This phase II trial tests how well propranolol and pembrolizumab work to cause tumor re-sensitization and therefore treatment in patients with triple negative breast cancer that has not responded to previous checkpoint inhibitor therapy (refractory), cannot be removed by surgery (unresectable) 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. Beta-blockers, like propranolol, may help to counteract effects of certain stress hormones produced by the body during cancer treatment and may increase the effectiveness of the pembrolizumab. Pembrolizumab is a drug that is classified as an immune checkpoint inhibitor. 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. Propranolol may be able to re-sensitize the cells of the immune system to respond to the checkpoint inhibitor pembrolizumab in patients with checkpoint inhibitor refractory metastatic or unresectable triple negative breast cancer.

PRIMARY OBJECTIVE:

I. Determine the efficacy of propranolol on tumor re-sensitization, when given in combination with pembrolizumab in patients with checkpoint inhibitor refractory metastatic triple negative breast cancer.

SECONDARY OBJECTIVES:

I. Assess 6-month progression-free and overall survival per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

II. Safety and tolerability of propranolol when given in combination with pembrolizumab.

EXPLORATORY OBJECTIVES:

I. Assess changes in immune markers (pre-treatment versus [vs] post-treatment) in biopsy and peripheral blood.

II. Correlate perceived stress scale with immune exhaustion markers and immune cells in the peripheral blood and tumor.

OUTLINE: Patients receive propranolol orally (PO) and pembrolizumab intravenously (IV) while on study. Patients undergo computed tomography (CT) scan, blood sample collection and may undergo tumor biopsy during screening and on study.

Inclusion Criteria:

• Age >= 18 years of age

• Have pathologically confirmed diagnosis of unresectable or metastatic triple negative breast cancer (TNBC) with no curative treatment options

• No chemotherapy, radiotherapy, or major surgery within 4 weeks of protocol treatment

• Checkpoint inhibitor refractory patients (i.e., no longer responding to chemotherapy and checkpoint inhibitor) who have disease progression on prior line of chemotherapy and pembrolizumab, and, who in the opinion of the physician, can continue checkpoint inhibitor

• Patients must be agreeable to pre- and 6-week post treatment biopsy in part 1 of the study

  • The pre-treatment biopsy for this study must be taken at least 4 weeks after all previous chemotherapy (pembrolizumab is allowed during this period)

• Participants of child-bearing potential must 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

• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 1

• Platelets >= 100,000/uL

• Hemoglobin >= 9.0 g/dL

• Absolute neutrophil count (ANC) >= 1500/uL

• Total bilirubin =< institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional ULN

• Creatinine clearance >= 50 mL/min per Cockcroft-Gault equation

• HbA1C <=8.5

• Have measurable disease per RECIST 1.1 criteria present

• Ability to swallow and retain oral medication

• 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 currently treated with systemic immunosuppressive agents, including steroids, are ineligible until 3 weeks after removal from immunosuppressive treatment
• Patients with active autoimmune disease, requiring ongoing immunosuppressive therapy or history of transplantation
• Patients with rapidly progressive disease/ symptomatic disease
• Patients with primary resistance (i.e., did not respond to initial treatment with chemotherapy plus checkpoint inhibitor) with progressive disease at 12 weeks after starting chemotherapy and pembrolizumab
• Patients who are pregnant or nursing. Women of childbearing potential (WOCBP) will have to undergo a urine pregnancy test as part of screening
• Participants with symptomatic known brain metastases < 4 weeks from radiation treatment should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• History of malignancy other than breast cancer within 5 years prior to screening, with the exception of those with a negligible risk of metastases or death
• 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
• Unwilling or unable to follow protocol requirements
• Contraindications to the use of beta-blockers, like: 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 (hemoglobin A1C [HbA1C] > 8.5 or fasting plasma glucose > 160 mg/dl at screening), symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma, current use of beta-blockers or non-dihydropyridine calcium channel blockers
• Any additional condition which in the investigator's opinion deems the participant an unsuitable candidate to receive the study drugs