Pembrolizumab and Palliative Radiation Therapy in Treating Patients With Metastatic Esophagus, Stomach, or Gastroesophageal Junction Cancer

PRIMARY OBJECTIVES I. To establish that the combination of pembrolizumab and traditional
external beam multifractionated radiation therapy (RT) to the primary tumor or a single
target metastatic site of patients with metastatic gastric, esophageal, and/or
gastroesophageal junction (GEJ) cancers will lead to an increase in tumor infiltrating
cytotoxic T-cells and circulating cytotoxic T cells and a reduction in immunosuppressive
regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in metastatic sites.

SECONDARY OBJECTIVES:

I. To establish that the combination of pembrolizumab and RT is feasible in the patient
population and evaluate toxicities per National Cancer Institute (NCI) Common Toxicity
Criteria for Adverse Events (CTCAE) version (ver.) 4.03.

II. To evaluate overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 and immune related (ir)RECIST in this treatment population and correlate with
tumor T-cell response.

III. To evaluate progression-free (PFS) and overall survival (OS) in this treatment
population.

TERTIARY OBJECTIVES:

I. To measure changes in whole genome serum micro ribonucleic acid (miRNA) signature before
and after protocol therapy and correlate with tumor/immune/stromal cell miRNA expression
profiling determined by deep sequencing.

II. To measures changes in fecal and oral microbiomic diversity and correlative with ORR,
PFS, and OS.

III. To assess germline mutations in a panel of miRNA regulatory genes using the MiraDx assay
as predictors of response and toxicity to pembrolizumab and RT.

OUTLINE:

INITIAL TREATMENT: Patients undergo palliative external beam RT daily. On day 1, patients
undergo the first RT fraction and then receive pembrolizumab intravenously (IV) over 30
minutes. Courses repeat every 3 weeks for up to 35 courses in the absence of disease
progression or unacceptable toxicity.

SECOND PHASE: Patients who achieve a complete response, stop study treatment, and then
experience radiographic disease progression may be eligible for the second phase at the
discretion of the investigator if no cancer treatment was administered since the last dose of
pembrolizumab and trial eligibility safety parameters are met. Patients receive pembrolizumab
IV over 30 minutes on day 1. Courses repeat every 3 weeks for up to 17 courses in the absence
of disease progression or unacceptable toxicity.

After completion of treatment, patients are followed up at 30 days, every 6 weeks for 1 year,
and then every 9 and 12 weeks for up to 2 years.

Inclusion Criteria:

- Documented informed consent of the participant

- Willing to provide tumor tissue amenable to ultrasound or computed tomography
(CT)-guided biopsy for biomarker analyses

- Patients with malignant ascites are permitted to participate and provide ascites
samples for biomarker analyses

- Patients receiving radiation to a single metastatic site in which only the
primary tumor is accessible for biopsy by endoscopy will also be eligible

- Eastern Cooperative Oncology Group (ECOG) performance status of =< 1

- Life expectancy of >= 3 months

- Diagnosis of metastatic squamous cell carcinoma and/or adenocarcinoma of the
esophagus, gastroesophageal junction, or stomach in need of palliative radiotherapy to
the primary tumor or a single metastatic site for symptoms such as pain, dysphagia,
and/or gastrointestinal bleeding

* Patients with adenocarcinoma histology and known human epidermal growth factor
receptor 2 (HER2) overexpressing disease are permitted to participate if they
progressed or are intolerant of prior trastuzumab-containing therapy

- Measurable metastatic sites of disease outside of the target lesion undergoing
palliative radiation based on RECIST 1.1 as assessed by the investigator

- Have no limits on prior lines of therapy or may be treatment-naive if in need of
palliative RT provided the patient has not received prior anti-programmed cell death
protein 1(PD-1), anti-programmed cell death 1 ligand 1 (PD-L1), or anti-programmed
cell death 1 ligand 2 (PD-L2) therapy

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelets >= 100,000/mm^3

- Hemoglobin >= 9 g/dL

* May receive transfusion to meet this goal

- Total serum bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN
if total bilirubin levels > 1.5 x ULN

- Albumin >= 2.5 mg/dL

- Aspartate aminotransaminase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR
=< 5.0 x ULN if liver metastases present

- Serum creatinine =< 1.5 x ULN OR creatinine clearance (if measured or calculated per
institutional standard) >= 60 mL/min if creatinine levels > 1.5 x ULN

- Glomerular filtration rate (GFR) can also be used in place of creatinine or
creatinine clearance (CrCl)

- If not receiving anticoagulants: international normalized ratio (INR) OR prothrombin
(PT) =< 1.5 x ULN; if on anticoagulant therapy: PT must be within therapeutic range of
intended use of anticoagulants

- If not receiving anticoagulants: activated partial thromboplastin time (aPTT) =< 1.5 x
ULN; if on anticoagulant therapy: aPTT must be within therapeutic range of intended
use of anticoagulants

- Negative urine or serum pregnancy test (female of childbearing potential only)

* If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required

- Female of childbearing potential: 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

* Childbearing potential defined as not being surgically sterilized or have not been
free from menses for > 1 year

- Male: 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:

- Anti-PD-1, anti-PD-L1, or anti-PD-L2 agents

- Prior radiation therapy within the field of the target lesion that in the opinion of
the treating radiation oncologist would preclude further palliative radiation to a
dose of 30 gray (Gy)

- 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

- 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

- If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy

- 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

- Immunosuppressive therapy within 7 days prior to the first dose of trial treatment

- Investigational device within 4 weeks of the first dose of treatment

- Currently receiving an investigational agent

- About to undergo palliative radiation for a symptomatic central nervous system (CNS)
metastasis

- Systemic steroid therapy

- Hypersensitivity to pembrolizumab or any of its excipients

- Diagnosis of immunodeficiency

- 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

- Known history of, or any evidence of active, non-infectious pneumonitis

- Current active infection requiring systemic therapy

- Known history of active tuberculosis (TB), human immunodeficiency virus (HIV) 1/2,
hepatitis B or hepatitis C

- 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

- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis

* Subjects with previously treated brain metastases may participate provided they are
stable, 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

- 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

- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial

- Pregnant or breastfeeding (female only)