Immune Checkpoint Inhibitors With or Without Propranolol Hydrochloride In Patients With Urothelial Carcinoma
Phase: PHASE2
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
Sponsor: Emory University

Immune Checkpoint Inhibitors (ICI) With or Without
Propranolol Hydrochloride In Patients With Urothelial Carcinoma
WINSHIP5200-20
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Immune Checkpoint Inhibitors With or Without Propranolol Hydrochloride In 
Patients With Urothelial Carcinoma
WINSHIP PROTOCOL #: WINSHIP5200-20
COORDINATING CENTER:
Winship Cancer Institute of Emory University
PRINCIPAL INVESTIGATOR:
Bassel Nazha, MD, MPH 
Assistant Professor, Department of Hematology and Medical Oncology
Winship Cancer Institute of Emory University
1365 Clifton Road NE,
Atlanta, GA 30322 
E-mail address: bassel.nazha@emory.edu
CO-INVESTIGATORS:
Mehmet Asim Bilen, MD
Assistant Professor, Department of Hematology and Medical Oncology
Winship Cancer Institute of Emory University
Bradley Carthon, MD, PhD
Associate Professor, Department of Hematology and Medical Oncology
Winship Cancer Institute of Emory University
Omer Kucuk, MD
Professor, Department of Hematology and Medical Oncology
Winship Cancer Institute of Emory University
Haydn T. Kissick, PhD
Assistant Professor, Department of Microbiology and Immunology
Winship Cancer Institute of Emory University 
Michael C. Lowe, MD, MA
Assistant Professor, Division of Surgical Oncology, Department of Surgery
Winship Cancer Institute of Emory University 

Immune Checkpoint Inhibitors (ICI) With or Without
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Anant Mandawat, MD
Assistant Professor, Division of Cardiology, Department of Medicine
Winship Cancer Institute of Emory University
Viraj A. Master, MD, PhD
Professor, Department of Urology
Winship Cancer Institute of Emory University
 
Vikas P. Sukhatme, MD, ScD
Dean, Emory School of Medicine
STATISTICIAN:
Yuan Liu, PhD, MS
Assistant Research Professor
Department of Biostatistics and Bioinformatics 
Rollins School of Public Health
VERSION:  Version 10; 6/1/22
FUNDING SOURCE: Internal-Morningside
INVESTIGATIONAL PRODUCT (IP): [Propranolol]
OTHER AGENT(S): [Pembrolizumab] [Nivolumab] [Avelumab]
☒  Study Exempt from IND Requirements per 21 CFR 312.2(b).  
REVISION HISTORY
Revision #
Version Date
Summary of Changes
Original
11/19/2020
#1
6/1/2022
See SOC document

Immune Checkpoint Inhibitors (ICI) With or Without
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1. Study Summary
1.1 Synopsis
Title:
Immune Checkpoint Inhibitors With or Without Propranolol Hydrochloride In 
Patients With Urothelial Carcinoma
Study Description:
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. 
Objectives:
Primary Objectives:
To evaluate the safety of the combination of propranolol hydrochloride and 
immune checkpoint inhibitors in urothelial cancer.
Secondary Objective:
To describe response and survival outcomes for ICI plus or minus propranolol in 
patients with urothelial cancer
To measure overall response rate (ORR) along with correlative changes in 
peripheral T-cell subsets, myeloid derived suppressor cells (MDSC), blood 
inflammatory markers and blood cytokines before and after treatment for patients 
receiving ICI plus propranolol vs. ICI alone. Available archival tissue will also be 
collected for tissue-based assays. 
Endpoints:
Primary Endpoint:  
Safety:  Incidence of adverse events according to the Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0.
Secondary Endpoint:
Response:  ORR per RECIST 1.1 (only for subjects receiving avelumab and 
pembrolizumab as ICI), profession free survival (PFS) and overall survival (OS). 
Correlatives:  Changes in selected biomarkers in circulation before and after 
treatment for ICI plus propranolol vs. ICI alone. 
Study Population:
The patient population consists of a total of 24 subjects ≥18 years of age with 
urothelial carcinoma (renal pelvis, ureter, bladder, or urethra), planned for 
treatment with nivolumab (adjuvant setting), pembrolizumab (advanced or 
metastatic), or avelumab (advanced or metastatic), under an FDA approved 
indications (listed below) at the genitourinary oncology clinics of Emory 
University’s Winship Cancer Institute practice sites. 
Phase:
Pilot study
Description of Sites / 
Facilities Enrolling:
Winship Cancer Institute of Emory University (Atlanta, GA)

Immune Checkpoint Inhibitors (ICI) With or Without
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Study Design:
Patients who meet eligibility criteria and consent for enrollment in the trial will be 
on one of the two study cohorts. Assignment to cohorts will be sequentially, in a 
1:1 fashion, starting with the ICI plus propranolol cohort. The specific ICI that the 
subject would receive will be dependent on the clinical need and associated FDA 
approval.
ICI PLUS PROPRANOLOL COHORT:
1. Propranolol: Participants will remain on propranolol 30mg twice daily for the 
duration of the trial unless unacceptable toxicity or withdrawal of consent. 
Patients who develop toxicity and stop propranolol will remain on trial for 
endpoint measurement.
PLUS
Pembrolizumab: Participants will receive 200mg IV on Day 1, every 3 weeks. 
Pembrolizumab would be continued for up to 2 years in the absence of disease 
progression or unacceptable toxicity. 
OR
Avelumab: Participants will receive Avelumab at a dose of 10 mg per kilogram of 
body weight, IV on Day 1 every 2 weeks until disease progression or unacceptable 
toxicity.
OR
Nivolumab: Participants will receive Nivolumab (480mg) IV on every 4 weeks for 
up to 1 year or until disease recurrence or discontinuation from the trial.
ICI ALONE COHORT:
Pembrolizumab: Participants will receive 200mg IV on Day 1, every 3 weeks. 
Pembrolizumab would be continued for up to 2 years in the absence of disease 
progression or unacceptable toxicity. 
OR
Avelumab: Participants will receive Avelumab  at a dose of 10 mg per kilogram of 
body weight, IV on Day 1 every 2 weeks until disease progression or unacceptable 
toxicity
OR
Nivolumab: Participants will receive Nivolumab (480mg) IV on every 4 weeks for 
up to 1 year or until disease recurrence or discontinuation from the trial.
Study Duration:
Nivolumab +/- propranolol: up to 1 year or until disease recurrence or 
discontinuation from the trial
Pembrolizumab +/- propranolol: up to 2 years or until disease progression or 
unacceptable toxicity
Avelumab +/- propranolol: until disease progression or unacceptable toxicity

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1.2 Schema
Dose of Pembrolizumab 
(advanced/metastatic setting)
200mg IV on Day 1, every 3 weeks
Dose of Avelumab 
(advanced/metastatic setting)
10mg/kg every 2 weeks
Dose of Nivolumab 
(adjuvant setting)
480mg IV every 4 weeks
Dose of Propranolol
30mg oral BID
Screeni
ng
Treatment
Cycle=42 days
Discontiu
ation
Safety 
Follow-
up
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to -
1
C1D1
#
C1D8
C1D15
C1D22
C2D
1
C2D22
C3‡ D1
C3‡ 
D22
At time of 
Discont.
30 days 
post 
Discont.
Every 12 
weeks
Informed Consent
X

Immune Checkpoint Inhibitors (ICI) With or Without
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1.3.1 Subjects receiving pembrolizumab as ICI (ICI plus propranolol cohort or ICI alone cohort)
# Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
*Subjects are enrolled to either the ICI plus propranolol cohort or ICI alone cohort. 
† At Screening, a single ECG will be obtained on which QTcF must be <450 ms.  In case of clinically significant ECG abnormalities, including a QTcF value 
>450 ms, 2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.  ‡ For C3 and all subsequent cycles. 
§ Stool sample will be collected at baseline and at the first radiographic tumor assessment only
Inclusion/Exclusion Criteria
X
Demographics and Medical 
History
X
Prior and Con Med. Review
X
X
X
X
X
X
X
X
X
ICC PLUS PROPRANOLOL 
COHORT: Propranolol 
Treatment (continuous, 
daily)*
X
X
X
X
X
X
X
X
ICC ALONE COHORT*
BOTH COHORT:
PEMBROLIZUMAB
(once every 3 weeks)
X
X
X
X
X
X
Patient-reported Outcomes
X
X
X
X
X
X
X
Survival Status
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Pregnancy Test – Urine or 
Serum β-HCG
X
CBC with Differential
X
X
X
X
X
X
X
X
X
Comprehensive Serum 
Chemistry Panel
X
X
X
X
X
X
X
X
X
ECG†
X
Stool sample for 
microbiome analysis
(Only with at Screening and 
Cycle 3)§
X
X §
Radiographic Tumor 
Assessment 
(every 12 weeks +/- 7 days)
X
X
X
Archival Tissue Collection
X
Correlative Blood Collection
X
X
X
X
X
 1.3 Schedule of Assessments 
Scree
ning
Treatment
Cycle=42 days
Disconti
uation
Safety 
Follow-
up
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 
-1
C1D
1#
C1
D8
C1D
15
C1D
29
C2D
1
C2D
15
C2
D29
C3‡
D1
C3‡
D15
C3‡
D29
At time 
of 
Discont.
30 days 
post 
Discont.
Every 12 
weeks
Informed Consent
X
Inclusion/Exclusion Criteria
X

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1.3.2 Subjects receiving avelumab as ICI (ICI plus propranolol cohort or ICI alone cohort)
# Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
*Subjects are enrolled to either the ICI plus propranolol cohort or ICI alone cohort. 
† At Screening, a single ECG will be obtained on which QTcF must be <450 ms.  In case of clinically significant ECG abnormalities, including a QTcF value 
>450 ms, 2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.  
‡ For C3 and all subsequent cycles
§ Stool sample will be collected at baseline and at the first radiographic tumor assessment only
Demographics and Medical 
History
X
Prior and Con Med. Review
X
X
X
X
X
X
X
X
X
X
X
X
ICC PLUS PROPRANOLOL 
COHORT: Propranolol 
Treatment (continuous, 
daily)*
   X
X
X
X
X
X
X
X
X
X
ICC ALONE COHORT*
BOTH COHORT:
AVELUMAB
(once every 2 weeks)
X
X
X
X
X
X
X
X
X
Patient-reported Outcomes
X
X
X
X
X
X
X
Survival Status
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test – Urine or 
Serum β-HCG
X
CBC with Differential
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum 
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
X
ECG†
X
Stool sample for 
microbiome analysis
(Only with Screening & 
Cycle 3)
X
     
X §
Radiographic Tumor 
Assessment 
(every 12 weeks +/- 7 days)
X
X
X
Archival Tissue Collection
X
Correlative Blood Collection
X
X
X
X
X
Screening
Treatment
Cycle=28 days
Discontiu
ation
Safety 
Follow-
up
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to -1
C1D1#
C1D8
C2D1
C2D15
C3D1
C4D1‡
At time of 
Discont.
30 days 
post 
Discont.
Every 12 
weeks
Informed Consent
X

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1.3.3 Schedule of Assessments for subjects receiving nivolumab (ICI plus propranolol cohort or ICI alone cohort)
# Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do not need to be repeated on C1D1.
*Subjects are enrolled to either the ICI plus propranolol cohort or ICI alone cohort. 
† At Screening, a single ECG will be obtained on which QTcF must be <450 ms.  In case of clinically significant ECG abnormalities, including a QTcF value 
>450 ms, 2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.  
‡ For C4 and all subsequent cycles 
§ Stool sample will be collected at baseline and at the first radiographic tumor assessment only
2. Objectives (and Endpoints)
OBJECTIVES
ENDPOINTS
Primary
Inclusion/Exclusion Criteria
X
Demographics and Medical 
History
X
Prior and Con Med. Review
X
X
X
X
X
X
X
ICC PLUS PROPRANOLOL 
COHORT: Propranolol 
Treatment (continuous, 
daily)*
X
X
X
X
X
ICC ALONE COHORT*
BOTH COHORT:
NIVOLUMAB
(once every 4 weeks)
X
X
X
X
Patient-reported Outcomes
X
X
X
X
X
X
Survival Status
X
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Pregnancy Test – Urine or 
Serum β-HCG
X
CBC with Differential
X
X
X
X
X
X
X
Comprehensive Serum 
Chemistry Panel
X
X
X
X
X
X
X
ECG†
X
Stool sample for 
microbiome analysis
(Screening and Cycle 4 only)
X
X §
Radiographic Tumor 
Assessment 
(every 12 weeks +/- 7 days)
X
X
X
Archival Tissue Collection
X
Correlative Blood Collection
X
X
X
X
X

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OBJECTIVES
ENDPOINTS
To safety as measured by incidence of adverse events 
assessed for ICI plus propranolol vs. ICI alone in patients 
with urothelial cancer
Safety: Incidence of adverse events 
according to the Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0.
Secondary
- To describe response to ICI plus or minus propranolol in 
metastatic urothelial cancer
- 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.
Response: ORR (for subjects receiving 
avelumab and pembrolizumab only), PFS, 
OS.
Correlatives: Baseline tissue immune 
profile and changes in selected 
biomarkers and cell subsets before and 
after treatment.
3. Background
Propranolol is a commonly used non-selective beta-adrenergic receptor antagonist for the treatment chronic 
angina, cardiac arrhythmias, essential tremor, hypertension, and as prophylaxis for migraine headaches, among 
other indications. There are generic forms of propranolol available worldwide and it is listed on the WHO List of 
Essential Medicines. In recent years, there has been a mounting evidence of propranolol’s potential anticancer 
properties. In-vitro and in-vivo data support prominent effects on limiting malignant cell proliferation, 
promoting tumor immune cells infiltration, blocking angiogenesis, and enhancing sensitivity to existing 
treatments1.  The effects are seen among several tumor types. For instance, propranolol has anti-proliferative 
effects, attenuates migration of malignant cells, reduces VEGF and induces cell cycle arrest and apoptosis in 
both uveal melanoma and cutaneous melanoma in a dose-dependent manner2. In HER-2 amplified breast cancer 
where a strong association exists between trastuzumab-resistance and beta2 adrenergic signaling, propranolol 
inhibits the antagonist effect of catecholamine epinephrine to trastuzumab and can resensitize resistant cells 
both in vitro and in a xenograft model3. Interestingly, in a study of Irish women with breast cancer, the 
probability of breast cancer-specific mortality was lower in those women who used propranolol in the year prior 
to their breast cancer diagnosis compared to matched nonusers (HR = 0.19; 95% CI = 0.06 – 0.60)4. Further, the 
use of beta-blockers including propranolol is associated with reduced cancer-related psychological distress and 
better adjustment following a diagnosis of breast or colorectal cancer5. 
Immune checkpoint inhibition with PD-1/PD-L1 and CTLA-4 inhibitors has emerged as a bedrock of cancer 
therapy. However, those agents continue to have low response rates in the range of 10 to 25% and result in 
immune-related adverse events in some patients6. In fact, only a small subset of patients treated with immune 
checkpoint inhibitors derive long and durable responses. Drug combination approaches including drug 
repurposing are critically needed to allow a larger number of oncology patients to derive benefits from those 
treatments with fewer adverse events. Drug repurposing consists of finding new uses for already approved drugs 
that extend beyond the scope of the original medical indication. Advantages of this approach include the 
knowledge of the repurposed drug’s safety profile, an expected lower development costs, and the reduced time 
frame for drug development. An example of approval using this approach include raloxifene to reduce the risk 
of hormone-receptor positive breast cancer in postmenopausal women at higher-than-average risk of 
developing breast cancer7.

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Urothelial carcinoma accounts for 90% of all bladder cancers in the United States. Less commonly, this histology 
can arise in the renal pelvis, ureter, or urethra. Each year, there are approximately 80,000 new cases and 18,000 
deaths due to bladder cancer, with a median age of 69 years for men and 71 years for women8. The preferred 
frontline treatment of advanced or metastatic disease is cisplatin-based chemotherapy. However, over half of 
all patients cannot receive this treatment due to poor functional status, renal dysfunction, or other 
comorbidities. 
Urothelial carcinoma is characterized by a high prevalence of tumor somatic mutations that is attributed to 
tobacco smoking and chronic environmental exposure of the urothelium to potential carcinogens that excreted 
in the urine. In turn, this is hypothesized to generate neoantigens recognized by activated antitumor T-cells and 
has led to the regulatory approval in this disease of immune checkpoint inhibitors (ICI) such as pembrolizumab, 
nivolumab, and avelumab. 
The most common uses of ICI in urothelial cancer are: 
i.
Nivolumab as adjuvant treatment for high-risk muscle-invasive urothelial cancer after radical surgery. 
This is based on CheckMate 274 that demonstrated a disease-free survival benefit of adjuvant nivolumab 
vs. placebo [20.8 months (95% CI 16.5-27.6) vs 10.8 months (95% CI 8.3-13.9)]9, leading to the FDA 
approval in this setting.
ii.
Avelumab as maintenance after platinum-based chemotherapy with no progression in advanced or 
metastatic urothelial cancer. The Javelin Bladder 100 trial showed a medial overall survival of 21.4 
months vs. 14.3 months in patients received maintenance avelumab vs. best supportive care (Hazard 
ratio for death 0.69; 95% CI 0.56-0.86, P=0.001)10, leading to the FDA approval in this setting. 
iii.
Pembrolizumab as frontline treatment in patients with advanced or metastatic urothelial cancer who are 
ineligible for platinum-based chemotherapy or as second line therapy in advanced or metastatic 
urothelial cancer. In the setting of recurrent or progressive disease after frontline platinum-based 
chemotherapy, the Keynote 045 phase III trials had significantly better ORR in the pembrolizumab arm 
(21.1%; 95% CI, 16.4-26.5) than in the chemotherapy group (11.4%; 95% CI, 7.9-15.8) (P=0.001) with 
fewer adverse events in the pembrolizumab arm (60.9%) compared with  the chemotherapy arm 
(90.2%)11. 
Preclinical and clinical studies provide rationale for combining propranolol with ICI to enhance the anticancer 
activity of the latter. Beta adrenergic signaling significantly influences myeloid-derived suppressor cells (MDSC) 
frequency and survival in tumors and other tissues. It also modulates tumors expression of immunosuppressive 
molecules such as arginase-I and PD-L12,12. Those effects can be mitigated by treatment with beta-adrenergic 
receptor antagonists, or enhanced by beta-AR agonists13. In a recent Phase II trial of breast cancer patients 
undergoing surgery with curative intent, perioperative treatment with propranolol resulted in favorable tumor 
immune infiltration of CD68+ macrophages and CD8+ cytotoxic T cells among patients who had clinical evidence 
of drug response (lower heart rate and blood pressure)14.  
We propose conducting a single-institution of ICI plus or minus propranolol in the treatment of urothelial 
cancer (adjuvant setting or advanced/metastatic setting) under an FDA-approved indications. 
3.1 Clinical Experience
The combination of propranolol and ICI as planned in this trial has not been previously tested in urothelial 
carcinoma. In a retrospective analysis of 195 patients with metastatic melanoma treated with an immune-based 

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therapy, OS was significantly improved in patients receiving a non-selective beta-blocker compared to no-beta 
blocker15. This has led to an ongoing Phase Ib/II trial testing the combination of propranolol and pembrolizumab 
in metastatic melanoma (NCT03384836). Gandhi et al. recently reported the Phase I part of this trial. Nine 
patients with metastatic melanoma received pembrolizumab and increasing doses of propranolol in 10mg, 
20mg, and 30mg BID escalation levels. No dose-limiting toxicities were reported. Rash, fatigue, and vitiligo were 
the most common side effects, with observed incidence of 44%. The objective response rate was a remarkable 
78%. Propranolol 30mg BID was selected as the recommended phase 2 (RP2D) dose in addition to ICI based on 
safety, tolerability, and preliminary efficacy data16. 
The drugs are used separately for an extensive list of FDA-approved indications in oncology (ICI: metastatic 
melanoma, non-small cell lung cancer, urothelial cancer, among others) and cardiology (propranolol: 
hypertension, angina pectoris, atrial fibrillation, among others) with well documented toxicity profiles. 
Propranolol’s usual dose range for most indications is 40mg to 320mg daily. The RP2D dosing of propranolol of 
30mg BID in this trial is therefore on the lower end of what can be used in clinical practice. There are no contra-
indications for the combined use of propranolol and pembrolizumab when this is routinely done for separate 
oncological and cardiac indications. 
4. Study Intervention/Investigational Agent
4.1 Description
PROPRANOLOL
Propranolol hydrochloride (Inderal®) is a synthetic beta-adrenergic receptor blocking agent chemically 
described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. Its molecular 
and structural formulae are:
C16H21NO2
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. 
Its molecular weight is 295.80. It is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral 
administration.
Mechanism of Action
Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous 
system activity. It specifically competes with beta-adrenergic receptor agonist agents for available receptor 
sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator 
responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for 
beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the 
cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
The mechanism of the antihypertensive effect of propranolol has not been established. Factors that may 
contribute to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release 
by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. 
Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with 

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chronic use of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat 
variable. 
In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of 
effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the 
velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing 
left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of 
beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain 
and increased work capacity. 
Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and 
this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta 
blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac 
action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. 
The mechanism of the antimigraine effect of propranolol has not been established. Beta-adrenergic 
receptors have been demonstrated in the pial vessels of the brain. 
The specific mechanism of propranolol's anti-tremor effects has not been established, but beta-2 (noncardiac) 
receptors may be involved. A central effect is also possible. Clinical studies have demonstrated that Inderal is of 
benefit in exaggerated physiological and essential (familial) tremor.
Absorption: Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, 
it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the 
systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose.  Administration of 
protein-rich foods increase the bioavailability of propranolol by about 50% with no change in time to peak 
concentration, plasma binding, half-life, or the amount of unchanged drug in the urine.  
Refer to the package insert for complete details: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016418s080,016762s017,017683s008lbl.pdf
Pembrolizumab
Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 kDa.  
Pembrolizumab will be provided as a sterile, preservative-free, clear to slightly opalescent, colorless to slightly 
yellow solution that requires dilution for IV infusion.  

Pembrolizumab solution is provided in single-dose vials containing 100 mg/4 mL (25 mg/mL).  Each 1 mL 
of solution contains 25 mg of pembrolizumab and is formulated in L-histidine (1.55 mg), polysorbate 80 
(0.2 mg), sucrose (70 mg), and Water for Injection, USP. 

The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
and administration of the infusion solution.  An infusion of pembrolizumab in this study will require 2 
vials of solution.
   
Pembrolizumab will be supplied in commercial packaging, which includes the package insert or patient 
information leaflet. Refer to the latest package insert for complete details:
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
Avelumab
Avelumab is a programmed death ligand1 (PD-L1) blocking antibody. Avelumab- is a human IgG1 lambda 

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monoclonal antibody produced in Chinese hamster ovary cells and has a molecular weight of approximately 147 
kDa. 
BAVENCIO (avelumab) Injection for intravenous use is a sterile, preservative-free, nonpyrogenic, clear, 
colorless to slightly yellow solution. Each single-dose vial contains 200 mg avelumab in 10 mL (20 mg/mL). 
Each mL contains 20 mg avelumab, D-mannitol (51 mg), glacial acetic acid (0.6 mg), polysorbate 20 (0.5 mg), 
sodium hydroxide (0.3 mg), and Water for Injection. The pH range of the solution is 5.0 – 5.6.
Refer to the latest package insert for complete details:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761049s006lbl.pdf
Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4 kappa 
immunoglobulin that has a calculated molecular mass of 146 kDa.  It is expressed in a recombinant Chinese 
Hamster Ovary (CHO) cell line.
OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that 
may contain light (few) particles.
OPDIVO (nivolumab) injection for intravenous use is supplied in single-dose vials. Each mL of OPDIVO solution 
contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride 
(2.92 mg), sodium citrate dihydrate (5.88 mg), and water for injection, USP.  May contain hydrochloric acid 
and/or sodium hydrozide to adjust pH to 6.
Refer to the latest package insert for complete details:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/225554s112lbl.pdf
4.2 Drug/Device Handling
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on 
the label.  Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Propranolol
Propranolol will be stored at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted 
to 15° to 30° C (59° to 86° F).
 
Dispense in a well-closed, light-resistant container as defined in the USP. Protect from light. 
Use carton to protect contents from light.
Propranolol is claimed for IND exemption. It is already FDA-approved for many indications. Its addition to 
standard of care ICI in this study involves a relatively low dose (30mg BID) compared to its maximal dose in 
clinical use (up to 320mg daily) that is not expected to significantly increase the risk associated with propranolol. 
The investigation is not intended to be reported to FDA as a well-controlled study. Also, the investigation will be 
conducted in compliance with the requirements for IRB review and informed consent. 
Pembrolizumab (Keytruda)
The product does not contain a preservative. Store reconstituted and diluted solution from the pembrolizumab 
50 mg vial either:

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At room temperature for no more than 6 hours from the time of reconstitution. This includes room 
temperature storage of reconstituted vials, storage of the diluted solution, and the duration of infusion. 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. 
If refrigerated, allow the diluted solution to come to room temperature prior to administration. 
Store the diluted solution from the pembrolizumab 100 mg/4 mL vial either: 
At room temperature for no more than 6 hours from the time of dilution. This includes room temperature 
storage of the diluted solution, and the duration of infusion. 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. If 
refrigerated, allow the diluted solution to come to room temperature prior to administration. Discard 
after 6 hours at room temperature or after 24 hours under refrigeration. 
Do not freeze.
Avelumab (BAVENCIO)
Preparation
Visually inspect vial for particulate matter and discoloration. BAVENCIO is a clear, colorless to slightly 
yellow solution. Discard vial if the solution is cloudy, discolored, or contains particulate matter.
Withdraw the required volume of BAVENCIO from the vial(s) and inject it into a 250 mL infusion bag 
containing either 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride injection.
Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing.
Inspect the solution to ensure it is clear, colorless, and free of visible particles.
Discard any partially used or empty vials.
Storage of diluted BAVENCIO solution
Protect from light.
Store diluted BAVENCIO solution:
At room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution.  Or
Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If 
refrigerated, allow the diluted solution to come to room temperature prior to administration.
Do not freeze or shake diluted solution.
Nivolumab (OPDIVO)
Visually inspect for particulate matter and discoloration. OPDIVO is a clear to opalescent, colorless to pale-
yellow solution. Discard if cloudy, discolored, or contains extraneous particulate matter other than a few 
translucent-to-white, proteinaceous particles. Do not shake. 
Preparation 
Withdraw the required volume of OPDIVO and transfer into an intravenous container. 
Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to 
prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of 
infusion must not exceed 160 mL. 
For adult and pediatric patients with body weight ≥40 kg, do not exceed a total volume of infusion of 
160 mL.
Mix diluted solution by gentle inversion. Do not shake. 

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Discard partially used vials or empty vials of OPDIVO. 
The product does not contain a preservative. 
After preparation, store the diluted solution either: 
At room temperature and room light for no more than 8 hours from the time of preparation to end of 
the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or 
Under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light for no more than 7 days from 
the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the 
time of preparation. 
Do not freeze.
4.3 Accountability
The study drug provided for this study will be used only as directed in the study protocol. The Winship IDS 
(Investigational Drug Service) personnel will account for all study drugs. Drug accountability should be 
performed until the patient stops study treatment completely. Study site personnel will account for all study 
drugs received at the site.
Study drug supplies must be kept in an appropriate, secure locked area and stored in accordance with the 
conditions specified on the labels. The Investigator, pharmacist, or designee must maintain an accurate record 
of dispensing the study drug/s in a Drug Accountability Log.
The Drug Accountability Log may record specifics to study drug dispensation such as: 
• Records of product delivery, inventory, temperature monitoring, destruction, and return.
• Dosages prepared, time prepared, doses dispensed. 
• Doses and/or vials destroyed. 
• The Drug Accountability Log may be reviewed by the monitor during site visits and at the completion of 
the study.
Drug accountability may be noted by the internal monitor during site visits and at the completion of the study. 
Patients will be asked to return all unused study treatment and packaging on a regular basis, at the end of the 
study or at the time of study treatment discontinuation.
The study drug supply will be disposed of per Winship’s Investigational Drug Service (IDS) SOP. Compliance will 
be assessed by the investigator and/or study personnel at each patient visit and information provided by the 
patient and/or caregiver (collection of drug diary) will be captured in the Drug Accountability Form. This 
information must be captured in the source document at each patient visit. The patient might be requested to 
maintain a medication diary of each dose of medication.  The medication diary (Appendix C) will be returned to 
clinic staff at the end of each cycle. Dose changes and interruptions of study drug must be specifically 
documented in the patient source documents and eCRF.
5. Procedures Involved
5.1 Study Design
This is a pilot study on safety and correlative translational markers of the combination of propranolol 
hydrochloride in combination with ICI in the treatment of urothelial cancer under an FDA-approved indication.
The trial plans to enroll 24 patients. The study is divided into a Screening period, Treatment period, End of 
Treatment (EOT) period, and Follow-up period. 

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During Screening period, patients will provide written informed consent to participate in the study before 
completing any protocol-specified procedures or evaluations not considered to be part of the patient’s 
standard care.  
Subjects will be assigned to either ICI + propranolol arm or the ICI (standard of care) arm sequentially. The first 
patient on the trial will be assigned to the ICI + propranolol arm. The specific ICI the subject would receive 
depends on the clinic need and would follow FDA-approved indications (i.e. nivolumab for high-risk urothelial 
bladder cancer after radical surgery, avelumab for advanced or metastatic disease as maintenance after 
platinum-based chemotherapy with no progression, or pembrolizumab for first line if ineligible for platinum-
based chemotherapy or as subsequent line therapy). The specific ICI would not influence assignment to either 
arms. Procedures that were performed for standard of care prior to signing informed consent may be used for 
screening purposes (e.g., full physical exam) as long as the procedures were completed within the 28-day 
screening period. After signing the ICF, patients will be evaluated for entry criteria during the screening period 
within 28 days before administration of study drug(s).  Rescreening after screen failure will be allowed.
For subjects receiving Treatment duration will continue until unacceptable toxicity, death, disease progression 
per RECIST 1.117, Investigator’s decision to discontinue treatment, the patient withdraws consent, lost to 
follow-up, or Institution decides to terminate the trial.
5.2 Dosing and Administration
Subjects receiving Pembrolizumab
Regimen Description
Arm
Agent
Premedications 
/ Precautions
Dose
Route
Schedule
Cycle 
Length
Pembrolizumab
None
200 mg
IV infusion over 
30 min
Q3W
ICI plus 
propranolol
Propranolol 
hydrochloride
None
30mg
Oral
BID, Continuous
ICI Alone
Pembrolizumab
None
200mg
IV infusion over 
30 min
Q3W
42 days 
(6 weeks)
Subjects receiving Avelumab

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Regimen Description
Arm
Agent
Premedications 
/ Precautions
Dose
Route
Schedule
Cycle 
Length
Avelumab
Acetaminophen 
and antihistamine 
prior to the first 4 
infusions
10mg/kg
IV infusion over 
60 min
Q2W
ICI plus 
propranolol
Propranolol 
hydrochloride
None
30mg
Oral
BID, 
Continuous
ICI Alone
Avelumab
Acetaminophen 
and antihistamine 
prior to the first 4 
infusions
10mg/kg
IV infusion over 
60 min
Q2W
42 days 
(6 weeks)
Subjects receiving Nivolumab 
Regimen Description
Arm
Agent
Premedications 
/ Precautions
Dose
Route
Schedule
Cycle 
Length
Nivolumab
None
480mg
IV infusion over 
30 min
Q4W
ICI plus 
propranolol
Propranolol 
hydrochloride
None
30mg
Oral
BID, 
Continuous
ICI Alone
Nivolumab
None
480mg
IV infusion over 
30 min
Q4W
28 days 
(4 weeks)
5.3 Dose Modification
The investigator will decide whether any AE that occurs is related to either or both drugs and determine 
whether dose modification or discontinuation of one or both drugs is required per the guidance below.
ICI (Pembrolizumab, Avelumab, and Nivolumab)
No dose reductions of ICI are recommended. Withhold or discontinue the drug to manage
Adverse reactions as described in Table 1. Any infusion or hypersensitivity reactions occurring during the 
infusion of the pembrolizumab are not considered dose-related and therefore will NOT be considered to be an 
adverse event. 
Table 1: Dose Modification for Adverse Events (AE) Associated with ICI (Pembrolizumab, Avelumab, and 
Nivolumab):
General instructions:
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks.

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2. For situations where ICI has been withheld, ICI can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. ICI should be permanently discontinued if AE does not resolve within 12 weeks of 
last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening AEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if AEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv5.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, 
or recurrent 
Grade 2
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper
Monitor participants for signs and 
symptoms of pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment
Add prophylactic antibiotics for 
opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / 
Colitis 
Grade 4
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper
Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in 
stool with or without fever) and of 
bowel perforation (ie, peritoneal signs 
and ileus).
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing 
endoscopy to rule out colitis. 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If sufficient 
oral fluid intake is not feasible, fluid 
and electrolytes should be substituted 
via IV infusion.
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 0.5- 
1 mg/kg 
prednisone or 
equivalent) 
followed by taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 4 
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable

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Type 1 diabetes 
mellitus (T1DM) 
or 
hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withhold
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
Monitor participants for hyperglycemia 
or other signs and symptoms of 
diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.  
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinuei
Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
Monitor for signs and symptoms of 
thyroid disorders. 
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine or 
liothyroinine) per 
standard of care
Monitor for signs and symptoms of 
thyroid disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue
Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper.
Monitor changes of renal function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue
Based on severity 
of AE administer 
corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Intolerable/ 
persistent 
Grade 2
Withhold
All other 
immune-related 
AEs
Grade 3
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Based on type and 
severity of AE 
administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes

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Syndrome, 
encephalitis
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
i.
Withhold or permanently discontinue ICI is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of ICI is required, ICI may be 
resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic 
control (in case of T1DM).  
Propranolol
No dose reductions of Propranolol are recommended (Table 2). 
Table 2: Dose Modification for Adverse Events (AE) Associated with Propranolol:
Grade 1
Continue, monitor closely
Grade 2
Withhold for 3 days, monitor closely. 
Grade 3
Permanently discontinue
Grade 4
Permanently discontinue
Propranolol will be permanently discontinued if Grade 3 or more cardiac (Table 3) and non-cardiac adverse 
events attributed to propranolol as defined by CTCAE Version 5. The full list of adverse events that have been 
attributed to Propranolol appears in the protocol section 14. Risk to Participants. 
Table 3: Cardiac Adverse Events Associated with Propranolol
Grade 1
Grade 2
Grade 3
Grade 4
Sinus bradycardia*
Asymptomatic, 
intervention not 
indicated
Symptomatic, 
intervention not 
indicated; change in 
medication initiated
Symptomatic, 
intervention indicated
Life-threatening 
consequences; urgent 
intervention indicated
Congestive Heart 
Failure
Asymptomatic with 
laboratory (e.g., BNP 
[B-Natriuretic 
Peptide]) or cardiac 
imaging 
abnormalities
Symptoms with 
moderate activity or 
exertion
Symptoms at rest or 
with minimal activity or 
exertion; 
hospitalization; new 
onset of symptoms
Life-threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical
Hypotension†
Asymptomatic, 
intervention not 
indicated
Non-urgent medical 
intervention indicated
Medical intervention 
indicated; 
hospitalization 
indicated
Life-threatening 
consequences and 
urgent intervention 
indicated

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Vascular disorders 
- Other, specify
Asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated
Moderate; minimal, 
local or noninvasive 
intervention 
indicated; limiting age 
appropriate 
instrumental ADL
Severe or medically 
significant but not 
immediately life 
threatening; 
hospitalization or 
prolongation of existing 
hospitalization 
indicated; limiting self-
care ADL
Life-threatening 
consequences; urgent 
intervention indicated
* CTCAE v5.0 definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node.
 †CTCAE v5.0 definition: A disorder characterized by a blood pressure that is below the normal expected for an individual in a given environment.
5.4 Concomitant medication
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial.  If there is a clinical indication for one of these or other medications or vaccinations specifically 
prohibited during the trial, discontinuation from trial therapy or vaccination may be required.
Propranolol
Caution should be exercised when Propranolol is administered with drugs that have an effect on CYP2D6, 1A2, 
or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant 
drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND 
DRUG METABOLISM).
Cardiovascular Drugs
• Antiarrhythmics
o Propafenone has negative inotropic and beta-blocking properties that can be additive to those of 
propranolol. 
o Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-
blockade and may cause postural hypotension.
o Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to 
those seen with β-blockers such as propranolol.
o The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been 
reported following co-administration with propranolol.
o Caution should be exercised when administering Inderal with drugs that slow A-V nodal conduction, 
e.g. digitalis, lidocaine and calcium channel blockers.
• Digitalis Glycosides
o
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. 
Concomitant use can increase the risk of bradycardia.
• Calcium Channel Blockers
o
Caution should be exercised when patients receiving a beta blocker are administered a calcium 
channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress 
myocardial contractility or atrioventricular conduction.
o
There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with 
concurrent use of verapamil and beta-blockers.
o
Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated 
with bradycardia, hypotension, high-degree heart block, and heart failure.

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• ACE Inhibitors
o
When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting 
of acute myocardial infarction.
o
The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be 
administered cautiously to patients withdrawing from clonidine.
• Alpha Blockers
o
Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-
blockers.
o
Postural hypotension has been reported in patients taking both beta-blockers and terazosin or 
doxazosin.
• Reserpine
o
Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for 
excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked 
bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
• Inotropic Agents
o
Patients on long-term therapy with propranolol may experience uncontrolled hypertension if 
administered epinephrine as a consequence of unopposed alpha-receptor stimulation.
o
Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE).
• Isoproterenol and Dobutamine
o
Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by 
administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce 
sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial 
ischemia.
Non-Cardiovascular Drugs
o
Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect 
of beta-adrenoreceptor blocking agents.
o
Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing 
blood pressure and heart rate.
• Antidepressants
o
The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when 
administered with beta-blockers by interfering with the beta blocking activity of propranolol.
• Anesthetic Agents
o
Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with 
propranolol.
• Warfarin
o
Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin 
time, therefore, should be monitored.
Neuroleptic Drugs
o
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and 
haloperidol.
• Thyroxine
o
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with 
propranolol.
• Alcohol
o
Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.

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ICI (Pembrolizumab, Avelumab, and Nivolumab)
Participants are prohibited from receiving the following therapies during the Screening and Treatment Phase 
(including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than ICI/propranolol

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the 
investigator’s discretion.  

Live vaccines within 30 days prior to the first dose of study treatment and while participating in the 
study.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) 
are live attenuated vaccines and are not allowed. 

Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.  The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  All treatments that the Investigator 
considers necessary for a participant’s welfare may be administered at the discretion of the Investigator in 
keeping with the community standards of medical care.  
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing 
study.  If there is a clinical indication for any medication or vaccination specifically prohibited during the study, 
discontinuation from study therapy or vaccination may be required.  The final decision on any supportive 
therapy or vaccination rests with the investigator and/or the participant's primary physician.  However, the 
decision to continue the participant on study treatment requires the mutual agreement of the Investigator, the 
Sponsor and the participant. There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.5 Study Procedures
Before study entry, throughout the study, and following study drug discontinuation, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed measurements is to 
ensure adequate safety and tolerability assessments.  Clinical evaluations and laboratory studies may be 
repeated more frequently if clinically indicated.  The Schedules of Assessments during the screening and 
treatment period is provided following the Protocol Synopsis. 
Screening Phase
Screening procedures will be performed up to 28 days prior to enrollment and initiation of radiation therapy as 
applicable, except for baseline imaging (up to 28 days allowed) unless otherwise specified.  All subjects must 
first read, understand, and sign the IRB-approved ICF before any study-specific screening procedures are 
performed.  After signing the ICF, completing all screening procedures, and being deemed eligible for entry, 
subjects will be enrolled in the study.  Procedures that are performed prior to the signing of the ICF and are 
considered standard of care may be used as screening assessments if they fall within the screening window. 

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The following procedures will be performed during the Screening Visit:

Informed Consent

Review of eligibility criteria

Medical history (prior history of cardiac disease will be evaluated) and demographics

Complete physical exam 

ECOG Performance Status

Patient-reported outcomes

Vitals signs, weight and height 

12-lead ECG

Review of prior/concomitant medications 

Imaging by CT/MRI

Archival tumor tissue collection

Blood collection for research

Clinical laboratory tests for:
o Hematology 
o Clinical chemistry 
o Creatinine Clearance
o Serum or urine pregnancy test (for women of childbearing potential)
o Stool sample for microbiome analysis
Treatment Phase 
Procedures to be conducted during the treatment phase of the study are presented in the Schedule of 
Assessments Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do not need to be 
repeated on C1D1.

Brief medical history

Symptom-directed physical exam 

ECOG Performance Status

Patient-reported outcomes

Vitals signs, weight 

12-lead ECG as clinically indicated

Review of prior/concomitant medications 

Review of Adverse events

Tumor imaging (every 12 weeks)

Blood collection for research

Clinical laboratory tests for:
o Hematology 
o Clinical chemistry
o Stool sample for microbiome analysis
End of Treatment
End of treatment is defined as the last planned dosing visit within the dosing period. For subjects who 
discontinue drug treatment, end of treatment is considered the last visit where the decision is made to 
discontinue treatment. All required procedures may be completed within ± 7 days of the end of treatment visit. 
Repeat disease assessment is not required if performed within 28 days prior to the end of treatment visit.
Assessments for subjects who have completed treatment and achieved disease control or have discontinued 
treatment due to toxicity in the absence of confirmed progressive disease are provided in the Schedule of Event 
(Section1.3).   

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5.6 Description of Study Procedures
Medical history
Findings from medical history (obtained at screening) and physical examination shall be given a baseline grade 
according to the procedure for AEs. All patients will be screened for prior history of cardiac disease that raise 
the risk of complications by the medical oncologist when the trial information is presented. 
Increases in severity of pre-existing conditions during the study will be considered AEs, with resolution occurring 
when the grade returns to the pre-study grade or below.
Physical examination
Physical examinations should be conducted according to the Schedule of Events.  Full physical examinations 
should be conducted at screening/baseline, and EOT (evaluate all major organ systems, including the following 
categories:  general, head, eyes, ears, mouth/throat, neck, heart, lungs, abdomen, lymph nodes, joints, 
extremities, integumentary, neurologic, and psychiatric). Other examinations during treatment may be focused, 
at the discretion of the Investigator, to identify changes from baseline or evaluate changes based on the 
patient’s clinical symptoms.  Weight is to be recorded at each visit, height at screening/baseline visit only. 
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated according to the 
assessment schedules.  Body weight is also recorded along with vital signs.  
On infusion days, patients receiving treatment will be monitored during and after infusion of study drug.  
Additional monitoring with assessment of vital signs is at the discretion of the Investigator per standard clinical 
practice or as clinically indicated.  
Patient-reported outcomes
The National Comprehensive Cancer Network FACT Bladder Symptom Index (NFBlSI-18) is a tool that allows 
measuring bladder cancer-specific symptoms in patients with advanced or metastatic disease. The tool was 
developed through qualitative assessment of the most important symptoms as perceived by patients and 
oncologists 18. The score includes 18 questions in three subscale scores (i.e. disease-related symptoms, 
treatment side effects, and general function/well-being) and a summary score. A 5-point Likert scale ranging 
from 0 = ‘not at all’ to 4 = ‘very much’ in the preceding 7 days is used. The Manual of Functional Assessment of 
Chronic Illness Therapy (FACIT) Measurement System is employed to calculate the subscale and summary 
scores 19.
Participants will be asked to fill out the assessment tool in paper form and return them to the clinical trial 
team (Appendix D). The dates of Schedule of Assessments are shown in the Schedule of Assessments section.  
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the study.  ECGs should 
be obtained after the patient has been in a supine position for 5 minutes and recorded while the patient remains 
in that position.
At Screening, a single ECG will be obtained on which QTcF must be <450 ms.  

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In case of clinically significant ECG abnormalities, including a QTcF value >450 ms, 2 additional 12-lead ECGs 
should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.  
The Investigator or qualified Sub-Investigator will review all ECG interpretations and interval duration 
measurements for clinical significance.  Any ECG interpretation deemed to be clinically significant in the 
treatment phase will be reported as an AE.  
Tumor and Radiographic Assessments 
Tumor assessments for all patients will be performed at Screening and every 12 weeks (± 3 days) until the patient 
withdraws consent or starts a new antineoplastic regimen.  Assessments will become less frequent during the 
long-term follow-up period. Tumor response or recurrence will be evaluated using RECIST 1.117.
Radiographic assessments (chest/abdomen/pelvis, and other known affected anatomical areas) are required for 
all patients for tumor measurements.  Additional scan assessments may be collected based on clinical 
symptoms, as appropriate. Documented tumor measurements are required using CT scans, MRI, physical 
examination, and/or digital photography, as appropriate.  Any imaging used to assess disease at any time point 
will be submitted for an independent radiology review. The same method of assessment (CT or MRI and/or 
digital photography) and the same technique for acquisition of images must be used for all study assessments 
(contrast must be used unless medically contraindicated).  Baseline imaging should be done at the same 
institution/facility which will be used to measure response during the patient’s participation in the study.  
Radiographic assessments and efficacy analyses will be conducted by the Investigator site as well as the 
independent radiology review committee.
Clinical laboratory tests
The following clinical laboratory tests will be performed (see the Schedule of Assessments)

Hematology and Clinical Chemistry

Pregnancy test (female subjects of childbearing potential only)

Stool sample for microbiome analysis
6.Data and Specimen Banking 
Tumor Tissue Collection
Tumor tissue will be collected prior to trial enrollment and allotment in the form of archival tissue. Tissue will 
be handled as follows: 

RNAlater for RNA stabilization and tissue storage

Formalin-fixed paraffin-embedded (FFPE) block with one cut H&E stained slide

Liquid nitrogen frozen tissue in cryo-preservation vials
All collected tissues are stabilized and stored in -80°C freezers (RNAlater stabilized, OCT embedded, short term 
storage) or the vapor phase of a liquid nitrogen freezer (long term storage) in single use aliquots. All FFPE tissue 
blocks are stored in a climate-controlled storage room that is temperature (less than 27ºC) and humidity 
controlled.
Tissue will be evaluated for assessment of mutations and/or immune markers including PD-1/PD-L1 and other 
relevant biomarkers (e.g. tumor infiltrating lymphocytes, T- cell repertoire, RNA signature profiles). When 
sufficient quantities of fresh tissue are available, it will also be dissociated, and flow cytometry will be used to 

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determine the phenotypic characteristics of cell populations in the tumor microenvironment. Tissue will be 
preserved for future exploratory studies including genomic profiling. 
Correlative Studies Blood Sampling
Correlative peripheral blood samples will be collected prior to study drug allotment, on [(Cycle 1 Day 1, Cycle 1 
Day 8, Cycle 2 Day 1 for subjects receiving avelumab or pembrolizumab as ICI) or (Cycle 1 Day 1, Cycle 1 Day 8, 
Cycle 2 Day 15 for subjects receiving nivolumab)]and in the post-treatment period as expanded in the Trial Flow 
Chart. Approximately 60 mL of peripheral blood will be collected at each time point. The samples will be stored 
in -80°C freezers until analysis. Stool sample will be collected at baseline, and at the time of the first restaging 
radiographic scan. Analysis may include but is not limited to:

Circulating tumor DNA (ctDNA) to explore genetic alterations that are present are baseline and/or 
emerge during treatment

Analysis of peripheral blood mononuclear cells (PBMCs) to assess for phenotypic/functional changes in 
T-cells or myeloid markers during and after treatment

Nuclear acid analysis for gene expression profiling

Stool sample for microbiome analysis
Shipping and handling instructions
After appropriate processing, the blood samples, tissue blocks, slides or frozen tissue samples, and stool samples 
will be sent: Kissick Laboratory, 1462 Clifton Rd, Room 420, Atlanta, Georgia, 30322
Data and specimens from this study may be useful for other research being done by investigators at Emory or 
elsewhere. To help further science, Investigators may provide de-identified data and/or specimens to other 
researchers. Any information that could identify participants will not be included. If data or specimens are labeled 
with study ID, we will not allow other investigators to link that ID to identifiable information.
Samples and data collected under this protocol may be used to study urothelial carcinoma. Access to stored 
samples will be limited to IRB-approved investigators. Samples and data will be stored using codes assigned by 
the investigators or their designees. Data will be kept in password-protected computers. Only investigators (or 
their designees) will have access to the samples and data.
All stored samples will be maintained in the laboratory to which it was sent initially for analysis. Study 
participants who request destruction of samples will be notified of compliance with such request and all 
supporting details will be maintained for tracking.
The results of some study tests and procedures will be used only for research purposes and will not be placed 
in subject’s medical record.  For this study, those items include research blood collection. 
7. Sharing of Results with Participants
In general, study staff will not provide any individual results to subjects (e.g. outcome trial results or results from 
subject’s samples studies). If something of urgent medical importance to the participating subjects will be found, 
the PI (or co-Is) will inform the subject, although we expect that this will be a very rare occurrence. Samples and 
data will only be used for research.

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8. Study Timelines
8.1 Duration of therapy
In the absence of treatment delays due to adverse event(s), patients will be treated until any one of the 
following: 
• Tumor progression per RECIST 1.1 for patients receiving avelumab; tumor progression per RECIST 1.1 
pembrolizumab or completion of 2 years of therapy (whichever is first); tumor progression per RECIST 
1.1 or completion of 1 year of therapy for patients receiving nivolumab (whichever is first)
• Death 
• Unacceptable toxicity 
• Symptomatic deterioration 
• Investigator’s decision to discontinue treatment 
• Patient decision to discontinue treatment 
• Patient withdraws consent 
• Lost to follow up 
In the event of a patient’s withdrawal, the Investigator will make every effort to complete the End of 
Treatment procedures specified in the Schedule of Events.
8.2 Duration of follow-up 
Patients will be followed for approximately 28 days (Safety Follow-up) after the last dose of study drug or before 
initiation of new antineoplastic or investigational therapy whichever occurs first.  Patients removed from study 
for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
Long-term follow-up should continue until the patient’s withdrawal of consent or loss to follow up, death, or 
study termination for a duration of up to two years. 
Patient records may be reviewed until death to assess progression and survival.  Survival information may be 
collected by clinic visit, email, or telephone after ending protocol treatment and until the study is terminated, 
the patient dies, or the patient is lost to follow-up.
A participant will be considered lost to follow-up if he or she fails to return for three scheduled visits and is 
unable to be contacted by the study site staff after three attempts at contact by phone.
The following actions must be taken if a participant fails to return to the clinic for a required study visit:
The site will attempt to contact the participant and reschedule the missed visit and counsel the participant on 
the importance of maintaining the assigned visit schedule and ascertain if the participant wishes to and/or 
should continue in the study.
Patients removed from study for unacceptable adverse event(s) will be followed until resolution or stabilization 
of the adverse event.
Patients who have not initiated a new antineoplastic regimen will have the following assessments:
•
Radiologic tumor assessments every 12 weeks (± 7 days) for up to two years as part of the trial
•
In case of a clinically significant AE, patient will be followed for safety until resolution or permanent 
sequelae of all toxicities attributable to study drug(s). If the patient discontinues study drug for a 
clinically significant AE, the patient will be followed until resolution of the AE or the event is considered 
to be stable and/or chronic. 

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9. Inclusion and Exclusion Criteria
Inclusion Criteria
1. Male or Female 
2. Age ≥18 years.  
3. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).  
4. 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:
o
 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)
o
Avelumab: maintenance treatment in locally advanced or metastatic urothelial carcinoma 
following no progression on first-line platinum-containing chemotherapy
o
Nivolumab: adjuvant treatment of urothelial carcinoma in high risk of disease recurrence after 
undergoing radical resection

High risk disease as defined in Checkmate 2749: pathological stage of pT3, pT4a, or pN+ 
and patient not eligible for20 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
5.
Patients must have adequate organ and marrow function, within 28 days of Cycle 1 Day 1, at the 
discretion of the investigator.
6.
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. 
7.
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.  
o
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).
8.
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.  
9.
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.
o
Patients without existing cardiac disease that raise the risk of complications who consent for 
the trial will proceed with trial participation.
o
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.
10. Life expectancy > 12 weeks as determined by the Investigator.
11. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-
specified laboratory tests, other study procedures, and study restrictions.  

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12. 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.
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study:
1. 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).
2. Patients who are receiving any other investigational agents or an investigational device within 21 days 
before administration of first dose of study drugs.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to the 
agents used in study. 
4. Contraindication to ICI per investigator discretion.
5. 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.
6. 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.
7. 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.
8. 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.  
10. Vulnerable Populations
N/A
11.  Local Number of Participants
We will be recruiting 24 participants at Winship.  Patients will be registered after signing of the informed consent 
document and meeting all entry requirements.
12. Recruitment Methods
Investigators, nurses (CRNs), research coordinators (CRCs) and/or data managers review lists of cancer patients 
who have cancer and will determine if there are patients who might be eligible for a clinical trial. The 
CRN/CRC/data manager reviews accessible medical records to screen further for eligibility. The CRN/CRC 
reviews the eligibility with the physician.  

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Subjects will be identified by their treating physicians. Clinical care team at Winship will inform potential subjects 
about the known benefits and potential risks of a clinical trial as well as other available treatment options. Some 
of the subjects recruited for this protocol will be patients being treated at Emory and under the care of one or 
more of the study investigators. Some potential subjects will be identified by their treating physician and 
referred to Emory for possible participation in the protocol.
No incentives are provided to patients for trial participation.
Study personnel will notify Winship Central Subject Registration (WCSR) by email at winshipcsr@emory.edu, 
once subject has been consented for a trial. 
Email notification must be done within 24 hours after consent has been obtained and it will include scanned 
copies of:
• Signed patient consent form
• HIPAA authorization form
• Emory Research Management System (ERMS; https://erms.emory.edu) Enrollment Fax Cover 
The WCSR will enter the subject into the OnCore Research Management System, which is the system of record 
for Winship Cancer Institute Clinical Trials.
Enrolling a subject requires careful screening and determination of eligibility. 
Eligible patients will be enrolled on study centrally at Winship Cancer Institute by the Study Coordinator.  
Assignment to ICI plus propranolol vs. ICI alone cohorts is not randomized and will be based on the physician-
patient discussion. When all required test results are available, complete the eligibility checklist and provide the 
checklist and the supporting documentation to the IRB approved investigator for review and sign-off. OnCore 
and ERMS must be updated to reflect eligibility and on treatment status. 
Following enrollment, patients should begin protocol treatment within 14 days. Issues that would cause 
treatment delays should be discussed with the Principal Investigator.  
13. Withdrawal of Participants
Participants are free to withdraw from participation in the study at any time upon request.
An investigator may discontinue or withdraw a participant from the study for the following reasons:

Pregnancy

Significant study intervention non-compliance 

If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the participant

Disease progression which requires discontinuation of the study intervention

If the participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation

Participant unable to receive ICI +/- propranolol for over 30 days
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case Report 
Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form, and are randomized and receive 

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the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the study, will be 
replaced.
14. Risks to Participants
Propranolol
Angina Pectoris
There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt 
discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage 
should be gradually reduced over at least a few weeks and the patient should be cautioned against interruption 
or cessation of therapy without the physician's advice. If propranolol therapy is interrupted and exacerbation of 
angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for 
the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to 
follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are 
given propranolol for other indications. 
Hypersensitivity and Skin Reactions 
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the 
administration of propranolol (see ADVERSE REACTIONS). Cutaneous reactions, including Stevens - Johnson 
syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been 
reported with use of propranolol (see ADVERSE REACTIONS). 
Cardiac Failure 
Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive 
heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta blockers 
should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used 
with close follow-up in patients with a history of failure who are well compensated and are receiving additional 
therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of 
digitalis on heart muscle. 
In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, lead to cardiac 
failure. 
Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) 
In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be 
administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking 
bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors. 
Major Surgery 
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, 
however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of 
general anesthesia and surgical procedures. 
Diabetes and Hypoglycemia 
Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate 
and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, 
it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly when given to infants 

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and children, diabetic or not, has been associated with hypoglycemia, especially during fasting as in preparation 
for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion 
and in patients with renal insufficiency. 
Thyrotoxicosis 
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of 
propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. 
Propranolol may change thyroid-function tests, increasing T4 and reverse T3 and decreasing T3. Wolff-
Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and 
tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, 
this result was reported after an initial dose of 5 mg propranolol. 
Pheochromocytoma 
Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) 
action unopposed. In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha 
blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to 
maintain blood pressure. 
General Precautions
-
Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol is 
not indicated for the treatment of hypertensive emergencies.
-
Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that 
Propranolol may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased 
intraocular pressure.
-
While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens 
may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may 
be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
-   Mild symptoms of fatigue are common during the titration phase of propranolol. If those persist, the patient 
will be referred to the cardio-oncologist co-investigator.
-    All patients will be provided with a dosing schedule, a home monitor for self-assessment of blood pressure 
and heart rate if they do not already have one, and a chart for daily recording of symptoms and hemodynamic 
data.
-    Upon cessation of trial participation, propranolol will be weaned off over 3 days.
Clinical Laboratory Tests
In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, 
serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been 
associated with increases in Blood Urea Nitrogen.
Adverse Events
The following adverse events were observed and have been reported in patients using propranolol:
Cardiovascular: Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of 
hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type.
Central Nervous System: Light-headedness, mental depression manifested by insomnia, lassitude, weakness, 
fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized 
by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, 
and decreased performance on neuropsychometrics. For immediate-release formulations, fatigue, lethargy, and 
vivid dreams appear dose-related.

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Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric 
arterial thrombosis, ischemic colitis.
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and 
agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory 
distress.
Respiratory: Bronchospasm.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Autoimmune: Systemic lupus erythematosus (SLE).
Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative 
dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasiform rashes. 
Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctivae reported for a beta 
blocker (practolol) have not been associated with propranolol.
Genitourinary: Male impotence; Peyronie's disease
ICI (Pembrolizumab, Avelumab, Nivolumab)
ICI’s most common adverse reactions (reported in ≥20% of patients) are fatigue, musculoskeletal pain, 
decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal 
pain. 
Other risks

Blood draws - The physical risk of drawing blood is local pain and bruising at the site of venipuncture. 
Qualified phlebotomists or designee will draw blood samples. Care will be taken to obtain these specimens 
in a safe and hygienic manner. A small number of people experience lightheadedness or fainting. There is a 
slight risk of infection. To minimize these risks, attempts will be made to draw study blood samples at the 
same time as blood draws needed for routine clinical care are obtained. Repeated blood drawing may be 
associated with iron deficiency anemia.

Data security - Subjects will be asked to provide personal health information (PHI). All attempts will be made 
to keep this PHI confidential within the limits of the law. However, there is a chance that unauthorized 
persons will see the subjects’ PHI. All records will be kept in a locked file cabinet or maintained in a locked 
room at the participating sites. Electronic files will be password protected behind an academic institutional 
firewall. Only people who are involved in the conduct, oversight, monitoring, or auditing of this study will 
be allowed access to the PHI that is collected. Any publications from this study will not use information that 
will identify subjects. Organizations that may inspect and/or copy research records maintained at the 
participating sites for quality assurance and data analysis include groups such as the National Cancer 
Institute (NCI) and Food and Drug Administration (FDA).
15.
 Potential Benefits to Participants
There is no guarantee of benefit to subjects who enroll in this protocol.
16.
 Statistical consideration: 
16. 1 Study Design and Sample Size
We plan to enroll up to 24 patients, 12 in the ICI plus propranolol cohort and 12 in the ICI alone cohort. 
Descriptive statistics will be provided for collected data including demographics, safety/toxicity, overall 
response rate (for subjects receiving avelumab and pembrolizumab alone), overall survival, progression free 
survival, quality of life, molecular biomarkers, correlative changes in T-cells etc. as appropriate. Descriptive 

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statistics on continuous data will include means, medians, standard deviations, and ranges, while categorical 
data will be summarized using frequency counts and percentages. Safety analysis will follow an as-treated 
principle.
16.2 Population for Analysis Sets
Safety Analysis Set will include all subjects who received at least one dose of study drug(s).
Full Analysis Set (FAS) will include all subjects who received at least one dose of study drug. 
16.3 Analysis of the safety and secondary endpoints.
Safety: Descriptive statistics will be used to summarize the toxicity profile of the intervention. Toxicities will be 
tabulated by grade, association, and cycle number.
Response: Descriptive statistics will be used to summarize overall response rate (for patients receiving 
avelumab and pembrolizumab), overall survival, and progression free survival.
Correlatives: Correlative changes in peripheral T-cell subsets, myeloid derived suppressor cells (MDSC), blood 
inflammatory markers and blood cytokines before and after treatment, will first be described by summary 
statistics. This would be separately for the ICI plus propranolol cohorts and the ICI alone cohort. Descriptive 
statistics on continuous data will include mean, median, standard deviation, and range (as well as geometric 
means and geometric coefficient of variation for PK parameters), while categorical data will be summarized 
using frequency counts and percentages. Graphical summaries of the data may be presented. 
17.
Data Management and Confidentiality
17.1 Data/specimens
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the Principal Investigator. The study 
participant’s contact information will be securely stored at each clinical site for internal use during the study. 
At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated 
by local IRB and Institutional regulations.
Data and/or data forms will be submitted in the clinical management system - Online Collaborative Research 
Environment (ONCORE) - per Winship SOP 4.2 Data Completion Metrics.
All information in original records and certified copies of original records or clinical findings, observations, or 
other activities necessary for the reconstruction and evaluation of the trial is considered source data. Source 
data are contained in source documents, which can be original records or certified copies of hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects' diaries of evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
Case Report Forms (CRFs) - Source data may be collected in the source documents or entered directly onto the 
case report forms.

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All documentation of adverse events, records of study drug receipt and dispensation, and all IRB correspondence 
will be maintained for at least 2 years after the investigation is completed.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
stored. This will not include the participant’s contact or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. The study data entry and 
study management systems used by clinical sites and research staff will be secured and password protected. At 
the end of the study, all study databases will be de-identified and archived.
Samples and data collected under this protocol may be used to study urothelial carcinoma. Access to stored 
samples will be limited to IRB-approved investigators. Samples and data will be stored using codes assigned by 
the investigators or their designees. Data will be kept in password-protected computers. Only investigators will 
have access to the samples and data.
All stored samples will be maintained in the laboratory to which it was sent initially for analysis. Study 
participants who request destruction of samples will be notified of compliance with such request and all 
supporting details will be maintained for tracking.
18. Provisions to Monitor the Data to Ensure the Safety of Participants
Definition of Adverse Events (AE)
Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related (21 CFR 312.32 (a)).
Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event 

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. 

Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. (Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse).
Classification of an Adverse Event
Severity of Event
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will be 
used to describe severity. 
•
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning.

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•
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the 
term “severe” does not necessarily equate to “serious”.
Relationship to Study Intervention
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect. 
•
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary.
•
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable 
time after administration of the study intervention, is unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.
•
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although 
an AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as appropriate.
•
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the study intervention) and in which 
other drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s 
clinical condition, other concomitant treatments).
•
Not Related – The AE is completely independent of study intervention administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician.
Adverse Event and Serious Adverse Event Reporting 
Expectedness 
Principal Investigator will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention.
Adverse Event Reporting 
From the time of treatment allocation/randomization through 28 days following cessation of treatment, all 
adverse events, that begin or worsen after informed consent, must be recorded by the investigator or designee 
at each examination on the Adverse Event case report forms/worksheets.  
The investigator will make every attempt to follow all subjects with non-serious adverse events for outcome.
Conditions that were already present at the time of informed consent should be recorded in the Medical History 
page of the patient’s CRF/worksheet.

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Adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. Grade 1 to 5 will be used to characterize the severity of the Adverse Event. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, 
death related to the AE corresponding respectively to Grades 1 - 5, will be used. Information about any deaths 
(related to an Adverse Event or not) will also be collected through a Death form (or EOT/SEC/Survival 
Information in NOVDD). The occurrence of adverse events should be sought by non-directive questioning of the 
patient (patient) during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments. As far as possible, each 
adverse event should be evaluated to determine: 
1.
The severity grade (CTCAE Grade 1-5) 
2.
Its duration (Start and end dates)  
3.
Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) or its 
relationship to the study treatment (Reasonable possibility that AE is related: No, Yes, investigational 
treatment, Yes, the study treatment (non-investigational), Yes, both and/or indistinguishable) 
4.
Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable) 
5.
Whether medication or therapy was given (no concomitant medication/non-drug therapy, concomitant 
medication/non-drug therapy) 
6.
Whether it is serious, where a serious adverse event (SAE) is defined as in Section 9.2 and which 
seriousness criteria have been met (include for NCDS trials).
7.
Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved 
with sequelae, fatal, unknown)  
 
If the event worsens the event should be reported a second time in the CRF noting the start date when the event 
worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a lower grade is determined a new 
entry for this event should be reported in the CRF noting the start date when the event improved from having 
been Grade 3 or Grade 4.   All adverse events should be treated appropriately. If a concomitant medication or 
non-drug therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged to be permanent, 
and assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, the 
suspected relationship to the study treatment, the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate method (for 
example, as per RECIST criteria for solid tumors), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis at the time of 
progression or hemoptysis concurrent with finding of disease progression) will be reported as per usual 
guidelines used for such events with proper attribution regarding relatedness to the drug.
Laboratory abnormalities that constitute an Adverse event in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes in study 
treatment), should be recorded on the Adverse Events CRF.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be reported as 
adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE unless it meets 

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the definition of serious as defined below and/or as per investigator’s discretion. A dose hold or medication for 
the lab abnormality may be required by the protocol in which case the lab abnormality would still, by definition, 
be an adverse event and must be reported as such.
Serious Adverse Event Reporting 
For the time period beginning at treatment allocation/randomization through 28 days following cessation of 
treatment, or 28 days following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier, any serious adverse event, or follow up to a serious adverse event, including death due to any cause 
whether or not related to the study drug, must be submitted on an SAE form and assessed by PI in order to 
determine reporting criteria to IRB, DSMC, FDA, supporter or IND Sponsor. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by the 
IND sponsor and should be provided as soon as possible. The IND sponsor will be responsible for notifying FDA 
of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.
Reporting to study supporter/IRB and or FDA
All subjects with serious adverse events must be followed up for outcome.
Any additional information for the SAE including complications, progression of the initial SAE, and recurrent 
episodes must be reported to the principal investigator as follow-up to the original episode within 2 days of the 
investigator receiving the follow-up information. 
An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously 
reported one should be reported separately as a new event. 
Any SAEs experienced after the reporting period described above should only be reported to FDA/IRB if the 
investigator suspects a causal relationship to the study treatment.   
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable 
sections of the form must be completed in order to provide a clinically thorough report. The investigator must 
assess and record the relationship of each SAE to each specific study treatment (if there is more than one study 
treatment), complete the SAE Report Form, and submit the completed form.  
Each reoccurrence, complication, or progression of the original event should be reported as a follow-up to that 
event regardless of when it occurs. The follow-up information should describe whether the event has resolved 
or continues, if and how it was treated, whether the blind was broken or not, and whether the patient continued 
or withdrew from study participation. 
Definition of unanticipated problems (UP) and reporting requirements
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or an outcome that meets all the following 
criteria:  Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed consent 

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document; and (b) the characteristics of the participant population being studied; Related or possibly related to 
participation in the research (“possibly related” means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the research); and Suggests that 
the research places participants or others at a greater risk of harm (including physical, psychological, economic, 
or social harm) than was previously known or recognized.  This study will use the OHRP definition of 
unanticipated problems. Incidents or events that meet the OHRP criteria for UPs require the creation and 
completion of a UP report form. It is the site investigator’s responsibility to report UPs to their IRB and to the 
DCC/study sponsor. The UP report will include the following information:  Protocol identifying information: 
protocol title and number, PI’s name, and the IRB project number; A detailed description of the event, incident, 
experience, or outcome; An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP.  The IND sponsor will make an assessment of whether the 
event constitutes an unanticipated problem posing risks to subjects or others (UP). This assessment will be 
provided to the Emory University IRB.  If the Emory IRB determines an event is a UP it will notify the appropriate 
regulatory agencies and institutional officials. 
The Data and Safety Monitoring Committee (DSMC)
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide oversight for 
the conduct of this study. The DSMC functions independently within Winship Cancer Institute to conduct 
internal monitoring functions to ensure that research being conducted by Winship Cancer Institute Investigators 
produces high-quality scientific data in a manner consistent with good clinical practice (GCP) and appropriate 
regulations that govern clinical research. Since this is a Simon 2-Stage design study, The PI or designee must 
provide the DSMC a report outlining the overall enrollment and path to decision to open the next enrollment 
cohort. Depending on the risk level of the protocol as determined by CTRC, the DSMC review may occur every 6 
months or annually. For studies deemed Moderate Risk, initial study monitoring will occur within 1 year from 
the date of the first subject accrued, with 2 of the first 5 subjects being reviewed. Subsequent monitoring will 
occur in routine intervals per the Winship Data and Safety Monitoring Plan (DSMP).  The DSMC will review 
pertinent aspects of the study to assess subject safety, compliance with the protocol, data collection, and risk-
benefit ratio. Specifically, the Winship Cancer Institute Internal Monitors assigned to the DSMC may verify 
informed consent, eligibility, data entry, accuracy and availability of source documents, AEs/SAEs, and essential 
regulatory documents. Following the monitoring review, monitors will provide a preliminary report of 
monitoring findings to the PI and other pertinent individuals involved in the conduct of the study. The PI is 
required to address and respond to all the deficiencies noted in the preliminary report. Prior to the completion 
of the final summary report, monitors will discuss the preliminary report responses with the PI and other team 
members (when appropriate). A final monitoring summary report will then be prepared by the monitor. Final 
DSMC review will include the final monitoring summary report with corresponding PI response, submitted CAPA 
(when applicable), PI Summary statement, and available aggregate toxicity and safety data.  The DSMC will 
render a recommendation and rating based on the overall trial conduct. The PI is responsible for ensuring that 
instances of egregious data insufficiencies are reported to the IRB. Continuing Review submissions will include 
the DSMC recommendation letter. Should any revisions be made to the protocol-specific monitoring plan after 
initial DSMC approval, the PI will be responsible for notifying the DSMC of such changes. The Committee reserves 
the right to conduct additional audits if necessary.  
19.  Provisions to Protect the Privacy Interests of Participants
Participants will be assured of their voluntary participation in the study, their choice to answer or not answer 
any question, and the protocol for maintaining confidentiality.

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Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the sponsor(s) 
and their agents. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence. No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of the sponsor.
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by local IRB and Institutional regulations.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored. This will not include the participant’s contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study identification number. The 
study data entry and study management systems used by clinical sites and research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived
20.   Economic Burden to Participants
The study sponsor will pay for certain items and services the subject may receive in this study.  Specifically, the 
cost of propranolol will be covered by the sponsor (being the study drug) for patients on the ICI plus propranolol 
cohort while ICI will be covered as part of the patient’s regular medical care (being an FDA-approved standard 
of care for the trial’s patient population). Subjects will have to pay for the items or services for which the study 
sponsor does not pay. The sponsor will not pay for regular medical care. If subjects have insurance, Emory will 
submit claims to the insurance for items and services that the sponsor does not cover.  Emory will send in only 
those claims for items and services that it reasonably believes the insurance will pay and that the sponsor has 
not paid. The actual amount that participants have to pay depends on whether or not they have health 
insurance and whether or not that insurance will pay for any research study costs. Generally, insurance 
companies will not pay for items and services that are required just for a research study. Some insurance 
companies will not pay for regular medical treatment or treatment for complications if in a study.  If subject do 
not have insurance, Emory will review that particular case as part of its program for low-income patient care.  
The standard policies of that program will apply.  The program will figure out if subjects have to pay any costs 
for taking part in the study and what those costs will be.
21.  Consent Process
The initial informed consent discussion will occur in Winship Cancer Institute or the Emory Clinic. At Winship 
Cancer Institute, the informed consent is an ongoing, interactive process rather than a one-time information 
session. The consent form document is designed to begin the informed consent process, which provides the 
patient with ongoing explanations that will help them make educational decisions about whether to begin or 
continue participating in the trial. The research team knows that a written document alone may not ensure that 
the patient fully understands what participation means. Therefore, the research team will discuss with the 
patient the trial's purpose, procedures, risks and potential benefits, and their rights as a participant. The team 
will continue to update the patient on any new information that may affect their situation.

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Consent will be obtained prior to any research-driven procedures. The investigator will assess the patient’s 
capacity during his/her encounters with him or her. The investigator will give the person providing consent 
adequate opportunity to read the consent document before it is signed and dated.
It will be explained to prospective participants that the study involves research, the purpose of the research, the 
expected duration of participation, as well as the approximate number of participants to be enrolled. The study 
procedures, and identification of research procedures v. non-research will also be thoroughly discussed. It will 
be explained to participants that participation is voluntary and that the subject may discontinue at any time.
Refusal to participate or withdraw will not involve a penalty or loss of benefits to which the participant is 
otherwise entitled. Refusal will in no way affect the participant's future are. The participant will also be told of 
the possible consequences of the decision to withdraw from the research, and procedures for orderly 
termination of participation.
Any significant new findings developed during the course of the research that may affect the participant's 
willingness to continue to participate will be provided. Also explained will be anticipated circumstances under 
which the subject's participation may be terminated by the investigator without the participant's consent.
Prospective participants will be provided with a description of any reasonably foreseeable risks or discomforts 
as well as a description of any benefits to the participant or to others that might be reasons expected from the 
research. Alternative procedures or courses of treatment will also be thoroughly discussed.
Prospective participants will also be given detailed information describing the extent to which confidentiality of 
records identifying the participant will be maintained and what records may be examined by the research staff, 
IRBs, sponsor, their representatives, and possibly the FDA or OHRP.
Also communicated to the participant will be an explanation that emergency medical care will be arranged for 
a study-related illness or injury, and an explanation of whether funds are set aside to pay for this care and/or 
compensation, and if so by whom (e.g., sponsor, subject, insurer). The participant is told the source of the study's 
funding.
All participants will be told of any additional costs that may result from participation in the research.
Non-English-Speaking Participants  
A certified translator/interpreter will be present during the consenting process and all questions and concerns 
will be answered by the treating physician. 
A Short Form in that specific language will be used. A certified translator/interpreter will be present during the 
consenting process and this will be documented. We will use what's available on Emory IRB website. For the 
languages that are not available, we will have the short form translated to that language and submit the IRB for 
review and approval prior to use. Process to Document Consent in Writing: Winship SOP 2.1:” Obtaining 
Informed consent for Interventional clinical trial” will be followed.
Participants who are not yet adults (infants, children, teenagers) : N/A
Cognitively Impaired Adults: N/A
Adults Unable to Consent: N/A 
Waiver or Alteration of Consent Process (consent will not be obtained, required information 
will not be disclosed, or the research involves deception) N/A

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22.   Setting
The research will be conducted at Emory University.
Potential participants will be identified in medical oncology clinics, multidisciplinary cancer clinic, surgical 
oncology clinics, and multidisciplinary tumor board at Winship Cancer Institute of Emory University clinical 
practice sites (Emory University Hospital campus, Emory University Hospital Midtown campus, Emory Saint 
Joseph’s Hospital, Grady Memorial Hospital). 
23.  Resources Available
Emory University was founded in 1836 and is a national center for teaching, research, and service. Emory 
University has been named as one of the nation’s top 25 universities for more than a decade by the U.S. News 
and World Report. Emory University research partners include the Georgia Institute of Technology, the 
University of Georgia, Morehouse School of Medicine, the US Centers for Disease Control and Prevention, 
Children's Healthcare of Atlanta, and the Georgia Clinical and Translational Science Alliance (GACTSA). Emory 
University researchers received $734 million from external funding agencies in fiscal year 2018, including 
approximately $441 million in funding from federal agencies, $359 million of this from the National Institutes of 
Health (NIH).
Winship Cancer Institute (Winship) is Georgia's first and only National Cancer Institute (NCI)-designated 
Comprehensive Cancer Center (P30CA138292) and is dedicated to the integration of innovative clinical and basic 
science research with outstanding patient care for the prevention, treatment and control of cancer. First 
designated in 2009, Winship’s NCI designation was renewed in 2012 and 2016, achieving an “outstanding” 
rating. Winship earned the prestigious Comprehensive Cancer Center designation from the NCI in 2016, after 
demonstrating that its outstanding programs are reducing the cancer burden on the state of Georgia through 
research conducted in its laboratories, its clinical trial program, and its population-based science. The 
institutional support for Winship was rated as ‘exceptional’ by the review panel.
The Winship Clinic Building C houses the primary offices and clinical space for cancer services including the 
medical oncology, hematology, and surgical oncology clinics, the radiation oncology program, and the Winship 
Ambulatory Infusion Center.  In summer 2017, Emory Healthcare completed the expansion of Emory University 
Hospital Tower on Clifton Road. This nine-floor facility adds 144 inpatient beds to the hospital, of which more 
than 80% are dedicated to cancer care. The hospital expansion also accommodates cancer patient-specific 
intensive care units, an expanded BMT Unit with peri-transplant clinics to facilitate continuity of care, and a 24-
hour cancer urgent care center, which serves as both a triage facility and short stay treatment center for patients 
with cancer-related medical concerns. 
The Winship Phase I Unit, on the fourth floor of the Emory University Hospital Tower, is the largest unit in 
Georgia dedicated to the earliest and most critical phase of new cancer therapy evaluation. There is space for 
15 private treatment bays, four clinic rooms, its own lab for doing patient blood work, a dedicated secure 
medication room, computer workspace for research and other support staff, and a "fast track" bay with three 
chairs for rapid use in patients who, for example, might need only a research lab test done.
The Winship at Emory University Hospital Midtown offers clinical space for specialized cancer care including 
gynecological oncology, surgical oncology, head & neck program, benign hematology, medical oncology, and 
the Ambulatory Infusion Center. 

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The Winship at Emory Saint Joseph offers clinical space for a variety of specialized cancer care by Emory-
employed physicians, advanced practice providers, nurses, and clinical care team.
The Georgia Cancer Center for Excellence at Grady Health System services a critical role to Atlanta’s population 
by being committed to providing the best possible care to all members of the community, regardless of their 
financial means. The Center is primarily staffed by Emory-employed physicians along with Emory-employed 
clinical trial research coordinators.  

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24.  References
1.
Pantziarka P, Bouche G, Sukhatme V, Meheus L, Rooman I, Sukhatme VP. Repurposing Drugs in Oncology 
(ReDO)-Propranolol as an anti-cancer agent. Ecancermedicalscience. 2016;10: 680-680.
2.
Bustamante P, Miyamoto D, Goyeneche A, et al. Beta-blockers exert potent anti-tumor effects in 
cutaneous and uveal melanoma. Cancer Med. 2019;8: 7265-7277.
3.
Liu D, Yang Z, Wang T, et al. β2-AR signaling controls trastuzumab resistance-dependent pathway. 
Oncogene. 2016;35: 47-58.
4.
Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a 
population- based study. J Clin Oncol. 2011;29: 2635-2644.
5.
Lindgren ME, Fagundes CP, Alfano CM, et al. Beta-blockers may reduce intrusive thoughts in newly 
diagnosed cancer patients. Psychooncology. 2013;22: 1889-1894.
6.
Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and 
potential biomarkers. Exp Mol Med. 2018;50: 1-11.
7.
Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nat 
Rev Drug Discov. 2019;18: 41-58.
8.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70: 7-30.
9.
Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial 
Carcinoma. N Engl J Med. 2021;384: 2102-2114.
10. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial 
Carcinoma. N Engl J Med. 2020;383: 1218-1230.
11. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial 
Carcinoma. N Engl J Med. 2017;376: 1015-1026.
12. Calvani M, Bruno G, Dal Monte M, et al. β3-Adrenoceptor as a potential immuno-suppressor agent in 
melanoma. British journal of pharmacology. 2019;176: 2509-2524.
13. Mohammadpour H, MacDonald CR, Qiao G, et al. beta2 adrenergic receptor-mediated signaling regulates 
the immunosuppressive potential of myeloid-derived suppressor cells. J Clin Invest. 2019;129: 5537-5552.
14. Hiller JG, Cole SW, Crone EM, et al. Preoperative beta-Blockade with Propranolol Reduces Biomarkers of 
Metastasis in Breast Cancer: A Phase II Randomized Trial. Clin Cancer Res. 2020;26: 1803-1811.
15. Kokolus KM, Zhang Y, Sivik JM, et al. Beta blocker use correlates with better overall survival in metastatic 
melanoma patients and improves the efficacy of immunotherapies in mice. Oncoimmunology. 2018;7: 
e1405205.
16. Gandhi S, Pandey MR, Attwood K, et al. Phase I clinical trial of combination propranolol and 
pembrolizumab in locally advanced and metastatic melanoma: Safety, Tolerability, and Preliminary 
Evidence of Antitumor Activity. Clinical Cancer Research. 2020.
17. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45: 228-247.
18. Jensen SE, Beaumont JL, Jacobsen PB, Abernethy A, Syrjala KL, Cella DJTjoso. Measuring priority symptoms 
in advanced bladder cancer: development and initial validation of a brief symptom index2013;11: 86.
19. Webster K, Cella D, Yost KJH, outcomes qol. The F unctional A ssessment of C hronic I llness T herapy 
(FACIT) Measurement System: properties, applications, and interpretation2003;1: 1-7.

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APPENDIX A   Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade Descriptions
Percent
Description
100
Normal, no complaints, no evidence of 
disease.
0
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction.
90
Able to carry on normal activity; minor signs 
or symptoms of disease.
80
Normal activity with effort; some signs or 
symptoms of disease.
1
Symptoms, but ambulatory.  Restricted in 
physically 
strenuous 
activity, 
but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on normal 
activity or to do active work.
60
Requires occasional assistance but is able to 
care for most of his/her needs.
2
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours.
50
Requires 
considerable 
assistance 
and 
frequent medical care.
40
Disabled, 
requires 
special 
care 
and 
assistance.
3
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours.
30
Severely disabled, hospitalization indicated.  
Death not imminent.
20
Very sick, hospitalization indicated. Death not 
imminent.
4
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair.
10
Moribund, 
fatal 
processes 
progressing 
rapidly.
5
Dead.
0
Dead.
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair

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APPENDIX B New York Heart Association (NYHA) Functional Classification
The NYHA Functional Classification consists of a Patient Symptoms (I to IV) score and an Objective Assessment 
(A to D) score. 
Class
Patient Symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea (shortness of breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea (shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any 
physical activity is undertaken, discomfort increases.
Class
Objective Assessment
A
No objective evidence of cardiovascular disease. No symptoms and no limitation in ordinary physical 
activity.
B
Objective evidence of minimal cardiovascular disease. Mild symptoms and slight limitation during 
ordinary activity. Comfortable at rest.
C
Objective evidence of moderately severe cardiovascular disease. Marked limitation in activity due to 
symptoms, even during less-than-ordinary activity. Comfortable only at rest.
D
Objective evidence of severe cardiovascular disease. Severe limitations. Experiences symptoms even 
while at rest.
As published in American Heart Association website – Classes of Heart Failure – accessed 07/20/20:
https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/classes-of-heart-failure 

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APPENDIX C  Drug Diary
Study ID: WINSHIP5200-20
Subject Initials: __________             Subject ID: __________        Arm: __________       Cycle: ______
Instructions:
Planned Dose: __________ mg BID po
1. 
Reminders:
2.
Day
Date
Time
# of tablets taken
Comments
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32

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Day
Date
Time
# of tablets taken
Comments
33
34
35
36
37
38
39
40
41
42
Record all medications taken during this cycle for example prescriptions and over-the-counter medications 
including vitamins.
Name of Medication
Reason for 
taking 
medication
Dose
How many times 
per day?
Date 
Medication 
Started
Date 
Medication 
Stopped
If you have any questions, please call: __________________________

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APPENDIX D   Patient-reported Outcome Questionnaire - NFBlSI-18 tool
Study ID: WINSHIP5200-20
Subject Initials: __________             Subject ID: __________        Arm: __________       Cycle: ______
This questionnaire asks about your health and feelings. For each question, please rate your response from 0 
(not at all) to 4 (very much) by writing an X in the one box that best describes your answer.
0 
= ‘not at all’ 
1
2
3
4 
= ‘very much’
Subscale
Item
 
 
 
 
 
Disease-related symptoms
I have pain
 
I am losing weight
 
 
 
 
 
 
I have trouble controlling my urine
 
 
 
 
 
 
I feel weak all over
 
 
 
 
 
 
I feel light-headed (dizzy)
 
 
 
 
 
 
Because of my physical condition, I have 
trouble meeting the needs of my family
 
 
 
 
 
 
I worry that my condition will get worse
 
 
 
 
 
 
I feel sad
 
 
 
 
 
 
I have a good appetite
 
 
 
 
 
 
(For men only) I am able to have and 
maintain an erection
 
 
 
 
 
Treatment side effects
I am sleeping well
 
I have nausea
 
 
 
 
 
 
I have a lack of energy
 
 
 
 
 
 
I feel ill
 
 
 
 
 
 
I have control of my bowels
 
 
 
 
 
 
I am bothered by side effects of 
treatment
 
 
 
 
 
General function/ well-being
I am able to enjoy life
 
 
 
 
 
 
I am content with the quality of my life 
right now
 
 
 
 
 

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APPENDIX E   Abbreviations and definition of terms
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special term
Explanation
AE
Adverse event
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BoR
Best objective response
BP
Blood pressure
C
Cycle
CL
Clearance
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDoR
Expected duration of response
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
IB
Investigator’s Brochure
ICF
Informed consent form
IFN
Interferon
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IHC
Immunohistochemistry

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Abbreviation or special term
Explanation
IL
Interleukin
IP
Investigational product 
irAE
Immune-related adverse event
IRB
Institutional Review Board
IV
Intravenous
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PFS
Progression-free survival
PFS2
Time to second progression
PGx
Pharmacogenetic research
PK
Pharmacokinetic(s)
PR
Partial response
q2w
Every 2 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RR
Response rate
SAE
Serious adverse event
SD
Stable disease
SoC
Standard of Care
ULN
Upper limit of normal