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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

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ClinicalTrials.gov Identifier: NCT02694822
Recruitment Status : Recruiting
First Posted : March 1, 2016
Last Update Posted : October 10, 2019
Sponsor:
Information provided by (Responsible Party):
Agenus Inc.

Brief Summary:

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 portions consists of approximately 40 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).


Condition or disease Intervention/treatment Phase
Advanced Solid Cancers Advanced Solid Cancers Refractory to PD-1 Drug: AGEN1884 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : April 2016
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: AGEN1884
anti-CTLA-4 antibody
Drug: AGEN1884
anti-CTLA-4 antibody




Primary Outcome Measures :
  1. Dose limiting toxicities (DLTs) of AGEN1884 [ Time Frame: 1 year ]
  2. Frequency, Duration and Severity of Drug-Related Adverse Events [ Time Frame: 1 year ]
    To assess safety and tolerability

  3. Maximum drug concentration at steady-state (Cmax-ss) [ Time Frame: 1 year ]
  4. Minimum drug concentration at steady state (Cmin-ss) [ Time Frame: 1 year ]
  5. Area under the drug concentration-time curve within time span t1 to t2 at steady-state (AUC(t1-t2)-ss) [ Time Frame: 1 year ]
  6. Area under the drug concentration-time curve from time of dosing to time of last observation (AUC(0-t)) [ Time Frame: 1 year ]
  7. Area under the drug concentration-time curve from time of dosing extrapolated to infinity (AUC(0-∞)) [ Time Frame: 1 year ]
  8. Time to reach maximum drug concentration (tmax) [ Time Frame: 1 year ]
  9. Terminal elimination rate constant (λz) [ Time Frame: 1 year ]
  10. Terminal elimination half-life (t½) [ Time Frame: 1 year ]
  11. Systemic Clearance (CL [ Time Frame: 1 year ]
  12. Volume of Distribution (Vd) [ Time Frame: 1 year ]

Secondary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: 1 year ]
    To evaluate the preliminary efficacy of AGEN1884

  2. Disease Control Rate (DCR) [ Time Frame: 1 year ]
  3. Duration of Response (DOR) [ Time Frame: 1 year ]


Information from the National Library of Medicine

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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:

  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.
  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 ≥60,000×106/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 ≥ 3.0 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 and PT ≤ 6 seconds 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: a. Recent encephalopathy episodes in the last 6 months. Subjects taking rifaximin/lactulose as encephalopathy prophylaxis are excluded.

b. Recent (within the last 6 months) gastro-esophageal varices bleeding. c. Subject whose tumors have invasion at main portal vein, inferior vena cava, or cardiac involvement, as determined by imaging.


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): NCT02694822


Contacts
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Contact: Agenus Medical Monitor, MD 781-674-4508

Locations
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United States, California
City of Hope National Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Sanna Kabbinavar    626-218-0979    skabbinavar@coh.com   
Principal Investigator: Daneng Li, MD         
USC Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Xiomara Menendez       xiomara.menendez@med.usc.edu   
Principal Investigator: Anthony El-Khoueiry, MD         
United States, Colorado
Rocky Mountain Cancer Center Recruiting
Denver, Colorado, United States, 80218
Contact: Allen Cohn, MD    303-388-4876    allen.cohn@usoncology.com   
Principal Investigator: Allen Cohn, MD         
United States, Florida
School of Medicine at the University of Miami Recruiting
Miami, Florida, United States, 33136
Contact: Yvonne Dinh    305-243-9899    Y.dinh@med.miami.edu   
Principal Investigator: Yanel Diaz, MD         
United States, Illinois
Comprehensive Cancer Center of Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Amy Hoyer, MS, CCRC    312-695-1341      
Principal Investigator: Priya Kumthekar, MD         
United States, Louisiana
Ochsner Cancer Institute Recruiting
New Orleans, Louisiana, United States, 70121
Contact: Heather Scuderi    504-703-2654    heather.scuderi@ochsner.org   
Principal Investigator: Marc Matrana, MD         
United States, New Jersey
Atlantic Health System/Morristown Medical Center Recruiting
Morristown, New Jersey, United States, 07962
Contact: Barbara Peloquin    973-971-6298    barbara.peloquin@atlantichealth.org   
Principal Investigator: Angela Alistar, MD         
United States, North Carolina
Levine Cancer Institute Recruiting
Charlotte, North Carolina, United States, 28204
Contact: Chari Granger, RN, BSN, OCN    980-442-5225      
Principal Investigator: Jimmy Hwang, MD         
United States, Ohio
The Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Susan Gillespie    614-293-0069    susan.gillespie@osumc.edu   
Principal Investigator: Robert Wesolowski, MD         
United States, Texas
Texas Oncology, Tyler Texas Recruiting
Tyler, Texas, United States, 75702
Contact: Donald Richards, MD    903-579-9800    donald.richards@usoncology.com   
Principal Investigator: Donald Richards, MD         
Sponsors and Collaborators
Agenus Inc.
Investigators
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Study Director: Waldo Ortuzar, MD Agenus Inc.

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Responsible Party: Agenus Inc.
ClinicalTrials.gov Identifier: NCT02694822     History of Changes
Other Study ID Numbers: C-500-01
First Posted: March 1, 2016    Key Record Dates
Last Update Posted: October 10, 2019
Last Verified: October 2019
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
Additional relevant MeSH terms:
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Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs