This study is an open-label, Phase 1, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) profiles of a novel fragment crystallizable (Fc)-engineered immunoglobulin G1 anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) human monoclonal antibody (botensilimab) monotherapy and in combination with an anti-programmed cell death protein-1 (PD-1) antibody (balstilimab), and to assess the maximum tolerated dose (MTD) in participants with advanced solid tumors. This study will also determine the recommended phase 2 dose (RP2D) of botensilimab monotherapy and in combination with balstilimab.



Eligible Ages
Over 18 Years
Eligible Genders
Accepts Healthy Volunteers

Inclusion Criteria

For inclusion in the trial, all of the following inclusion criteria must be fulfilled, as no waivers will be permitted: 1. Provision of signed and dated written informed consent prior to any study specific procedures. Participation in pharmacogenomics testing is optional. 2. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumor for which no standard therapy is available or standard therapy has failed. 3. Measurable disease on imaging based on RECIST 1.1. 4. Life expectancy of ≥ 3 months and Eastern Cooperative Oncology Group performance status of 0 or 1. 5. Adequate organ and bone marrow reserve function, as indicated by the following laboratory values: 1. Adequate hematological function, defined as absolute neutrophil count ≥ 1.5 × 10^9/liter (L), platelet count ≥ 100 × 10^9/L, and hemoglobin ≥ 8 grams/deciliter without recent transfusion (defined as a transfusion that has occurred within 2 weeks of the hemoglobin measurement). 2. Adequate liver function, defined as total bilirubin level ≤ 1.5 × institutional upper limit of normal (IULN), aspartate aminotransferase ≤ 2.5 × IULN, and alanine aminotransferase ≤ 2.5 × IULN. 3. Adequate renal function defined as creatinine ≤ 1.5 × IULN or measured or calculated creatinine clearance ≥ 40 milliliters/minute per institutional standard. Assessment methods should be recorded. 4. Adequate coagulation, defined as international normalized ratio or prothrombin time ≤ 1.5 × IULN and activated partial thromboplastin time ≤ 1.5 × IULN (unless participant receiving anticoagulant therapy). 6. No history of prior or concomitant malignancy that requires other active treatment. 7. Participants must provide a sufficient and adequate formalin-fixed paraffin embedded tumor tissue sample (fresh biopsy) collected within 28 days before the first dose from a site not previously irradiated and agree to a mandatory on-treatment biopsy if clinically feasible. 8. Female participants of childbearing potential must have a negative serum pregnancy test at screening (within 72 hours of first dose of study medication). Non-childbearing potential is defined as 1 of the following: 1. ≥ 45 years of age and has not had menses for > 1 year. 2. Amenorrheic for > 2 years without a hysterectomy and/or oophorectomy and follicle stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation. 3. Status is post-hysterectomy, -oophorectomy, or -tubal ligation. 9. Female participants of childbearing potential must be willing to use highly effective contraceptive measures starting with the Screening visit through 90 days after last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the participant. 10. Male participants with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the trial starting with the Screening visit through 90 days after the last dose of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner. Note: Abstinence is acceptable if this is the established and preferred contraception method for the participant.

Exclusion Criteria

For inclusion in the trial, participant must meet none of the following exclusion criteria, as no waivers will be permitted: 1. Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 3 weeks of first dose of current study drug. 2. Received prior systemic cytotoxic chemotherapy, biological therapy, radiotherapy, or major surgery within 3 weeks prior to first dose of study drug. A 1-week washout is permitted for palliative radiation to non-central nervous system (CNS) disease, with Sponsor approval. 3. Participants who have received prior CTLA-4 therapy may be enrolled in selected indications upon agreement with the Sponsor. Note: Selected expansion cohorts may accept prior therapy with anti-CTLA-4 antibody or agent. 4. Persistent toxicity of NCI CTCAE version 5.0 Grade > 1 severity that is related to prior therapy. Note: Sensory neuropathy, endocrinopathy requiring hormonal replacement therapy, or alopecia of Grade ≤ 2 are acceptable. 5. Expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent, radiation therapy, and/or surgical resection). 6. Known severe (Grade ≥ 3) hypersensitivity reactions to fully human monoclonal antibodies, antibody, or severe reaction to immuno-oncology agents, such as colitis or pneumonitis requiring treatment with steroids; or has a history of interstitial lung disease, any history of anaphylaxis, or uncontrolled asthma. 7. Receiving systemic corticosteroid therapy 1 week prior to the first dose of study drug or receiving any other form of systemic immunosuppressive medication. Note: Corticosteroid use as a premedication for IV contrast allergies/reactions is allowed. Participants who are receiving daily corticosteroid replacement therapy are also an exception to this rule. Daily prednisone at doses of ≤ 7.5 mg or equivalent hydrocortisone dose are examples of permitted replacement therapy. Use of inhaled or topical corticosteroids is permitted. 8. CNS tumor, metastasis(es), and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period or identified prior to consent. Note: Participants with history of brain metastases that have been treated may participate provided they show evidence of stable supra-tentorial lesions at screening (defined as 2 brain images, both of which are obtained after treatment to the brain metastases and obtained ≥ 4 weeks apart). Any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved. Any steroids administered as part of this therapy must be completed ≥3 days prior to first dose of study medication. 9. Active or history of autoimmune disease that requires systemic treatment within 2 years of the start of study drug (that is, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Note: Participants with autoimmune conditions requiring hormone replacement therapy or topical treatments are eligible. 10. Has had an allogeneic tissue/solid organ transplant, except for corneal transplants. 11. Active infection requiring treatment. 12. Known history of human immunodeficiency virus type 1 or 2 antibodies. 13. Known active infection with hepatitis B and/or hepatitis C virus. 14. Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication. 15. History or current evidence of any condition, therapy, any active infections, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator. 16. Known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study. 17. Legally incapacitated or has limited legal capacity. 18. Pregnant or breastfeeding. 19. For participants in the colorectal cancer expansion cohort only: current or previous evidence of liver metastases as determined by computed tomography, magnetic resonance imaging, or biopsy.

Study Design

Phase 1
Study Type
Intervention Model
Single Group Assignment
Intervention Model Description
Dose escalation
Primary Purpose
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
3-Week Monotherapy
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.
  • Drug: Botensilimab
    An Fc-engineered anti-CTLA-4 monoclonal antibody
    Other names:
    • AGEN1181
    • Anti-CTLA-4
6-Week Monotherapy
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.
  • Drug: Botensilimab
    An Fc-engineered anti-CTLA-4 monoclonal antibody
    Other names:
    • AGEN1181
    • Anti-CTLA-4
6-Week Combination Therapy
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. 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.
  • Drug: Botensilimab
    An Fc-engineered anti-CTLA-4 monoclonal antibody
    Other names:
    • AGEN1181
    • Anti-CTLA-4
  • Drug: Balstilimab
    A fully human monoclonal anti-PD-1 antibody
    Other names:
    • AGEN2034
    • Anti-PD-1

Recruiting Locations

The University of Texas Health Science Center at San Antonio
San Antonio, Texas 78229
Hope Moreno, RN

More Details

Agenus Inc.

Study Contact

Agenus Inc. Clinical Trial Information

Detailed Description

This Phase 1 study will enroll up to approximately 195 evaluable adult participants with refractory cancer (solid tumors) regardless of diagnosis. The study will consist of a 3+3 dose escalation. Different dose levels of botensilimab, both monotherapy and in combination with balstilimab, will be evaluated in individual cohorts based upon dose. Each participant will remain in the cohort of the dose level and schedule assigned at study entry. Participants can be replaced for any reason other than a dose-limiting toxicity (DLT). Participants will receive treatment for ≤ 2 years or until progressive disease, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal of trial occurs. Additionally, the study is intended to further explore the safety, PK, PD, and clinical activity in selected cancer types at dose levels (botensilimab monotherapy and combination therapy with balstilimab) determined as potentially effective. Indications of interest include, but are not limited to, non-small-cell lung cancer, melanoma, endometrial cancer, ovarian cancer, angiosarcoma, colorectal cancer without liver metastases, and fibrolamellar carcinoma.


Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.