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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding propranolol, a beta-blocker used to manage stress-related hormones, to pembrolizumab (an immunotherapy) and standard chemotherapy can improve treatment outcomes for individuals with certain types of esophageal or gastroesophageal junction cancer that are inoperable or have metastasized. The trial seeks participants newly diagnosed with these advanced cancers who have not yet received treatment. Those with a history of stress-related health issues or concerns about tumor growth and spread may find this trial suitable. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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).

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

Research has shown that the combination of mFOLFOX6 chemotherapy, pembrolizumab, and propranolol has been safe in previous studies. Studies indicate that mFOLFOX6 has a manageable safety profile, with generally acceptable side effects. Most patients tolerated this chemotherapy well, although some experienced nausea or tiredness.

Studies have found that pembrolizumab, when combined with chemotherapy, does not introduce new safety issues. It has been used for advanced esophageal cancer with good results. Patients reported side effects similar to those of other cancer treatments, which are generally manageable.

Research on propranolol, a type of beta-blocker, suggests it can be safely added to cancer treatments. It has been tested with other therapies and usually has a good safety record. Some patients might experience mild side effects like dizziness or tiredness, but these are typically not severe.

Overall, each of these treatments has been tested separately and is well-tolerated. While researchers continue to study their combination, early findings suggest it is a safe approach. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for esophageal cancer?

Researchers are excited about this treatment for esophageal cancer because it combines propranolol, a beta-blocker, with pembrolizumab, an immunotherapy, and a chemotherapy regimen known as mFOLFOX6. Unlike standard treatments that primarily rely on chemotherapy and radiation, this approach aims to enhance the immune system's ability to fight cancer by using pembrolizumab, which blocks a protein that prevents immune cells from attacking cancer cells. Additionally, propranolol may help reduce stress-induced cancer progression, potentially improving outcomes. This combination could offer a more comprehensive attack on the cancer, making it a promising new option for patients.

What evidence suggests that this trial's treatments could be effective for esophageal cancer?

In this trial, participants will receive a combination of pembrolizumab, chemotherapy, and propranolol. Research has shown that combining pembrolizumab with chemotherapy can extend the lives of patients with advanced esophageal cancer. Studies have found that pembrolizumab reduces the risk of disease progression compared to chemotherapy alone. Chemotherapy drugs like fluorouracil, leucovorin, and oxaliplatin have successfully shrunk tumors and improved survival rates in esophageal cancer. Propranolol, a beta-blocker, might enhance these effects by reducing stress hormones that can weaken the immune system. Early evidence suggests that adding propranolol to this treatment could increase its effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

Kannan Thanikachalam

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

Citations

1. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-025-14011-4

Real-world safety and efficacy of neoadjuvant docetaxel ... Outcomes of preoperative chemotherapy with docetaxel, cisplatin, and 5-fluorouracil followed by esophagectomy in patients with resectable node- ...

2. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0326056

Efficacy and safety of cisplatin + docetaxel + 5-FU + leucovorin ... Reported response rates range from 25% to 45%, with a median overall survival of 6–10 months in phase II and III trials [11–15]. However, the outcomes remain ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1053429697800276

Combination of 5-Fluorouracil and radiation in esophageal ... The preponderance of evidence indicates that concomitant chemotherapy and radiation is superior to either modality above.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.365

Safety and efficacy of neoadjuvant docetaxel, cisplatin, and ... Recurrence-free survival as a surrogate for overall survival in esophageal squamous cell carcinoma: Nationwide real-world data from Japan.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12523764/

Real-World Effectiveness of Cisplatin, 5-Fluorouracil, and ... This study aimed to evaluate the real-world effectiveness and safety of CF plus Pem therapy and assess survival outcomes based on the initial dose intensity.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.250

5-year outcomes from the phase 3 KEYNOTE-590 study. After 5 yrs, use of pembro + chemo showed durable efficacy versus pbo + chemo, with no new safety concerns in pts with untreated advanced esophageal cancer.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38077159/

Long-term efficacy and predictors of pembrolizumab-based ... Pembrolizumab combined with chemotherapy or radiotherapy resulted in favorable long-term survival in patients with locally advanced or metastatic ESCC.

8. merck.com merck.com/news/mercks-keytruda-pembrolizumab-significantly-improved-overall-survival-os-compared-to-chemotherapy-in-patients-with-advanced-esophageal-or-esophagogastric-junction-carcinoma-whose-tu/

Merck's KEYTRUDA® (pembrolizumab) Significantly ... “In this pivotal trial, KEYTRUDA resulted in a statistically significant and clinically meaningful improvement over standard chemotherapy in overall survival ...

9. asco.org asco.org/abstracts-presentations/ABSTRACT148482

Pembrolizumab (MK-3475) for Patients with Advanced ... Background: Expression of the PD-1 ligands PD-L1 and PD-L2 has been associated with poor prognosis in esophageal cancer. Pembrolizumab is a highly selective ...

10. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2798101

Evaluation of Clinical and Safety Outcomes of Neoadjuvant ... This systematic review and meta-analysis of 27 clinical trials with 815 patients found promising clinical and safety outcomes of neoadjuvant immunotherapy ...