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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 : September 23, 2020
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, PK, and PD profiles of a novel Fc-engineered IgG1 anti-CTLA-4 human monoclonal antibody (AGEN1181) monotherapy and in combination with a human monoclonal IgG4 antibody (AGEN2034), and to assess the maximum tolerated dose (MTD) in subjects with advanced solid tumors. This study will also determine the RP2D of AGEN1181 monotherapy and in combination with AGEN2034.

Condition or disease Intervention/treatment Phase
Advanced Cancer Drug: AGEN1181 Drug: AGEN2034 Phase 1

Detailed Description:

This Phase 1 study will enroll up to approximately 86 evaluable adult subjects with refractory cancer (solid tumors) regardless of diagnosis. Subjects may be enrolled into the following cohorts:

Cohort 1: AGEN1181 every 3 weeks at 0.1, 0.3, 1, 2, and 4 mg/kg Cohort 2: AGEN1181 every 6 weeks at 1, 2, and 3 mg/kg Cohort 3: AGEN2034 every 2 weeks at 3 mgkg + AGEN1181 every 6 weeks at 0.1, 0.3, 1, 2, and 4 mg/kg.

The trial will consist of a 3+3 dose escalation that will evaluate different dose levels of AGEN1181 monotherapy and in combination with AGEN2034. Each subject will stay on the dose level an schedule assigned at trial entry. Subjects can be replaced for any reason other than a DLT. Subjects will receive treatment for ≤ 2 years or until PD, 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, pharmacodynamics, and clinical activity in selected cancer types at dose levels (AGEN1181 monotherapy and combination therapy with AGEN2034) determined as potentially effective. Indications of interest include, but are not to limited to Non-Small-Cell Lung Cancer (NSCLC) refractory to prior PD-1/PD-L1 inhibitor treatment, melanoma refractory to prior PD-1/PD-L1 inhibitor treatment, hepatocellular carcinoma (HCC), endometrial cancer, and angiosarcoma.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 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, an Anti-PD-1 Monoclonal Antibody, in Subjects With Advanced Cancer
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Arm Intervention/treatment
Experimental: 3-Week Monotherapy
Experimental: Open Label 3+3 Dose escalation of AGEN1181, every 3 weeks, starting at dose level 0.1 mg/kg up to 4 mg/kg administered by IV.
Drug: AGEN1181
An Fc-Engineered Anti-CTLA-4 Monoclonal Antibody
Other Name: Anti-CTLA-4

Experimental: 6-Week Monotherapy
3+3 Dose escalation of AGEN1181, every 6 weeks, starting at dose level 1 mg/kg up to 4 mg/kg administered by IV.
Drug: AGEN1181
An Fc-Engineered Anti-CTLA-4 Monoclonal Antibody
Other Name: Anti-CTLA-4

Experimental: 6-Week Combination Therapy
3+3 Dose escalation of AGEN2034, every 3 weeks, at dose level 3 mg/kg in combination with AGEN1181, every 6 weeks, starting at dose level 0.1 mg/kg up to 4 mg/kg administered by IV.
Drug: AGEN1181
An Fc-Engineered Anti-CTLA-4 Monoclonal Antibody
Other Name: Anti-CTLA-4

Drug: AGEN2034
A fully human monoclonal Anti-PD-1 Antibody
Other Name: Anti-PD-1




Primary Outcome Measures :
  1. Incidence of Adverse Events (AEs) [ Time Frame: Screening through 90 days following last study dose ]
    AEs, including AESIs, irAE, ADRs, according to NCI CTCAE Version 5.0

  2. Dose Limiting Toxicity (DLT) [ Time Frame: First 28 days of treatment ]
    Any Grade 2 or greater drug related toxicity for all dose groups, according to NCI CTCAE version 5.0 with described protocol exceptions.

  3. Recommended Phase 2 Dose (RP2D) [ Time Frame: First dose through 90 days following last study dose ]
    Maximum Tolerated Dose (MTD) based on DLT occurrence at DLT period (28 days after first dose) and all AEs seen through 90 days following last study dose.


Secondary Outcome Measures :
  1. Response rate according to RECIST 1.1 (ORR) [ Time Frame: Evaluated throughout the protocol, up to 2 years ]
    Confirmed objective response rate (ORR) in analysis population

  2. Response rate according to RECIST 1.1 (DOR) [ Time Frame: First observation of documented DP (or death within 12 weeks of last tumor assessment). ]
    Duration of Response (DOR)

  3. Response rate according to RECIST 1.1 (DCR) [ Time Frame: First study dose through 24 weeks ]
    Disease Control (DCR) including CR, PR and SD for at least 12 weeks

  4. Response rate according to RECIST 1.1 (PFS) [ Time Frame: First study dose to first observation of documented disease progression (or death within 12 weeks of last tumor assessment)] ]
    Progression Free Survival (PFS) time

  5. Overall survival time (OS) [ Time Frame: First study dose through 1 year after discontinuation. ]
    Duration of survival

  6. Maximum drug concentration at steady-state (Cmax-ss) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose ]
    Serum AGEN1181 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 ]
    Serum AGEN1181 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. ]
    Serum AGEN1181 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. ]
    Serum AGEN1181 concentrations measured throughout the study.

  10. Terminal disposition rate constant (λz) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose. ]
    Serum AGEN1181 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 ]
    Serum AGEN1181 concentrations measured throughout the study.

  12. Systemic clearance (CL) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose ]
    Serum AGEN1181 concentrations measured throughout the study.

  13. Volume of distribution (Vd) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose ]
    Serum AGEN1181 concentrations measured throughout the study.

  14. Anti-drug antibody (ADA) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose ]
    Serum AGEN1181 ADA 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 (PGx) testing is optional.
  2. ≥ 18 years of age.
  3. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumor for which no standard therapy is available or standard therapy has failed.
  4. Measurable disease on imaging based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
  5. Life expectancy of ≥ 3 months and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  6. Adequate organ and bone marrow reserve function, as indicated by the following laboratory values:

    1. Adequate hematological function, defined as absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 8 g/dL 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 (AST) ≤ 2.5 × IULN, and alanine aminotransferase (ALT) ≤ 2.5 × IULN.
    3. Adequate renal function defined as creatinine ≤ 1.5 × IULN OR measured or calculated creatinine clearance ≥ 40 mL/min per institutional standard. Assessment methods should be recorded.
    4. Adequate coagulation, defined as international normalized ratio (INR) or prothrombin time ≤ 1.5 × IULN and activated partial thromboplastin time (aPTT) ≤ 1.5 × IULN (unless patient receiving anticoagulant therapy).
  7. No history of prior or concomitant malignancy that requires other active treatment.
  8. Patients must provide a sufficient and adequate formalin-fixed paraffin embedded (FFPE) 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
  9. Female patients 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.
  10. Female patients 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 patient.
  11. Male patients 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 patient

Exclusion Criteria:

For inclusion in the trial, subject 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. Patients 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 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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.

    Patients 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: Patients 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). In C-800-01 Agenus, Inc. Protocol Amendment 4 22 July 2020 Confidential Page 15 of 124 addition, 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 trial medication.
  9. Active or history of autoimmune disease that requires systemic treatment within 2 years of the start of study drug (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Note: Patients 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 (HIV) type 1 or 2 antibodies.
  13. Known active infection with hepatitis B and/or hepatitis C virus.
  14. Clinically significant (i.e., 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 patient's participation for the full duration of the trial, or is not in the best interest of the patient 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 trial.
  17. Legally incapacitated or has limited legal capacity.
  18. Pregnant or breastfeeding.

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: Joyce Schaffer    480-323-1364    clinicaltrials@honorhealth.com   
Principal Investigator: Michael Gordon, MD         
United States, California
University of Southern California Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Xiomara Menendez    323-409-4368    Xiomara.Menendez@med.usc.edu   
Contact: Lorraine Martinez    323-865-0458    Lorraine.Martinez@med.usc.edu   
Principal Investigator: Anthony El-Khoueiry, MD         
John Wayne Cancer Institute Recruiting
Santa Monica, California, United States, 90404
Contact: Aleksandra Dubinchik    310-582-7455    aleksandra.dubinchik@providence.org   
Principal Investigator: Steven O'Day, MD         
United States, Colorado
University of Colorado Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Dr. Breelyn Wilky, MD    303-724-6429    breelyn.wilky@cuanschutz.edu   
Principal Investigator: Breelyn Wilky, MD         
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center Not yet recruiting
Miami, Florida, United States, 33136
Contact: Dr. Jonathan Trent, MD    305-243-5302    JTrent@med.miami.edu   
Principal Investigator: Jonathan Trent, MD         
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Susan Gotthardt, RN    617-975-7452    sgotthar@bidmc.harvard.edu   
Principal Investigator: Andrea Bullock, MD         
United States, Texas
MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Dr. Apostolia Tsimberidou, MD    713-792-4259    atsimber@mdanderson.org   
Principal Investigator: Apostolia Tsimberidou, MD         
The University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Goodwine Epp    210-450-5798    GOODWINE@uthscsa.edu   
Principal Investigator: Chethan Ramamurthy, 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: September 23, 2020
Last Verified: September 2020
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
Additional relevant MeSH terms:
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Neoplasms