Pembrolizumab, Capecitabine, and Radiation Therapy in Treating Patients With Mismatch-Repair Deficient and Epstein-Barr Virus Positive Gastric Cancer

PRIMARY OBJECTIVES:

I. To assess efficacy (disease-free survival) of operable gastric cancer treated with PD-1
blockade using pembrolizumab.

SECONDARY OBJECTIVES:

I. To characterize the safety and tolerability of pembrolizumab in the preoperative setting
and postoperative setting with chemoradiation.

II. To evaluate response rates, recurrence rates, and patterns of recurrence/metastasis.

III. To characterize adverse events (AE) of pembrolizumab in combination with radiation
therapy and capecitabine.

IV. To evaluate overall survival rates.

TERTIARY OBJECTIVES:

I. To assess T cell responses and pathological responses in the tumor specimen. II. To
correlate PD-L1 expression in tumor tissue and stroma with tumor tissue response.

III. To evaluate ribonucleic acid (RNA) expression via Nanostring technology with tumor
tissue response.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 21 days for up to 2 courses in the absence of disease progression or unacceptable
toxicity. Within 2-6 weeks, patients undergo surgery. Beginning up to 56 days after surgery,
patients receive pembrolizumab IV over 30 minutes on day 1 and capecitabine orally (PO) twice
daily (BID) on days 1-14. Treatment repeats every 21 days for up to 5 courses in the absence
of disease progression or unacceptable toxicity. Within 2-6 weeks of resting, patients
continue to receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21
days for up to 11 courses in the absence of disease progression or unacceptable toxicity.
Beginning course 4, patients undergo radiation therapy over 15-30 minutes on days 1-5 for up
to 5 weeks.

After completion of study treatment, patients are followed up every 12 weeks for 1 year,
every 16 weeks for 2 years, every 4 months for year 2, and every 6 months for 2 years.

Inclusion Criteria:

- Written informed consent for the trial

- Must have operable gastric adenocarcinoma, T2-T4a, N0-N3, M0

- Staging evaluation within 42 days of enrollment consisting of staging laparoscopy,
computed tomography (CT) scan of the abdomen and pelvis, and positron emission
tomography (PET) scan will be acquired; also endoscopic ultrasound (EUS) tumor and
nodal staging will be required

- Mismatch repair deficiency as identified by immunohistochemistry or other
institutional standard, or Epstein-Barr virus positivity as determined by in situ
hybridization or other institutional standard

- 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 10 weeks (70
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 (if available from prior biopsy) only upon agreement from the
sponsor

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale

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

- Platelets >= 100,000 / mcL

- Hemoglobin >= 7 g/dL or >= 5.6 mmol/L with transfusion or erythropoietin (EPO)
dependency

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 1.5 X institutional ULN

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN

- Albumin >= 2.5 mg/dL

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (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

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 7 days of enrollment; 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 an adequate method of
contraception for the course of the study through 120 days after the last dose of
study medication; Note: abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the subject

- Male subjects of childbearing potential 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; Note: abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the subject

Exclusion Criteria:

- Presence of metastatic disease is not allowed; subjects must be evaluated with imaging
consisting of CT scan and PET scan prior to enrollment for protocol therapy to exclude
metastatic disease

- Prior chemotherapy, adjuvant therapy, or radiotherapy for gastric cancer

- Prior radiotherapy that overlaps with planned radiotherapy portal

- 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

- 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 are an exception to this criterion and
may qualify for the study

- Note: if subject received major surgery, 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 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 a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis

- Evidence of interstitial lung disease

- Has an active infection requiring systemic therapy

- 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., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus (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