Pembrolizumab, Combination Chemotherapy, and Radiation Therapy Before Surgery in Treating Adult Patients With Locally Advanced Gastroesophageal Junction or Gastric Cardia Cancer That Can Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab when combined with radiotherapy
plus carboplatin and paclitaxel in locally advanced gastroesophageal junction (GEJ)/cardia
adenocarcinoma. (Phase Ib) II. To determine the safety and tolerability of pembrolizumab when
combined with oxaliplatin, leucovorin calcium, and fluorouracil (mFOLFOX6) (without
radiation) in locally advanced GEJ/cardia adenocarcinoma. (Phase Ib) (re-initiated) III. To
evaluate the pathological complete response (pathCR) rate of pembrolizumab when combined with
radiotherapy plus carboplatin and paclitaxel in locally advanced GEJ/cardia adenocarcinoma.
(Phase II) IV. To determine the 1-year progression-free survival (PFS) rate of pembrolizumab
when combined with mFOLFOX6 (without radiation) in locally advanced GEJ/cardia
adenocarcinoma. (Phase II) (only if Phase Ib is re-initiated)

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS), determine time to relapse (TTR),
disease-free survival (DFS), complete resection with no tumor within 1 mm of the resection
margins (R0) rate, and overall survival (OS) of pembrolizumab when combined with radiotherapy
plus carboplatin and paclitaxel.

II. To determine the progression-free survival (PFS), pathCR rate, time to relapse (TTR),
disease-free survival (DFS), R0 rate, and overall survival (OS) of pembrolizumab when
combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX) chemotherapy. (only if Phase
Ib is re-initiated)

TERTIARY OBJECTIVES:

I. To identify tissue and/or circulating biomarkers that are associated with pathCR, DFS, and
other clinical outcomes in patients with locally advanced GEJ/cardia adenocarcinoma treated
with neoadjuvant pembrolizumab-based therapy.

II. To determine differences in pre-treatment vs post-treatment tissue expression of immune
markers, including programmed death ligand (PDL)1 and tumor infiltrating lymphocytes (cluster
of differentiation [CD]8+, forkhead box P3 [FOXP3]+ regulatory t cells [Tregs], CD45RO,
granzyme B), in patients treated with neoadjuvant pembrolizumab-based therapy.

III. To identify immune markers in pretreatment tissues that correlate with pathCR and
long-term outcome in patients treated with neoadjuvant pembrolizumab-based therapy.

IV. To explore whether an Epstein-Barr virus (EBV)-associated tumor molecular profile is
associated with pathCR and long-term outcome in patients treated with neoadjuvant
pembrolizumab-based therapy.

V. To explore whether a microsatellite-unstable (MSI) tumor molecular profile is associated
with pathCR and long-term outcome in patients treated with neoadjuvant pembrolizumab-based
therapy.

OUTLINE:

NEOADJUVANT TREATMENT: Patients receive pembrolizumab intravenously (IV) over 30 minutes on
days -7, 15, and 36 and carboplatin IV and paclitaxel IV over 1-96 hours on days 1, 8, 15, 22
and 29. Patients also undergo radiation therapy once daily (QD) 5 days per week for 4 weeks
and 3 days (23 fractions).

Patients with progressive disease receive pembrolizumab IV over 30 minutes, paclitaxel IV
over 1-96 hours, and carboplatin IV on day 1. Treatment repeats every 21 days for 2-4 courses
in the absence of disease progression or unacceptable toxicity.

NEOADJUVANT TREATMENT (RE-INITIATED): Patients receive pembrolizumab IV over 30 minutes on
days 1 and 22 and oxaliplatin IV over 2-6 hours, leucovorin calcium IV over 15 minutes to 2
hours, and fluorouracil IV over 46-48 hours on days 1, 15, and 29. Treatment repeats every 21
days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients with progressive disease receive pembrolizumab IV over 30 minutes on days 1 and 22,
oxaliplatin IV over 2-6 hours, leucovorin calcium over 15 minutes to 2 hours, and
fluorouracil IV over 46-48 hours on days 1, 15, and 29. Treatment repeats every 41 days (6
weeks) for 1-3 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Within 5-8 weeks after completion of radiation therapy or 3-6 weeks after completion
of chemotherapy for patients receiving chemotherapy alone, patients undergo curative-intent
surgery.

ADJUVANT TREATMENT: Patients receive pembrolizumab IV over 30 minutes every 21 days.
Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for
1 year, every 4 months for 1 year, and then every 6 months for 1 year.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma involving the
gastroesophageal junction or gastric cardia

- Central pathology review to determine evaluability of archived
esophagogastroduodenoscopy (EGD)/biopsy sample

- NOTE: If archived sample was collected > 8 weeks prior to pre-registration (reg),
is not available in a timely manner, or was collected outside of Mayo Clinic and
considered unevaluable, then baseline EGD with primary tumor biopsy at Mayo
Clinic must be performed unless clinically contraindicated; patient is allowed to
enroll regardless of whether this Mayo Clinic tissue sample is evaluable; (Only 1
EGD with primary tumor biopsy performed at Mayo Clinic =< 8 weeks prior to
pre-reg is required)

- NOTE: For both archival or newly obtained tissue, only biopsies are adequate
(fine needle aspiration [FNA] is not adequate)

- Willing to provide mandatory tissue samples for research purposes

- Baseline imaging with an fludeoxyglucose (FDG)-positron emission tomography (PET) scan
negative for distant metastatic disease must be obtained =< 28 days prior to
registration

- Surgically resectable (T2N0, T3N0, Tany with node positivity, M0), as determined by
endoscopic ultrasound (EUS) and the following minimum diagnostic work-up:

- Whole-body PET/computed tomography (CT) (PET/CT of skull base to mid-thigh is
acceptable)

- EUS =< 21 days prior to registration

- NOTE: Patients may have regional adenopathy including para-esophageal, gastric,
gastrohepatic and celiac nodes; if celiac adenopathy is present, it must be < 2
cm

- NOTE: If patient unable to have PET/CT then CT chest/abdomen/pelvis with contrast
(preferred) or MRI chest/abdomen/pelvis with contrast

- Surgical consultation at enrolling site to confirm that patient will be able to
undergo curative resection after completion of chemoradiation =< 56 days prior to
registration

- Tumor is amenable to standard resection and reconstruction

- Radiation oncology consultation at enrolling site to confirm that disease can be
encompassed in a radiotherapy field =< 56 days prior to registration

- NOTE: Radiotherapy quality assurance rapid review must be performed before the
first fraction of radiation therapy (RT) is administered; if RT constraints
cannot be met, the patient will be removed from the protocol prior to treatment

- Consultation with a medical oncologist at enrolling site =< 56 days prior to
registration, with determination that treatment with neoadjuvant chemoradiotherapy
with weekly carboplatin and paclitaxel is considered acceptable

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Adequate oral intake and nutritional status without current or likely need for enteral
or parenteral feeding during chemoradiation or the preoperative period

- Pre-treatment pulmonary function tests (PFTs), collected =< 90 days prior to
enrollment, must show forced expiratory volume in one second (FEV1) > 60% of predicted

- Adequate organ function =< 21 days prior to registration:

- Aspartate transaminase (AST) level =< 2.5 x upper limit of normal (ULN) and
alanine transaminase (ALT) =< 3 x upper limit of normal (ULN)

- Total bilirubin level of =< 1.5 x ULN

- Creatinine level =< 1.2 x ULN or creatinine clearance > 60 mL/min/1.73 m^2 for
patients with creatinine levels above or below the institutional normal

- Hemoglobin (Hgb) >= 9 g/dl without transfusion or epoetin dependency (=< 7 days
prior to assessment)

- Absolute neutrophil count >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Albumin >= 2.5 g/dl

- Female patients 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

- NOTE: Patients of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 1 year

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test =< 7 days prior to registration

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

- Male patients 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 established and preferred method of
contraception for the subject

- Provide signed written informed consent

- Willing to return to enrolling institution for follow-up

- Willing to provide mandatory tissue and blood samples for research purposes

- NOTE: Patients must be willing to provide at the time surgical resection; for
patients who do not undergo surgery, any on-study tumor biopsy obtained for
clinical purposes subsequent to the baseline biopsy must also be available for
analysis

Exclusion Criteria:

- Tumor characteristics - any of the following are excluded:

- Evidence of distant metastases

- Tumors whose location is restricted to the tubular esophagus (i.e., without
involvement of the GEJ or cardia)

- Tumors whose proximal end are at the level of the carina or higher

- Invasion of the tracheobronchial tree or presence of tracheoesophageal fistula

- Palpable supraclavicular nodes, biopsy-proven involvement of supraclavicular
nodes, or radiographically involved supraclavicular nodes (> 1.5 cm in greatest
dimension)

- T1N0M0, T4Nany, or in situ carcinoma

- Tumor must not extend 5 or more cm into the stomach

- Received prior treatment or receiving current treatment for this malignancy

- Prior radiation to chest or abdomen, or to > 30% of the marrow cavity

- Inadequate caloric or fluid intake whereby there is a current or likely future need
for enteral or parenteral feeding during chemoradiation or the preoperative period

- Major surgery =< 4 weeks prior to registration

- Active autoimmune disorders, including patients known to be human immunodeficiency
virus (HIV) positive, or those requiring chronic steroid administration (excluding
inhaled steroids)

- Uncontrolled diabetes (i.e., will interfere with the performance of the FDG PET/CT
scans)

- Prior allergic reactions to drugs containing Cremophor, such as teniposide or
cyclosporine, or study drugs involved in this protocol, or to a monoclonal antibody or
prior hypersensitivity to platinum-containing agents

- Heart conditions - any of the following:

- Any atrial fibrillation =< 3 months prior to registration

- Unstable angina =< 12 months prior to registration

- Prior symptomatic congestive heart failure

- Documented myocardial infarction =< 6 months prior to registration (pretreatment
electrocardiogram [ECG] evidence of infarct only will not exclude patients)

- Prior significant ventricular arrhythmia requiring medication

- Prior 2nd or 3rd degree heart block or other types of clinically significant
conduction delay =< 6 months prior to registration

- Clinically significant pericardial disease (including pericardial effusion,
pericarditis) or cardiac valvular disease =< 12 months prior to registration

- NOTE: As part of history and physical, all patients must be assessed for signs or
symptoms of cardiac disease, or for prior history of cardiac disease; these
conditions include but are not limited to diseases related to cardiac valves,
pericardium, myocardium, atrioventricular delays or arrhythmias; it is strongly
recommended that signs or symptoms of potentially clinically significant disease
be evaluated with comprehensive cardiac echo

- Prior pancreatitis that was symptomatic or required medical intervention =< 6 months
prior to registration (known toxicity of pembrolizumab)

- Prior enteritis that was symptomatic or required medical intervention =< 6 months
prior to registration (known toxicity of pembrolizumab)

- Uncontrolled hyper/hypothyroidism or hyper/hypocorticism =< 6 months prior to
registration (known toxicity of pembrolizumab)

- Pulmonary conditions - any of the following:

- Respiratory condition that required any oxygen supplementation =< 6 months prior
to registration

- Prior or current pneumonitis

- Clinically significant pulmonary hypertension =< 12 months prior to registration

- Lung infection requiring treatment =< 3 months prior to registration

- Pulmonary embolism requiring treatment =< 6 months prior to registration

- Pleural effusion requiring drainage =< 12 months prior to registration

- Prior fistula within thorax, including bronchoalveolar or esophageal

- Body mass index (BMI) >= 35 mg/m^2 =< 56 days prior to registration

- Pre-existing motor or sensory neurotoxicity greater than Common Terminology Criteria
for Adverse Events (CTCAE) grade 1

- Acute bacterial, viral, or fungal infection requiring treatment at the time of
registration

- Active infection or other serious underlying medical condition which would impair the
ability of the patient to receive the planned treatment

- Uncontrolled intercurrent illness including, but not limited to, psychiatric
illness/social situations, or other co-morbid systemic illnesses or severe concurrent
diseases which, in the judgment of the investigator, would make the patient
inappropriate for entry into this study or interfere significantly with the proper
assessment of safety and toxicity of the prescribed regimens

- Prior malignancy =< 5 years prior to registration (except non-melanotic skin cancer or
carcinoma-in-situ of the cervix) (must be disease free for a minimum of 5 years); if
there is a history of prior malignancy, patient must not be receiving other specific
treatment (other than hormonal therapy) for cancer

- Dementia or altered mental status that would prohibit the understanding and giving of
informed consent

- Any of the following because this study involves an agent where the genotoxic,
mutagenic and teratogenic effects are unknown:

- Pregnant or breastfeeding

- Patient of childbearing potential who is unwilling to employ adequate
contraception

- Received live vaccine =< 30 days prior to registration