Immune Checkpoint Inhibitors + Propranolol for Bladder Cancer

Overseen By Bassel Nazha, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must be taking: Immune checkpoint inhibitors

Must not be taking: Beta blockers

Disqualifiers: Cardiovascular disease, Uncontrolled illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 32

Duration: Up to 2 years

24 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

If you are currently taking a beta blocker (a type of heart medication), you will need to stop it at least 14 days before starting the trial and switch to a different type of medication. For other medications, the trial protocol does not specify if you need to stop them.

What data supports the effectiveness of the drug combination of immune checkpoint inhibitors and propranolol for bladder cancer?

Pembrolizumab, an immune checkpoint inhibitor, has been approved by the FDA for treating certain types of bladder cancer that do not respond to BCG therapy, showing its effectiveness in this area. Additionally, studies have shown pembrolizumab to be effective as a treatment for muscle-invasive bladder cancer, both alone and in combination with other drugs. ^{1 2 3 4 5}

Is the combination of immune checkpoint inhibitors and propranolol safe for humans?

Pembrolizumab, an immune checkpoint inhibitor, has been studied for safety in bladder cancer and is generally considered safe, though it can cause immune-related side effects. Propranolol, a beta-blocker, is widely used for heart conditions and is generally safe, but combining it with pembrolizumab specifically for bladder cancer needs more research to fully understand the safety profile. ^{1 2 6 7 8}

How is the drug pembrolizumab combined with propranolol unique for bladder cancer treatment?

This treatment is unique because it combines pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with propranolol, a beta-blocker typically used for heart conditions, potentially enhancing the immune response against bladder cancer. ^{1 2 3 5 6}

Research Team

Bassel Nazha, MD, MPH

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Eligibility Criteria

Adults with urothelial carcinoma eligible for Pembrolizumab, Avelumab, or Nivolumab treatment can join. They should be relatively healthy (ECOG ≤2), have a life expectancy over 12 weeks, and proper organ/marrow function. Women must test negative for pregnancy and use birth control. Participants need to have finished previous cancer treatments at least 4 weeks prior and not have severe heart issues or other illnesses that could interfere with the trial.

Inclusion Criteria

I am either male or female.

I am 18 years old or older.

I am a woman who can have children, not pregnant, and agree to use birth control.

Exclusion Criteria

You have had allergic reactions to similar medications in the past.

I cannot take beta blocker medications due to health reasons.

I am currently taking a beta blocker and cannot safely switch to another medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive immune checkpoint inhibitors with or without propranolol hydrochloride. Treatment continues until disease progression or unacceptable toxicity.

Up to 2 years

Every 2-4 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

2 years

30 days post-treatment, then every 12 weeks

Treatment Details

Interventions

• Pembrolizumab
• Propranolol Hydrochloride

Trial Overview The study is testing if adding Propranolol Hydrochloride to immune checkpoint inhibitors like Pembrolizumab, Avelumab, or Nivolumab improves outcomes in urothelial carcinoma patients. It's an open-label trial where everyone knows what treatment they're getting.

Participant Groups

Group I: Treatment (propranolol hydrochloride, immune checkpoint inhibitor) Experimental Treatment 4 Interventions

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

Group II: Treatment (immune checkpoint inhibitor) Experimental Treatment 3 Interventions

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

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Pembrolizumab (Keytruda) has been approved by the FDA for treating high-risk, non-muscle invasive bladder cancer (NMIBC) in patients who are unresponsive to BCG therapy and are either ineligible for or have opted not to undergo cystectomy.

This approval specifically targets patients with carcinoma in situ (CIS) with or without papillary tumors, highlighting its role as a treatment option for those with limited surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. Wright, KM.[2021]

In a study of 39 patients with muscle-invasive bladder cancer, the combination of gemcitabine, cisplatin, and the immune checkpoint inhibitor pembrolizumab was effective, achieving pathologic downstaging in 56% of patients and complete pathologic response in 36%.

The treatment was generally safe, with common side effects including thrombocytopenia, anemia, and neutropenia, but no severe immune-related adverse events were reported, indicating a manageable safety profile for this neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. Rose, TL., Harrison, MR., Deal, AM., et al.[2022]

In a study of 74 Japanese patients with metastatic urothelial carcinoma treated with pembrolizumab, the objective response rate was 30.2%, with a median overall survival of 13.3 months, indicating its effectiveness as a second-line treatment.

The safety profile showed that over half of the patients experienced adverse events, with 10.9% suffering from severe adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety profile of pembrolizumab for metastatic urothelial cancer: A retrospective single-center analysis in Japan. Fujiwara, M., Yuasa, T., Urasaki, T., et al.[2022]

In the PURE-01 study involving 50 patients with muscle-invasive bladder carcinoma, neoadjuvant treatment with pembrolizumab resulted in a pathologic complete response (pT0) in 42% of patients, demonstrating its efficacy as a pre-surgery immunotherapy.

The study found that patients with high PD-L1 expression (CPS ≥ 10%) had a significantly higher rate of pT0 (54.3%) compared to those with lower expression (13.3%), suggesting that pembrolizumab may be particularly effective in patients with PD-L1-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. Necchi, A., Anichini, A., Raggi, D., et al.[2021]

In the PURE-01 study involving 84 patients with muscle-invasive bladder cancer, higher RNA-based immune signature scores were significantly associated with a complete response to pembrolizumab, indicating its potential effectiveness as a neoadjuvant therapy.

Unlike pembrolizumab, the same immune signatures did not predict outcomes for patients receiving standard chemotherapy, suggesting that gene expression profiling could help personalize treatment strategies for better outcomes in bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer. Necchi, A., Raggi, D., Gallina, A., et al.[2021]

In a Phase 1 safety study involving six patients with non-muscle-invasive bladder cancer (NMIBC), intravesical administration of pembrolizumab was well tolerated, with no dose-limiting toxicities observed during dose escalation.

The treatment resulted in low-grade adverse events such as dysuria and fatigue, and importantly, there was no evidence of systemic absorption or immune effects, suggesting a localized action of the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PemBla: A Phase 1 study of intravesical pembrolizumab in recurrent non-muscle-invasive bladder cancer. Woodcock, VK., Chen, JL., Purshouse, K., et al.[2023]

In a study of 43 patients with advanced urothelial cancer treated with pembrolizumab, 51.2% experienced immune-related adverse events (irAEs), which were linked to better survival outcomes.

Patients with grade 2 or higher irAEs had not reached median overall survival (OS) or time to treatment failure (TTF), while those with lower grade irAEs had median OS of 160 days, suggesting that the presence of irAEs may indicate a more effective response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma. Kobayashi, K., Suzuki, K., Hiraide, M., et al.[2020]

In a study of 105 advanced urothelial carcinoma patients treated with pembrolizumab, those who experienced immune-related adverse events (irAEs) had significantly better clinical outcomes, including higher objective response rates and longer overall survival compared to those without irAEs.

An increase in the relative eosinophil count (REC) three weeks after starting pembrolizumab was not linked to the occurrence of irAEs, suggesting that while irAEs are associated with improved survival, changes in REC may not be a reliable predictor of irAE incidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-Related Adverse Events and Efficacy and Changes in the Relative Eosinophil Count Among Patients with Advanced Urothelial Carcinoma Treated by Pembrolizumab. Furubayashi, N., Minato, A., Negishi, T., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Effectiveness and safety profile of pembrolizumab for metastatic urothelial cancer: A retrospective single-center analysis in Japan. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

PemBla: A Phase 1 study of intravesical pembrolizumab in recurrent non-muscle-invasive bladder cancer. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma. [2020]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Association Between Immune-Related Adverse Events and Efficacy and Changes in the Relative Eosinophil Count Among Patients with Advanced Urothelial Carcinoma Treated by Pembrolizumab. [2022]