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

Recruiting in Palo Alto (17 mi)

+19 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: Agenus Inc.

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing two new drugs that help the immune system fight cancer. It targets adults with advanced cancers that haven't responded to other treatments. The drugs work by blocking proteins that usually prevent the immune system from attacking cancer cells.

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.

What data supports the idea that Fc-Engineered Anti-CTLA-4 Monoclonal Antibody for Advanced Cancer (also known as: Botensilimab, AGEN1181) is an effective treatment?

The available research shows that blocking CTLA-4, a protein that stops the immune system from attacking cancer cells, can help the immune system fight cancer more effectively. Studies on similar treatments have shown that they can shrink tumors in some patients with melanoma, a type of skin cancer. These treatments have been found to work well and are generally safe for patients with advanced cancer. This suggests that Botensilimab, which also targets CTLA-4, could be effective in treating advanced cancer by boosting the body's immune response against tumors. ^{1 2 3 4 5}

What safety data exists for Fc-Engineered Anti-CTLA-4 Monoclonal Antibody (Botensilimab, AGEN1181)?

The safety data for anti-CTLA-4 monoclonal antibodies, such as Botensilimab (AGEN1181), indicates that these treatments can cause immune-related adverse events (irAEs) affecting various organ systems. These side effects are similar to those observed with other CTLA-4 targeting antibodies like Ipilimumab, which can cause severe irAEs, especially when combined with anti-PD-1 antibodies. Strategies to manage these side effects include temporary immunosuppression with corticosteroids and other agents. Research suggests that complete CTLA-4 occupation and systemic T cell activation are linked to irAEs, but not necessary for tumor rejection, indicating potential for developing safer CTLA-4-targeting therapies. ^{1 3 6 7 8}

Is the drug Botensilimab a promising treatment for advanced cancer?

Yes, Botensilimab is a promising treatment for advanced cancer because it is an Fc-engineered anti-CTLA-4 monoclonal antibody. This type of drug can help the immune system recognize and fight cancer cells by blocking certain molecules that usually stop the immune system from attacking tumors. This approach has shown potential in boosting the body's natural defenses against cancer. ^{1 4 9 10 11}

Research Team

Medical Director

Principal Investigator

Agenus Inc.

Eligibility Criteria

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.

Treatment Details

Interventions

• Botensilimab (Monoclonal Antibodies)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

Agenus Inc.

Lead Sponsor

Trials

58

Recruited

4,900+

Findings from Research

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]

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]

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]

References

1. United States 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. [2022]

2. England 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. [2021]

3. United States 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. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. [2022]

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

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

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

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

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

Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. [2021]

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

Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. [2023]

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

Anti-CTLA-4 therapy requires an Fc domain for efficacy. [2018]

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

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

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

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade. [2023]