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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03860272
Recruitment Status : Recruiting
First Posted : March 1, 2019
Last Update Posted : May 4, 2022
Sponsor:
Information provided by (Responsible Party):
Agenus Inc.

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 a human monoclonal immunoglobulin G4 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.

Condition or disease Intervention/treatment Phase
Advanced Cancer Drug: Botensilimab Drug: Balstilimab Phase 1

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, hepatocellular carcinoma, endometrial cancer, ovarian cancer, angiosarcoma, colorectal cancer without liver metastases, pancreatic cancer, and fibrolamellar carcinoma.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 195 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: Dose escalation
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of AGEN1181, an Fc-Engineered Anti-CTLA-4 Monoclonal Antibody as Monotherapy and in Combination With AGEN2034 (Balstilimab), an Anti-PD-1 Monoclonal Antibody, in Subjects With Advanced Cancer
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024

Arm Intervention/treatment
Experimental: 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

Experimental: 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

Experimental: 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-programmed cell death protein-1 (PD-1) antibody
Other Names:
  • AGEN2034
  • Anti-PD-1




Primary Outcome Measures :
  1. Incidence Of Treatment-emergent Adverse Events (TEAEs) [ Time Frame: First dose through 90 days following last study dose (up to 2 years) ]
    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.

  2. DLT Of Botensilimab [ Time Frame: First 28 days of treatment ]
    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.

  3. RP2D Of Botensilimab [ Time Frame: First dose through 90 days following last study dose ]
    MTD based on DLT occurrence at DLT period (28 days after first dose) and all TEAEs seen through 90 days following last study dose.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) According To Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: First dose through up to 2 years ]
    Confirmed ORR will be in the analysis population.

  2. Duration Of Response (DOR) According To RECIST 1.1 [ Time Frame: From first dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 2 years) ]
  3. Disease Control Rate (DCR) According To RECIST 1.1 [ Time Frame: First study dose through 24 weeks ]
    DCR will include complete response, partial response, and stable disease for at least 12 weeks.

  4. Progression-free Survival (PFS) According To RECIST 1.1 [ Time Frame: First study dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment) (up to 2 years) ]
    PFS time will be assessed.

  5. Overall Survival Time [ Time Frame: First study dose through up to 3 years ]
    Duration of survival will be assessed.

  6. Maximum Drug Concentration At Steady-state (Cmax-ss) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab concentrations measured throughout the study

  7. Minimum Drug Concentration At Steady-state (Cmin-ss) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab concentration measured throughout the study

  8. Area Under The Drug Concentration-time Curve Within Time Span t1 To t2 At Steady-state (AUC(t1-t2)-ss) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab concentrations measured throughout the study

  9. Area Under The Drug Concentration-time Curve From Time Zero To Infinity [AUC(0-∞)] [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab concentrations measured throughout the study

  10. Terminal Elimination Rate Constant (λz) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab concentrations measured throughout the study

  11. Terminal Elimination Half-life (t1/2) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab concentrations measured throughout the study

  12. Systemic Clearance (CL) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab concentrations measured throughout the study

  13. Volume Of Distribution (Vd) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab concentrations measured throughout the study

  14. Anti-drug Antibodies (ADAs) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose (up to 2 years) ]
    Serum botensilimab ADAs measured throughout the study



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03860272


Contacts
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Contact: Agenus Inc. Clinical Trial Information 781-674-4265 clinicaltrialinfo@Agenusbio.com

Locations
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United States, Arizona
HonorHealth Research Institute Recruiting
Scottsdale, Arizona, United States, 85258
Contact: Paul Hoffmeister    480-323-1285    phoffmeister@honorhealth.com   
Principal Investigator: Michael Gordon, MD         
United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Erin Morones       emorones@coh.org   
Principal Investigator: Marwan G Fakih, MD         
The Angeles Clinic & Research Institute, a Cedars-Sinai Affiliate Recruiting
Los Angeles, California, United States, 90025
Contact: Candice Benhamou    310-582-7906    CBenhamou@theangelesclinic.org   
Principal Investigator: Ani Balmanoukian, MD         
University of Southern California Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Arthur Alvarez    323-409-4365    arthur.alvarez@med.usc.edu   
Principal Investigator: Anthony El-Khoueiry, MD         
Saint John's Cancer Institute Recruiting
Santa Monica, California, United States, 90404
Contact: Irving Ledesma    310-582-7047    irving.ledesmaprado@providence.org   
Principal Investigator: Kim Margolin, MD         
United States, Colorado
University of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Meghan Ayers    720-848-5278    meghan.ayers@cuanschutz.edu   
Principal Investigator: Breelyn Wilky, MD         
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Nailet Real Bestard       nxr518@med.miami.edu   
Principal Investigator: Jonathan Trent, MD         
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Eileen Kim       nkim10@bidmc.harvard.edu   
Principal Investigator: Andrea Bullock, MD         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Benjamin Schlechter, MD       Benjamin_Schlechter@dfci.harvard.edu   
Principal Investigator: Benjamin Schlechter, MD         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Samantha Petruzzelli       sp40992@cumc.columbia.edu   
Principal Investigator: Gary K Schwartz, MD         
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Amin Yaqubie    212-639-2000    yaqubiea@mskcc.org   
Contact: Olivia Heffernan    212-639-2000    hefferno@mskcc.org   
Principal Investigator: Ghassan Khaled Abou-Alfa, MD         
United States, Ohio
Ohio State University Withdrawn
Columbus, Ohio, United States, 43210
United States, Oregon
Providence Portland Cancer Center Recruiting
Portland, Oregon, United States, 97213
Principal Investigator: Rachel E Sanborn, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Becky Norris       bnorris@mdanderson.org   
Principal Investigator: Apostolia Tsimberidou, MD, PhD         
The University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Hope Moreno, RN       MorenoH@uthscsa.edu   
Principal Investigator: Mahadevan Daruka, MD         
Sponsors and Collaborators
Agenus Inc.
Investigators
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Study Director: Medical Director Agenus Inc.
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Responsible Party: Agenus Inc.
ClinicalTrials.gov Identifier: NCT03860272    
Other Study ID Numbers: C-800-01
First Posted: March 1, 2019    Key Record Dates
Last Update Posted: May 4, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Agenus Inc.:
Solid Tumors
Advanced Cancer
Open-label
Dose Escalation
Monotherapy
Combination Therapy
Anti-CTLA-4
Anti-PD-1
Immunotherapy
Additional relevant MeSH terms:
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Neoplasms