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

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ClinicalTrials.gov Identifier: NCT03860272
Recruitment Status : Recruiting
First Posted : March 1, 2019
Last Update Posted : February 21, 2021
Sponsor:
Information provided by (Responsible Party):
Agenus Inc.

Tracking Information
First Submitted Date  ICMJE February 12, 2019
First Posted Date  ICMJE March 1, 2019
Last Update Posted Date February 21, 2021
Actual Study Start Date  ICMJE April 1, 2019
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 17, 2019)
  • 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
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • Incidence of Adverse Events according to NCI CTCAE version 5.0 [ Time Frame: Screening to 30 days from last dose. ]
    AEs, including AESIs, irAE, ADRs, according to NCI CTCAE Version 5.0
  • Dose Limiting Toxicity [ Time Frame: First 28 days of treatment ]
    Any Grade 3 or greater drug related toxicity for all dose groups, according to NCI CTCAE version 5.0 with described protocol exceptions.
  • Recommended Phase II Dose (RP2D) [ Time Frame: First dose to 30 days from last dose. ]
    Maximum Tolerated Dose (MTD) based on DLT occurrence at DLT period and all AEs seen during safety period.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 17, 2019)
  • 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
  • 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)
  • 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
  • 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
  • Overall survival time (OS) [ Time Frame: First study dose through 1 year after discontinuation. ]
    Duration of survival
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Systemic clearance (CL) [ Time Frame: First study dose (pre-dose) through 3 months following last study dose ]
    Serum AGEN1181 concentrations measured throughout the study.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • Response rate according to RECIST 1.1 [ Time Frame: 12 Weeks from first dose. ]
    Unconfirmed response
  • Response rate according to RECIST 1.1 [ Time Frame: Evaluated throughout the protocol up to 2 years. ]
    Confirmed Best Overall Response (BOR) in analysis population.
  • Response rate according to RECIST 1.1 [ Time Frame: First observation of documented DP (or death within 12 weeks of last tumor assessment). ]
    Duration of Response (DOR)
  • Response rate according to RECIST 1.1 [ Time Frame: 24 Weeks of first dose. ]
    Stable Disease (SD) and duration of SD and Disease Control (DCR)
  • Response rate according to RECIST 1.1 [ Time Frame: First treatment administration to first observation of documented disease progression (or death within 12 weeks of last tumor assessment). ]
    Progression Free Survival (PFS) time.
  • Overall survival time [ Time Frame: Up to 1 year after discontinuation. ]
    Duration of survival
  • Maximum observed concentration at steady-state (Cmax-ss) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Minimum observed concentration at steady-state (Cmin-ss) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Area under the concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Area under the concentration-time curve from time zero to infinity (AUC(0-∞) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Time to maximum observed concentration (tmax) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Terminal disposition rate constant (λz) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Terminal elimination half-life (t1/2) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Systemic clearance (CL) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Volume of distribution (Vd) [ Time Frame: Pre-dose through 3 months after last dose. ]
    AGEN1181 blood levels measured throughout the study.
  • Evaluate the immunogenicity of AGEN1181 as monotherapy [ Time Frame: Pre-dose through 3 months after last dose ]
    Anti Drug Antibody (ADA) measurements throughout the study.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Fc-Engineered Anti-CTLA-4 Monoclonal Antibody in Advanced Cancer
Official Title  ICMJE A Phase 1/2 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
Brief Summary This study is an open-label, Phase 1/2, 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.
Detailed Description

This Phase 1/2 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:
Dose escalation
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Cancer
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Intervention: Drug: AGEN1181
  • 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.
    Intervention: Drug: AGEN1181
  • 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.
    Interventions:
    • Drug: AGEN1181
    • Drug: AGEN2034
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 17, 2019)
86
Original Estimated Enrollment  ICMJE
 (submitted: February 28, 2019)
36
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Agenus Inc. Clinical Trial Information 781-674-4265 clinicaltrialinfo@Agenusbio.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03860272
Other Study ID Numbers  ICMJE C-800-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Agenus Inc.
Study Sponsor  ICMJE Agenus Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Agenus Inc.
PRS Account Agenus Inc.
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP