions.

Please speak to your study doctor if you would like to stop receiving the study drug so this
can be done safely.

All participants will take part in the end-of-treatment and follow-up visits.

End-of-Treatment Visit:

About 3 months after your first dose of study drug or randomization:

- You will have a physical exam.

- Your tobacco and alcohol history will be collected.

- Blood (about 3-4 teaspoons) will be drawn for routine tests.

- Blood (about 4 tablespoons) will be drawn for biomarker testing.

- Oral lesions will be measured and biopsied to check the status of the disease. If you
had a lesion and it went away, the area where the lesion was located previously will be
biopsied.

- You will have 2 oral swabs collected for biomarker testing.

- If you are in Arm B, urine will be collected for routine tests.

- If you are in Arm B and can become pregnant, blood (about 2 teaspoons) or part of the
above urine sample will be collected for a pregnancy test.

Follow-Up Visits:

About 6, 9, 18, 24, and 30 months after your first dose of study drug or randomization:

- You will have a physical exam.

- Your tobacco and alcohol history will be collected.

- At 6 months only and if you are in Arm B, blood (about 3-4 teaspoons) will be drawn for
routine tests.

About 12 and 36 months after your first dose of study drug or randomization:

- You will have a physical exam.

- Your tobacco and alcohol history will be collected.

- Blood (about 4 tablespoons) will be drawn for biomarker testing.

- You will have oral swabs collected for biomarker testing.

- At 12 months only, blood (about 2 teaspoons) will be drawn for routine tests.

- At 12 months only, if you have a lesion, it will be measured and biopsied. If you had a
lesion and it went away, the area where the lesion was located previously will be
biopsied.

Long-Term Follow Up:

You will be contacted (either called, mailed, or e-mailed) to check on how you are doing and
your cancer status. This information may also be collected from your medical record, if
needed. The study doctor will tell you how often you may be contacted. Each phone call should
last about 10 minutes. This contact will continue unless you withdraw from the study.

If you cannot be contacted for any reason, your family members may also be contacted to learn
how you are doing. The study staff will ask you for their contact information (such as a
phone number or email address). If you do not want to have your family members contacted, you
do not have to give the researchers this information.

Inclusion Criteria:

1. Histological evidence of oral intra-epithelial neoplasia within 12 months prior to
enrollment. Subjects with a history or clinical diagnosis suggestive of oral
intra-epithelial neoplasia, or patients with a history of invasive oral cancer are
eligible, but must have a confirmed histological diagnosis of oral intra-epithelial
neoplasia before randomization. Histological evidence of oral intraepithelial
neoplasia on an invasive oral cancer resection specimen is acceptable. A visible,
measurable, clinical lesion (such as leukoplakia and/or erythroplakia) is not
required. Only individuals with high risk profiles will be considered eligible for
randomization. High risk profiles are defined as patients without a prior oral cancer
and have LOH at 3p14 and/or 9p21 plus at least at one additional chromosomal site
(4q,8p,11p,13q, or 17p) or patients with a prior oral cancer history and have LOH at
3p14 and/or 9p21. All high risk patients must also meet the additional eligibility
criteria (2-9).

2. Be willing and able to provide written informed consent.

3. Be >/= 18 years of age on day of signing informed consent for the trial.

4. Be willing to provide tissue from a newly obtained oral biopsy.

5. Have a performance status of 0-2 on the ECOG Performance Scale.

6. Demonstrate adequate organ function as defined: Hematological: Absolute Neutrophil
Count >/=1,500/mcL, Platelets >/= 75,000/mcL. Hepatic: Serum total bilirubin ULN or Direct Bilirubin 1.5 ULN.
AST (SGOT) and ALT (SGPT)
7. Female subject of childbearing potential should have a negative urine or serum
pregnancy test < 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.

8. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of study therapy through 120 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses > 1 year.

9. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of the study
therapy.

Exclusion Criteria:

1. Is currently participating and receiving study therapy with potential anti-neoplastic
activity, or has participated in a study of an investigational agent and received
study therapy with potential anti-neoplastic activity within 4 weeks of the first dose
of treatment.

2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.

3. Has a known history of active TB (Bacillus Tuberculosis).

4. Hypersensitivity to pembrolizumab or any of its excipients.

5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., to agents administered more than 4 weeks earlier.

6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., baseline) from adverse events due to a previously administered agent. Note: If the
subject received major surgery, they must have recovered adequately from the toxicity
and/or complications from the intervention prior to starting therapy.

7. Has a known additional malignancy that is progressing or requires active treatment
other than adjuvant hormonal therapy. Exceptions include basal cell carcinoma of the
skin or squamous cell carcinoma of the skin or in situ cervical cancer.

8. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

9. Has a known history of, or any evidence of active, non-infectious pneumonitis.

10. Has an active infection requiring systemic therapy.

11. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

12. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

13. Is pregnant, or breastfeeding, or expecting to conceive or father children within the
projected duration of treatment with pembrolizumab, starting with the pre-screening or
screening visit through 120 days after the last dose of trial treatment.

14. Has received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

15. Has a history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

17. Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines are live attenuated vaccines, and
are not allowed.