Clinical Trials /

AGEN1884, an Anti-CTLA-4 Human Monoclonal Antibody in Subjects With Advanced or Refractory Cancer and Who Have Progressed With PD-1/PD-L1 Inhibitor as Their Most Recent Therapy

NCT02694822

Description:

This is an open-label, Phase 1/2, multicenter study to evaluate the safety, PK, and PD of an anti-CTLA-4 human monoclonal antibody (AGEN1884) in subjects with advanced or refractory cancer and in subjects who have progressed during treatment with a PD-1/PD-L1 inhibitor as their most recent therapy. The phase 1 portion of the study has been completed; It enrolled adult subjects with refractory, advanced cancer in a 3+3 dose escalation cohort. The phase 2 portion consists of up to 60 patients who have progressed during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug).

Related Conditions:
  • Hepatocellular Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: AGEN1884, an Anti-CTLA-4 Human Monoclonal Antibody in Subjects With Advanced or Refractory Cancer and Who Have Progressed With PD-1/PD-L1 Inhibitor as Their Most Recent Therapy
  • Official Title: Phase 1/2, Open-Label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of an Anti-CTLA-4 Human Monoclonal Antibody (AGEN1884) in Subjects With Advanced or Refractory Cancer and in Subjects Who Have Progressed During Treatment With a PD 1/PD-L1 Inhibitor as Their Most Recent Therapy

Clinical Trial IDs

  • ORG STUDY ID: C-500-01
  • NCT ID: NCT02694822

Conditions

  • Advanced Solid Cancers
  • Advanced Solid Cancers Refractory to PD-1

Interventions

DrugSynonymsArms
AGEN1884AGEN1884

Purpose

This is an open-label, Phase 1/2, multicenter study to evaluate the safety, PK, and PD of an anti-CTLA-4 human monoclonal antibody (AGEN1884) in subjects with advanced or refractory cancer and in subjects who have progressed during treatment with a PD-1/PD-L1 inhibitor as their most recent therapy. The phase 1 portion of the study has been completed; It enrolled adult subjects with refractory, advanced cancer in a 3+3 dose escalation cohort. The phase 2 portion consists of up to 60 patients who have progressed during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug).

Trial Arms

NameTypeDescriptionInterventions
AGEN1884Experimentalanti-CTLA-4 antibody
  • AGEN1884

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent.

          2. ≥18 years of age.

          3. Histological or cytological diagnosis of solid cancer or lymphoma that is considered
             incurable and without therapies with established benefit. Biopsy is not necessary for
             subjects with known prior diagnosis, and clinical or radiographic evidence of
             recurrence. For Phase 2 only: Subjects who experienced documented disease progression
             during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their
             most recent therapy (2-6 weeks prior to first dose of study drug). This cohort
             includes subjects with histological diagnoses of HCC (not including atypical histology
             such as cholangiocarcinoma mix or fibrolamellar hepatocellular carcinoma) who
             experienced documented disease progression during treatment with an approved or
             investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to
             first dose of study drug).

          4. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.

          5. Subjects in Phase 2 with HCC should have a Child-Pugh score of A or B7 with no
             encephalopathy or ascites.

          6. Life expectancy ≥12 weeks.

          7. Adequate cardiac function (New York Heart Association [NYHA] class ≤II).

          8. Adequate organ function, defined as absolute neutrophil count (ANC) ≥1,500×106/L,
             absolute lymphocyte count ≥500/mm3, hemoglobin ≥8.0 g/dL, and platelet count
             ≥100,000×106/mm3 without blood growth factors or without transfusions within 1 week of
             first dose.

             For subjects in Phase 2 with HCC: Platelet count ≥60×106/mm3 and ANC ≥1,000×106/L are
             acceptable provided that the principal investigator assesses these abnormalities as
             due to liver disease.

          9. Adequate liver function, defined as AST and ALT ≤2.5× institutional upper limit of
             normal (ULN), and bilirubin ≤1.5 mg/dL × ULN.

             For subjects in Phase 2 with HCC: AST and ALT ≤5 × ULN, bilirubin ≤2 mg/dL × ULN, and
             albumin ≥ 2.8 mg/dL.

         10. Adequate renal function, defined as estimated creatinine clearance ≥50 mL/min
             according to Cockcroft-Gault formula, or measured 24-hour creatinine clearance (or
             local institutional standard method).

         11. Adequate coagulation defined by international normalized ratio (INR) or prothrombin
             time (PT) ≤ 1.5 x ULN (unless the patient is receiving anticoagulant therapy); and
             activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (unless the subject is
             receiving anticoagulant therapy). Subjects in Phase 2 with HCC can have an INR ≤2.3 x
             ULN.

             Note: Subjects in Phase 2 with HCC and on anticoagulant treatment would have an
             assigned value of 1 point when scoring PT/INR so the overall Child-Pugh score is not
             adversely affected.

         12. Female subjects of childbearing potential and fertile male subjects must agree to use
             adequate contraception or abstain from sexual activity from the time of consent
             through 90 days after the end of study drug. Adequate contraception includes condoms
             with contraceptive foam; oral, implantable, or injectable contraceptives;
             contraceptive patch; intrauterine device; diaphragm with spermicidal gel; or a sexual
             partner who is surgically sterilized or postmenopausal. Note: Abstinence is acceptable
             if this is the established and preferred contraception for the subject.

         13. In the expansion phase, all subjects must provide a sufficient and adequate
             formalin-fixed paraffin embedded (FFPE) tumor tissue sample preferably collected after
             progression on the last therapy and/or collected at screening, if clinically feasible.
             If a recent biopsy is not available, an archival FFPE sample should be provided from a
             site not previously irradiated. If no tumor tissue is available, a fresh biopsy will
             be required if clinically feasible.

        Exclusion Criteria

          1. Other malignancies treated within the last 5 years, except in situ cervix carcinoma or
             non-melanoma skin cancer.

          2. Other form(s) of antineoplastic therapy anticipated during the period of the study.

          3. Previous severe hypersensitivity reaction to another fully human monoclonal antibody
             or severe reaction to immuno-oncology agents, such as colitis or pneumonitis requiring
             treatment with steroids.

          4. History of interstitial lung disease.

          5. Primary or secondary immunodeficiency, including immunosuppressive disease, autoimmune
             disease (including autoimmune endocrinopathies), or usage of immunosuppressive
             medications.

             Note: Subjects with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid
             disease not requiring immunosuppressive treatment are eligible. Subjects with Type 2
             diabetes mellitus are allowed.

          6. Subjects with a known history of human immunodeficiency virus 1 and 2, human T
             lymphotropic virus 1.

             Subjects in Phase 2 with HCC: Subjects with active hepatitis B infection who are
             receiving effective antiviral therapy are permitted. Subjects with active hepatitis C
             infection are allowed (antiviral therapy not required).

          7. Administration of anticancer medications or investigational drugs within the following
             intervals before the first administration of study drug: a. ≤14 days for chemotherapy,
             targeted small molecule therapy, or radiation therapy. Subjects must also not have had
             radiation pneumonitis as a result of treatment and cannot participate in the study if
             they are on chronic corticosteroids for radiation pneumonitis. A 1-week washout is
             permitted for palliative radiation to non-central nervous system (CNS) disease, with
             medical monitor approval.

             Note: Bisphosphonates and denosumab are permitted medications. b. ≤14 days for prior
             immunotherapy. Subjects in the dose escalation cohorts are excluded if they have
             received prior checkpoint inhibitors, costimulatory agonists, or immune modulating
             therapy except as described below. Once a dose level is determined to be safe by the
             SRC, subjects will be allowed to enroll in dose-level expansion cohorts if they have
             received other non-CTLA-4 targeting immunotherapies.

             c. Subjects enrolling in Phase 2 must have cancer that has progressed after prior
             treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most
             recent therapy (2-6 weeks prior to first dose of study drug). The minimum requirement
             of 2 weeks (14 days) from prior anti-PD-1/PD-L1 therapy is to allow resolution of any
             lower-grade (≤2) adverse events observed with the therapy. If the investigator feels
             the subject has tolerated prior anti-PD-1/PD-L1 therapy well, then treatment with
             study agent may begin sooner.

             d. ≤7 days for prior corticosteroid treatment, with the following exceptions:

               -  Use of an inhaled or topical corticosteroid is permitted.

               -  Corticosteroid premedication for radiographic imaging for dye allergies is
                  permitted.

               -  Use of physiologic corticosteroid replacement therapy may be approved after
                  consultation with the medical monitor. e. ≤21 days for prior monoclonal antibody
                  used for anticancer therapy, with the exception of denosumab. This does not apply
                  to subjects being enrolled in Phase 2, who have received a PD-1/PD-L1 inhibitor
                  as their most recent therapy (2-6 weeks prior to first dose of study drug; see
                  above).

                  f. ≤7 days for immunosuppressive-based treatment for any reason, with the
                  exceptions noted above for prior corticosteroid treatment (exclusion criterion
                  d).

                  g. ≤21 days or 5 half-lives before first dose of study treatment for all other
                  investigational study drugs or devices. For investigational agents with long
                  half- lives (e.g., >5 days), enrollment before the fifth half-life requires
                  medical monitor approval.

                  h. For subjects in Phase 2 with HCC < 6 weeks for prior locoregional therapy to
                  the liver e.g., transcatheter chemoembolization (TACE), radiation, surgery, or
                  radioembolization.

          8. Has not recovered to grade ≤1 from toxic effects of prior therapy and/or complications
             from prior surgical intervention before starting therapy.

             Note: Subjects with grade ≤2 neuropathy and alopecia are an exception and may enroll.

          9. Uncontrolled infection or other serious medical illnesses.

         10. History or presence of an abnormal ECG that, in the investigator's opinion, is
             clinically meaningful.

         11. Any medical conditions that, in the opinion of the investigator, would preclude use of
             AGEN1884, including AGEN1884 hypersensitivity.

         12. Women who are pregnant or breastfeeding.

         13. Concurrent participation in other investigational drug trials.

         14. Has a 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 are obtained after
             treatment to the brain metastases. These imaging scans should both be 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.
             For individuals who received steroids as part of brain metastases treatment, steroids
             must be discontinued ≥ 7 days prior to first dose of study drug.

         15. For subjects in Phase 2 with HCC, the following exclusions also apply:

               1. Recent encephalopathy episodes in the last 6 months.

               2. Recent (within the last 6 months) gastro-esophageal varices bleeding.

               3. Subject whose tumors have cardiac involvement, as determined by imaging.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLTs) of AGEN1884
Time Frame:throughout protocol, up to 3 years
Safety Issue:
Description:Summary of changes from baseline in weight and systolic and diastolic blood pressure, frequency of abnormal and clinically significant findings in overall ECG interpretation and QT interval > 470 msec; frequency of occurrence of grade 3 findings by CTCAE version 5 any time during the study for anemia, decreased leucocyte, platelet counts, increased creatinine, ALT, AST, or bilirubin, hypokalemia, hyperkalemia, hyponatremia, hypernatremia, proteinuria

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:throughout protocol, up to 3 years
Safety Issue:
Description:To evaluate the preliminary efficacy of AGEN1884
Measure:Disease Control Rate (DCR)
Time Frame:throughout protocol, up to 3 years
Safety Issue:
Description:
Measure:Duration of Response (DOR)
Time Frame:throughout protocol, up to 3 years
Safety Issue:
Description:
Measure:Progression-Free Survival (PFS)
Time Frame:throughout protocol, up to 3 years]
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:throughout protocol, up to 3 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Agenus Inc.

Last Updated

June 23, 2020