Propranolol in Combination With Pembrolizumab and Standard Chemotherapy for the Treatment of Unresectable Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Adenocarcinoma

Inclusion Criteria:

• Age >= 18 years of age.

• Participants must be newly diagnosed, treatment-naive with unresectable locallyadvanced 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 morethan 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 biopsycollected within 1 year or, participant must be willing to have a tissue biopsytaken 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 forparticipants with total bilirubin levels > 2 × ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase) (SGOT)and alanine transaminase (ALT) (serum glutamic-pyruvic transaminase) (SGPT) =< 3 Xinstitutional ULN (=< 5 × ULN for participants with liver metastases)

• Participants of child-bearing potential must have a negative pregnancy test at studyentry and then agree to use adequate contraceptive methods (e.g., hormonal orbarrier method of birth control; abstinence) prior to study entry. Should a womanbecome pregnant or suspect she is pregnant while she or her partner is participatingin this study, she should inform her treating physician immediately.

• Ability to swallow and retain oral medication. If a patient is not able to swallowor is experiencing dysphagia that limits ability to swallow oral medication, theyare still eligible for study provided they can swallow liquid formula propranolol orhave an enteric feeding tube placed which will permit administration of crushedtablets or liquid formula propranolol. Liquid and tablet formulations may be usedinterchangeably for patients in the event of a shortage of either formulation

• Participant must understand the investigational nature of this study and sign anIndependent Ethics Committee/Institutional Review Board approved written informedconsent 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 leptomeningealdisease.

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

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

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired 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) andHepatitis C virus (defined as anti-HCV antibody [Ab] positive and detectable HCVribonucleic acid [RNA]) infection. Note: Hepatitis B and C screening tests are notrequired unless known history of HBV and HCV infection.

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

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

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

• Pregnant or nursing female participants, where pregnancy is defined as the state ofa female after conception and until the termination of gestation, confirmed by apositive 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 pulmonarydisease (COPD), uncontrolled type I or type II diabetes mellitus (HbA1C > 8.5 orfasting plasma glucose > 160 mg/dl at screening), symptomatic peripheral arterialdisease or Raynaud's syndrome, untreated pheochromocytoma etc.

• Has received a live vaccine or live-attenuated vaccine within 30 days prior to thefirst dose of trial treatment and while participating in the trial. Examples of livevaccines 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 anunsuitable candidate to receive study drug.