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

80 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is studying a combination of drugs with radiation therapy as a possible treatment for Microsatellite Stable Colorectal Cancer, Pancreatic Cancer, or MSI High Colorectal Cancer. The interventions involved in this study are: * Nivolumab * Ipilimumab * Radiation Therapy

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.

What data supports the effectiveness of the treatment Nivolumab + Ipilimumab + Radiation for Colorectal and Pancreatic Cancer?

Research shows that combining radiation with immune checkpoint drugs like nivolumab and ipilimumab can help control disease in some patients with colorectal and pancreatic cancers that are resistant to other treatments. In a study, 25% of colorectal cancer patients and 20% of pancreatic cancer patients experienced disease control with this combination. ^{1 2 3 4 5}

What safety data exists for the combination of Nivolumab, Ipilimumab, and Radiation Therapy?

The combination of Nivolumab, Ipilimumab, and Radiation Therapy has been studied for safety in various cancers. Common side effects include immune-related issues like colitis (inflammation of the colon), skin rash, and liver problems. These treatments can increase the risk of gastrointestinal and liver toxicities, but serious or fatal side effects are rare. ^{4 5 6 7 8}

How is the treatment of Nivolumab, Ipilimumab, and Radiation unique for colorectal and pancreatic cancer?

This treatment is unique because it combines immune checkpoint inhibitors (drugs that help the immune system attack cancer) with radiation therapy to potentially overcome resistance in colorectal and pancreatic cancers that do not usually respond well to immunotherapy alone. ^{1 3 4 9 10}

Research Team

Theodore S Hong, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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). [2023]

2. China pubmed.ncbi.nlm.nih.gov

Immunotherapy and radiation therapy for gastrointestinal malignancies: hope or hype? [2023]

3. England 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). [2023]

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

Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. [2023]

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

Phase 1 Dose Escalation Trial of Ipilimumab and Stereotactic Body Radiation Therapy in Metastatic Melanoma. [2019]

6. United States 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. [2023]

7. Switzerland 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. [2021]

8. England 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. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Dramatic Response to Concurrent Anti-PD-1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation. [2020]

10. England 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. [2018]