Immunotherapy + Chemotherapy for Stomach Cancer

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must be taking: FOLFOX, Nivolumab

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Pregnancy, HIV, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 8

Duration: 16 weeks

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to be on specific chemotherapy and immunotherapy drugs (FOLFOX and nivolumab) and does not allow certain prior therapies like IL-2, chronic corticosteroids, or immunosuppressive agents. Inhaled corticosteroids are allowed, but if you are on other medications, it's best to discuss with the trial team to see if they are permitted.

What data supports the effectiveness of the drug combination used in the Immunotherapy + Chemotherapy for Stomach Cancer trial?

Research shows that high levels of certain immune cells (tumor-infiltrating lymphocytes) in the tumor are linked to better outcomes in patients treated with FOLFOX, a chemotherapy regimen that includes some of the drugs in this trial. This suggests that the combination of these drugs may improve treatment effectiveness in stomach cancer. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemotherapy for stomach cancer safe?

Immunotherapy drugs like nivolumab, used in cancer treatment, can cause immune-related side effects such as diarrhea, colitis (inflammation of the colon), and other gastrointestinal issues. These side effects can range from mild to severe, and management often involves medications to suppress the immune response. ^{6 7 8 9 10}

What makes the Immunotherapy + Chemotherapy treatment for stomach cancer unique?

This treatment combines immunotherapy (using drugs like Nivolumab, which helps the immune system attack cancer cells) with chemotherapy (using drugs like Fluorouracil and Oxaliplatin, which kill cancer cells directly), offering a novel approach that targets cancer in multiple ways. This combination is particularly promising because it leverages the body's immune response alongside traditional chemotherapy, potentially improving outcomes for patients with advanced gastric cancer. ^{1 3 4 5 11}

What is the purpose of this trial?

This phase Ib trial test effects of aldesleukin in combination with nivolumab and standard chemotherapy in treating patients with gastric cancer that has spread to the tissue lining of the abdomen (peritoneal metastasis). Aldesleukin is similar to a protein that naturally exists in the body that stimulates the immune system to fight infections. 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. Chemotherapy drugs, such as leucovorin calcium, 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. Giving aldesleukin in combination with nivolumab and standard chemotherapy may work better in treating patients with gastric cancer with peritoneal metastasis.

Research Team

Travis E. Grotz, MD

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

Adults with confirmed gastric or gastroesophageal junction adenocarcinoma that has spread to the abdominal lining, who are in relatively good health (ECOG 0-2) and have not shown non-peritoneal metastasis. They must be able to provide blood and tissue samples, return for follow-up, and meet specific blood count and organ function criteria. Pregnant or nursing individuals, those unwilling to use contraception, or those with certain prior treatments or severe concurrent diseases cannot participate.

Inclusion Criteria

Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula (obtained =< 15 days prior to registration)

Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only

My cancer is confirmed as stomach or GEJ adenocarcinoma.

Exclusion Criteria

I have not had a heart attack in the last 6 months and don't need ongoing therapy for severe heart rhythm problems.

Nursing persons

My cancer has spread beyond the peritoneum, found during a laparoscopy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive aldesleukin intraperitoneally, nivolumab intravenously, and standard chemotherapy drugs over 8 cycles, with diagnostic procedures and sample collections

16 weeks

8 cycles, each with multiple visits for treatment and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits at 30 days, 90 days, and every 3 months for up to 3 years

3 years

Regular follow-up visits at specified intervals

Treatment Details

Interventions

• Aldesleukin
• Leucovorin Calcium; Fluorouracil; Oxaliplatin
• Nivolumab

Trial Overview The trial is testing aldesleukin combined with nivolumab (an immune system booster) alongside standard chemotherapy drugs fluorouracil, leucovorin calcium, and oxaliplatin. The goal is to see if this combination is more effective for patients whose stomach cancer has spread to the peritoneum compared to standard treatment alone.

Participant Groups

Group I: Treatment (aldesleukin, nivolumab, chemotherapy) Experimental Treatment 11 Interventions

Patients receive aldesleukin IP over at least 40 minutes on days 1 and 8 of each cycle. Patients also receive standard of care nivolumab IV over 30 minutes on day 1, leucovorin calcium IV over 2 hours on day 1, oxaliplatin IV over 2 hours on day 1, and flurouracil IV continuously over 46 hours on days 1-3 for each cycle. Cycles repeat every 14 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo diagnostic laparoscopy with biopsy, PET/CT or PET/MRI, and collection of blood and tissue samples throughout the trial.

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

Approved in United States as Proleukin for:

• Metastatic renal cell carcinoma
• Metastatic melanoma

Approved in European Union as Proleukin for:

• Metastatic renal cell carcinoma

Approved in Canada as Proleukin for:

• Metastatic renal cell carcinoma
• Metastatic melanoma

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

In a study of 60 gastric cancer patients undergoing FOLFOX4 chemotherapy, levels of the Th1 cytokine IFN-gamma increased significantly after treatment, indicating an enhanced immune response (11.4% after vs. 9.5% before, P < 0.05).

Patients who achieved a partial response to chemotherapy showed even greater increases in IFN-gamma and TNF-alpha levels, along with a significant improvement in the Th1/Th2 ratio, suggesting that effective chemotherapy may enhance immune function and help combat cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pre- and post-chemotherapy expressions of Th1 and Th2 type cytokines and their clinical significance in gastric cancer patients]. Liu, XL., Gao, J., Han, CZ., et al.[2013]

In a study of 129 gastric cancer patients, those with high levels of tumor-infiltrating lymphocytes (TILs), specifically CD3+ and FoxP3+ T cells, showed better clinical outcomes when treated with the chemotherapy regimen FOLFOX.

The findings suggest that incorporating TIL levels into treatment algorithms could enhance the effectiveness of chemotherapy for gastric cancer patients, particularly those with stage III disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High levels of tumor-infiltrating lymphocytes showed better clinical outcomes in FOLFOX-treated gastric cancer patients. Li, W., Wang, W., Liao, P., et al.[2021]

Combination chemotherapy regimens, such as FAMTX and ECF, show promising response rates in treating locally advanced and metastatic gastric adenocarcinomas, but they come with significant toxicity.

While chemotherapy has been shown to improve overall survival and quality of life compared to best supportive care, adjuvant chemotherapy after surgery has not demonstrated a survival benefit, and the effectiveness of preoperative chemotherapy remains uncertain pending further randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy of gastric cancer. Schipper, DL., Wagener, DJ.[2019]

A 63-year-old woman with unresectable T4 gastric adenocarcinoma showed a complete histologic response after receiving two cycles of neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil, indicating potential effectiveness of this treatment regimen.

The chemotherapy regimen consisted of specific dosages of docetaxel and cisplatin on day 1, followed by leucovorin and fluorouracil over five days, suggesting a well-structured approach that may improve outcomes for patients with advanced gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histological complete response to a combined docetaxel/cisplatin/fluorouracil neoadjuvant chemotherapy for T4 stage gastric adenocarcinoma. Guo, Mg., Zheng, Q., zhong Di, J., et al.[2021]

In stomach cancer patients, Th2 cytokines were predominantly expressed before chemotherapy, indicating an immune response skewed towards Th2.

After chemotherapy, the dominance of Th2 cytokines decreased, suggesting a potential reversal of immune deviation towards a more balanced Th1/Th2 response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Influence of chemotherapy on Th1/Th2 cytokine switching in stomach cancer patients]. Li, Y., Liang, J., Liu, WB., et al.[2018]

Immune-mediated diarrhea and colitis (IMDC) is a common side effect in cancer patients treated with immune checkpoint inhibitors (ICIs), with preexisting inflammatory bowel disease significantly increasing the risk of these adverse events.

Early endoscopic evaluation and the use of inflammatory markers like calprotectin can help identify high-risk patients for IMDC, allowing for timely management with corticosteroids and potential add-on therapies, improving clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitor-Mediated Diarrhea and Colitis: A Clinical Review. Gong, Z., Wang, Y.[2021]

Immune checkpoint inhibitors (ICIs) can significantly benefit cancer patients but may cause immune-related adverse events (irAEs), particularly affecting the gastrointestinal tract, leading to diarrhea and colitis.

Management of ICI-induced colitis varies by severity, with mild cases treated using anti-diarrheal agents and severe cases requiring immunosuppressants like corticosteroids or infliximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors-Induced Colitis. Tian, Y., Abu-Sbeih, H., Wang, Y.[2019]

A 78-year-old man undergoing nivolumab therapy for metastatic lung cancer developed severe gastrointestinal inflammation, including aphthous ulcers and colitis, highlighting a serious immune-related adverse event associated with immunotherapy.

Endoscopic and histological examinations confirmed extensive inflammation in both the upper and lower gastrointestinal tract, demonstrating that immunotherapy can lead to complications that mimic inflammatory bowel disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-Induced Concomitant Severe Upper and Lower Gastrointestinal Immune-Related Adverse Effects. Alhatem, A., Patel, K., Eriksen, B., et al.[2020]

Nivolumab and ipilimumab, two FDA-approved immunotherapeutic agents targeting PD-1 and CTLA-4, are effective in treating various cancers but can cause significant immune-related adverse effects (irAEs).

In a case study of a 66-year-old female patient, steroid-resistant colitis induced by these checkpoint inhibitors was successfully treated with infliximab, highlighting a potential management strategy for severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. Tidwell, C., Gutnik, S.[2020]

Atezolizumab, an immune checkpoint inhibitor used for treating non-small cell lung cancer, can cause rare but serious immune-related adverse events (irAEs) such as acute kidney injury (AKI) and immune thrombocytopenic purpura (ITP).

In a case study of a patient receiving atezolizumab, the development of AKI and ITP occurred one week after treatment initiation, but with appropriate management including IVIG and steroids, the patient's condition improved and was discharged for routine follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible atezolizumab-associated acute kidney injury and immune thrombocytopenia. Yılmaz, A., Mirili, C., Bilici, M., et al.[2022]

A patient with HER2- and PD-L1-positive locally advanced gastric carcinoma achieved a pathologic complete response after receiving a neoadjuvant therapy regimen that included toripalimab, Herceptin, and FLOT chemotherapy, followed by surgery.

This case suggests that combining immunotherapy with chemotherapy may be an effective neoadjuvant treatment strategy for gastric carcinoma, but further large-scale phase III clinical trials are needed to confirm the safety and efficacy of such approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toripalimab combined with targeted therapy and chemotherapy achieves pathologic complete response in gastric carcinoma: A case report. Liu, R., Wang, X., Ji, Z., et al.[2022]

References

1. China pubmed.ncbi.nlm.nih.gov

[Pre- and post-chemotherapy expressions of Th1 and Th2 type cytokines and their clinical significance in gastric cancer patients]. [2013]

2. England pubmed.ncbi.nlm.nih.gov

High levels of tumor-infiltrating lymphocytes showed better clinical outcomes in FOLFOX-treated gastric cancer patients. [2021]

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

Chemotherapy of gastric cancer. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Histological complete response to a combined docetaxel/cisplatin/fluorouracil neoadjuvant chemotherapy for T4 stage gastric adenocarcinoma. [2021]

5. China pubmed.ncbi.nlm.nih.gov

[Influence of chemotherapy on Th1/Th2 cytokine switching in stomach cancer patients]. [2018]

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

Immune Checkpoint Inhibitor-Mediated Diarrhea and Colitis: A Clinical Review. [2021]

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

Immune Checkpoint Inhibitors-Induced Colitis. [2019]

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

Nivolumab-Induced Concomitant Severe Upper and Lower Gastrointestinal Immune-Related Adverse Effects. [2020]

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

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Possible atezolizumab-associated acute kidney injury and immune thrombocytopenia. [2022]

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

Toripalimab combined with targeted therapy and chemotherapy achieves pathologic complete response in gastric carcinoma: A case report. [2022]