Botensilimab + Balstilimab for Colorectal Cancer

Recruiting at 83 trial locations

Overseen By Agenus, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Agenus Inc.

Must not be taking: Immune checkpoint inhibitors

Disqualifiers: Active brain metastases, Cardiovascular disease, Autoimmune 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

Duration: Up to 2 years

234 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests botensilimab alone or with balstilimab in adults with advanced colorectal cancer who didn't respond to previous chemotherapy. The new drugs aim to enhance the immune system's ability to fight cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you have taken certain treatments like cytotoxic or targeted therapies within a few weeks before starting the trial. It's best to discuss your current medications with the study team.

What safety information is available for Botensilimab and Balstilimab in humans?

Immune checkpoint inhibitors like Balstilimab (anti-PD-1) and Botensilimab (anti-CTLA-4) can cause side effects such as diarrhea and colitis (inflammation of the colon). These side effects are more common with CTLA-4 inhibitors, with diarrhea occurring in about 35% of patients and colitis in about 9% of patients. PD-1 inhibitors have lower rates, with diarrhea in about 14% and colitis in about 2% of patients. ^{1 2 3 4 5}

How is the drug Botensilimab + Balstilimab unique for treating colorectal cancer?

The combination of Botensilimab and Balstilimab is unique because it involves two immune checkpoint inhibitors that may work together to enhance the body's immune response against colorectal cancer, offering a novel approach compared to traditional chemotherapy or targeted therapies. ^{6 7 8 9 10}

Research Team

Medical Director

Principal Investigator

Agenus Inc.

Eligibility Criteria

This trial is for adults with metastatic colorectal cancer that's unremovable and has worsened after at least one chemotherapy regimen. They must have tried specific standard treatments, be in good physical condition (ECOG 0 or 1), and have a life expectancy of at least 12 weeks. Women should not be pregnant, and men must use contraception if their partners can bear children.

Inclusion Criteria

Life expectancy ≥ 12 weeks

Voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures

Women of childbearing potential must have a negative serum pregnancy test at screening and prior to study drug administration

Exclusion Criteria

Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients

I have an uncontrolled HIV infection.

My condition causes fluid buildup in my abdomen that is hard to treat.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive botensilimab as monotherapy or in combination with balstilimab, or standard of care treatment

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Balstilimab
• Botensilimab
• Standard of Care

Trial Overview The study tests botensilimab alone or combined with balstilimab/standard care in patients with refractory metastatic colorectal cancer. It's an open-label Phase 2 trial to see how well these treatments work, how safe they are, what side effects occur, and how the body processes the drugs.

Participant Groups

Group I: Monotherapy Botensilimab Dose 2 Experimental Treatment 1 Intervention

Participants will receive botensilimab dose 2 given IV.

Group II: Monotherapy Botensilimab Dose 1 Experimental Treatment 1 Intervention

Participants will receive botensilimab dose 1 given IV.

Group III: Combination Botensilimab Dose 2 plus Balstilimab Experimental Treatment 2 Interventions

Participants will receive botensilimab at dose 2 given IV and balstilimab given IV.

Group IV: Combination Botensilimab Dose 1 plus Balstilimab Experimental Treatment 2 Interventions

Participants will receive botensilimab at dose 1 given IV and balstilimab given IV.

Group V: Standard of Care Active Control 1 Intervention

Participants will receive select standard of care as determined by the investigator.

Who Is Running the Clinical Trial?

Agenus Inc.

Lead Sponsor

Trials

58

Recruited

4,900+

Findings from Research

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]

A study involving 448 patients with advanced cancers showed that immune checkpoint inhibitors, like anti-PD-1 and anti-CTLA4 therapies, are safe and well tolerated across different age groups, including those aged 75 and older.

Older patients (≥75 years) experienced fewer endocrine toxicities compared to younger patients, while they had a higher incidence of dermatological toxicities, indicating that age does not significantly increase the risk of severe adverse effects from these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of age on the toxicity of immune checkpoint inhibition. Samani, A., Zhang, S., Spiers, L., 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]

Pembrolizumab significantly improved progression-free survival (PFS) in patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer, with a median PFS of 16.5 months compared to 8.2 months for standard chemotherapy, indicating its efficacy as a first-line treatment.

The FDA found no safety concerns during the approval process, and while both pembrolizumab and standard of care had similar adverse reactions, the duration of treatment with pembrolizumab was nearly double that of standard care, suggesting a potentially more favorable treatment profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. Casak, SJ., Marcus, L., Fashoyin-Aje, L., et al.[2022]

The PI3K pathway is crucial in cancer progression and immune response, and several PI3K inhibitors, including idelalisib, copanlisib, duvelisib, and umbralisib, have been approved for treating hematological malignancies.

This review highlights a lack of real-world data on the incidence and gastrointestinal toxicity, specifically colitis, associated with PI3K inhibitors, emphasizing the need for better understanding and management of these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies. Breal, C., Beuvon, F., de Witasse-Thezy, T., et al.[2023]

T138067, a novel microtubule targeting agent, was well tolerated in patients with metastatic colorectal cancer, showing only moderate hematologic and gastrointestinal toxicity, while neurotoxicity was minimal.

Despite being well tolerated, T138067 did not demonstrate any clinical activity in patients who had previously been treated with irinotecan and 5-fluorouracil, with a median time to tumor progression of only 1.4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of T138067, a novel microtubule inhibitor, in patients with metastatic, refractory colorectal carcinoma. Berlin, JD., Venook, A., Bergsland, E., et al.[2018]

In a phase II study involving 99 patients with wild-type KRAS colorectal cancer, the biweekly combination of cetuximab and FOLFOX-4 achieved an overall response rate (ORR) of 60.6%, indicating significant efficacy as a first-line treatment.

The safety profile was consistent with previous studies, with common grade 3-4 toxicities including neutropenia (32.3%) and acne-like rash (15.2%), suggesting that the biweekly regimen is both effective and manageable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study). Fernandez-Plana, J., Pericay, C., Quintero, G., et al.[2023]

In a study of 40 frail elderly patients (aged ≥ 75 years) with metastatic RAS-BRAF wild-type colorectal cancer, single-agent panitumumab demonstrated an objective response rate of 32.5% and a disease control rate of 72.5%, indicating its efficacy as a treatment option for this population.

Panitumumab was found to be well-tolerated, with a median progression-free survival of 6.4 months and overall survival of 14.3 months, while only 23% of patients experienced dose reductions due to adverse events, primarily skin rash, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Agent Panitumumab in Frail Elderly Patients With Advanced RAS and BRAF Wild-Type Colorectal Cancer: Challenging Drug Label to Light Up New Hope. Pietrantonio, F., Cremolini, C., Aprile, G., et al.[2022]

In the phase I/II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib showed a high disease control rate of 87% in patients with metastatic colorectal cancer when used alone, with a progression-free survival of 5.6 months.

When adagrasib was combined with the EGFR inhibitor cetuximab, the disease control rate improved to 100%, indicating a potentially more effective treatment strategy, although progression-free survival data for this combination is still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adagrasib Data Create Buzz at ESMO. [2022]

In a study involving 54 patients with BRAF-mutant metastatic colorectal cancer, the combination of the RAF inhibitor encorafenib and the EGFR-targeting antibody cetuximab showed promising clinical activity, with overall response rates of 19% for dual therapy and 18% for triple therapy including a PI3Kα inhibitor.

Both treatment combinations were well-tolerated, with no maximum tolerated dose reached, indicating that these therapies could be viable options for patients with difficult-to-treat BRAF-mutant metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. van Geel, RMJM., Tabernero, J., Elez, E., et al.[2022]

References

1. 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]

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

Impact of age on the toxicity of immune checkpoint inhibition. [2023]

3. 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]

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

FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies. [2023]

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

Phase II trial of T138067, a novel microtubule inhibitor, in patients with metastatic, refractory colorectal carcinoma. [2018]

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

Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study). [2023]

8. England pubmed.ncbi.nlm.nih.gov

Single-Agent Panitumumab in Frail Elderly Patients With Advanced RAS and BRAF Wild-Type Colorectal Cancer: Challenging Drug Label to Light Up New Hope. [2022]

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

Adagrasib Data Create Buzz at ESMO. [2022]

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

A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. [2022]