Immune Checkpoint Inhibitors With or Without Propranolol Hydrochloride In Patients With Urothelial Carcinoma

NCT04848519 | Active Not Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: STUDY00002186NCI-2021-00437WINSHIP5200-20P30CA138292
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This research study is an open label study designed to evaluate the safety and translational correlative changes of the combination of propranolol hydrochloride and immune checkpoint inhibitors (ICI) in subjects with urothelial carcinoma.

Conditions

Locally Advanced Bladder Urothelial Carcinoma; Locally Advanced Renal Pelvis Urothelial Carcinoma; Locally Advanced Ureter Urothelial Carcinoma; Locally Advanced Urethral Urothelial Carcinoma; Locally Advanced Urothelial Carcinoma; Metastatic Bladder Urothelial Carcinoma; Metastatic Renal Pelvis Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; Metastatic Urethral Urothelial Carcinoma; Metastatic Urothelial Carcinoma; Stage IV Bladder Cancer AJCC v8; Stage IV Renal Pelvis Cancer AJCC v8; Stage IV Ureter Cancer AJCC v8; Stage IV Urethral Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• Incidence of adverse events

  Assessed according to the Common Terminology Criteria for Adverse Events version 5.0. Descriptive statistics will be used to summarize the toxicity profile of the intervention. Toxicities will be tabulated by grade, association, and cycle number.

  2 years

Secondary Outcomes (3)

• Progression free survival (PFS)

  2 years

• Overall survival (OS)

  2 years

• Objective Response Rate (ORR)

  2 years

Other Outcomes (1)

• Immune profile and changes in selected biomarkers and cell subsets

  2 years

Study Arms (2)

Treatment (propranolol hydrochloride, immune checkpoint inhibitor)

EXPERIMENTAL

The specific ICI that the subject would receive will be dependent on the clinical need and associated FDA approval.

Drug: Pembrolizumab; Drug: Propranolol Hydrochloride; Drug: Nivolumab; Drug: Avelumab

Treatment (immune checkpoint inhibitor)

OTHER

The specific ICI that the subject would receive will be dependent on the clinical need and associated FDA approval.

Drug: Pembrolizumab; Drug: Nivolumab; Drug: Avelumab

Interventions

Nivolumab DRUG

Given IV as adjuvant treatment of urothelial carcinoma in high risk of disease recurrence after undergoing radical resection

Treatment (immune checkpoint inhibitor); Treatment (propranolol hydrochloride, immune checkpoint inhibitor)

Avelumab DRUG

Given IV as maintenance treatment in locally advanced or metastatic urothelial carcinoma following no progression on first-line platinum-containing chemotherapy

Treatment (immune checkpoint inhibitor); Treatment (propranolol hydrochloride, immune checkpoint inhibitor)

Pembrolizumab DRUG

Given IV as 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

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Treatment (immune checkpoint inhibitor); Treatment (propranolol hydrochloride, immune checkpoint inhibitor)

Propranolol Hydrochloride DRUG

Given PO for patients on the ICI plus propranolol arm

Also known as: Inderal

Treatment (propranolol hydrochloride, immune checkpoint inhibitor)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or Female
• Age ≥18 years
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
• 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 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+ 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
• Patients must have adequate organ and marrow function, within 28 days of Cycle 1 Day 1, at the discretion of the investigator.
• 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.
• 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).
• 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.
• 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 (Appendix B). 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.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier (i.e., have residual toxicities \> Grade 2).
• Patients who are receiving any other investigational agents or an investigational device within 21 days before administration of first dose of study drugs.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in study.
• Contraindication to ICI per investigator discretion.
• Uncontrolled current 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.
• Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite antihypertensive therapy.
• Contraindication to a beta blocker: cardiac conditions that significantly raise the risk of cardiopulmonary complications, including unstable angina, uncontrolled heart failure, symptomatic bradycardia, and severe asthma.
• Current use of an oral or intravenous beta blocker (e.g. atenolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, sotalol, among other beta blockers) with inability to safely switch to a non-beta blocker agent. The washout for current users should be at least 14 days with enough transition period.

Sponsors & Collaborators

• Emory University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Ureteral Neoplasms; Urethral Neoplasms

Interventions

pembrolizumab; Propranolol; Nivolumab; avelumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Ureteral Diseases; Urethral Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Jacqueline Brown, MD

  Emory University Hospital/Winship Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 14, 2021
• First Posted: April 19, 2021
• Study Start: May 20, 2021
• Primary Completion: October 15, 2025
• Study Completion (Estimated): December 4, 2026
• Last Updated: February 19, 2026

Record last verified: 2026-02

Locations

US (1)