Botensilimab + Balstilimab for Colorectal Cancer

(BBOpCo Trial)

Overseen By Emily Bolch

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Nicholas DeVito, MD

Must not be taking: Corticosteroids, Immunosuppressants, Live vaccines, others

Disqualifiers: Liver metastases, 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: 4

Duration: Up to 2 years

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with colorectal cancer that has spread and cannot be surgically removed. It focuses on two drugs, botensilimab and balstilimab (also known as AGEN1884), assessing their effectiveness before considering additional treatments if the cancer progresses. Suitable candidates have colorectal cancer that has not been treated with systemic therapy and does not involve the liver, bones, or brain. The trial aims to determine if this treatment can control the disease and assess its safety for participants. As a Phase 2 trial, the research measures the treatment's effectiveness 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, if you are using medications that are prohibited in combination with the study drug, you may need to stop those. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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 has a safety profile that most people can handle well. In previous studies, most patients tolerated the treatment without major issues. No new immune-related safety problems have emerged with this combination. These results come from studies involving patients whose colorectal cancer returned or did not respond to other treatments. While all treatments can have side effects, current data suggests that botensilimab and balstilimab are generally safe for people. ^{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 they work differently from traditional chemotherapy options like FOLFOX or FOLFIRI. Most current treatments focus on directly attacking cancer cells, but Botensilimab and Balstilimab are immunotherapies that help the immune system recognize and fight cancer more effectively. Botensilimab is an anti-CTLA-4 antibody, and Balstilimab is an anti-PD-1 antibody, both targeting specific checkpoints that can otherwise turn off immune responses against tumors. This approach could potentially lead to longer-lasting responses and fewer side effects compared to conventional therapies.

What evidence suggests that botensilimab and balstilimab might be an effective treatment for colorectal cancer?

Research has shown that the combination of two drugs, botensilimab and balstilimab, may be promising for treating colorectal cancer. Earlier studies found this drug pair to be safe and effective in patients whose cancer had returned or was difficult to treat. Notably, these drugs helped patients with a specific type of colorectal cancer, called MSS (microsatellite stable) colorectal cancer, live for an average of 21 months. This trial will evaluate the effectiveness of botensilimab and balstilimab, initially as a combination, and later with mFOLFOX6 and either bevacizumab or panitumumab, for patients with difficult-to-treat colorectal cancer. ^{2 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for patients with colorectal cancer. Participants must have tumor-informed ctDNA testing at baseline to start treatment. The study excludes certain individuals, but specific exclusion criteria are not provided.

Inclusion Criteria

The participant (or legally acceptable representative if applicable) provides written informed consent for the trial

I have not had any drug treatments for colon cancer.

I may have had chemotherapy before or after surgery with the study leader's approval.

Exclusion Criteria

I have had a blockage in my intestines in the last 3 months.

A WOCBP who is pregnant or breastfeeding or has a positive pregnancy test within 72 hours prior to receiving study treatment

I haven't had any cancer except for certain treated types in the past 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive botensilimab and balstilimab in 6-week cycles until progression, with mFOLFOX6 and bevacizumab or panitumumab added upon progression.

Up to 2 years

Visits every 2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a safety follow-up visit 30 days after the last treatment and survival follow-up every 12 weeks for up to 2 years.

Up to 2 years

1 visit (in-person) at 30 days, then phone calls every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Balstilimab
• Botensilimab

Trial Overview The BBOpCo trial tests botensilimab and balstilimab treatments in cycles until the disease progresses. If progression occurs, mFOLFOX6 chemotherapy with bevacizumab or panitumumab is added. Safety is monitored every two weeks during treatment.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 7 Interventions

botensilimab + balstilimab until disease progression, then botensilimab + balstilimab + mFOLFOX6 (leucovorin, fluorouracil, oxaliplatin) + {bevacizumab or panitumumab}

Who Is Running the Clinical Trial?

Nicholas DeVito, MD

Lead Sponsor

Trials

1

Recruited

20+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Published Research Related to This Trial

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 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 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 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 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 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 the FIRE-3 trial involving 592 patients with KRAS wild-type metastatic colorectal cancer, those who received first-line treatment with FOLFIRI plus cetuximab (arm A) had significantly longer progression-free survival (6.5 months) and overall survival (16.3 months) compared to those treated with FOLFIRI plus bevacizumab (arm B).

The study found that the choice of subsequent therapy was influenced by the initial treatment, with a higher percentage of patients from arm A receiving bevacizumab and those from arm B receiving cetuximab or panitumumab, suggesting that the sequence of drug administration may be crucial for optimizing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer. Modest, DP., Stintzing, S., von Weikersthal, LF., et al.[2022]

Older adults (70 years and older) were less likely to receive second-line therapy for metastatic colorectal cancer compared to younger adults, with a decrease in odds of receiving treatment by 11% for each additional decade of age.

Despite the lower likelihood of receiving second-line therapy, older and younger adults showed similar median time to progression (TTP) and overall survival (OS) outcomes after treatment, indicating that age alone may not impact the effectiveness of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic Colorectal Cancer Outcomes by Age Among ARCAD First- and Second-Line Clinical Trials. McCleary, NJ., Harmsen, WS., Haakenstad, E., et al.[2022]

In a phase II trial involving 35 patients with untreated metastatic colorectal cancer, the combination of gefitinib, capecitabine, and oxaliplatin resulted in an 80% disease control rate, with 8.6% achieving a complete response and 40% a partial response.

The treatment led to a median overall survival of 21.9 months, which is promising compared to previous regimens, and the side effects were manageable, primarily consisting of diarrhea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of gefitinib in combination with capecitabine and oxaliplatin as first-line chemotherapy in patients with advanced colorectal cancer. Gelibter, AJ., Gamucci, T., Pollera, CF., et al.[2018]

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]

Citations

1. 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.

2. 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 ...

3. 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.

4. physicianresources.dana-farber.org physicianresources.dana-farber.org/news/in-a-first-immune-checkpoint-inhibitors-show-effectiveness-in-metastatic-colorectal-cancer

In a First, Immune Checkpoint Inhibitors Show Effectiveness in ... A new combination of drugs, botensilimab and balstilimab, has shown promising results for patients with difficult-to-treat colorectal cancer ...

5. 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 ...

6. investor.agenusbio.com investor.agenusbio.com/news/news-details/2025/Agenus-BOTBAL-Achieves-42-Two-Year-Survival-in-Refractory-MSS-CRC-Advances-Toward-Registration-with-FDA-Alignment-on-Phase-3/default.aspx

Agenus' BOT/BAL Achieves 42% Two-Year Survival in ... In the MSS CRC cohort, patients received botensilimab (1 or 2 mg/kg every six weeks) plus balstilimab (3 mg/kg every two weeks) for up to two ...

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

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

8. 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 ...