Pembrolizumab in Refractory Advanced Esophageal 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 the
participant specific disease 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 other types of diseases.

The goal of this research study is to

-Evaluate the safety and efficacy of pembrolizumab in participants with advanced esophageal
cancer that have not responded to standard treatment.

Inclusion Criteria:

- Histologically confirmed, measurable, unresectable adenocarcinoma or squamous cell
carcinoma of the esophagus. For the purposes of this study, undifferentiated
carcinomas or adenosquamous carcinomas will be categorized as adenocarcinomas.

- The primary tumor must originate in the esophagus. Tumors that involve the GE junction
must meet Sievert Type 1 criteria: "Adenocarcinoma of the distal oesophagus which
usually arises from an area with specialized intestinal metaplasia of the oesophagus
(i.e. Barrett's oesophagus) and which may infiltrate the oesophagogastric junction
from above." For the purposes of this protocol, this will be interpreted as: greater
than 50% of the tumor must be above the GE junction or, alternatively, the tumor must
involve the GE junction and arise in the setting of biopsy-documented Barrett's
esophagus (specialized intestinal metaplasia).

- Patients must have received at least one prior therapy for unresectable disease.
Patients with recurrence within 6 months of completion of neoadjuvant or adjuvant
therapy may be considered as having received one prior therapy for unresectable
disease.

- 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 irRECIST.

- Be willing to provide tissue from a newly obtained biopsy of a tumor lesion, most
commonly an EGD biopsy from the esophagus. 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.
Please note, patients may not initiate therapy until the biopsy specimen is received
at the Dana-Farber Cancer Institute.

- The first 15 patients with adenocarcinoma will be offered an optional tumor biopsy
(typically EGD biopsy) at 8 weeks. Starting with adenocarcinoma patient #16, patients
must have an accessible tumor and must agree to tumor biopsy at 8 weeks; this will
continue to be mandatory until a total of 20 patients have undergone biopsy at 8
weeks.

- Have a performance status of 0 or 1 on the ECOG Performance Scale (Appendix A).

- 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 6.3.2). 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.

- Demonstrate adequate organ function as defined below, all screening labs should be
performed within 10 days of treatment initiation.

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 ≤1.5 X upper limit of normal (ULN) OR Measured creatinine clearance
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (GFR can also
be used in place of creatinine or CrCL) Creatinine clearance should be calculated per
institutional standard.

-Hepatic

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

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

- 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

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.

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

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

- 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.