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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining radiation therapy with immune checkpoint inhibitors can treat metastatic pancreatic ductal adenocarcinoma, a type of pancreatic cancer that has spread. Radiation therapy uses high-energy rays to attack cancer cells, while immune checkpoint inhibitors help the immune system recognize and fight these cells. Participants will receive Stereotactic Body Radiation Therapy along with two medications, Balstilimab and Botensilimab, to evaluate the effectiveness of this approach. This trial may suit those with pancreatic cancer unresponsive to other treatments and who have at least one tumor suitable for biopsy. 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 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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of botensilimab and balstilimab is generally safe and well-tolerated. Studies have found this treatment safe for patients with various cancers, such as colorectal and pancreatic cancers. In these studies, patients experienced manageable side effects, which were not too severe compared to the potential benefits.

The treatments have also shown promise in other cancer types, with patients experiencing long-lasting positive effects, indicating the drugs continue to work well over time. While these results are promising, they come from smaller or earlier studies. Ongoing research aims to confirm the safety and effectiveness of this treatment combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Balstilimab and Botensilimab for pancreatic cancer because these treatments leverage the body's immune system to fight cancer in a novel way. Unlike the standard chemotherapy treatments that directly target and kill cancer cells but can also harm healthy cells, Balstilimab and Botensilimab are immunotherapies that enhance the immune system's ability to identify and attack cancer cells specifically. These drugs target immune checkpoints, potentially leading to more precise and effective treatment with fewer side effects. Additionally, their combination with Stereotactic Body Radiation Therapy (SBRT) might enhance the overall effectiveness by making cancer cells more susceptible to immune attack.

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

In this trial, participants will receive a combination of Stereotactic Body Radiation Therapy (SBRT), Botensilimab, and Balstilimab. Studies have shown that using Balstilimab and Botensilimab together can help treat certain cancers. Earlier research demonstrated that this combination allowed 40% of patients to live without their cancer worsening for at least 6 months, and 20% of patients experienced tumor shrinkage or disappearance. On average, patients who responded to the treatment did so for about 19.4 months. Another study found that patients lived for an average of about 20.9 months after starting treatment. These findings suggest that this treatment combination can help manage the disease for a significant time, offering hope for difficult-to-treat cancers like advanced pancreatic cancer. ^{2 3 6 7 8}

Who Is on the Research Team?

Benjamin Spieler, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

Citations

1. investor.agenusbio.com investor.agenusbio.com/news/news-details/2023/Agenus-Unveils-New-and-Updated-Botensilimab-Data-in-Colorectal-Pancreatic-Lung-Melanoma-and-Sarcoma/default.aspx

Agenus Unveils New and Updated Botensilimab Data in ... BOT/BAL combination demonstrated 6-month progression-free survival of 40%, ORR of 20%, and median response duration of 19.4 months (iRECIST).

2. onclive.com onclive.com/view/dr-schlechter-on-updated-data-for-botensilimab-plus-balstilimab-in-mss-mcrc

Dr Schlechter on Updated Data for Botensilimab Plus ... Median progression-free survival (PFS) was 4.0 months (95% CI, 2.8-4.1), and the median overall survival (OS) reached 20.9 months (95% CI, 16.2- ...

3. cancernetwork.com cancernetwork.com/view/botensilimab-balstilimab-elicits-sustained-efficacy-in-mss-metastatic-crc

Botensilimab/Balstilimab Elicits Sustained Efficacy in MSS ... Botensilimab plus balstilimab achieves 42% two-year survival in refractory MSS mCRC without active liver metastases. Presented at: European ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.LBA8

Results from a phase 1a/1b study of botensilimab (BOT) ... In heavily pretreated metastatic MSS CRC pts, BOT + BAL continues to demonstrate promising clinical activity with durable responses and was well tolerated.

5. oncodaily.com oncodaily.com/oncolibrary/immune-oncology/battman-trial-bot-bal-q4

BOT/BAL Advancements, BATTMAN Trial, FDA Approval ... In Hepatocellular Carcinoma (HCC), BOT/BAL achieved a 17% overall response rate and 72% disease control rate, with a 12.3-month median overall ...

6. onclive.com onclive.com/view/dr-schlechter-on-the-safety-of-botensilimab-plus-balstilimab-in-pretreated-mss-crc

Dr Schlechter on the Safety of Botensilimab Plus ... The study authors concluded that the safety profile of botensilimab in combination with balstilimab was manageable in this patient population ...

7. oncodaily.com oncodaily.com/oncolibrary/botensilimab-balstilimab-esmo

Dual CTLA 4 and PD 1 Blockade With Botensilimab ... Botensilimab plus balstilimab shows durable responses and 2 year survival benefit across refractory solid tumors including MSS colorectal ...

8. asco.org asco.org/abstracts-presentations/ABSTRACT490012

A phase Ib study of a pooled synthetic long peptide mutant ... A phase Ib study of a pooled synthetic long peptide mutant KRAS vaccine combined with balstilimab/botensilimab in metastatic pancreatic cancer and metastatic ...