Fc-Engineered Anti-CTLA-4 Monoclonal Antibody for Advanced Cancer

Not currently recruiting at 19 trial locations

Overseen By Agenus Inc. Clinical Trial Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Agenus Inc.

Must not be taking: Systemic corticosteroids, Immunosuppressives

Disqualifiers: Autoimmune disease, Brain metastases, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the safety of a new treatment for advanced cancers unresponsive to other therapies. It tests a new therapy, botensilimab (an Fc-engineered anti-CTLA-4 monoclonal antibody), both alone and with another drug, balstilimab, to evaluate their combined effectiveness. Individuals with advanced solid tumors lacking standard treatment options may qualify for this study. The research examines the body's response to these treatments and seeks to identify the best dose for future studies. As a Phase 1 trial, it focuses on understanding the treatment's effects in people, offering participants the chance to be among the first to receive this new therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently receiving other study therapies or certain treatments close to the trial start. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should not be on systemic corticosteroid therapy or other systemic immunosuppressive medications one week prior to the first dose of the study drug, with some exceptions for certain conditions. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that botensilimab, whether used alone or with balstilimab, is generally safe. In studies involving over 1,200 patients, botensilimab alone was well-tolerated, with no unexpected safety issues. In studies with 343 patients using the combination therapy, no new immune-related side effects emerged, indicating it is also well-tolerated. However, this trial is in an early stage, primarily focusing on safety and determining the correct dose. While the initial results are promising, further research is needed to fully understand the safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about botensilimab because it represents a different approach to treating advanced cancers. Unlike traditional immunotherapies that often target surface proteins on cancer cells, botensilimab is an Fc-engineered anti-CTLA-4 monoclonal antibody. This means it helps activate the immune system by enhancing immune cell activity, potentially leading to a stronger attack on cancer cells. Additionally, botensilimab is being tested both alone and in combination with balstilimab, offering versatile treatment regimens that could suit different patient needs. This novel mechanism and varied delivery schedule provide new hope in the fight against advanced cancers.

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

Research has shown that botensilimab, a specially designed antibody, can help treat cancers that usually don't respond well to standard treatments. In earlier studies, about 39% of patients who received this antibody survived for two years. In this trial, some participants will receive botensilimab alone, while others will receive it with balstilimab, another type of antibody. When combined with balstilimab, the results were even more encouraging. Specifically, this combination treatment led to an average survival time of 20.9 months. These findings suggest that botensilimab, both alone and with balstilimab, could be promising options for treating advanced solid tumors. ^{1 2 3 4 5}

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 certain advanced cancers, like colorectal or ovarian cancer, who have no standard treatment options left or those that failed. They must expect to live at least 3 more months, be relatively active and healthy enough for daily life (ECOG status of 0-1), have proper organ function, not be pregnant, agree to use contraception, and provide a recent tumor tissue sample.

Inclusion Criteria

My blood tests show my organs and bone marrow are working well.

I have signed the consent form for this study.

I have a specific type of cancer like Angiosarcoma, HCC, NSCLC, Prostate, or Breast Cancer.

Exclusion Criteria

Additional exclusion criteria for specific cohorts such as HCC and specific exclusion criterion for the UK.

I do not have a psychiatric condition, substance abuse issue, or another cancer that would affect my study participation. I am not pregnant or breastfeeding.

I have had chemotherapy, biological therapy, radiation, or major surgery recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive botensilimab monotherapy or in combination with balstilimab, with dose escalation every 3 or 6 weeks, for up to 2 years

up to 2 years

Every 3 or 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months following last study dose

Open-label extension (optional)

Participants enrolled at sites in the UK may have the option for extended treatment

What Are the Treatments Tested in This Trial?

Interventions

• Botensilimab

Trial Overview The study tests botensilimab alone and combined with balstilimab in patients with advanced solid tumors. It's an early-phase trial aiming to find the safest dose levels (MTD) and the recommended doses for future studies (RP2D). The effects on the body are closely monitored through lab tests.

How Is the Trial Designed?

Group I: 6-Week Monotherapy Experimental Treatment 1 Intervention

3+3 Dose escalation: botensilimab, every 6 weeks, starting at dose level 1 mg/kg up to 4 mg/kg, administered IV for up to 2 years.

Group II: 6-Week Combination Therapy Experimental Treatment 2 Interventions

3+3 Dose escalation: balstilimab, every 2 weeks, at dose level 3 mg/kg in combination with botensilimab, every 6 weeks, starting at dose level 0.1 mg/kg up to 4 mg/kg, administered IV for up to 2 years. Participants enrolled at sites in the United Kingdom (UK) may have the option for extended treatment. An additional cohort will investigate balstilimab, every 3 weeks, at 450 mg in combination with botensilimab every 6 weeks, at 150 mg, administered IV for up to 2 years.

Group III: 3-Week Monotherapy Experimental Treatment 1 Intervention

3+3 Dose escalation: botensilimab, every 3 weeks, starting at dose level 0.1 milligrams/kilogram (mg/kg) up to 4 mg/kg, administered intravenously (IV) for up to 2 years.

Botensilimab is already approved in United States for the following indications:

Approved in United States as Botensilimab for:

• None approved yet; Fast Track designation granted for non-MSI-H colorectal cancer

Who Is Running the Clinical Trial?

Agenus Inc.

Lead Sponsor

Trials

58

Recruited

4,900+

Published Research Related to This Trial

In a study of 12 advanced melanoma patients treated with the CTLA4-blocking antibody tremelimumab, 3 patients experienced long-lasting tumor regression for over 2 years, indicating potential efficacy in a subset of individuals.

While there were no significant changes in MART1-specific T cells or other immune markers, T-cell activation and memory markers were associated with clinical responses and inflammatory toxicity, suggesting these could be important indicators of treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma. Comin-Anduix, B., Lee, Y., Jalil, J., et al.[2021]

PF-06801591, a monoclonal antibody targeting the PD-1 receptor, was found to be safe and tolerable in a phase 1 trial with 40 patients, showing no dose-limiting toxic effects and manageable adverse events for both intravenous and subcutaneous administration.

The study demonstrated that monthly subcutaneous administration of PF-06801591 is a convenient and effective alternative to intravenous delivery, with an overall objective response rate of 18.4% and full PD-1 receptor occupancy achieved across all dose levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Subcutaneous vs Intravenous Administration of Anti-PD-1 Antibody PF-06801591 in Patients With Advanced Solid Tumors: A Phase 1 Dose-Escalation Trial. Johnson, ML., Braiteh, F., Grilley-Olson, JE., et al.[2022]

Checkpoint-blocking antibodies, like ipilimumab, enhance the immune system's ability to recognize and eliminate tumors by blocking the CTLA-4 receptor, which normally inhibits T-cell activation.

The review discusses the clinical development of CTLA-4 blocking antibodies, highlighting their effectiveness in cancer treatment, associated toxicities, and the exploration of biomarkers to predict patient responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity, Toxicity, Biomarkers, and Future Development of CTLA-4 Checkpoint Antagonists. Callahan, MK., Wolchok, JD.[2017]

Ipilimumab, an anti-CTLA-4 antibody, and nivolumab/pembrolizumab, anti-PD-1 antibodies, are FDA-approved treatments that enhance the immune system's ability to fight various cancers, particularly melanoma.

While these immune checkpoint inhibitors are effective, they can cause immune-related adverse events (irAEs) affecting multiple organ systems, which can be managed with temporary immunosuppression using corticosteroids and other agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing immune checkpoint-blocking antibody side effects. Postow, MA.[2022]

A new mouse model with a humanized Ctla4 gene shows that while the anti-CTLA-4 drug Ipilimumab can cause severe immune-related adverse events (irAE), another monoclonal antibody, L3D10, can achieve similar cancer immunotherapy effects with much milder side effects.

The study found that severe irAE requires complete engagement of the CTLA-4 gene, while effective cancer treatment can occur with partial engagement, suggesting that targeting CTLA-4 can be optimized to improve safety without sacrificing efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Du, X., Liu, M., Su, J., et al.[2023]

The study identifies that the effectiveness and safety of anti-4-1BB monoclonal antibody agonists (mAb-AG) are influenced by their isotype and intrinsic agonistic strength, which can lead to either robust anti-tumor activity or severe liver toxicity.

The newly developed LVGN6051 mAb-AG demonstrates high anti-tumor efficacy without causing liver toxicity in mouse models, suggesting a promising approach for improving cancer immunotherapy by balancing agonistic activity and FcγR interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. Qi, X., Li, F., Wu, Y., et al.[2021]

Ipilimumab, a monoclonal antibody targeting CTLA-4, requires an Fc domain to effectively enhance antitumor responses, as shown by the development of the high-affinity alpaca antibody fragment H11, which lacks this domain and has minimal antitumor effects.

The study revealed that while H11 can visualize CTLA-4 expression in tumors, its blockade alone does not significantly impact antitumor activity, highlighting the importance of Fc-dependent functions in the efficacy of CTLA-4-targeting therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CTLA-4 therapy requires an Fc domain for efficacy. Ingram, JR., Blomberg, OS., Rashidian, M., et al.[2018]

Zimberelimab (GLS-010) is a highly effective human monoclonal antibody that binds strongly to the PD-1 receptor, blocking its interaction with PD-L1/2, which is crucial for T cell activation.

In preclinical studies, GLS-010 demonstrated significant anti-tumor effects in mice, indicating its potential as a promising treatment for cancer, warranting further investigation in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. Lou, B., Wei, H., Yang, F., et al.[2022]

The anti-ICOS antibody feladilimab has shown promise in stimulating T-cell activation and inducing antitumor activity in both nonclinical models and early-phase clinical trials involving patients with advanced solid tumors.

Preliminary results indicate that feladilimab, when used alone or in combination with the PD-1 inhibitor pembrolizumab, may provide clinical benefits, although further studies are needed to confirm its efficacy and identify the best patient populations for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade. Yadavilli, S., Waight, JD., Brett, S., et al.[2023]

Local administration of CTLA-4 blocking antibodies using a slow-release formulation near tumors allows for an eight-fold lower dose to effectively induce tumor eradication compared to systemic delivery.

This method significantly reduces serum antibody levels, which decreases the risk of autoimmune and inflammatory side effects commonly associated with CTLA-4 blockade, while still activating tumor-specific CD8(+) T cells for an effective antitumor response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects. Fransen, MF., van der Sluis, TC., Ossendorp, F., et al.[2022]

Blocking CTLA-4 with anti-CTLA-4 monoclonal antibodies enhances T-cell activation, leading to a stronger immune response against tumors, particularly in metastatic melanoma.

Preliminary studies show that anti-CTLA-4 mAbs are effective and well-tolerated in cancer treatment, with ongoing trials exploring their use in various cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4: negative regulator of the immune response and a target for cancer therapy. Keilholz, U.[2022]

Citations

1. investor.agenusbio.com investor.agenusbio.com/news/news-details/2025/Agenus-Reports-39-of-Patients-Alive-at-Two-Years-with-BOTBAL-Across-Multiple-Refractory-Solid-Tumors-at-ESMO-2025/default.aspx

Agenus Reports 39% of Patients Alive at Two-Years with ... Agenus Reports 39% of Patients Alive at Two-Years with BOT/BAL Across Multiple Refractory Solid Tumors at ESMO 2025 · Cervical cancer: Results ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05529316

NCT05529316 | A Study of Botensilimab (AGEN1181) for ... This study is an open-label, 2-part, Phase 2, multicenter study to evaluate the efficacy, safety, tolerability, and pharmacokinetic profiles of botensilimab

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11609826/

Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is ... Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy.

4. 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 ...

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

Preliminary results from a randomized, open-label, phase 2 ... Preliminary results from a randomized, open-label, phase 2 study of botensilimab (BOT) with or without balstilimab (BAL) in refractory ...