Pembrolizumab in Refractory Metastatic Anal Cancer

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

The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for Advanced
Anal Cancer, but it has been approved for other uses.

Pembrolizumab, also known as KEYTRUDA or MK-3475, is approved in the USA and several other
countries to treat a type of skin cancer called Malignant Melanoma.

In this research study the investigators are studying an investigational drug called
Pembrolizumab, which is a monoclonal antibody. Monoclonal antibodies are manmade and mimic
proteins in the immune system by attaching to specific proteins in the body. T cells are
cells in the immune system that are controlled by PD-1. PD-1 is a protein on the T cells that
prevent the body from overproducing T cells. Pembrolizumab targets PD-1, attaches to it and
blocks its action. By preventing PD-1 from working, T cell production rises and the body's
immune system may increase its action against Cancer cells. Clinical and laboratory studies
using pembrolizumab suggest that pembrolizumab may be useful in shrinking certain tumors.

Inclusion Criteria:

- Participants must have metastatic anal cancer that has been histologically confirmed.

- Participants must have received platinum and 5-FU-based chemotherapy. All patients who
stopped chemotherapy because of progressive disease or toxicity are eligible. There is
no limit to the number of prior therapies.

- Be willing and able to provide written informed consent/assent for the trial.

- Be ≥18 years of age on day of signing informed consent.

- Have measurable disease based on RECIST 1.1.

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
cannot be provided (e.g. inaccessible or subject safety concern) may submit an
archived specimen only upon agreement from the Sponsor.

- Have a performance status of 0 or 1 on the ECOG Performance Scale.

- Demonstrate adequate organ function, all screening labs must be performed within 10
days of treatment initiation.

Adequate Organ Function Laboratory Values

System Laboratory Value

- Hematological

- Absolute neutrophil count (ANC) ≥1,500 /mcL

- Platelets ≥80,000 / mcL

- Hemoglobin ≥8.5 g/dL or ≥5.6 mmol/L

- Renal

--Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min
for subject with creatinine levels > 1.5 X institutional ULN

- Hepatic

- Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN

- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver
metastases

- Albumin >2.8 mg/dL

- Coagulation

- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants

- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants

- Creatinine clearance should be calculated per institutional standard.

- Female subject of childbearing potential must have a negative urine or serum pregnancy
within 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.

- Female subjects of childbearing potential must be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication (Reference
Section 7.4). Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year.

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

Exclusion Criteria:

- 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. Subjects requiring systemic steroids are excluded from the trial. The use
of physiologic doses of corticosteroids may be approved after discussion with the
sponsor.

- Has a known history of active TB (Bacillus Tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients.

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.

- 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., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent.

- Note: Subjects with ≤ Grade 2 neuropathy and alopecia are an exception to this
criterion and may qualify for the study.

- Note: If subject received major surgery, they must wait ≥ 3 weeks prior to
starting study treatment. They must have recovered adequately from the toxicity
and/or complications from the intervention prior to starting therapy.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.

- 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 (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Has an active infection requiring systemic therapy.

- Patients that require supplemental oxygen are excluded.

- 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.

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

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

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

- HIV+ positive patients are eligible if their CD4+ count ≥ 300/μL and they have an
undetectable viral load. In addition, they must be currently receiving Highly Active
Antiretroviral Therapy (HAART) and be under the care of an Infectious Diseases
specialist.

- Patients with hepatitis B and hepatitis C must be under the care of viral hepatitis
expert consultant. Patients with hepatitis B are required to be treated with anti-HBV
treatment (e.g., entecavir). Patients with hepatitis C need to have received prior
and/or ongoing hepatitis C treatment.

- 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 (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.

- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.