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

Status
Temporarily Closed
Cancer Type
Bladder Cancer
Kidney Cancer
Unknown Primary
Ureter Cancer
Urethral Cancer
Trial Phase
Phase II
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCT ID
NCT04848519
Protocol IDs
WINSHIP5200-20 (primary)
NCI-2021-00437
Study Sponsor
Emory University Hospital/Winship Cancer Institute

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 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.

Objectives

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.

Eligibility

  1. Age >= 18 years
  2. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  3. 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
  4. 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, magnetic resonance imaging (MRI)
  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. * 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. 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
  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
  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
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts... Click here to learn more about clinical trials.
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