Immunotherapy + Chemoradiation for Gastric Cancer

Overseen By Mariela Blum

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Autoimmune disease, HIV, Hepatitis, 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: 20

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This pilot phase I/II trial studies the side effects and how well nivolumab and ipilimumab in combination with chemotherapy and radiation therapy work in treating patients with gastric cancer that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as oxaliplatin and fluorouracil, 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. Intensity-modulated radiation therapy uses thin beams of radiation of different strengths aimed at the tumor from many angles. This type of radiation therapy may reduce the damage to healthy tissue near the tumor. Giving nivolumab, ipilimumab, chemotherapy and radiation therapy may work better in treating patients with gastric cancer.

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 corticosteroids or other immunosuppressive medications, you may need to stop them 14 days before starting the study treatment.

What data supports the effectiveness of this treatment for gastric cancer?

Research shows that combining 5-fluorouracil (5-FU) with radiation therapy, like IMRT, can improve outcomes in gastric cancer patients, especially when used after surgery. Additionally, the FOLFOX regimen, which includes oxaliplatin and 5-FU, has been found effective in completely resected gastric cancer patients. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemoradiation generally safe for humans?

Research on chemoradiation for gastric cancer using drugs like 5-fluorouracil and oxaliplatin shows that it can be safe, but there are risks of serious side effects like low white blood cell counts and mouth sores. The combination of these drugs with radiation therapy has been studied to find safe dosage levels, and some side effects were observed, but a specific regimen was recommended as safer for patients. ^{6 7 8 9 10}

What makes the Immunotherapy + Chemoradiation treatment for gastric cancer unique?

This treatment is unique because it combines immunotherapy drugs like Ipilimumab and Nivolumab, which help the immune system fight cancer, with chemoradiation using 5-Fluorouracil and Oxaliplatin, which directly target cancer cells. This combination aims to enhance the overall effectiveness by attacking the cancer from multiple angles. ^{5 11 12 13 14}

Research Team

Mariela Blum

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for patients with resectable gastric or gastroesophageal junction adenocarcinoma, without prior systemic treatment for advanced disease. Participants must have adequate organ function and performance status, not be pregnant or breastfeeding, and agree to contraception if applicable. Exclusions include previous immunotherapy, certain allergies, active autoimmune diseases requiring steroids, other cancers within 3 years (with exceptions), HIV/AIDS positive status, and serious uncontrolled medical disorders.

Inclusion Criteria

Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.

My kidney function is within the required range for the study.

Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days of treatment initiation).

Exclusion Criteria

I haven't taken high-dose steroids or immunosuppressants in the last 14 days.

White blood cell (WBC) < 2000/uL.

I haven't had any cancer except for certain skin, bladder, prostate, cervix, or breast cancers in the last 3 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Patients receive oxaliplatin and fluorouracil intravenously. Treatment repeats every 14 days for up to 4 courses.

8 weeks

4 visits (in-person)

Immunotherapy and Chemoradiation

Patients receive nivolumab and ipilimumab, followed by fluorouracil and intensity-modulated radiation therapy (IMRT).

10 weeks

6 visits (in-person)

Surgical Resection

Patients undergo surgical resection 5-7 weeks after completing radiation therapy.

1 week

Adjuvant Nivolumab

Patients with residual disease may receive nivolumab post-surgery. Treatment repeats every 2 weeks for 8 courses, then every 4 weeks for up to 2 courses.

24 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up at 30 and 84 days, every 12 weeks for 2 years, then every 6-12 months for up to 3 years.

5 years

Treatment Details

Interventions

• Fluorouracil
• Intensity-Modulated Radiation Therapy
• Ipilimumab
• Nivolumab
• Oxaliplatin
• Therapeutic Conventional Surgery

Trial Overview The study tests the combination of nivolumab and ipilimumab (immunotherapies) with chemotherapy drugs oxaliplatin and fluorouracil plus intensity-modulated radiation therapy in treating resectable gastric cancer. The goal is to see how well this combo works by helping the immune system attack cancer while minimizing damage to healthy tissue.

Participant Groups

Group I: Treatment (chemotherapy, immunotherapy, IMRT) Experimental Treatment 6 Interventions

INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin IV over 2 hours and fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients undergo surgical resection 5-7 weeks after completing radiation therapy. Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

S-1, an oral chemotherapy drug combining tegafur with modulators, has shown advantages over standard 5-FU-based treatments for gastric cancer in large Phase III studies, making it a recommended option in treatment guidelines.

S-1, either alone or in combination with cisplatin, is non-inferior to traditional 5-FU regimens while offering greater convenience and reduced toxicity, highlighting its potential for higher efficacy in treating gastrointestinal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-1 for the treatment of gastrointestinal cancer. Satoh, T., Sakata, Y.[2022]

In a phase 2 trial involving 63 anal cancer patients, dose-painted intensity modulated radiation therapy (DP-IMRT) did not significantly reduce the overall rate of grade 2+ gastrointestinal and genitourinary adverse events compared to conventional treatment, but it did show a notable reduction in grade 3+ gastrointestinal (21% vs. 36%) and dermatologic (23% vs. 49%) toxicities.

DP-IMRT was found to be feasible, but a high rate of pretreatment planning revisions (81%) highlights the need for careful real-time quality assurance in radiation therapy to ensure patient safety and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Kachnic, LA., Winter, K., Myerson, RJ., et al.[2022]

Capecitabine, an oral prodrug of 5-fluorouracil, has been shown to be an effective and convenient alternative to infusional 5-FU in the treatment of esophageal, stomach, and pancreatic cancers when combined with irradiation.

Research is ongoing into the benefits of adding a COX-2 inhibitor to treatment regimens for upper gastrointestinal cancers, as these cancers often show high levels of COX-2 expression, which may enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COX-2 inhibitors as radiation sensitizers for upper GI tract cancers: esophagus, stomach, and pancreas. Rich, TA., Shepard, R.[2015]

References

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

Phase 1/2 Study of the Addition of Cisplatin to Adjuvant Chemotherapy With Image Guided High-Precision Radiation Therapy for Completely Resected Gastric Cancer. [2017]

2. Japan pubmed.ncbi.nlm.nih.gov

A phase II trial of concurrent 3D-CRT/IMRT and oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) in gastric cancer patients with R0 gastrectomy and D2 lymph node dissection. [2018]

3. India pubmed.ncbi.nlm.nih.gov

Use of simultaneous radiation boost achieves high treatment response rate in patients with metastatic gastric cancer. [2022]

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

IMRT for adjuvant radiation in gastric cancer: a preferred plan? [2016]

5. England pubmed.ncbi.nlm.nih.gov

S-1 for the treatment of gastrointestinal cancer. [2022]

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

Chemoradiation in female patients with anal cancer: Patient-reported outcome of acute and chronic side effects. [2022]

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

Predictors of Radiation Therapy-Related Gastrointestinal Toxicity From Anal Cancer Dose-Painted Intensity Modulated Radiation Therapy: Secondary Analysis of NRG Oncology RTOG 0529. [2018]

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

RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. [2022]

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

Postoperative chemoradiotherapy in gastric cancer: a phase I study of radiotherapy with dose escalation of oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX regimen). [2021]

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

Oxaliplatin and capecitabine-based chemoradiotherapy for gastric cancer--an extended phase I MARGIT and AIO trial. [2022]

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

COX-2 inhibitors as radiation sensitizers for upper GI tract cancers: esophagus, stomach, and pancreas. [2015]

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

The role of radiation therapy in gastric cancer. [2007]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Combined modality of radiation and chemotherapy for the treatment of gastric carcinoma. A review. [2018]

14. Germany pubmed.ncbi.nlm.nih.gov

Four consecutive multicenter phase II trials of adjuvant chemoradiation in patients with completely resected high-risk gastric cancer: the experience of the German AIO/ARO/CAO group. [2018]