Immunotherapy + Radiation for Gastroesophageal Cancer

(REACTION Trial)

Recruiting at 2 trial locations

Overseen By Peggy Fitzpatrick, MSN, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Systemic steroids

Disqualifiers: Autoimmune disease, Cardiovascular disease, Brain metastasis, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1B study assessing the safety of immune checkpoint inhibition after SBRT in patients with recurrent or metastatic gastroesophageal cancer (limited metastatic disease).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic steroids or immune-suppressive medications, you may need to stop them, as ongoing use of these is an exclusion criterion.

What data supports the effectiveness of the treatment Nivolumab, Opdivo, Relatlimab, Opdualag, BMS-986016, relatlimab-rmbw for gastroesophageal cancer?

Research shows that combining immunotherapy (treatments that help the immune system fight cancer) with radiation can improve survival in some patients with gastroesophageal cancer. This combination has shown promising results in enhancing the body's immune response to tumors, potentially leading to better outcomes. ^{1 2 3 4 5}

Is the combination of immunotherapy and radiation generally safe for treating gastroesophageal cancer?

Nivolumab, an immunotherapy drug, has been approved for certain types of esophageal cancer and generally has a safety profile similar to its use in other cancers, though it may cause some serious side effects like esophageal fistula (an abnormal connection between the esophagus and other organs) and pneumonitis (lung inflammation). Combining immunotherapy with radiation therapy is being studied for its potential to enhance immune responses, but safety data specific to this combination is still being evaluated. ^{3 5 6 7 8}

How is the treatment of Nivolumab and Relatlimab with radiation unique for gastroesophageal cancer?

This treatment is unique because it combines two immunotherapy drugs, Nivolumab and Relatlimab, with radiation to potentially enhance the immune system's ability to fight cancer, offering a novel approach compared to traditional chemotherapy or radiation alone. ^{1 2 3 9 10}

Research Team

Vincent Lam, M.D.

Principal Investigator

Johns Hopkins University

Eligibility Criteria

Adults aged 18+ with recurrent or metastatic gastroesophageal cancer who haven't had systemic chemotherapy for metastatic disease can join. They need good heart function, normal blood counts and organ function, no severe heart issues or autoimmune diseases, and must not be pregnant or nursing. Participants should agree to use contraception and have a performance status of 0-1.

Inclusion Criteria

Creatinine ≤ 2.0 mg/dL

prothrombin time (PT) such that international normalized ratio (INR) is ≤ 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) ≤ institutional upper limit of normal

(Relatlimab arm only) LVEF assessment with documented left ventricular ejection fraction ( LVEF) >/=50% by either echocardiogram TTE or multigated acquisition scan (MUGA) (TTE preferred test) within 6 months from first study drug administration,whichever is most recent.

Exclusion Criteria

My heart's pumping ability is normal, confirmed by a heart test within the last 6 months.

Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug or radiation hazardous or obscure the interpretation of toxicity or adverse events

Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive targeted high dose radiation (SBRT) to metastatic lesions

3 sessions

Treatment

Participants receive Nivolumab or Nivolumab plus Relatlimab every 2 weeks for up to one year

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Nivolumab
• Relatlimab

Trial Overview The trial is testing the safety of Nivolumab alone or combined with other immuno-oncology agents after targeted radiation in patients with advanced esophagogastric cancer. It's an early-phase study focusing on how well patients tolerate this treatment approach.

Participant Groups

Group I: Arm B Nivolumab + Relatlimab Experimental Treatment 2 Interventions

stereotactic body radiation (SBRT) 8G x 3 followed by Nivolumab 240mg administered IV over 30 minutes every 2 weeks and Relatlimab (anti-LAG3) every 2 weeks for one year or until evidence of disease progression or unresolved toxicity.

Group II: Arm A Nivolumab Only Experimental Treatment 1 Intervention

stereotactic body radiation (SBRT) 8G x 3 followed by Nivolumab 240mg administered IV over 30 minutes every 2 weeks for one year or until evidence of disease progression or unresolved toxicity.

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

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

The ARION trial is investigating the efficacy of the anti-PD-L1 drug durvalumab combined with standard chemoradiotherapy (CRT) in patients with locally advanced unresectable esophageal cancer, aiming to improve progression-free survival from 50% to 68% at 12 months.

This multicenter phase II trial will also explore potential biomarkers, such as PD-L1 expression and gut microbiota, to better understand the immune response and treatment outcomes, highlighting the importance of combining immunotherapy with traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Radiochemotherapy to Immunotherapy in unresectable locally advanced Oesophageal carciNoma-randomized phase 2 trial ARION UCGI 33/PRODIGE 67: the study protocol. Modesto, A., Tougeron, D., Tremolières, P., et al.[2023]

In a study of 14 patients with metastatic gastroesophageal cancer, combining palliative radiation therapy with the PD-1 inhibitor pembrolizumab resulted in an objective response rate of 28.6%, indicating potential effectiveness in this challenging cancer type.

While the combination therapy showed promising durable responses, the study did not find significant changes in PD-L1 expression that could explain the observed effects, suggesting that further research is needed to identify other biomarkers that may predict patient benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 2 Trial Combining Pembrolizumab and Palliative Radiation Therapy in Gastroesophageal Cancer to Augment Abscopal Immune Responses. Chao, J., He, TF., D'Apuzzo, M., et al.[2022]

Immunotherapy is a promising new approach in cancer treatment, but its effectiveness can vary widely among patients, even those with tumors that are expected to respond well.

Combining immunotherapy with radiation therapy may enhance treatment outcomes for patients with gastrointestinal cancers, supported by strong preclinical evidence and ongoing research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy and radiation therapy for gastrointestinal malignancies: hope or hype? Badiyan, S., Kaiser, A., Eastman, B., et al.[2023]

In a study of 86 patients with oligometastatic esophageal cancer, combining radiotherapy with PD-1 inhibitors resulted in a median progression-free survival of 15.2 months, indicating effective treatment outcomes.

While the combination therapy was generally safe, with no new safety concerns identified, nearly 49% of patients experienced significant treatment-related adverse events, highlighting the need for careful risk-benefit assessments before starting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Concurrent or Sequential Radiotherapy Plus (PD-1) Inhibitors in Oligometastatic Esophageal Cancer. Duan, Y., Qin, W., Yang, L., et al.[2023]

Preoperative treatment with pembrolizumab combined with chemoradiotherapy was found to be safe for 20 patients with resectable esophageal squamous cell carcinoma, with a high pathologic complete response (pCR) rate of 55.6%.

Despite some patients experiencing significant adverse events, including grade III lymphopenia in 65% of cases, the treatment did not delay surgery, indicating its feasibility for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Li, C., Zhao, S., Zheng, Y., et al.[2021]

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 2 study involving 65 patients with treatment-refractory advanced squamous-cell carcinoma of the esophagus, nivolumab demonstrated a 17% objective response rate, indicating its potential effectiveness as a treatment option.

The safety profile of nivolumab was manageable, with no treatment-related deaths reported, although some patients experienced serious adverse events like lung infections and dehydration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Kudo, T., Hamamoto, Y., Kato, K., et al.[2022]

In a phase II study involving 29 patients with locally advanced head and neck squamous cell carcinoma who were ineligible for cisplatin, the combination of pembrolizumab and radiotherapy showed promising efficacy, with a 24-month progression-free survival rate of 71%.

The treatment was generally well-tolerated, although a significant number of patients experienced grade 3/4 lymphopenia (58.6%), indicating the need for monitoring immune cell changes during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. Weiss, J., Sheth, S., Deal, AM., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Association of Radiochemotherapy to Immunotherapy in unresectable locally advanced Oesophageal carciNoma-randomized phase 2 trial ARION UCGI 33/PRODIGE 67: the study protocol. [2023]

2. China pubmed.ncbi.nlm.nih.gov

A narrative review of combining radiation and immunotherapy in gastroesophageal cancers. [2022]

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

A Phase 2 Trial Combining Pembrolizumab and Palliative Radiation Therapy in Gastroesophageal Cancer to Augment Abscopal Immune Responses. [2022]

4. China pubmed.ncbi.nlm.nih.gov

Immunotherapy and radiation therapy for gastrointestinal malignancies: hope or hype? [2023]

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

Safety and Efficacy of Concurrent or Sequential Radiotherapy Plus (PD-1) Inhibitors in Oligometastatic Esophageal Cancer. [2023]

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

Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). [2021]

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

Severe upper gastrointestinal disorders in pembrolizumab-treated non-small cell lung cancer patient. [2020]

8. 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]

9. England pubmed.ncbi.nlm.nih.gov

Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. [2022]

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

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. [2023]