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Propranolol Hydrochloride and Pembrolizumab for the Treatment of Recurrent or Metastatic Urothelial Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04848519
Recruitment Status : Recruiting
First Posted : April 19, 2021
Last Update Posted : June 9, 2022
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Bassel Nazha, Emory University

Brief Summary:
This phase II trial studies the effect of propranolol hydrochloride and pembrolizumab in treating patients with urothelial cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Propranolol hydrochloride is used for the treatment of chronic angina, cardiac arrhythmias, essential tremor, hypertension, and as prophylaxis for migraine headaches, and may have anticancer properties. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving propranolol hydrochloride and pembrolizumab may enhance the anticancer activity of pembrolizumab.

Condition or disease Intervention/treatment Phase
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 Drug: Pembrolizumab Drug: Propranolol Hydrochloride Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate the anti-tumor activity of the combination of propranolol hydrochloride and pembrolizumab by assessing the overall response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1.).

SECONDARY OBJECTIVE:

I. To evaluate the efficacy of the combination as measured by progression free survival (PFS; from treatment initiation until disease progression, death due to disease, or lost to follow up) and overall survival (OS; from treatment initiation until death due to any cause or loss to follow up), and safety as measured by incidence of adverse events assessed up to 2 years.

TERTIARY/EXPLORATORY OBJECTIVE:

I. To assess tissue-based assays in archival tissue and correlative changes in peripheral T-cell subsets, myeloid derived suppressor cells (MDSC), blood inflammatory markers and cytokines.

OUTLINE:

Patients receive propranolol hydrochloride orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for propranolol hydrochloride and every 3 or 6 weeks for pembrolizumab for up to 2 years in the absence of disease progression or unacceptable toxicity.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Propranolol Hydrochloride and Pembrolizumab in Patients With Recurrent or Metastatic Urothelial Carcinoma: A Single Center Phase II Trial
Actual Study Start Date : May 20, 2021
Estimated Primary Completion Date : January 1, 2024
Estimated Study Completion Date : January 1, 2024


Arm Intervention/treatment
Experimental: Treatment (propranolol hydrochloride, pembrolizumab)
Patients receive propranolol hydrochloride PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for propranolol hydrochloride and every 3 or 6 weeks for pembrolizumab for up to 2 years in the absence of disease progression or unacceptable toxicity.
Drug: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Propranolol Hydrochloride
Given PO
Other Name: Inderal




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 2 years post treatment ]
    Defined as the proportion of subjects with a best overall response of complete or partial response as assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1. This will be summarized with the 2-sided 95% confidence interval using the Clopper-Pearson method.


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: From start of study treatment to the first objective documentation of radiological disease progression or death due to any cause, assessed up to 2 years ]
    Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with 95% confidence interval for PFS.

  2. Overall survival (OS) [ Time Frame: From the start of study treatment to the date of death due to any cause, assessed up to 2 years ]
    Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with 95% confidence interval for OS.

  3. Incidence of adverse events [ Time Frame: Up to 28 days ]
    Assessed according to the Common Terminology Criteria for Adverse Events version 5.0. Descriptive statistics will be used to summarize the toxicity profile of the intervention. Toxicities will be tabulated by grade, association, and cycle number.


Other Outcome Measures:
  1. Immune profile and changes in selected biomarkers and cell subsets [ Time Frame: Baseline up to 2 years ]
    Correlative changes in peripheral T-cell subsets, myeloid derived suppressor cells, blood inflammatory markers and blood cytokines before and after treatment, will first be described by summary statistics. Descriptive statistics on continuous data will include mean, median, standard deviation, and range (as well as geometric means and geometric coefficient of variation for pharmacokinetic parameters), while categorical data will be summarized using frequency counts and percentages. Graphical summaries of the data may be presented. Their correlation with clinical efficacy endpoints will be carried out by logistic regression model for ORR or Cox proportional hazard mode for time to even outcomes (OS or PFS).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
  • Patients must have histologically confirmed recurrent or metastatic urothelial carcinoma (renal pelvis, ureter, bladder, or urethra), planned for treatment with pembrolizumab under an Food and Drug Administration (FDA) approved indication (listed below) at the genitourinary oncology clinics of Emory University's Winship Cancer Institute:

    • First line: locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 10) as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status
    • Second line: locally advanced or metastatic urothelial carcinoma after progression on platinum-based chemotherapy
  • Patients must have measurable disease as defined by RECIST criteria as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded as ≥ 10 mm (≥ 1 cm) on computed tomography (CT) scan or magnetic resonance imaging (MRI)
  • Patients must have adequate organ and marrow function, within 28 days of cycle 1 day 1, at the discretion of the investigator
  • The effects of study drugs on the developing human fetus are unknown. For this reason, female of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy
  • FCBP and men treated or enrolled on this protocol must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 3 months after completion of study drug administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

    • A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ≥ 4 weeks before the start of study therapy
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class IIB or better

    • Patients without existing cardiac disease that raise the risk of complications who consent for the trial will proceed with trial participation
    • Patients with existing cardiac disease that could raise the risk of complications will be referred at the discretion of the investigator to a cardio-oncologist who is a co-investigator on the trial (or general cardiologist) for cardiac optimization prior to starting propranolol
  • Life expectancy > 12 weeks as determined by the investigator
  • Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions
  • 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:

  • 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 1)
  • Patients who are receiving any other investigational agents or an investigational device within 21 days before administration of first dose of study drugs
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in study
  • Contraindication to pembrolizumab per investigator discretion
  • Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association class 3 or 4 congestive heart failure; or uncontrolled grade ≥ 3 hypertension (diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥ 160 mmHg) despite antihypertensive therapy
  • Contraindication to a beta blocker: cardiac conditions that significantly raise the risk of cardiopulmonary complications, including unstable angina, uncontrolled heart failure, symptomatic bradycardia, and severe asthma
  • Current use of an oral or intravenous beta blocker (e.g. atenolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, sotalol, among other beta blockers) with inability to safely switch to a non-beta blocker agent. The washout for current users should be at least 14 days with enough transition period

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04848519


Contacts
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Contact: Bassel Nazha, MD, MPH 404-251-5996 bassel.nazha@emory.edu

Locations
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United States, Georgia
Emory University Hospital/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Wilena Session    404-778-3448    wsessio@emory.edu   
Principal Investigator: Bassel Nazha, MD, MPH         
Sponsors and Collaborators
Emory University
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Bassel Nazha, MD, MPH Emory University Hospital/Winship Cancer Institute
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Responsible Party: Bassel Nazha, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT04848519    
Other Study ID Numbers: STUDY00002186
NCI-2021-00437 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
WINSHIP5200-20 ( Other Identifier: Emory University Hospital/Winship Cancer Institute )
P30CA138292 ( U.S. NIH Grant/Contract )
First Posted: April 19, 2021    Key Record Dates
Last Update Posted: June 9, 2022
Last Verified: June 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Urethral Neoplasms
Ureteral Neoplasms
Pelvic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urologic Diseases
Urethral Diseases
Ureteral Diseases
Pembrolizumab
Propranolol
Antineoplastic Agents, Immunological
Antineoplastic Agents
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents