Nivolumab + Standard Treatment for Stomach and Esophageal Cancer

Recruiting at 266 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Autoimmune disease, Major surgery, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase II/III trial compares the addition of nivolumab to the usual treatment of paclitaxel and ramucirumab to paclitaxel and ramucirumab alone in treating patients with gastric or esophageal adenocarcinoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab is a monoclonal antibody that may prevent the growth of new blood vessels that tumors need to grow. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Adding nivolumab to ramucirumab and paclitaxel may work better to treat patients with advanced stomach or esophageal cancer.

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 certain immunosuppressive medications or plan to receive other cancer treatments while participating. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Nivolumab for stomach and esophageal cancer?

Research shows that Nivolumab, when used alone or with other treatments, has improved survival rates in patients with advanced gastric and esophageal cancers, especially those who have not responded to previous chemotherapy. Studies like CheckMate-032 and ATTRACTION-2 have demonstrated its effectiveness in extending overall survival in these patients. ^{1 2 3 4 5}

Is Nivolumab safe for treating stomach and esophageal cancer?

Nivolumab, also known as Opdivo, is generally considered safe for treating various cancers, including stomach and esophageal cancer, but it can cause some side effects. Common side effects include diarrhea and colitis (inflammation of the colon), and in rare cases, it can cause esophagitis (inflammation of the esophagus) and gastritis (inflammation of the stomach). In patients with esophageal cancer, there is a risk of developing an esophageal fistula (an abnormal connection between the esophagus and other organs) and pneumonitis (lung inflammation). ^{6 7 8 9 10}

What makes the drug Nivolumab unique for treating stomach and esophageal cancer?

Nivolumab is unique because it is a PD-1 inhibitor that helps the immune system attack cancer cells, and it is used in combination with standard chemotherapy for advanced stomach and esophageal cancers, offering a new option for patients who have limited treatments available. ^{2 3 10 11 12}

Research Team

Anwaar Saeed

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

The PARAMUNE trial is for adults with advanced stomach or esophageal cancer that has spread. They must have had no more than one prior systemic therapy, not be on high-dose steroids or other immunosuppressants, and should not have severe previous reactions to immunotherapy. No recent live vaccines and controlled brain metastases are required. Participants need a PD-L1 CPS score ≥ 1 and must show disease progression after standard chemotherapy.

Inclusion Criteria

I am 18 years old or older.

My recent urine test shows low or normal protein levels.

My cancer is in the stomach or esophagus and cannot be removed with surgery.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab, ramucirumab, and paclitaxel or ramucirumab and paclitaxel alone in 28-day cycles

28-day cycles, repeated until disease progression or unacceptable toxicity

Visits on days 1, 8, and 15 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Follow-up at 30, 60, 90 days, then every 6 months

Treatment Details

Interventions

• Nivolumab (Monoclonal Antibodies)

Trial Overview This study tests if adding Nivolumab (a monoclonal antibody that boosts the immune system) to the usual treatment of Paclitaxel and Ramucirumab (drugs that stop cancer growth) improves outcomes in patients with advanced gastric or esophageal adenocarcinoma compared to just Paclitaxel and Ramucirumab alone.

Participant Groups

Group I: Arm 1 (nivolumab, ramucirumab, paclitaxel) Experimental Treatment 7 Interventions

Patients receive nivolumab IV over 30 minutes on day 1 of each cycle, ramucirumab IV over 30-60 minutes on days 1 and 15 of each cycle, and paclitaxel IV over 60 minutes on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI throughout the study. Patients may also optionally undergo blood sample collection on study.

Group II: Arm 2 (ramucirumab, paclitaxel) Active Control 6 Interventions

Patients receive ramucirumab IV over 30-60 minutes on days 1 and 15 of each cycle and paclitaxel IV over 60 minutes on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI throughout the study. Patients may also optionally undergo blood sample collection on study.

Nivolumab is already approved in Canada, Switzerland for the following indications:

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Nivolumab and pembrolizumab, both PD-1 inhibitors, have shown significant improvements in overall survival (OS) for patients with esophageal carcinoma, particularly in combination with chemotherapy or ipilimumab, based on multiple landmark trials.

In the second-line treatment setting, monotherapy with nivolumab, pembrolizumab, and other PD-1 inhibitors also demonstrated improved OS compared to traditional chemotherapy, highlighting the effectiveness of immunotherapy in treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy in Squamous Cell Cancer of the Esophagus. Thuss-Patience, P., Stein, A.[2022]

In a study of 160 Western patients with chemotherapy-refractory esophagogastric cancer, nivolumab and nivolumab plus ipilimumab showed clinically meaningful antitumor activity, with objective response rates of 12% to 24% across different treatment groups.

The treatments demonstrated encouraging long-term overall survival rates of 24% to 39% at 12 months, with a manageable safety profile, as only 17% to 47% of patients experienced severe treatment-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. Janjigian, YY., Bendell, J., Calvo, E., et al.[2021]

In a phase 3 trial involving 493 patients with advanced gastric or gastro-oesophageal junction cancer who had previously undergone two or more chemotherapy regimens, nivolumab significantly improved overall survival compared to placebo, with a median survival of 5.26 months versus 4.14 months.

Nivolumab was associated with a 12-month overall survival rate of 26.2%, compared to 10.9% for placebo, and while some patients experienced grade 3 or 4 treatment-related adverse events, the safety profile was consistent with previous studies, indicating it may be a viable treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Kang, YK., Boku, N., Satoh, T., 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 58 esophageal squamous cell carcinoma (ESCC) patients treated with nivolumab after chemotherapy failure, the objective response rate was 19.3%, with a median response duration of 6.5 months, indicating that nivolumab can be an effective second-line therapy.

Patients with higher PD-L1 expression (CPS ≥ 20) experienced significantly longer progression-free survival (7.5 months) compared to those with lower expression, suggesting that PD-L1 levels may help predict treatment outcomes with nivolumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab for esophageal squamous cell carcinoma and the predictive role of PD-L1 or CD8 expression in its therapeutic effect. Lee, J., Kim, B., Jung, HA., et al.[2021]

Nivolumab, an immune checkpoint inhibitor approved for treating various metastatic cancers, is associated with autoimmune-related side effects, particularly gastrointestinal issues like diarrhea and colitis.

This report highlights a previously unreported case of nivolumab-induced esophagitis and gastritis, suggesting that upper gastrointestinal adverse events may also occur with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Esophagitis and Gastritis from Nivolumab Therapy. Boike, J., Dejulio, T.[2020]

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]

Anti-PD-1 therapies, specifically nivolumab and pembrolizumab, show promising efficacy and acceptable safety in treating gastrointestinal cancers, particularly in advanced gastroesophageal cancer and refractory MSI positive metastatic colorectal cancer.

The effectiveness of these therapies appears to be linked to tumor PD-L1 levels, although clinical benefits in patients with MSI positive advanced colorectal cancer have been limited according to recent phase 2 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers. Bilgin, B., Sendur, MA., Bülent Akıncı, M., et al.[2022]

In a study of 52 patients with advanced gastric cancer treated with nivolumab, those who experienced immune-related adverse events (irAEs) had significantly higher disease control rates (88% vs. 24%) compared to those without irAEs.

Patients with irAEs also showed a significantly longer median overall survival, suggesting that the occurrence of these adverse events may be a positive indicator of treatment efficacy with nivolumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-Related Adverse Events and the Prognosis of Patients with Advanced Gastric Cancer Treated with Nivolumab. Kono, Y., Choda, Y., Nakagawa, M., et al.[2021]

Nivolumab combined with chemotherapy shows promising efficacy in advanced gastric and esophageal cancers, with a number needed to treat (NNT) for overall survival of approximately 15.15 over one year, indicating that this treatment can significantly benefit patients.

While the treatment is effective, it also carries a risk of serious side effects, with a number needed to harm (NNH) for grade ≥3 treatment-related adverse events being 7.02, suggesting that about 7 patients may experience severe side effects for every patient who benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: Analysis of Number Needed To Treat and Number Needed To Harm. Sugarman, R., Betts, KA., Nie, X., et al.[2023]

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 study of 15 patients with advanced gastric cancer, nivolumab therapy resulted in a 6-month overall survival rate of 67.7% and a median survival time of 6.3 months, indicating its efficacy as a treatment option.

The study identified that higher baseline absolute lymphocyte counts (ALC) and lower neutrophil-to-lymphocyte ratios (NLR) were associated with better survival outcomes and a higher incidence of immune-related adverse events, suggesting these could be useful markers for predicting treatment response and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Evaluation of the Efficacy and Adverse Effects of Nivolumab Treatment for Patients with Advanced Gastric Cancer]. Ohta, A., Komatsu, S., Tsuji, R., et al.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Immunotherapy in Squamous Cell Cancer of the Esophagus. [2022]

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

CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. [2022]

4. 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]

5. Germany pubmed.ncbi.nlm.nih.gov

Nivolumab for esophageal squamous cell carcinoma and the predictive role of PD-L1 or CD8 expression in its therapeutic effect. [2021]

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

Severe Esophagitis and Gastritis from Nivolumab Therapy. [2020]

7. 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]

8. England pubmed.ncbi.nlm.nih.gov

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers. [2022]

9. France pubmed.ncbi.nlm.nih.gov

Association Between Immune-Related Adverse Events and the Prognosis of Patients with Advanced Gastric Cancer Treated with Nivolumab. [2021]

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

Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: Analysis of Number Needed To Treat and Number Needed To Harm. [2023]

11. England pubmed.ncbi.nlm.nih.gov

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

12. Japan pubmed.ncbi.nlm.nih.gov

[Clinical Evaluation of the Efficacy and Adverse Effects of Nivolumab Treatment for Patients with Advanced Gastric Cancer]. [2020]