Nivolumab + Ipilimumab + Radiation for Pancreatic Cancer

Recruiting at 2 trial locations

Overseen By Theodore S Hong, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: Immunosuppressants, Anti-CTLA-4

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: 2

Duration: 24 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This research is being done to study the effects of the combination of ipilimumab, nivolumab, and radiation therapy in people with microsatellite stable pancreatic cancer. The names of the study interventions involved in this study are: * Ipilimumab * Nivolumab * Radiation Therapy

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on corticosteroids or other immunosuppressive medications, you may need to adjust your dosage or stop them 14 days before starting the trial, unless they are at a stable, low dose.

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

Research shows that combining radiation with immune checkpoint drugs like nivolumab and ipilimumab can help control disease in some patients with pancreatic cancer, with a disease control rate of 20% in a study of patients with metastatic pancreatic cancer. ^{1 2 3 4 5}

Is the combination of Nivolumab, Ipilimumab, and Radiation generally safe for humans?

The combination of Nivolumab and Ipilimumab, often used with radiation, can cause immune-related side effects like skin rash, diarrhea, and inflammation of organs such as the pancreas and liver. These side effects are usually manageable with treatment, but it's important for patients and doctors to communicate well and address any symptoms early. ^{1 5 6 7 8}

How is the drug combination of Nivolumab, Ipilimumab, and Radiation unique for treating pancreatic cancer?

This treatment is unique because it combines two immune checkpoint inhibitors, Nivolumab and Ipilimumab, with radiation therapy to potentially enhance the body's immune response against pancreatic cancer, which is typically resistant to standard treatments. ^{1 2 4 9 10}

Research Team

Theodore S Hong, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults over 18 with metastatic MSS pancreatic cancer who have had at least one prior chemotherapy treatment. They must be in good health otherwise, with proper organ and marrow function, and a life expectancy of more than 3 months. Participants need to have tumors suitable for radiation therapy and measurable disease outside the radiation field.

Inclusion Criteria

My cancer has worsened after at least one chemotherapy treatment.

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

I can do most of my daily activities without help.

Exclusion Criteria

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

Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 5 months for woman and 7 months for men, after the last dose of trial treatment

You have had a serious allergic reaction to any type of monoclonal antibody in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Nivolumab and Ipilimumab with Radiation Therapy. Nivolumab is administered every 2 weeks, Ipilimumab on day 1 of each 6-week cycle, and Radiation during week 1 of cycle 1.

24 weeks

Nivolumab every 2 weeks, Ipilimumab every 6 weeks, Radiation during week 1

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Radiation Therapy

Trial Overview The study tests a combination of two immunotherapy drugs, Nivolumab and Ipilimumab, along with Radiation Therapy on patients with microsatellite stable (MSS) pancreatic cancer to see how effective this trio is against the disease.

Participant Groups

Group I: Nivolumab + Ipilimumab + Radiation Experimental Treatment 3 Interventions

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits, (Study cycles are 6 weeks.) * Nivolumab via iv, at predetermined dose every 2 weeks for duration of study. * Ipilimumab via iv at a predetermined dose on day 1 of 4 study cycles. * Radiation treatments will be administered every other weekday or 2 days during week 1 of cycle 1.

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]

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 2 trial involving 147 patients with post-operative locally recurrent pancreatic cancer, combining high-dose stereotactic body radiation therapy (SBRT) with pembrolizumab and trametinib showed a significant improvement in progression-free survival (PFS) compared to gemcitabine, particularly in patients receiving higher radiation doses (BED10 ≥65Gy).

Although the combination treatment did not significantly extend overall survival (OS) compared to gemcitabine, the results suggest that further research is needed to explore the potential synergy of high-dose SBRT with immunotherapy and targeted therapy in larger phase 3 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of stereotactic body radiotherapy dose escalation plus pembrolizumab and trametinib versus stereotactic body radiotherapy dose escalation plus gemcitabine for locally recurrent pancreatic cancer after surgical resection on survival outcomes: A secondary analysis of an open-label, randomised, controlled, phase 2 trial. Zhu, X., Liu, W., Cao, Y., et al.[2022]

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]

In a case series of seven patients treated with immune checkpoint inhibitors (ICIs), two developed diabetic ketoacidosis (DKA) and five experienced pancreatitis, highlighting the potential for serious pancreatic adverse events associated with ICI therapy.

Pancreatitis was often asymptomatic and could be managed effectively by holding the ICI treatment and administering steroids, with some patients able to safely resume ICI therapy after recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events in patients treated with immune checkpoint inhibitors. Hana, C., Rehman, T., Park, K., 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]

Irreversible electroporation (IRE) combined with nivolumab shows a promising safety profile, as no dose-limiting toxicities were observed in a phase 1b clinical trial involving 10 patients, with a median follow-up of 12 months.

The combination therapy resulted in a mean time to progression of 6.3 months and a median overall survival of 18.0 months, suggesting potential efficacy in treating locally advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b trial of concurrent immunotherapy and irreversible electroporation in the treatment of locally advanced pancreatic adenocarcinoma. O'Neill, C., Hayat, T., Hamm, J., et al.[2023]

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. 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]

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

Effect of stereotactic body radiotherapy dose escalation plus pembrolizumab and trametinib versus stereotactic body radiotherapy dose escalation plus gemcitabine for locally recurrent pancreatic cancer after surgical resection on survival outcomes: A secondary analysis of an open-label, randomised, controlled, phase 2 trial. [2022]

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. Australia pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events in patients treated with immune checkpoint inhibitors. [2023]

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

Practical management of immune-related adverse events from immune checkpoint protein antibodies for the oncologist. [2020]

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

A phase 1b trial of concurrent immunotherapy and irreversible electroporation in the treatment of locally advanced pancreatic adenocarcinoma. [2023]

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]