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

Propranolol Hydrochloride and Pembrolizumab in Patients With Recurrent or Metastatic Urothelial Carcinoma: A Single Center Phase II Trial

INTRODUCTION

  • Org Study ID: STUDY00002186
  • Secondary ID: NCI-2021-00437, WINSHIP5200-20, P30CA138292
  • NTC ID: NCT04848519
  • Sponsor: 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.

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.

  • Overall Status
    Recruiting
  • Start Date
    May 20, 2021
  • Phase
    Phase 2
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Overall response rate (ORR)

Primary Outcome 1 - Timeframe: Up to 2 years post treatment

CONDITION

  • 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

ELIGIBILITY

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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Bassel Nazha, MD, MPH

Role: Principal Investigator

Affiliation: Emory University Hospital/Winship Cancer Institute

Overall Contact

Name: Bassel Nazha, MD, MPH

Phone: 404-251-5996

Email: bassel.nazha@emory.edu

LOCATION

Facility Status Contact
Facility: Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia 30322
United States
Status: Recruiting Contact: Contact
Wilena Session
404-778-3448
wsessio@emory.edu