Clinical Trials /

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

NCT03860272

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Fc-Engineered Anti-CTLA-4 Monoclonal Antibody in Advanced Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: C-800-01
  • NCT ID: NCT03860272

Conditions

  • Advanced Cancer

Interventions

DrugSynonymsArms
AGEN1181Anti-CTLA-43-Week Monotherapy
AGEN1181Anti-CTLA-46-Week Monotherapy
AGEN2034Anti-PD-16-Week Combination Therapy

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
3-Week MonotherapyExperimentalExperimental: 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.
  • AGEN1181
6-Week MonotherapyExperimental3+3 Dose escalation of AGEN1181, every 6 weeks, starting at dose level 1 mg/kg up to 4 mg/kg administered by IV.
  • AGEN1181
6-Week Combination TherapyExperimental3+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.
  • AGEN1181
  • AGEN2034

Eligibility Criteria

        Inclusion Criteria:

        For inclusion in the trial, all of the following inclusion criteria must be fulfilled, as
        no waivers will be permitted:

          1. Voluntarily agree to participate by giving written informed consent. Participation in
             pharmacogenomics 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 RECIST 1.1.

          5. Life expectancy of ≥3 months and ECOG performance status of 0 or 1.

          6. Adequate organ function, as indicated by the following laboratory values:

               1. Adequate hematological function, defined as absolute neutrophil count (ANC) ≥
                  1500/ µL, platelet count ≥ 100,000/µL, and hemoglobin ≥ 8 g/dL without recent
                  transfusion (defined as a transfusion that has occurred within 2 weeks of the
                  hemoglobin measurement).

               2. Adequate hepatic function, defined as total bilirubin level ≤ 1.5 x institutional
                  upper limit of normal (IULN), aspartate aminotransferase (AST) ≤ 2.5 x IULN, and
                  alanine aminotransferase (ALT) ≤ 2.5 x IULN.

               3. Adequate renal function defined as creatinine ≤ 1.5 x 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 x IULN and activated partial thromboplastin time (aPTT) ≤
                  1.5 x IULN (unless subject receiving anticoagulant therapy).

          7. No history of prior or concomitant malignancy, with the exception of resected basal
             cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the
             skin, and in situ cervical cancer or other malignancies that have undergone
             potentially curative therapy with no evidence of disease recurrence for 5 years since
             initiation of that therapy.

          8. Subjects 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.

          9. Female subjects 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 subjects of childbearing potential must be willing to use highly effective
             contraceptive measures starting with the screening visit through 120 days after last
             dose of study treatment.

             Note: Abstinence is acceptable if this is the established and preferred contraception
             for the subject.

         11. Male subjects 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 120 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 subject.

         12. Willing and able to comply with the requirements of the protocol.

        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, or major surgery
             within 3 weeks prior to first dose of study drug. A 1-week washout is permitted for
             palliative radiation to non-CNS disease, with sponsor approval.

          3. Received prior therapy with an anti-CTLA-4 antibody or drug.

          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 is 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 monoclonal antibodies, antibody,
             or severe reaction to immuno-oncology agents, such as colitis or pneumonitis requiring
             treatment with steroids; or current or history of interstitial lung disease,
             anaphylaxis, uncontrolled asthma (i.e., ≥3 features of partly controlled asthma), or
             pneumonitis that has required oral or IV corticosteroids.

          7. Receiving systemic corticosteroid therapy 1 week prior to the first dose of study drug
             or receiving any other form of systemic immunosuppressive medication. Corticosteroid
             use as a premedication for IV contrast allergies/reactions is allowed. Subjects 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.

          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: Subjects 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 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: Subjects with diabetes type 1, vitiligo, psoriasis, or hypo- or hyperthyroid
             disease not requiring immunosuppressive treatment are eligible.

         10. Has had an allogeneic tissue/solid organ transplant.

         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 (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, or laboratory abnormality that
             might confound the results of the trial, interfere with the subject's participation
             for the full duration of the trial, or is not in the best interest of the subject 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Adverse Events (AEs)
Time Frame:Screening through 90 days following last study dose
Safety Issue:
Description:AEs, including AESIs, irAE, ADRs, according to NCI CTCAE Version 5.0

Secondary Outcome Measures

Measure:Response rate according to RECIST 1.1 (ORR)
Time Frame:Evaluated throughout the protocol, up to 2 years
Safety Issue:
Description:Confirmed objective response rate (ORR) in analysis population
Measure:Response rate according to RECIST 1.1 (DOR)
Time Frame:First observation of documented DP (or death within 12 weeks of last tumor assessment).
Safety Issue:
Description:Duration of Response (DOR)
Measure:Response rate according to RECIST 1.1 (DCR)
Time Frame:First study dose through 24 weeks
Safety Issue:
Description:Disease Control (DCR) including CR, PR and SD for at least 12 weeks
Measure: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)]
Safety Issue:
Description:Progression Free Survival (PFS) time
Measure:Overall survival time (OS)
Time Frame:First study dose through 1 year after discontinuation.
Safety Issue:
Description:Duration of survival
Measure:Maximum drug concentration at steady-state (Cmax-ss)
Time Frame:First study dose (pre-dose) through 3 months following last study dose
Safety Issue:
Description:Serum AGEN1181 concentrations measured throughout the study.
Measure:Minimum drug concentration at steady-state (Cmin-ss)
Time Frame:First study dose (pre-dose) through 3 months following last study dose
Safety Issue:
Description:Serum AGEN1181 concentration measured throughout the study.
Measure: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.
Safety Issue:
Description:Serum AGEN1181 concentrations measured throughout the study.
Measure: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.
Safety Issue:
Description:Serum AGEN1181 concentrations measured throughout the study.
Measure:Terminal disposition rate constant (λz)
Time Frame:First study dose (pre-dose) through 3 months following last study dose.
Safety Issue:
Description:Serum AGEN1181 concentrations measured throughout the study.
Measure:Terminal elimination half-life (t1/2)
Time Frame:First study dose (pre-dose) through 3 months following last study dose
Safety Issue:
Description:Serum AGEN1181 concentrations measured throughout the study.
Measure:Systemic clearance (CL)
Time Frame:First study dose (pre-dose) through 3 months following last study dose
Safety Issue:
Description:Serum AGEN1181 concentrations measured throughout the study.
Measure:Volume of distribution (Vd)
Time Frame:First study dose (pre-dose) through 3 months following last study dose
Safety Issue:
Description:Serum AGEN1181 concentrations measured throughout the study.
Measure:Anti-drug antibody (ADA)
Time Frame:First study dose (pre-dose) through 3 months following last study dose
Safety Issue:
Description:Serum AGEN1181 ADA measured throughout the study.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Agenus Inc.

Trial Keywords

  • Solid Tumors
  • Advanced Cancer
  • Open-Label
  • Dose Escalation
  • Monotherapy
  • Combination Therapy
  • Anti-CTLA-4
  • Anti-PD-1

Last Updated

January 22, 2020