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

NCT03860272 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: C-800-01
• Study Type: interventional
• Target: 499
• Locations: 2 countries
• Sites: 18

Brief Summary

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.

Conditions

Advanced Cancer; Angiosarcoma; Colorectal Cancer Without Liver Metastases; Endometrial Cancer; Fibrolamellar Carcinoma; Non-small-cell Lung Cancer; Ovarian Cancer; Prostate Cancer

Keywords

Solid Tumors; Advanced Cancer; Open-label; Monotherapy; Combination Therapy; Anti-CTLA-4; Anti-PD-1; Immunotherapy

Outcome Measures

Primary Outcomes (3)

• Incidence Of Treatment-emergent Adverse Events (TEAEs)

  TEAEs will include adverse events of special interest, immune-related adverse events, and adverse drug reactions, according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

  First dose through 90 days following last study dose (up to 2 years)

• DLT Of Botensilimab

  DLTs will include any Grade 2 or greater drug related toxicity for all dose groups, according to NCI CTCAE version 5.0 and protocol specifications.

  First 28 days of treatment

• RP2D Of Botensilimab

  MTD based on DLT occurrence at DLT period (28 days after first dose) and all TEAEs seen through 90 days following last study dose.

  First dose through 90 days following last study dose

Secondary Outcomes (18)

• Objective Response Rate (ORR) According To Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)

  First dose through up to 2 years

• ORR According to Prostate Cancer Working Group 3 (PCWG3)

  First dose through up to 2 years

• Duration Of Response (DOR) According To RECIST 1.1

  From first dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 2 years)

• DOR According to PCWG3

  From first dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 2 years)

• Disease Control Rate (DCR) According To RECIST 1.1

  First study dose through 24 weeks

Study Arms (3)

3-Week Monotherapy

EXPERIMENTAL

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

6-Week Monotherapy

EXPERIMENTAL

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

6-Week Combination Therapy

EXPERIMENTAL

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.

Drug: Botensilimab; Drug: Balstilimab

Interventions

Botensilimab DRUG

An Fc-engineered anti-CTLA-4 monoclonal antibody

Also known as: AGEN1181, Anti-CTLA-4

3-Week Monotherapy; 6-Week Combination Therapy; 6-Week Monotherapy

Balstilimab DRUG

A fully human monoclonal anti-PD-1 antibody

Also known as: AGEN2034, Anti-PD-1

6-Week Combination Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated written informed consent prior to any study specific procedures. Participation in pharmacogenomics testing is optional.
• Histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumor for which no standard therapy is available or standard therapy has failed.
• Measurable disease on imaging based on RECIST 1.1, except for prostate cancer.
• Life expectancy of ≥ 3 months and Eastern Cooperative Oncology Group performance status of 0 or 1.
• Adequate organ and bone marrow reserve function, as indicated by the following laboratory values:
• 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).
• Adequate liver function, defined as total bilirubin level ≤ 1.5 × institutional upper limit of normal (IULN) (except for participants with Gilbert syndrome who must have a total bilirubin level of ≤ 3.0 × IULN), aspartate aminotransferase ≤ 2.5 × IULN, and alanine aminotransferase ≤ 2.5 × IULN.
• Adequate renal function defined as creatinine ≤ 1.5 × IULN or measured or calculated creatinine clearance ≥ 40 milliliters (mL)/minute per institutional standard. Assessment methods should be recorded.
• 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) or stable known coagulopathy with sponsor approval.
• A sufficient and adequate formalin-fixed paraffin embedded tumor tissue sample (fresh or archival tumor tissue) collected since last treatment and before the first dose from a site not previously irradiated, if clinically feasible.
• 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:
• ≥ 45 years of age and has not had menses for \> 1 year and there is no alternative medical cause.
• Amenorrheic for \> 2 years without a hysterectomy and/or oophorectomy and follicle stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation.
• Status is post-hysterectomy, -oophorectomy, or -tubal ligation.
• 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. For the UK only, highly effective contraceptive measures are defined as follows:

You may not qualify if:

• 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.
• Received prior systemic cytotoxic chemotherapy, biological therapy, radiotherapy, or major surgery within 3 weeks prior to first dose of study drug; for tyrosine kinase inhibitor or similar within 4 × half-life prior to first dose of study drug. A 1-week washout is permitted for palliative radiation to non-central nervous system disease, with Sponsor approval.
• Participants who have received prior CTLA-4 therapy may be enrolled in selected indications upon agreement with the Sponsor.
• Persistent toxicity of NCI CTCAE version 5.0 Grade \> 1 severity that is related to prior therapy. Note: Sensory neuropathy, hypothyroidism or alopecia of Grade ≤ 2 are acceptable. Other Grade 2 toxicities of prior treatments that are controlled with medication (for example, diabetes or hypertension) may be permitted with sponsor approval.
• 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).
• History of:
• Severe (Grade ≥ 3) hypersensitivity reaction to a fully human monoclonal antibodies
• Immune-related adverse event requiring treatment with systemic steroids for \> 7 days excluding Grade 1 or 2 rash.
• Interstitial lung disease or lung disease which may interfere with the assessment of pneumonitis.
• Uncontrolled asthma (that is, ≥ 3 features of partly controlled asthma)
• Pneumonitis that has required oral or IV corticosteroids.
• 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.
• Brain metastases or leptomeningeal metastases with the following exceptions: Note: Brain metastases which have been treated with either surgical resection or stereotactic radio surgery. These participants must be off steroids ≥ 10 days prior to enrollment for the purpose of managing their brain metastases. Repeat brain imaging following surgical resection or stereotactic radiosurgery is not required if their last brain magnetic resonance imaging is within screening window. Note: Untreated isolated brain metastases that are too small for treatment by surgical resection or stereotactic radiosurgery (that is, 1-2 mm) and/or of uncertain etiology are potentially eligible but must be approved by the sponsor.
• 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.
• Has had an allogeneic tissue/solid organ transplant, except for corneal transplants.

Sponsors & Collaborators

• Agenus Inc.: lead

Study Sites (18)

HonorHealth Research Institute

Scottsdale, Arizona, 85258, United States

Location

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

The Angeles Clinic & Research Institute, a Cedars-Sinai Affiliate

Los Angeles, California, 90025, United States

Location

University of Southern California Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

UCLA Santa Monica Hematology Oncology

Los Angeles, California, 90095, United States

Location

Saint John's Cancer Institute

Santa Monica, California, 90404, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

University of Miami Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Providence Portland Cancer Center

Portland, Oregon, 97213, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Royal Marsden Hospital NHS Foundation Trust

London, SW3 6JJ, United Kingdom

Location

Related Publications (3)

• Bengala E, Santini D, Picone V. Refractory microsatellite-stable metastatic colorectal cancer: a comparison between botensilimab + balstilimab and current standard of care. Immunooncol Technol. 2025 Nov 28;29:101558. doi: 10.1016/j.iotech.2025.101558. eCollection 2026 Mar.

  PMID: 41502912 DERIVED

• Wilky BA, Schwartz GK, Gordon MS, El-Khoueiry AB, Bullock AJ, Henick B, Agulnik M, Singh A, Mahadevan D, Stebbing J, Delepine C, Chand D, Avagyan M, Wu W, Johnson B, Grossman JE, O'Day S, Trent JC, Jones RL, Tsimberidou AM. Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas. J Clin Oncol. 2025 Apr 10;43(11):1358-1368. doi: 10.1200/JCO-24-02524. Epub 2025 Jan 27.

  PMID: 39869830 DERIVED

• Bullock AJ, Schlechter BL, Fakih MG, Tsimberidou AM, Grossman JE, Gordon MS, Wilky BA, Pimentel A, Mahadevan D, Balmanoukian AS, Sanborn RE, Schwartz GK, Abou-Alfa GK, Segal NH, Bockorny B, Moser JC, Sharma S, Patel JM, Wu W, Chand D, Rosenthal K, Mednick G, Delepine C, Curiel TJ, Stebbing J, Lenz HJ, O'Day SJ, El-Khoueiry AB. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med. 2024 Sep;30(9):2558-2567. doi: 10.1038/s41591-024-03083-7. Epub 2024 Jun 13.

  PMID: 38871975 DERIVED

MeSH Terms

Conditions

Hemangiosarcoma; Endometrial Neoplasms; Fibrolamellar hepatocellular carcinoma; Carcinoma, Non-Small-Cell Lung; Ovarian Neoplasms; Prostatic Neoplasms

Interventions

Ipilimumab; balstilimab; spartalizumab

Condition Hierarchy (Ancestors)

Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Vascular Tissue; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Endocrine System Diseases; Gonadal Disorders; Genital Neoplasms, Male; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Medical Director

  Agenus Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Dose escalation

Study Record Dates

• First Submitted: February 12, 2019
• First Posted: March 1, 2019
• Study Start: March 20, 2019
• Primary Completion: January 13, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1); US (17)