Botensilimab + Balstilimab for Colorectal Cancer

Not currently recruiting at 101 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the effectiveness and safety of two new drugs, botensilimab and balstilimab (an experimental treatment), used alone or together, for treating advanced colorectal cancer. Participants will receive different treatments, including these drugs or standard care, to determine which works best. The trial seeks individuals with metastatic colorectal cancer who have not responded to standard treatments. As a Phase 2 trial, the research focuses on measuring how well the treatment works in an initial, smaller group of people.

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.

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

Research shows that both botensilimab alone and combined with balstilimab have promising safety results. Botensilimab activates the body's T-cells to fight colorectal cancer effectively. Studies found that, whether used alone or with balstilimab, it was generally well-tolerated by patients. Importantly, no new immune-related safety issues emerged. For the combination treatment, most side effects were mild and manageable. These findings suggest that the treatments are relatively safe for humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Botensilimab and Balstilimab for colorectal cancer because these treatments offer a novel approach compared to traditional chemotherapy and targeted therapies. Botensilimab is an innovative immune checkpoint inhibitor, which works by unleashing the body's immune system to attack cancer cells more effectively. Balstilimab, another immune checkpoint inhibitor, complements this by targeting PD-1, a protein that tumors use to hide from immune cells. Together, these drugs could potentially enhance the body's natural defenses against cancer, offering new hope for patients who may not respond well to existing treatments.

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

Research shows that botensilimab, both alone and with balstilimab, holds promise for treating colorectal cancer. In this trial, participants may receive botensilimab as monotherapy or combined with balstilimab. Studies found that the combination treatment led to a 42% survival rate at two years, with an average survival time of 20.9 months. The treatments were generally safe and well-tolerated, with no unexpected side effects. The positive impact on cancer was encouraging. These findings suggest that botensilimab, alone or with balstilimab, could be effective for patients with colorectal cancer. ^{1 3 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Agenus Inc.

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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 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]

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]

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]

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]

Citations

1. nature.com nature.com/articles/s41591-024-03083-7

Botensilimab plus balstilimab in relapsed/refractory ... The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with ...

2. investor.agenusbio.com investor.agenusbio.com/news/news-details/2025/Agenus-Presents-Data-at-ASCO-GI-Demonstrating-Impact-of-BOTBAL-in-Colorectal-Cancer-Across-Neoadjuvant-and-Advanced-Disease/default.aspx

Agenus Presents Data at ASCO GI Demonstrating Impact ... Data from five presentations underscore the transformative potential of BOT/BAL across multiple lines of therapy in colorectal cancer.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.23

Preliminary results from a randomized, open-label, phase 2 ... Here we present preliminary data from a randomized, open-label, phase 2 study in patients (pts) with MSS mCRC NLM treated with BOT ± BAL (anti-PD−1; NCT ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05608044

NCT05608044 | A Study of Botensilimab and Balstilimab ... This is an open-label, Phase 2, multicenter study to evaluate the efficacy, safety, tolerability, and pharmacokinetic profiles of botensilimab as monotherapy ...

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

Botensilimab/Balstilimab Elicits Sustained Efficacy in MSS ... Specifically, the combination attained a 42% 2-year survival rate as well as a median overall survival (OS) of 20.9 months among 123 patients ...

6. investor.agenusbio.com investor.agenusbio.com/news/news-details/2025/Agenus-Presents-New-Data-at-ASCO-Highlighting-Botensilimabs-Immune-Activation-in-MSS-Colorectal-Cancer/default.aspx

Agenus Presents New Data at ASCO Highlighting ... Study shows botensilimab “switches on” the body's own T-cells to attack a common, treatment-resistant form of colorectal cancer.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38871975/

Botensilimab plus balstilimab in relapsed/refractory ... - PubMed Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med. 2024 Sep ...

8. oncodaily.com oncodaily.com/oncolibrary/botensilimab-balstilimab-esmo-gi-2025

Botensilimab and Balstilimab Show Durable Survival in ... Botensilimab plus balstilimab delivers 21-month overall survival in MSS colorectal cancer, per updated Phase 1b data at ESMO GI 2025.