Nivolumab + Ipilimumab + Radiation for Colorectal and Pancreatic Cancer

Overseen By Tarin Grillo

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Active infection, HIV, 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

Compensation: Varies

Number of Visits: 3

Duration: 6-12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining two drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), with radiation therapy can effectively treat certain colorectal and pancreatic cancers. It specifically targets cancers that are microsatellite stable or MSI high (a genetic trait) in colorectal cases. Suitable candidates for this trial include those with confirmed colorectal or pancreatic cancer that has not responded to other treatments, such as chemotherapy. Participants will receive these medications through an IV and undergo radiation therapy according to hospital standards. As a Phase 2 trial, the research focuses on measuring 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. However, you cannot participate if you have had chemotherapy or certain therapies within 14 days before starting the trial. 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 and ipilimumab with radiation therapy yields promising results for treating certain colorectal and pancreatic cancers. This combination appears particularly effective when tumors resist the body's usual immune defenses.

Regarding safety, the FDA has already approved nivolumab and ipilimumab for certain cancers, indicating their general safety for humans. However, the addition of radiation therapy remains under study, and there may be additional risks or side effects.

In earlier studies, some patients experienced side effects such as tiredness, skin rash, and digestive problems. Prospective participants should discuss these potential side effects with their doctor. This trial aims to further understand the safety and effectiveness of the combination treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Nivolumab and Ipilimumab combined with radiation for colorectal and pancreatic cancer because these drugs work by boosting the immune system to fight cancer cells. Unlike traditional chemotherapy, which directly attacks cancer cells but can also harm healthy cells, these drugs specifically target immune checkpoints, helping the body's natural defenses to better recognize and destroy cancer cells. Additionally, adding radiation therapy aims to enhance the effectiveness of this immunotherapy approach by increasing the vulnerability of cancer cells to the immune response. This innovative combination could potentially offer a more targeted and less toxic alternative to existing treatment options.

What evidence suggests that this trial's treatments could be effective for colorectal and pancreatic cancer?

Research has shown that using nivolumab and ipilimumab with radiation therapy can help treat certain colorectal and pancreatic cancers. In this trial, participants will receive a combination of nivolumab and ipilimumab, with radiation therapy administered according to hospital standards. Ipilimumab stops cancer cells from growing, while nivolumab helps kill them. One study found that patients receiving both nivolumab and ipilimumab had a 38% lower risk of disease progression or death compared to those who only received nivolumab. Specifically, in certain types of colorectal and pancreatic cancer, radiation therapy has improved the effectiveness of immunotherapy. These findings suggest that this combination treatment could be a promising option for these cancers. ^{1 3 4 6 7}

Who Is on the Research Team?

Theodore S Hong, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults over 18 with colorectal or pancreatic cancer that's stable and haven't had certain treatments. They need a lesion for radiotherapy, another measurable one outside the radiation field, normal organ/marrow function, and an ECOG status ≤1. Women must use contraception; no severe infections or psychiatric issues that affect trial participation.

Inclusion Criteria

My organ and bone marrow functions are normal as per recent tests.

I've been on a stable dose of dexamethasone (2 mg or less) for the last week.

Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception

Exclusion Criteria

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

I do not have any serious illnesses or social situations that would stop me from following the study's requirements.

I have not had specific immune therapies if I have colorectal cancer, but it's okay for pancreatic cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Nivolumab and Ipilimumab intravenously, along with Radiation Therapy

6-12 weeks

Nivolumab administered 3 times per cycle, Ipilimumab once per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Radiation Therapy

Trial Overview

The study tests Nivolumab and Ipilimumab combined with Radiation Therapy on patients with Microsatellite Stable (MSS) Colorectal Cancer, Pancreatic Cancer, or MSI High Colorectal Cancer to evaluate their effectiveness as a treatment option.

How Is the Trial Designed?

Group I: Nivolumab+Ipilimumab Experimental Treatment 3 Interventions

* Nivolumab will be administered intravenously 3 times per cycle * Ipilimumab will be administered intravenously once per cycle * Radiation Therapy will be administered per hospital standard

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

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

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

Published Research Related to This Trial

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]

Gene expression profiling in 162 advanced melanoma patients identified potential biomarkers associated with gastrointestinal immune-related adverse events (GI irAEs) during ipilimumab treatment, particularly markers related to neutrophil activation like CD177 and CEACAM1.

While a set of biomarkers was found to correlate with the occurrence of GI irAEs, their low sensitivity means they cannot reliably predict which patients will experience these adverse effects, indicating a need for further research in larger cohorts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events. Shahabi, V., Berman, D., Chasalow, SD., et al.[2022]

Combining anti-PD-1 therapy (nivolumab) with radiation has been shown to be safe and effective in treating patients with relapsed sarcomatoid renal carcinoma and heavily pretreated pleomorphic sarcoma, leading to dramatic and durable responses in both cases.

This approach may help overcome resistance to immune checkpoint inhibitors, particularly in tumor types that are typically less responsive to such treatments, suggesting a potential new strategy for enhancing cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dramatic Response to Concurrent Anti-PD-1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation. Tolay, S., Nair, R., McIntosh, AF., et al.[2020]

Two cases of patients with multiple in-transit metastatic melanomas were successfully treated using intensity-modulated radiotherapy (IMRT) combined with immune checkpoint inhibitors ipilimumab or nivolumab.

The combination of IMRT and immune checkpoint inhibitors suggests a potential enhancement of antitumor effects, indicating a promising approach for improving treatment outcomes in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two cases. Fujimura, T., Kambayashi, Y., Furudate, S., et al.[2018]

In a study of 84 patients with refractory metastatic pancreatic cancer, the combination of stereotactic body radiotherapy (SBRT) with nivolumab and ipilimumab showed a clinical benefit rate of 37.2%, indicating a significant improvement compared to 17.1% for SBRT with nivolumab alone.

The treatment was associated with a manageable safety profile, with 24.4% of patients experiencing grade 3 or higher adverse events in the SBRT/nivolumab group and 30.2% in the SBRT/nivolumab/ipilimumab group, suggesting that this combination therapy may be a viable option for patients despite the unknown contribution of SBRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Study of Nivolumab With or Without Ipilimumab Combined With Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC). Chen, IM., Johansen, JS., Theile, S., et al.[2023]

In a phase II trial involving 65 patients with metastatic microsatellite stable colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), combining radiation with immune checkpoint inhibitors ipilimumab and nivolumab achieved a disease control rate of 25% for CRC and 20% for PDAC, indicating some effectiveness in these challenging cancers.

The study found that patients who experienced disease control had higher levels of natural killer (NK) cells and expression of HERVK repeat RNA, suggesting that these immune factors may play a role in the response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. Parikh, AR., Szabolcs, A., Allen, JN., et al.[2023]

A meta-analysis of 21 trials involving 11,454 patients found that immune checkpoint inhibitors (ICIs) significantly increase the risk of various immune-related adverse events (irAEs), including colitis, liver enzyme elevation, rash, hypothyroidism, and pneumonitis compared to non-ICI treatments.

While the incidence of fatal irAEs was less than 1%, the study highlights the importance of early recognition and intervention for these adverse events to prevent complications, particularly noting that ipilimumab was linked to a higher risk of certain skin and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients. De Velasco, G., Je, Y., Bossé, D., et al.[2023]

A study analyzing 70,330 adverse events reported to the FDA found that immune checkpoint inhibitors (ICIs) significantly increase the risk of gastrointestinal (GI) toxicities, particularly colitis, hepatobiliary disorders, and pancreatitis, with colitis showing the highest reporting odds ratio of 17.2.

The risk of these GI adverse events was notably higher with anti-CTLA-4 treatments compared to anti-PD-1 and anti-PD-L1 therapies, and factors such as female gender and polytherapy were identified as strong risk factors for these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System. Bai, X., Jiang, S., Zhou, Y., et al.[2021]

In a phase 1 trial with 13 patients suffering from metastatic melanoma, the combination of ipilimumab and high-dose radiation therapy was found to be feasible and safe, with 25% of patients experiencing grade 3 or 4 adverse events.

Local control of the treated lesions was achieved in 11 out of 12 patients, and while only 3 patients showed clinical benefit in non-irradiated lesions, the results suggest that early radiation therapy may enhance the effectiveness of ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Dose Escalation Trial of Ipilimumab and Stereotactic Body Radiation Therapy in Metastatic Melanoma. Sundahl, N., De Wolf, K., Kruse, V., et al.[2019]

In a phase 2 study involving 26 patients with refractory pancreatic cancer, the combination of ipilimumab, nivolumab, tocilizumab, and stereotactic body radiotherapy (SBRT) did not result in any objective responses, indicating limited efficacy for this treatment regimen.

While 19% of patients achieved stable disease, the median overall survival was only 5.3 months, and 73% experienced treatment-related adverse events, highlighting safety concerns associated with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy in patients with refractory pancreatic cancer (TRIPLE-R). Chen, IM., Donia, M., Chamberlain, CA., et al.[2023]

Citations

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clinicaltrials.gov

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The antibodies in ipilimumab work by not allowing cancer cell growth. The antibodies in nivolumab work by causing programmed cell death of the cancer cells.

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We pooled four prospective phase II single-arm studies of patients with metastatic MSS colorectal or pancreatic cancer treated with SBRT alone or with IO.

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Radiation Therapy Enhances Immunotherapy Response in ...

Radiation therapy enhances immunotherapy response in microsatellite-stable colorectal and pancreatic adenocarcinoma in a Phase II trial.

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Patients experienced a 38% reduction in the risk of disease progression or death when treated with Opdivo plus Yervoy versus Opdivo monotherapy across all ...

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View efficacy information for OPDIVO® (nivolumab) in MSI/dMMR colorectal cancer (CRC). Please see Indications and Important Safety Information.

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ascopubs.org

ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.3584

A phase II study of nivolumab and ipilimumab with ...

Treatment with ipilimumab, nivolumab, and RT starting on C1D1 showed promising activity in patients with traditionally immunoresistant metastatic MSS CRC.

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news.bms.com

news.bms.com/news/details/2025/U-S--Food-and-Drug-Administration-Approves-Opdivo-nivolumab-plus-Yervoy-ipilimumab-as-a-Treatment-for-Patients-with-Previously-Untreated-Microsatellite-Instability-High-or-Mismatch-Repair-Deficient-Unresectable-or-Metastatic-Colorectal-Cancer1/default.aspx

U.S. Food and Drug Administration Approves Opdivo ...

Based on the Phase 3 CheckMate-8HW trial, Opdivo plus Yervoy demonstrated reduction in the risk of disease progression or death by 79% vs.