Immuno-Radiation for Pancreatic Cancer

(EMPIRE Trial)

Overseen By Benjamin Spieler, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Benjamin Spieler

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Liver tumor burden, CNS metastases, Autoimmune disease, Cardiovascular disease, 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: Unknown

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you do not take certain medications, such as immunotherapy regimens, cytotoxic chemotherapy, immunosuppressive agents, and systemic corticosteroids. If you are on these medications, you may need to stop them before joining the trial.

What data supports the effectiveness of the treatment Balstilimab, Botensilimab, and Stereotactic Body Radiation Therapy for pancreatic cancer?

Research shows that combining radiation therapy with immune checkpoint inhibitors, like those used in other studies, can enhance the immune system's response to pancreatic cancer. For example, adding PD-L1 blockers to radiation improved tumor response in animal models, suggesting a potential benefit of combining similar treatments. ^{1 2 3 4 5}

Is the Immuno-Radiation treatment for pancreatic cancer safe?

Immune checkpoint inhibitors, which are part of the Immuno-Radiation treatment, can cause side effects like inflammation of the pancreas and other digestive issues. These side effects are more common when combined with other treatments, and women may be at higher risk. ^{5 6 7 8 9}

How is the treatment with Balstilimab and Botensilimab for pancreatic cancer different from other treatments?

The treatment with Balstilimab and Botensilimab is unique because it combines immune checkpoint inhibitors with radiation therapy, potentially enhancing the immune system's ability to fight pancreatic cancer, which is typically resistant to immunotherapy alone. ^{1 2 3 4 10}

What is the purpose of this trial?

The purpose of this study is to assess if radiation therapy (which uses high-energy radiation to damage or destroy cancer cells) combined with immune checkpoint inhibitors (medications that helps the body recognize and attack cancer cells) will be beneficial for patients with metastatic pancreatic ductal adenocarcinoma.

Research Team

Benjamin Spieler, MD

Principal Investigator

University of Miami

Eligibility Criteria

This trial is for adults with metastatic pancreatic cancer who've had at least one prior treatment. They should be in good physical condition (ECOG 0 or 1), have a life expectancy of over 3 months, and not be infected with HIV or Hepatitis B. Women must test negative for pregnancy and all participants must agree to use contraception.

Inclusion Criteria

I am fully active or have some restrictions but can still care for myself.

My cancer is microsatellite stable.

Patients must have a life expectancy of ≥3 months

Exclusion Criteria

I haven't needed treatment for an autoimmune disease in the last 2 years.

More than a quarter of my liver is affected by cancer.

I have had radiation or radioisotope therapy to the liver.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive Stereotactic Body Radiation Therapy (SBRT)

Up to 1 month

Immunotherapy Treatment

Participants receive Botensilimab immunotherapy for up to 24 weeks, in combination with Balstilimab immunotherapy for up to one year

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Balstilimab
• Botensilimab
• Stereotactic Body Radiation Therapy

Trial Overview The EMPIRE trial is testing if combining radiation therapy with immune checkpoint inhibitors Botensilimab and Balstilimab can help treat metastatic pancreatic cancer. Patients will receive high-energy radiation aimed at destroying cancer cells along with medications designed to boost the body's immune response against the tumor.

Participant Groups

Group I: Radiation, Botensilimab Combined with Balstilimab Treatment Group Experimental Treatment 3 Interventions

Participants in this group will receive Stereotactic Body Radiation Therapy (SBRT), followed by Botensilimab immunotherapy (ImT) for up to 24 weeks, in combination with Balstilimab ImT for up to one year. Total participation duration is up to five years.

Who Is Running the Clinical Trial?

Benjamin Spieler

Lead Sponsor

Trials

1

Recruited

20+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Findings from Research

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 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 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 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 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 systematic review of 59 randomized controlled trials involving 41,757 patients, immune checkpoint inhibitors (ICIs) were found to be associated with a 0.93% incidence of all-grade pancreatitis and higher rates of pancreatic enzyme elevations, indicating a notable risk of pancreatic adverse events (AEs) during treatment.

The study revealed that PD-1 inhibitors carry a greater risk of pancreatic AEs compared to PD-L1 inhibitors, and patients receiving dual ICI therapy face an even higher risk than those on single ICI therapy, highlighting the need for clinician awareness regarding these potential complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. Zhao, Z., Zhang, W., Pang, L., et al.[2023]

A study analyzing 2,364 cases of pancreatic adverse events (AEs) linked to immune checkpoint inhibitors (ICIs) found significant associations, particularly with ICI-associated pancreatitis and diabetes mellitus, indicating a notable risk for patients undergoing ICI treatment.

Combination therapy with ICIs showed a higher frequency of pancreatic AEs compared to monotherapy, suggesting that while the risk of these adverse events increases, the fatality rate remains lower, highlighting the importance of patient awareness regarding these potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis. Zhang, Y., Fang, Y., Wu, J., et al.[2022]

References

1. 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]

2. 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]

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

PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. [2022]

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. Switzerland pubmed.ncbi.nlm.nih.gov

An updated review of gastrointestinal toxicity induced by PD-1 inhibitors: from mechanisms to management. [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. Switzerland pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis. [2022]

10. Greece pubmed.ncbi.nlm.nih.gov

Robo1-specific CAR-NK Immunotherapy Enhances Efficacy of 125I Seed Brachytherapy in an Orthotopic Mouse Model of Human Pancreatic Carcinoma. [2023]