This phase II trial tests what effects the addition of propranolol to pembrolizumab and standard chemotherapy (mFOLFOX) may have on response to treatment in patients with esophageal or gastroesophageal junction cancer that cannot be removed by surgery and has spread to nearby tissue or lymph nodes (unresectable locally advanced) or has spread from where it first started (primary site) to other places in the body (metastatic). Propranolol is a drug that is classified as a beta-blocker. Beta-blockers affect the heart and circulation (blood flow through arteries and veins). Cancer patients may be under a tremendous amount of stress with elevated levels of norepinephrine (a hormone produced by the adrenal glands in response to stress). Increased adrenergic stress may dampen the immune system, which beta-blockers, like propranolol, may be able to counteract. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in the standard chemotherapy regimen, mFOLFOX (leucovorin, fluorouracil and oxaliplatin) work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding propranolol to pembrolizumab and standard mFOLFOX chemotherapy may increase the effectiveness of the pembrolizumab + mFOLFOX regimen.

PRIMARY OBJECTIVE:

I. To determine the clinical efficacy of propranolol in combination with pembrolizumab and standard chemotherapy in frontline metastatic esophageal or gastroesophageal junction (GEJ) adenocarcinoma.

SECONDARY OBJECTIVE:

I. To evaluate the progression-free survival, overall survival, overall response rate, and safety profile of the combination of pembrolizumab and propranolol with standard chemotherapy.

EXPLORATORY OBJECTIVE:

I. To correlate baseline or changes in the levels of biomarkers (e.g., like, peripheral T-cell subsets/myeloid-derived suppressor cells [MDSC]/cytokines), perceived stress and exercise Perceived Stress Scale (PSS) with efficacy (overall response rate [ORR], progression-free survival [PFS], overall survival [OS]), and chronotropic effect of exercise.

OUTLINE:

Patients receive mFOLFOX6 (leucovorin intravenously [IV], oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol orally (PO) on study. Patients also undergo tumor biopsy during screening and computed tomography (CT) scans and collection of blood samples during screening and on study.

Inclusion Criteria:

• Age >= 18 years of age.
• Participants must be newly diagnosed, treatment-naive with unresectable locally advanced or metastatic esophageal/gastroesophageal junction (GEJ) adenocarcinoma. Any prior systemic treatment for resectable disease must be six months or before. Prior PD-1/PD-L1 treatment is allowed as long as the treatment was completed more than 1 year ago.
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
• Available archival Formalin-Fixed Paraffin-Embedded (FFPE) from a prior biopsy collected within 1 year or, participant must be willing to have a tissue biopsy taken prior to start of study treatment.
• Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present.
• Platelet >= 75,000/uL
• Hemoglobin >= 8 g/dL (without transfusion in the past 14 days)
• Absolute Neutrophil Count (ANC) >= 1500/uL
• Creatinine clearance (Cockcroft Gault) >= 30 mL/min
• Total bilirubin: =< 2 × upper limit of normal (ULN) OR direct bilirubin =< ULN for participants with total bilirubin levels > 2 × ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase) (SGOT) and alanine transaminase (ALT) (serum glutamic-pyruvic transaminase) (SGPT) =< 3 X institutional ULN (=< 5 × ULN for participants with liver metastases)
• Participants of child-bearing potential must have a negative pregnancy test at study entry and then agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Ability to swallow and retain oral medication. If a patient is not able to swallow or is experiencing dysphagia that limits ability to swallow oral medication, they are still eligible for study provided they can swallow liquid formula propranolol or have an enteric feeding tube placed which will permit administration of crushed tablets or liquid formula propranolol. Liquid and tablet formulations may be used interchangeably for patients in the event of a shortage of either formulation
• Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.

Exclusion Criteria:

• Patients with HER 2-positive cancer.

• Patients with active, untreated central nervous system metastases or leptomeningeal disease.

• Patients with active autoimmune disease, requiring ongoing immunosuppressive therapy or history of transplantation.

  • Patients currently treated with systemic immunosuppressive agents: If a patient is currently on steroids, they must be on a steroid dose less than or equal to an equivalent prednisone dose of 10 mg daily.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required treatment.

• Has a concurrent Human Immunodeficiency Virus (HIV) infection.

• Concurrent active Hepatitis B (defined as Hepatitis B virus surface antigen [HBsAg] positive and/or detectable Hepatitis B virus [HBV] deoxyribonucleic acid DNA) and Hepatitis C virus (defined as anti-HCV antibody [Ab] positive and detectable HCV ribonucleic acid [RNA]) infection. Note: Hepatitis B and C screening tests are not required unless known history of HBV and HCV infection.

• Participants that are already on beta-adrenergic (B-AR) blockers for various indications.

• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=<2 weeks of radiotherapy) to non-central nervous system (CNS) disease.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Pregnant or nursing female participants, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.

• Other active cancers that require systemic treatment.

• Contraindications to the use of beta-blockers, e.g.: uncontrolled depression, unstable angina pectoris, uncontrolled heart failure ( Grade III or IV), hypotension (systolic blood pressure <100 mmHg), severe asthma or chronic obstructive pulmonary disease (COPD), uncontrolled type I or type II diabetes mellitus (HbA1C > 8.5 or fasting plasma glucose > 160 mg/dl at screening), symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma etc.

• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster etc.

• Unwilling or unable to follow protocol requirements.

• Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drug.