Nivolumab + Standard Treatment for Stomach and Esophageal Cancer

Recruiting at 365 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Autoimmune disease, Major surgery, 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 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 31

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

224 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding nivolumab, an immunotherapy drug, to the standard cancer treatments of ramucirumab and paclitaxel can more effectively combat advanced stomach or esophageal cancer. Nivolumab helps the immune system attack cancer cells, ramucirumab blocks the growth of blood vessels that nourish tumors, and paclitaxel prevents cancer cells from dividing. Individuals with advanced stomach or esophageal cancer who have experienced ineffective treatments or severe side effects may be suitable candidates for this trial. Participants will receive these treatments in cycles and undergo scans to monitor the cancer's response. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that combining nivolumab with chemotherapy can improve outcomes for patients with advanced stomach and gastroesophageal junction cancer. Studies indicate that patients live longer and experience slower disease progression with nivolumab. Safety data from these studies suggest that nivolumab is generally well-tolerated, with most side effects being manageable and similar to those from standard chemotherapy, such as tiredness, nausea, or loss of appetite.

For the combination of ramucirumab and paclitaxel, already a standard treatment, side effects are known and can include low blood cell counts, tiredness, and diarrhea. Both treatments have been used in previous studies and are considered safe, but patients should always discuss potential risks with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about nivolumab for stomach and esophageal cancer because it offers a novel approach by harnessing the body's immune system to fight cancer cells. Unlike traditional chemotherapy, which directly targets and kills cancer cells, nivolumab is an immunotherapy that works by blocking a protein called PD-1, enabling the immune system to better recognize and attack cancer cells. This mechanism provides a different angle of attack compared to standard treatments like ramucirumab and paclitaxel, which focus more on slowing tumor growth and spreading. By potentially enhancing the immune response, nivolumab could improve patient outcomes and offer hope for those whose cancer has not responded to existing therapies.

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

Research has shown that adding nivolumab to chemotherapy benefits patients with advanced stomach and esophageal cancers. In this trial, one group will receive nivolumab combined with ramucirumab and paclitaxel. Studies have found that nivolumab with chemotherapy extends patient survival and delays cancer progression. The FDA has approved this combination because it improves survival compared to chemotherapy alone. Nivolumab enhances the immune system's ability to attack cancer, potentially stopping tumors from growing and spreading. Previous trials consistently showed better outcomes with nivolumab and chemotherapy together than with chemotherapy alone. ^{1 2 4 5 6}

Who Is on the Research Team?

Anwaar Saeed

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

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

My recent urine test shows low or normal protein levels.

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

I haven't had major surgery in the last 28 days or a device placement in the last 7 days.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab

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.

How Is the Trial Designed?

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 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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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]

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 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 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 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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.01601

3-Year Follow-Up of the Phase III CheckMate 649 Trial At 12.1-month minimum follow-up, nivolumab plus chemotherapy demonstrated improvement in all efficacy measures, including superior overall ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11583461/

Efficacy and safety of Nivolumab in advanced gastric and ... Nivolumab, both alone and in combination with chemotherapy, improves OS and PFS in patients with advanced gastric and gastroesophageal junction cancer.

3. opdivo.com opdivo.com/gastroesophageal-cancer/clinical-trial-results/advanced-gastric-gej-esophageal-immunotherapy-chemo

Clinical trial results for advanced gastroesophageal cancer An FDA-approved combination of immunotherapy and chemotherapy that helped people live longer compared to chemotherapy alone.

4. targetedonc.com targetedonc.com/view/5-year-update-sustains-nivolumab-chemo-efficacy-in-frontline-gastric-gej-esophageal-cancer

5-Year Update Sustains Nivolumab/Chemo Efficacy in ... The first-line combination of nivolumab (Opdivo) and chemotherapy continued to show deep responses and an overall survival (OS) benefit vs chemotherapy alone.

5. opdivohcp.com opdivohcp.com/efficacy/gastro/opdivo-chemo

OPDIVO® (nivolumab) + Chemo Checkmate 649 ... View efficacy information from the Checkmate 649 & Checkmate 648 clinical trials for OPDIVO® (nivolumab) + chemotherapy (fluoropyrimidine- and ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2949819824000335

Safety and efficacy of first-line nivolumab plus ... At a median follow-up of 14.0 months, the median progression-free survival (PFS) and overall survival (OS) were 7.9 and 21.7 months, respectively. In patients ...