Immunotherapy Combinations for Colorectal Cancer with Liver Metastases

Overseen By Casey Owens

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Weill Medical College of Cornell University

Must not be taking: PD-1, PD-L1, CTLA-4

Disqualifiers: Uncontrolled infection, Diabetes, Cardiac, 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: 6

Duration: 6-8 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to to learn about different combinations of immunotherapy in patients with colorectal cancer whose cancer has spread to their liver and are planning to have surgery to remove tumor metastases from their liver. The main questions it aims to answer are: * whether these combinations of immunotherapy change the tumor microenvironment in the liver * whether these combinations of immunotherapy are safe and effective when used in colorectal cancer with liver metastases Participants will be randomly assigned to one of the following: * Botensilimab and balstilimab * Botensilimab, balstilimab, and AGEN1423 * Botensilimab, balstilimab, and radiation Participants will be asked to come in to receive drug infusions (and radiation, if applicable) before and after their surgical resection. Participants will be followed for up to 2 years.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot receive chemotherapy, growth factor support, transfusions, or albumin administration within 14 days before starting the study treatment.

What data supports the effectiveness of the drug combination including Balstilimab and Botensilimab for colorectal cancer with liver metastases?

In a study, two patients with a specific type of colorectal cancer (mismatch repair proficient/microsatellite stable) showed exceptional responses to the combination of Botensilimab and Balstilimab, suggesting potential effectiveness in similar settings. ^{1 2 3 4 5}

Is the immunotherapy combination treatment generally safe for humans?

The immunotherapy treatments, including those similar to Balstilimab and AGEN1884, have been associated with side effects like diarrhea and colitis (inflammation of the colon) in some patients. These side effects are more common and severe when treatments are combined, but they are generally manageable with medical care. ^{6 7 8 9 10}

What makes the drug Balstilimab and Botensilimab unique for treating colorectal cancer with liver metastases?

Balstilimab and Botensilimab are unique because they are part of an immunotherapy approach, which uses the body's immune system to fight cancer, unlike traditional chemotherapy that directly targets cancer cells. This combination may offer a new option for patients with liver metastases from colorectal cancer, where standard treatments are limited. ^{3 11 12 13 14}

Research Team

Manish Shah, M.D.

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

This trial is for adults with colorectal cancer that has spread to the liver and who are set to have surgery to remove these metastases. They must not be pregnant, agree to use contraception, and can't have had certain immune therapies or suffer from uncontrolled conditions like infections or heart disease.

Inclusion Criteria

I haven't had chemotherapy, growth factor support, transfusions, or albumin within the last 14 days.

My cancer can be measured by tests.

Women of childbearing potential (WOCBP), or anyone with a uterus, must not be pregnant or breastfeeding. All participants of childbearing potential must agree to use highly effective contraception during this study

Exclusion Criteria

I have no known allergies or reactions to immune therapy drugs.

Any medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient

I cannot have surgery for my condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive immunotherapy infusions and possibly radiation before and after surgical resection

6-8 weeks

4 visits (in-person)

Surgery

Surgical resection of tumor metastases from the liver

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

2 visits (in-person)

Long-term Follow-up

Participants are followed remotely for up to two years to assess long-term outcomes

Up to 2 years

Treatment Details

Interventions

• Balstilimab
• Botensilimab
• Radiation

Trial Overview The study tests different immunotherapy combinations (Botensilimab, Balstilimab, AGEN1423) plus radiation in some groups before and after liver surgery. It aims to see how these treatments affect the tumor environment in the liver and if they're safe and effective.

Participant Groups

Group I: Botensilimab, Balstilimab, and Radiation Experimental Treatment 3 Interventions

Participants will receive 3 doses of radiation prior to surgery. Additionally, two balstilimab infusions will be given prior to surgery and two infusions will be given after surgery, for a total of four doses. Each infusion will be scheduled approximately 3 weeks apart. On the same day as the first and third balstilimab infusions, botensilimab will also be given, for a total of two doses, one before and one after surgery.

Group II: Botensilimab, Balstilimab, and AGEN1423 Experimental Treatment 3 Interventions

Two balstilimab infusions will be given prior to surgery and two infusions will be given after surgery, for a total of four doses. On the same day as each balstilimab infusion, participants will also receive AGEN1423 infusions, for a total of four doses. Each infusion will be scheduled approximately 3 weeks apart. On the same day as the first and third balstilimab + AGEN1423 infusions, botensilimab will also be given, for a total of two doses, one before and one after surgery.

Group III: Botensilimab and Balstilimab Experimental Treatment 2 Interventions

Two balstilimab infusions will be given prior to surgery and two infusions will be given after surgery, for a total of four doses. Each infusion will be scheduled approximately 3 weeks apart. On the same day as the first and third balstilimab infusions, botensilimab will also be given, for a total of two doses, one before and one after surgery.

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Findings from Research

The addition of panitumumab to the chemotherapy regimen (FOLFOX) did not achieve the primary endpoint of a two-year progression-free survival (PFS) rate of 65%, with observed rates of 35.7% for the experimental group and 30.6% for the control group.

Despite not meeting the primary endpoint, there were positive trends in overall survival (OS) and PFS favoring the panitumumab group, and no new safety concerns were identified, suggesting potential for further research on anti-EGFR agents in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFOX plus panitumumab or FOLFOX alone as additive therapy following R0/1 resection of RAS wild-type colorectal cancer liver metastases - The PARLIM trial (AIO KRK 0314). Modest, DP., Karthaus, M., Kasper, S., et al.[2022]

In a study of 108 patients with advanced colorectal cancer and high MSI expression, the combination of PD-1 customization and autoimmune T-cell therapy resulted in a treatment efficiency of 90.74%, significantly higher than the 61.11% efficiency observed in the control group.

The study also found that after treatment, the levels of immune markers like CD107a, perforin, and GranB cells increased in both groups, but the study group showed a more pronounced expression of PD-1, particularly in patients with more advanced cancer stages (grade III-IV).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study of PD-1 Customization and Autoimmune T Cells for Advanced Colorectal Cancer with High MSI Expression. Li, N., Zhang, X., Zhang, Y., et al.[2022]

In a study of 63 patients with KRAS wild-type metastatic colorectal cancer, the combination of irinotecan, bevacizumab, and cetuximab/panitumumab as a 4th-line treatment was found to be safe and well tolerated, with a toxicity profile consistent with the individual drugs.

The treatment resulted in a median progression-free survival of 6.1 months and a median overall survival of 11.9 months, indicating a significant level of disease control in patients who had already undergone multiple lines of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Inhibition of EGFR and VEGF in Heavily Pretreated Patients with Metastatic Colorectal Cancer. Larsen, FO., Markussen, A., Nielsen, D., et al.[2018]

In a neoadjuvant setting for patients with locally advanced pMMR/MSS colon and rectal cancer, the combination of botensilimab (an anti-CTLA-4 antibody) and balstilimab (an anti-PD-1 antibody) showed exceptional responses, indicating potential efficacy of this immunotherapy approach.

The unique 'inside-out' tumor regression pattern observed suggests a novel mechanism of action for botensilimab, which may influence future clinical trial designs and offer alternatives to chemotherapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer. Kasi, PM., Hidalgo, M., Jafari, MD., et al.[2023]

The combination of regorafenib, ipilimumab, and nivolumab (RIN) was found to be safe and effective for treating patients with microsatellite stable (MSS) metastatic colorectal cancer, with a recommended phase 2 dose (RP2D) established at 80 mg of regorafenib daily, showing an overall response rate of 27.6%.

In patients without liver metastases, the treatment showed even better outcomes, with a response rate of 36.4% and a median overall survival of over 22 months, indicating that this combination therapy could be a promising option for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib, Ipilimumab, and Nivolumab for Patients With Microsatellite Stable Colorectal Cancer and Disease Progression With Prior Chemotherapy: A Phase 1 Nonrandomized Clinical Trial. Fakih, M., Sandhu, J., Lim, D., et al.[2023]

In a review of 18 studies involving 4,653 patients, anti-CTLA-4 inhibitors were associated with a significantly higher incidence of diarrhea (35.4%) and colitis (8.8%) compared to anti-PD-1 inhibitors, which had incidences of 13.7% and 1.6%, respectively.

The study found that patients receiving anti-PD-1 therapy had a lower relative risk of developing diarrhea (0.58) and colitis (0.16) compared to those on anti-CTLA-4 therapy, indicating that PD-1 inhibitors may be a safer option regarding these gastrointestinal toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. Tandon, P., Bourassa-Blanchette, S., Bishay, K., et al.[2019]

In a study of 274 elderly patients with advanced melanoma, the risk of developing colitis was similar for those treated with anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab or pembrolizumab) therapies.

However, when considering patients across all stages of melanoma, anti-PD1 treatment was associated with a significantly lower risk of colitis compared to anti-CTLA4, suggesting a safer profile for anti-PD1 in this broader patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. Almutairi, AR., Slack, M., Erstad, BL., et al.[2022]

Immune-related colitis occurred in 3.3% of cancer patients receiving immune checkpoint inhibitors (ICIs), with common symptoms including diarrhea, nausea, and abdominal pain, and typical imaging findings of bowel wall thickening and fluid-filled colon.

The onset of colitis was similar in patients receiving monotherapy and combination therapy, but those on combination therapy were more likely to experience other immune-related adverse events (irAEs), highlighting the need for careful monitoring in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging and clinical manifestations of immune checkpoint inhibitor-related colitis in cancer patients treated with monotherapy or combination therapy. Shieh, AC., Guler, E., Pfau, D., et al.[2021]

In the CheckMate 142 study involving 119 patients with previously treated MSI-H/dMMR metastatic colorectal cancer, the combination of nivolumab and low-dose ipilimumab showed a high objective response rate (ORR) of 55% and a promising 12-month overall survival (OS) rate of 85%.

Most treatment-related adverse events (sTRAEs) were manageable, occurring early and resolving quickly, with comparable efficacy outcomes between patients with and without sTRAEs, indicating a favorable benefit-risk profile for this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer. Morse, MA., Overman, MJ., Hartman, L., et al.[2020]

In a study of 1261 patients with advanced melanoma receiving anti-PD-1 therapy, colitis occurred in 109 patients, with a significantly higher incidence of 24.4% in those receiving combination therapy with ipilimumab compared to 3.2% in those on monotherapy.

Patients on combination therapy experienced earlier onset of colitis symptoms and required higher doses and longer tapering of steroids, indicating that combination therapy may lead to more severe immune-related adverse events, highlighting the need for improved management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical characterization of colitis arising from anti-PD-1 based therapy. Wang, DY., Mooradian, MJ., Kim, D., et al.[2023]

In a clinical trial involving two patients with colorectal cancer and liver metastasis, the immunotherapy Vigil, combined with standard chemotherapy (modified FOLFOX-6), led to no evidence of disease recurrence for over eight years.

Both patients showed a systemic immune response to Vigil therapy, indicating that the treatment not only helped control the cancer but also activated the immune system against it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Marked Survival Advantage of Two Colorectal Cancer Patients with Liver Metastases Treated with Vigil and FOLFOX-6. Barve, V., Adams, N., Stanbery, L., et al.[2023]

Multimodal treatment strategies for colorectal cancer liver metastases, which combine systemic therapies with surgical and interventional methods, have significantly improved patient outcomes, achieving median overall survival rates of 30 months or longer.

The use of predictive and prognostic biomarkers allows for more personalized treatment plans based on individual patient factors, including performance status and tumor characteristics, enhancing the effectiveness of therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tailored Systemic Therapy for Colorectal Cancer Liver Metastases. Czauderna, C., Luley, K., von Bubnoff, N., et al.[2021]

In a phase II trial involving 101 patients with initially unresectable colorectal liver-limited metastases, the addition of cetuximab to modified FOLFOXIRI significantly increased the rate of no evidence of disease (NED) achieved, with 70.1% in the cetuximab group compared to 41.2% in the control group.

The cetuximab group also showed improved objective response rates (95.5% vs. 76.5%) and trends towards better progression-free and overall survival, while the safety profile was similar between both treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild-Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial. Hu, H., Wang, K., Huang, M., et al.[2021]

Combination chemotherapy has improved survival rates for colorectal cancer patients with liver metastases, allowing 10-20% of previously unresectable cases to become operable.

Biologic agents like bevacizumab and cetuximab enhance surgical outcomes when added to standard chemotherapy, but dual biologic therapy has not shown the same effectiveness, highlighting the need for identifying biomarkers to better target treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic colorectal cancer: recent advances in its clinical management. Barugel, ME., Vargas, C., Krygier Waltier, G.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

FOLFOX plus panitumumab or FOLFOX alone as additive therapy following R0/1 resection of RAS wild-type colorectal cancer liver metastases - The PARLIM trial (AIO KRK 0314). [2022]

2. England pubmed.ncbi.nlm.nih.gov

Study of PD-1 Customization and Autoimmune T Cells for Advanced Colorectal Cancer with High MSI Expression. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Dual Inhibition of EGFR and VEGF in Heavily Pretreated Patients with Metastatic Colorectal Cancer. [2018]

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

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer. [2023]

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

Regorafenib, Ipilimumab, and Nivolumab for Patients With Microsatellite Stable Colorectal Cancer and Disease Progression With Prior Chemotherapy: A Phase 1 Nonrandomized Clinical Trial. [2023]

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

The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. [2022]

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

Imaging and clinical manifestations of immune checkpoint inhibitor-related colitis in cancer patients treated with monotherapy or combination therapy. [2021]

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

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer. [2020]

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

Clinical characterization of colitis arising from anti-PD-1 based therapy. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Marked Survival Advantage of Two Colorectal Cancer Patients with Liver Metastases Treated with Vigil and FOLFOX-6. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Tailored Systemic Therapy for Colorectal Cancer Liver Metastases. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild-Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Metastatic colorectal cancer: recent advances in its clinical management. [2015]