Propranolol + Pembrolizumab for Triple Negative Breast Cancer

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Roswell Park Cancer Institute

Must be taking: Checkpoint inhibitors

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Autoimmune disease, Brain metastases, 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: 1

Duration: Up to 6 months

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, propranolol and pembrolizumab, to determine their effectiveness in treating triple negative breast cancer that hasn't responded to previous treatments. Propranolol, a beta-blocker, may enhance the effectiveness of pembrolizumab, an immunotherapy drug that helps the body's immune system attack cancer. Participants should have triple negative breast cancer that has spread or cannot be removed by surgery and hasn't responded to other treatments. The study aims to determine if the combination can make the tumors respond to treatment again. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering participants a chance to potentially benefit from this novel combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on systemic immunosuppressive agents or beta-blockers. If you are on these, you may need to stop them before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using propranolol with pembrolizumab is generally safe and effective. In past studies with patients who have advanced melanoma, this combination was well-tolerated. Patients received propranolol at a dose of 30 mg twice a day without major issues.

Pembrolizumab, already used to treat various cancers like triple-negative breast cancer, has a manageable safety profile. However, it can cause the immune system to become overactive, leading to side effects, which are usually manageable.

Overall, similar patient groups have responded well to this combination. This suggests it could be safe for those interested in joining clinical trials for triple-negative breast cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for triple-negative breast cancer, which often include chemotherapy and radiation, the combination of propranolol and pembrolizumab offers a unique approach. Pembrolizumab is an immunotherapy that works by enhancing the body's immune response to target cancer cells more effectively. Propranolol, typically a beta-blocker for heart conditions, is being investigated for its potential to reduce cancer cell proliferation and improve the effectiveness of immunotherapy. Researchers are excited about this combination because it could potentially enhance the immune system's ability to fight cancer while also modulating the tumor environment, offering a novel strategy that differs from traditional therapies.

What evidence suggests that propranolol and pembrolizumab could be effective for triple negative breast cancer?

Research shows that combining propranolol with pembrolizumab may help treat cancer. In this trial, participants will receive both propranolol and pembrolizumab. Propranolol can enhance the immune system's response when used with pembrolizumab, a drug that helps the body fight cancer. Studies have found that pembrolizumab alone can shrink tumors in triple-negative breast cancer. Propranolol might also help control stress hormones, which can interfere with cancer treatment. Early trials in other cancers, such as melanoma, suggested that this combination is safe and effective. This offers hope for its potential success in treating triple-negative breast cancer. ^{1 2 3 4 6}

Who Is on the Research Team?

Sheheryar Kabraji

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with triple negative breast cancer that's spread, can't be surgically removed, or hasn't responded to checkpoint inhibitor therapy. Participants must have finished any major treatments at least 4 weeks prior and agree to biopsies. They should not have other cancers within the last 5 years, uncontrolled illnesses, or be on immunosuppressives.

Inclusion Criteria

My breast cancer cannot be surgically removed, has spread, and cannot be cured.

I can swallow and keep down pills.

I am fully active or can carry out light work.

Exclusion Criteria

I cannot take beta-blockers due to health reasons.

My cancer did not respond to initial treatment with chemotherapy and pembrolizumab.

I have an active autoimmune disease or a history of transplantation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive propranolol orally and pembrolizumab intravenously. Patients undergo CT scan, blood sample collection, and may undergo tumor biopsy.

Up to 6 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Periodic follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Propranolol

Trial Overview The trial tests propranolol (a beta-blocker) combined with pembrolizumab (an immune checkpoint inhibitor) in patients whose cancer didn't respond to previous therapies. The goal is to see if propranolol can make the immune system react better to pembrolizumab.

How Is the Trial Designed?

Group I: Treatment (propranolol and pembrolizumab) Experimental Treatment 6 Interventions

Patients receive propranolol PO and pembrolizumab IV while on study. Patients undergo CT scan, blood sample collection and may undergo tumor biopsy during screening and on study.

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?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In the phase III KEYNOTE-522 trial, pembrolizumab combined with chemotherapy showed increased effectiveness as a neoadjuvant treatment for triple-negative breast cancer, leading to a higher rate of pathologic complete response compared to chemotherapy alone.

This benefit was observed regardless of the PD-L1 expression levels in patients, suggesting that pembrolizumab may be a broadly effective option for this aggressive cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Pembrolizumab Takes on TNBC. [2020]

In a phase 3 trial involving 847 patients with untreated metastatic triple-negative breast cancer, the addition of pembrolizumab to chemotherapy significantly improved progression-free survival, especially in patients with a PD-L1 combined positive score (CPS) of 10 or more, with a median survival of 9.7 months compared to 5.6 months for placebo.

The safety profile of pembrolizumab-chemotherapy was comparable to placebo-chemotherapy, with similar rates of grade 3-5 treatment-related adverse events (68% vs. 67%), indicating that the combination therapy is both effective and manageable in terms of safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Cortes, J., Cescon, DW., Rugo, HS., et al.[2021]

In a multicenter retrospective analysis of early triple-negative breast cancer (eTNBC) patients treated with pembrolizumab and chemotherapy, the incidence of immune-related adverse events (irAEs) was found to be 63.9%, with 20% of patients experiencing severe (grade 3 or higher) irAEs.

The study reported a pathological complete response (pCR) rate of 57.1%, with a significant correlation between the occurrence of irAEs and higher pCR rates (72.2% vs. 30.8%), indicating that while irAEs are common, they may be associated with better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer. Marhold, M., Udovica, S., Halstead, A., et al.[2023]

In the KEYNOTE-355 trial, patients with previously untreated metastatic triple-negative breast cancer (mTNBC) who received pembrolizumab combined with chemotherapy experienced a significant improvement in quality-adjusted survival, gaining an average of 3.7 months more time without symptoms or treatment toxicity compared to those receiving chemotherapy alone.

The benefits of pembrolizumab plus chemotherapy increased over time, with a 20% relative gain in quality-adjusted survival at a maximum follow-up of 52 months, indicating both efficacy and manageable safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic triple-negative breast cancer that expresses PD-L1. Huang, M., O'Shaughnessy, J., Haiderali, A., et al.[2023]

The phase 3 KEYNOTE-522 trial demonstrated that adding pembrolizumab, a PD-1 axis blocker, to chemotherapy significantly improves pathological complete response rates in patients with advanced triple-negative breast cancer, regardless of their PD-L1 status.

This combination therapy not only enhances treatment effectiveness but also appears to improve overall survival rates for patients with this aggressive form of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanding the Role for Immunotherapy in Triple-Negative Breast Cancer. Savas, P., Loi, S.[2020]

In a phase II trial involving 50 patients with early triple-negative breast cancer, 66% achieved a pathological complete response (pCR) after treatment with nab-paclitaxel and pembrolizumab, indicating a promising efficacy of this combination therapy.

The treatment was associated with manageable side effects, with fatigue, peripheral sensory neuropathy, and neutropenia being the most common adverse events, suggesting that this regimen could be a viable alternative to platinum-based chemotherapy for patients who cannot tolerate it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in combination with nab-paclitaxel for the treatment of patients with early-stage triple-negative breast cancer - A single-arm phase II trial (NeoImmunoboost, AGO-B-041). Fasching, PA., Hein, A., Kolberg, HC., et al.[2023]

Pembrolizumab, when combined with chemotherapy, significantly improves pathological complete response (pCR) and event-free survival (EFS) in patients with high-risk, early-stage triple-negative breast cancer, as shown in the KEYNOTE-522 trial with 123 EFS events in the pembrolizumab group compared to 93 in the control group.

Despite 44% of patients experiencing immune-related adverse reactions, the benefits of pembrolizumab, including a 7.5% absolute improvement in pCR rates, support its use as an effective neoadjuvant and adjuvant treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Neoadjuvant and Adjuvant Treatment of Patients with High-Risk Early-Stage Triple-Negative Breast Cancer. Shah, M., Osgood, CL., Amatya, AK., et al.[2023]

In a phase 3 trial involving 622 patients with metastatic triple-negative breast cancer, pembrolizumab did not significantly improve overall survival compared to standard chemotherapy, with median survival times of 9.9 months for pembrolizumab and 10.8 months for chemotherapy.

Pembrolizumab showed a manageable safety profile, with fewer severe treatment-related adverse events compared to chemotherapy, suggesting it may be safer for some patients despite not demonstrating superior efficacy overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Winer, EP., Lipatov, O., Im, SA., et al.[2021]

In the KEYNOTE-086 study involving 254 patients with metastatic triple-negative breast cancer, several biomarkers such as PD-L1, CD8, stromal tumor-infiltrating lymphocytes (sTILs), tumor mutational burden (TMB), and T-cell-inflamed gene expression profile (TcellinfGEP) were significantly associated with better clinical outcomes when treated with pembrolizumab.

These findings suggest that assessing these biomarkers can help identify which patients are more likely to benefit from pembrolizumab monotherapy, enhancing personalized treatment strategies for metastatic triple-negative breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Biomarkers and Clinical Outcomes of Pembrolizumab Monotherapy in Patients With Metastatic Triple-Negative Breast Cancer: KEYNOTE-086 Exploratory Analysis. Loi, S., Salgado, R., Schmid, P., et al.[2023]

In the KEYNOTE-522 study involving 1174 patients, the addition of pembrolizumab to neoadjuvant chemotherapy significantly improved pathologic complete response (pCR) rates, with 58.7% achieving pCR compared to 40.0% in the placebo group, regardless of PD-L1 status.

Event-free survival (EFS) was also enhanced, with a 36-month EFS rate of 91.2% for the pembrolizumab group versus 77.2% for the placebo group, indicating that this treatment combination could be a new standard of care for early triple-negative breast cancer in Asian populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. Takahashi, M., Cortés, J., Dent, R., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05741164

Study Details | NCT05741164 | Propranolol and ... This phase II trial tests how well propranolol and pembrolizumab work to cause tumor re-sensitization and therefore treatment in patients with triple negative ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7785669/

Phase I clinical trial of combination propranolol and ... Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg BID was ...

3. withpower.com withpower.com/trial/phase-2-carcinoma-2-2023-3f301

Propranolol + Pembrolizumab for Triple Negative Breast ... Research shows that Pembrolizumab, when used alone or with chemotherapy, has been effective in treating triple-negative breast cancer by reducing tumor size ...

4. roswellpark.org roswellpark.org/newsroom/202405-study-reveals-worse-clinical-outcomes-breast-cancer-patients-who-reported-higher

Study Reveals Worse Clinical Outcomes in Breast Cancer ... Breast cancer patients who reported high levels of pain and stress were more likely than their study peers to experience worse invasive disease-free survival ( ...

5. aacrjournals.org aacrjournals.org/clincancerres/article/27/1/87/83678/Phase-I-Clinical-Trial-of-Combination-Propranolol

Phase I Clinical Trial of Combination Propranolol and ... Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day ...

6. clin.larvol.com clin.larvol.com/abstract-detail/ASCO%202023/65033886

ASCO 2023: A phase 2 trial of chemotherapy ... TPS4171 - A phase 2 trial of chemotherapy, pembrolizumab, and propranolol in patients with advanced esophageal/gastroesophageal junction adenocarcinoma ...