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

Biopsy

Biospecimen Collection

Computed Tomography

Propranolol Hydrochloride

Questionnaire Administration

Sarbajit Mukherjee

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.

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

A Phase 2 Trial of Chemotherapy, Pembrolizumab, and Propranolol in Advanced Esophageal/Gastroesophageal Junction Adenocarcinoma Patients

Efficacy of pembrolizumab in combination with propranolol with standard chemotherapy measured by ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, which is treated as a dichotomous variable and will be summarized using frequencies and relative frequencies.

Will be assessed as per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

Will be summarized using standard Kaplan Meier methods.

ORR as determined by Immune-Modified (i)RECIST.

United States Department of Defense

Roswell Park Cancer Institute

Spots Global Cancer Trial Database for locally advanced esophageal adenocarcinoma