Propranolol + Pembrolizumab + Chemotherapy for Esophageal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Roswell Park Cancer Institute

Must be taking: Beta-blockers

Must not be taking: Immunosuppressants, Beta-blockers

Disqualifiers: HER 2-positive, CNS 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

Compensation: Varies

Number of Visits: 1

Duration: 6 months

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests what effects the addition of propranolol to pembrolizumab and standard chemotherapy (mFOLFOX) may have on response to treatment in patients with esophageal or gastroesophageal junction cancer that cannot be removed by surgery and has spread to nearby tissue or lymph nodes (unresectable locally advanced) or has spread from where it first started (primary site) to other places in the body (metastatic). Propranolol is a drug that is classified as a beta-blocker. Beta-blockers affect the heart and circulation (blood flow through arteries and veins). Cancer patients may be under a tremendous amount of stress with elevated levels of norepinephrine (a hormone produced by the adrenal glands in response to stress). Increased adrenergic stress may dampen the immune system, which beta-blockers, like propranolol, may be able to counteract. 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. Drugs used in the standard chemotherapy regimen, mFOLFOX (leucovorin, fluorouracil and oxaliplatin) work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding propranolol to pembrolizumab and standard mFOLFOX chemotherapy may increase the effectiveness of the pembrolizumab + mFOLFOX regimen.

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 participate if you are already on beta-blockers or certain immunosuppressive agents. If you are on steroids, the dose must be low (10 mg of prednisone or less daily).

What data supports the effectiveness of the drug combination of Propranolol, Pembrolizumab, and Chemotherapy for esophageal cancer?

Research shows that Pembrolizumab, when combined with chemotherapy, is effective for treating advanced esophageal cancer, improving survival rates. It has been approved for use with chemotherapy in esophageal cancer, indicating its potential benefit in combination therapies. ^{1 2 3 4 5}

Is the combination of Propranolol, Pembrolizumab, and Chemotherapy safe for treating esophageal cancer?

Pembrolizumab combined with chemotherapy has been shown to have a safety profile similar to other cancer treatments, with some risks like esophageal fistula and pneumonitis. However, specific safety data for the combination with Propranolol is not available in the provided research. ^{1 2 6 7 8}

What makes the drug combination of Propranolol, Pembrolizumab, and Chemotherapy unique for esophageal cancer?

This drug combination is unique because it includes pembrolizumab, an immune therapy that helps the body's immune system attack cancer cells, combined with chemotherapy, which is a standard treatment for esophageal cancer. Pembrolizumab has been shown to be effective in treating advanced esophageal cancer, especially when used with chemotherapy, offering a potentially more effective option than chemotherapy alone. ^{2 3 4 7 8}

Research Team

Kannan Thanikachalam

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

Adults with unresectable locally advanced or metastatic esophageal/gastroesophageal junction adenocarcinoma, who haven't had treatment for it yet. They should be in good physical condition (ECOG 0-1), have adequate organ function, and no prior PD-1/PD-L1 therapy within the last year. Participants must not have HER2-positive cancer, active autoimmune diseases requiring immunosuppression, uncontrolled illnesses, or be on beta-blockers already.

Inclusion Criteria

I am fully active or can carry out light work.

Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Participants of child-bearing potential must have a negative pregnancy test at study entry and then agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. 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

Exclusion Criteria

I am currently taking beta-blockers for my condition.

I am living with HIV.

I have untreated brain or spinal cord metastases.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive mFOLFOX6, pembrolizumab, and propranolol. Tumor biopsy, CT scans, and blood sample collection are conducted.

6 months

Regular visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Periodic visits for monitoring progression-free survival and overall survival

Treatment Details

Interventions

• Fluorouracil
• Leucovorin
• Oxaliplatin
• Pembrolizumab
• Propranolol Hydrochloride

Trial Overview The trial is testing if adding propranolol to pembrolizumab (an immune system booster) and standard chemotherapy mFOLFOX can improve treatment response in patients with certain types of esophageal cancer. Propranolol is a beta-blocker that might help reduce stress effects on the immune system.

Participant Groups

Group I: Treatment (mFOLFOX6, pembrolizumab, propranolol) Experimental Treatment 9 Interventions

Patients receive mFOLFOX6 (leucovorin IV, oxaliplatin IV, and fluorouracil IV), pembrolizumab IV, and propranolol PO on study. Patients also undergo tumor biopsy during screening and CT scans and collection of blood samples during screening and on study.

Fluorouracil is already approved in United States, European Union, Canada for the following indications:

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

In a meta-analysis of 1231 patients, pembrolizumab and paclitaxel showed no significant difference in effectiveness for treating advanced gastroesophageal cancer, with similar objective response rates.

Both treatments can be considered viable options for patients, as they provide comparable time to response and similar rates of partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus paclitaxel for previously treated, advanced gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized clinical trials. Swed, S., Shaheen, N., Hafez, W., et al.[2022]

Pembrolizumab (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

In a study of 39 patients with locally advanced esophageal squamous cell carcinoma (ESCC), pembrolizumab combined with neoadjuvant chemotherapy resulted in a high objective response rate of 87.2% and a disease control rate of 100%.

The treatment led to significant surgical outcomes, with a major pathological response rate of 68.2% and a complete pathological response rate of 45.5% among those who underwent radical surgery, while maintaining a manageable safety profile with only 15.4% experiencing severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab combined with paclitaxel and platinum as induction therapy for locally advanced esophageal squamous cell carcinoma: a retrospective, single-center, three-arm study. Lin, W., Huang, Y., Zhu, L., et al.[2023]

In a study of 55 patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC), pembrolizumab combined with chemotherapy or radiotherapy showed favorable long-term survival outcomes, with a 12-month overall survival rate of 78.8%.

The treatment was found to be safe and manageable, with long-term adverse effects reported in only a small number of patients, indicating that pembrolizumab is a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world. Wang, HC., Huang, X., Chen, J., et al.[2023]

In a study of 340 Asian patients with advanced esophageal squamous cell carcinoma (ESCC), pembrolizumab significantly improved overall survival (10.0 months) compared to chemotherapy (6.5 months), indicating its efficacy as a second-line treatment.

Patients receiving pembrolizumab experienced fewer treatment-related adverse events (71.8%) compared to those on chemotherapy (89.8%), highlighting its safety profile, especially for those with PD-L1 combined positive score (CPS) ≥1, which was identified as a predictive marker for treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia. Cao, Y., Qin, S., Luo, S., et al.[2022]

Nivolumab (OPDIVO) was approved by the FDA for treating unresectable advanced esophageal squamous cell carcinoma (ESCC) after prior chemotherapy, showing a significant improvement in overall survival (10.9 months for nivolumab vs. 8.4 months for chemotherapy).

Patients treated with nivolumab experienced fewer treatment-emergent adverse events compared to those receiving chemotherapy, although there was a new risk of esophageal fistula and a higher incidence of pneumonitis in the ESCC population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefit-Risk Summary of Nivolumab for the Treatment of Patients with Unresectable Advanced, Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma After Prior Fluoropyrimidine- and Platinum-Based Chemotherapy. Pelosof, L., Saung, MT., Donoghue, M., et al.[2021]

In a phase III trial (KEYNOTE-590), pembrolizumab combined with cisplatin and fluorouracil (FP) showed superior efficacy compared to FP alone for treating advanced esophageal cancer, resulting in a mean gain of 0.86 life-years and 0.77 quality-adjusted life-years (QALYs).

The cost-effectiveness analysis indicated that pembrolizumab plus FP is a viable treatment option, with an incremental cost-effectiveness ratio of $147,097 per QALY, which is acceptable given the willingness-to-pay threshold of $150,000 per QALY in the US healthcare system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost Effectiveness of Adding Pembrolizumab to Platinum and Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A US Healthcare Payer's Perspective. Qu, T., Zhang, S., Zhong, Y., et al.[2022]

A post hoc analysis of the JUPITER-06 study demonstrated that adding PD-1 antibodies (like pembrolizumab or nivolumab) to chemotherapy significantly improves overall survival and progression-free survival in patients with advanced esophageal squamous cell carcinoma (ESCC), even in those with low PD-L1 expression (TPS < 1%).

The study found that patients with low PD-L1 expression also experienced a notable increase in objective response rates when treated with PD-1 antibodies plus chemotherapy, indicating that this combination therapy is effective regardless of PD-L1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Benefit of First-Line Programmed Death-1 Antibody Plus Chemotherapy in Low Programmed Cell Death Ligand 1-Expressing Esophageal Squamous Cell Carcinoma: A Post Hoc Analysis of JUPITER-06 and Meta-Analysis. Wu, HX., Pan, YQ., He, Y., et al.[2023]

References

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

Pembrolizumab versus paclitaxel for previously treated, advanced gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized clinical trials. [2022]

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]

3. China pubmed.ncbi.nlm.nih.gov

Pembrolizumab combined with paclitaxel and platinum as induction therapy for locally advanced esophageal squamous cell carcinoma: a retrospective, single-center, three-arm study. [2023]

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

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Benefit-Risk Summary of Nivolumab for the Treatment of Patients with Unresectable Advanced, Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma After Prior Fluoropyrimidine- and Platinum-Based Chemotherapy. [2021]

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

Cost Effectiveness of Adding Pembrolizumab to Platinum and Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A US Healthcare Payer's Perspective. [2022]

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

Clinical Benefit of First-Line Programmed Death-1 Antibody Plus Chemotherapy in Low Programmed Cell Death Ligand 1-Expressing Esophageal Squamous Cell Carcinoma: A Post Hoc Analysis of JUPITER-06 and Meta-Analysis. [2023]