Summary

This clinical trial studies the effect of propranolol hydrochloride with or without immune checkpoint inhibitors (pembrolizumab, nivolumab, or avelumab) in treating patients with urothelial cancer. Propranolol hydrochloride is used for the treatment of chronic angina, cardiac arrhythmias, essential tremor, and hypertension, and as prophylaxis for migraine headaches, and may have anticancer properties. Immunotherapy with monoclonal antibodies, such as pembrolizumab, nivolumab, and avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Objectives

PRIMARY OBJECTIVE:
I. To safety as measured by incidence of adverse events assessed for immune checkpoint inhibitors (ICI) plus propranolol versus ICI alone in patients with urothelial cancer.

SECONDARY OBJECTIVES:
I. To describe response to ICI plus or minus propranolol in metastatic urothelial cancer.
II. To assess tissue-based assays in archival tissue and correlative changes in peripheral T-cell subsets, myeloid
derived suppressor cells (MDSC), blood inflammatory markers and cytokines.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive propranolol hydrochloride orally (PO) on study, and receive ICI intravenously (IV) as clinically indicated. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), and blood sample collection throughout the study.

ARM II: Patients receive ICIs IV as clinically indicated. Patients undergo CT scan, MRI and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days, then every 12 weeks for up to 2 years for survival.

Eligibility

1. Age >= 18 years
2. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
3. Patients must have histologically confirmed urothelial carcinoma, planned for treatment with any of the following at the genitourinary oncology clinics of Emory University’s Winship Cancer Institute under the list Food and Drug Administration (FDA) approved indications: * Pembrolizumab first line for locally advanced or metastatic urothelial carcinoma who are not eligible for platinum-based chemotherapy; * or second line for locally advanced or metastatic urothelial carcinoma after progression on platinum-based chemotherapy * Avelumab: maintenance treatment in locally advanced or metastatic urothelial carcinoma following no progression on first-line platinum-containing chemotherapy * Nivolumab: adjuvant treatment of urothelial carcinoma in high risk of disease recurrence after undergoing radical resection ** High risk disease as defined in Checkmate 274: pathological stage of pT3, pT4a, or pN positive (+) and patient not eligible for or declined adjuvant cisplatin-based combination chemotherapy for patients who had not received neoadjuvant cisplatin-based chemotherapy and pathological stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant cisplatin
4. Patients must have adequate organ and marrow function, within 28 days of cycle 1 day 1, at the discretion of the investigator
5. The effects of study drugs on the developing human fetus are unknown. For this reason, female of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy
6. FCBP and men treated or enrolled on this protocol must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 3 months after completion of study drug administration. 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. * A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
7. Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer >= 4 weeks before the start of study therapy
8. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class IIB or better * Patients without existing cardiac disease that raise the risk of complications who consent for the trial will proceed with trial participation * Patients with existing cardiac disease that could raise the risk of complications will be referred at the discretion of the investigator to a cardio-oncologist who is a co-investigator on the trial (or general cardiologist) for cardiac optimization prior to starting propranolol
9. Life expectancy > 12 weeks as determined by the investigator
10. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions
11. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation