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A Study in Subjects With 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: NCT04121676
Recruitment Status : Recruiting
First Posted : October 10, 2019
Last Update Posted : April 28, 2020
Sponsor:
Information provided by (Responsible Party):
Agenus Inc.

Brief Summary:
This is a Phase I open-label, 3+3 dose escalation design Phase I trial to assess the safety, tolerability and dose-limiting toxicity (DLT) of AGEN2373 as monotherapy in subjects with solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Cancer Drug: AGEN2373 Phase 1

Detailed Description:
This is a Phase I open-label, dose escalation study of AGEN2373, an Anti-CD137 Monoclonal Antibody being assessed as monotherapy in subjects with solid tumors. The study is a 3+3 dose escalation design and the maximum recommended starting dose (RSD) was derived from the minimally anticipated biological effect level (MABEL). AGEN2373 will be administered via continuous IV infusion on Day 1 of each 4-week cycle for up to 2 years or until disease progression or unacceptable toxicity. The primary objectives are to assess the safety, tolerability, and DLT of AGEN2373 as monotherapy in subjects with advanced solid tumors and to determine the recommended Phase 2 dose (RP2D).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of AGEN2373, an Anti-CD137 Monoclonal Antibody, in Subjects With Advanced Cancer
Actual Study Start Date : September 12, 2019
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : December 2023

Arm Intervention/treatment
Experimental: 4-Week Monotherapy
Open Label 3+3 Dose escalation of AGEN2373, every 4 weeks, starting at dose level 0.03 mg/kg up to 3.0 mg/kg administered by IV.
Drug: AGEN2373
An Anti-CD137 Monoclonal Antibody
Other Name: Anti-CD137




Primary Outcome Measures :
  1. Occurrence of Dose Limiting Toxicity (DLT) [ Time Frame: First 28 days of treatment ]
    DLT in subjects in dose escalation phase


Secondary Outcome Measures :
  1. Frequency of treatment-emergent adverse events (TEAEs) [ Time Frame: Screening to 90 days from last dose ]
    According to NCI-CTCAE Version 5.0

  2. Severity of treatment-emergent adverse events (TEAEs) [ Time Frame: Screening to 90 days from last dose ]
    According to NCI-CTCAE Version 5.0

  3. Duration of treatment-emergent adverse events (TEAEs) [ Time Frame: Screening to 90 days from last dose ]
    According to NCI-CTCAE Version 5.0

  4. Maximum observed concentration at steady state (Cmax-ss) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  5. Minimum observed concentration at steady state (Cmin-ss) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  6. area under the plasma/serum concentration-time curve within time span t1 to t2 at steady-state (AUC(t1-t2)-ss) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  7. area under the plasma/serum concentration-time curve from time zero to time t (AUC(0-t)) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  8. area under the plasma/serum concentration-time curve from time zero to infinity (AUC(0-∞)) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  9. time to maximum observed concentration (tmax) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  10. terminal disposition rate constant (λz) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  11. terminal elimination half-life (t1/2) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  12. systemic clearance (CL) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  13. volume of distribution (Vd). [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373

  14. Immunogenicity of AGEN2373 [ Time Frame: Pre-dose through 3 months after the last dose. ]
    ADA Profile of AGEN2373

  15. Overall Response Rate (ORR) [ Time Frame: Evaluated throughout the protocol up to 2 years ]
    per RECIST 1.1

  16. Duration of Response (DOR) [ Time Frame: First observation of documented disease progression (or death within 12 weeks of the last tumor assessment). ]
    per RECIST 1.1

  17. Disease Control Rate (DCR) [ Time Frame: 24 weeks of first dose ]
    including complete and partial responders and stable disease [SD] for at least 12 weeks per RECIST 1.1

  18. Progression Free Survival (PFS) [ Time Frame: First treatment administration to first observation of documented disease progression (or death within 12 weeks of last tumor assessment). ]
    median and/or rate as defined in the statistical analysis plan


Other Outcome Measures:
  1. Changes in CD8+ T cells and natural killer (NK) cells and other immune cell subtypes at the periphery [ Time Frame: During treatment period, up to 2 years ]
    by flow cytometry

  2. Changes in pro-inflammatory cytokine levels in the blood [ Time Frame: During treatment period, up to 2 years ]
    including but not limited to interferon γ (IFN−γ), interleukin 10 (IL-10), IL-12p70, IL-13, IL1-β, IL-2, IL-4, IL-6, IL8, and tumor necrosis factor α (TNF−α).

  3. Median and/or rate of overall survival (OS) [ Time Frame: Up to 1 year after discontinuation ]
    As defined in the statistical analysis plan



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:

  1. Voluntarily agree to participate by giving written informed consent. 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 RECIST Version 1.1.
  5. Life expectancy of ≥3 months and Eastern Cooperative Oncology Group (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 calculated creatinine clearance

      ≥40 mL/min for subjects with creatinine levels >1.5 x IULN (if no local guideline is available, creatinine clearance should be calculated using the Cockcroft-Gault method).

    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 preferably from the most recent biopsy of a tumor lesion, collected either at the time of or after the diagnosis of advanced or metastatic disease has been made AND from a site not previously irradiated. If no tumor tissue is available, a fresh biopsy will be required.
  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: a ≥45 years of age and has not had menses for >1 year. b. Amenorrheic for >2 years without a hysterectomy and oophorectomy and follicle-stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation. c. 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 90 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 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 subject. 12. Willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

  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 trial treatment.
  2. Received prior systemic cytotoxic chemotherapy, biological therapy, or major surgery within 3 weeks prior to first dose of trial treatment. A 1-week washout is permitted for palliative radiation to non-central nervous system (CNS) disease, with sponsor approval.
  3. Received prior therapy with any anti-CD137 monoclonal antibody or agent.
  4. Persistent toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 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 intravenous (IV) corticosteroids.
  7. Receiving systemic corticosteroid therapy 1 week prior to the first dose of trial treatment 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. 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: 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 trial treatment (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 (HIV) type 1 or 2 antibodies.
  13. Current or chronic infection with hepatitis B and/or hepatitis C virus defined as:

    • Positive test for hepatitis B surface antigen (HBsAg) indicating active or chronic infection.

    Note: Patients with previous history of hepatitis B (who have cleared the infection and have natural immunity, i.e. hepatitis B core antibody positive cases) are excluded if prophylaxis against hepatitis B reactivation with antiviral agents is recommended.

    • Positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection. Note: Subjects with positive hepatitis C antibody and negative hepatitis C by polymerase chain reaction (PCR) are eligible.

  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.

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): NCT04121676


Contacts
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Contact: Agenus Medical Monitor, MD 781-674-4455 waldo.ortuzar@agenusbio.com

Locations
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United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Lisa Olmos    212-342-5162    cancerclinicaltrials@cumc.columbia.edu   
Principal Investigator: Richard Carvajal, MD         
United States, Texas
Mary Crowley Cancer Research Center Recruiting
Dallas, Texas, United States, 75230
Contact: Mary Crowley Referral Office    972-566-3000    referral@marycrowley.org   
Principal Investigator: James Strauss, MD         
NEXT Oncology Recruiting
San Antonio, Texas, United States, 78229
Contact: Sarah Gomez    210-580-9521    sgomez@nextoncology.com   
Principal Investigator: Anthony Tolcher, 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: NCT04121676    
Other Study ID Numbers: C-1100-01
First Posted: October 10, 2019    Key Record Dates
Last Update Posted: April 28, 2020
Last Verified: April 2020

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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
Anti-CD137
Advanced Cancer
Open-Label
Dose Escalation
Monotherapy
Additional relevant MeSH terms:
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Neoplasms