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Anti-CD137 and Anti-CTLA-4 Monoclonal Antibody in Patient 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 : May 3, 2022
Sponsor:
Information provided by (Responsible Party):
Agenus Inc.

Brief Summary:
This study is an open-label, Phase 1, multicenter study to evaluate the safety, tolerability, PK, and PD profiles of AGEN2373 as a monotherapy and in combination with AGEN1181, and to assess the maximum tolerated dose (MTD) in subjects with advanced solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Cancer Drug: AGEN2373 Drug: AGEN1181 Phase 1

Detailed Description:

This Phase 1 study will enroll up to approximately 200 evaluable adult patients with a histologically confirmed diagnosis of advanced cancer for which no standard therapy is available or standard therapy has failed, regardless of diagnosis and prior therapies. This also includes patients with PD-1/PD-L1 R/R melanoma. Patients may be enrolled into one of 5 treatment arms:

2-Week AGEN2373 monotherapy

3-Week AGEN2373 monotherapy

4-Week AGEN2373 monotherapy

Combination of AGEN2373 and AGEN1181 in patients with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) relapsed/refractory (R/R) melanoma.

Group 1 (Monotherapy Lead-in Combination): Q3W AGEN2373 lead-in followed by Q3W AGEN2373 in combination with Q6W AGEN1181. (AGEN2373 will be administered on Day 1 every 3 weeks. Starting with Cycle 4 Day 1, AGEN1181 will be added as combination therapy and administered every other cycle (Cycles 4, 6, 8, 10, etc.). AGEN1181 is administered every 6 weeks.)

Group 2 (Combination): AGEN2373 will be administered Q3W in combination with AGEN1181 administered every other cycle. (AGEN1181 is administered every 6 weeks.)

The trial will consist of a 3+3 dose escalation that will evaluate different combination dose levels of AGEN2373 monotherapy and in combination with AGEN1181. Each patient will stay on the dose level and schedule assigned at trial entry. Patients will receive treatment for ≤ 2 years (AGEN2373) as monotherapy and AGEN1181 ≤ 1 year as combination therapy with AGEN2373 or until PD, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal of trial occurs.

Patients who do not complete the DLT observation period (28 days for the 2-Week and 4-Week AGEN2373 Monotherapy arms and 21 days for the 3-Week AGEN2373 Monotherapy and Combination arms) after the first dose for reasons other than DLT will be replaced.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Dose escalation
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of AGEN2373, an Anti-CD137 Monoclonal Antibody, as Monotherapy and in Combination With AGEN1181, an Fc-Engineered Anti-CTLA-4 Monoclonal Antibody, in Patients With Advanced Cancer
Actual Study Start Date : September 26, 2019
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2027

Arm Intervention/treatment
Experimental: 2-Week Monotherapy with AGEN2373
3+3 Dose escalation of AGEN2373 administered by IV.
Drug: AGEN2373
An Anti-CD137 Monoclonal Antibody
Other Name: Anti-CD137

Experimental: 3-Week Monotherapy with AGEN2373
3+3 Dose escalation of AGEN2373 administered by IV.
Drug: AGEN2373
An Anti-CD137 Monoclonal Antibody
Other Name: Anti-CD137

Experimental: 4-Week Monotherapy with AGEN2373
3+3 Dose escalation of AGEN2373 administered by IV.
Drug: AGEN2373
An Anti-CD137 Monoclonal Antibody
Other Name: Anti-CD137

Experimental: Combination Therapy with 3-week AGEN2373 Monotherapy Lead-In Combination with 6-week AGEN1181
3+3+3 Dose escalation of AGEN2373. AGEN2373 and AGEN1181 administered by IV.
Drug: AGEN2373
An Anti-CD137 Monoclonal Antibody
Other Name: Anti-CD137

Drug: AGEN1181
Anti-CTLA-4 Monoclonal Antibody
Other Name: Anti-CTLA-4

Experimental: Combination Therapy with 3-week AGEN2373 in combination with 6-week AGEN1181
3+3+3 Dose escalation of AGEN2373. AGEN2373 and AGEN1181 administered by IV.
Drug: AGEN2373
An Anti-CD137 Monoclonal Antibody
Other Name: Anti-CD137

Drug: AGEN1181
Anti-CTLA-4 Monoclonal Antibody
Other Name: Anti-CTLA-4




Primary Outcome Measures :
  1. Occurrence of Dose Limiting Toxicity (DLT) [ Time Frame: First 28 days of treatment Q2W and Q4W and First 21 days Q3W ]
    DLT in patient in dose escalation phase

  2. Frequency of treatment-emergent adverse events (TEAEs) [ Time Frame: Screening to 90 days from last dose ]
    According to NCI-CTCAE Version 5.0, vital signs (blood pressure, heartrate, and temperature), physical examinations, 12-lead electrocardiogram, Eastern Cooperative Oncology Group (ECOG) performance status, and clinical laboratory assessments for all dose groups

  3. Severity of treatment-emergent adverse events (TEAEs) [ Time Frame: Screening to 90 days from last dose ]
    According to NCI-CTCAE Version 5.0, vital signs (blood pressure, heartrate, and temperature), physical examinations, 12-lead electrocardiogram, Eastern Cooperative Oncology Group (ECOG) performance status, and clinical laboratory assessments for all dose groups

  4. Duration of treatment-emergent adverse events (TEAEs) [ Time Frame: Screening to 90 days from last dose ]
    According to NCI-CTCAE Version 5.0, vital signs (blood pressure, heartrate, and temperature), physical examinations, 12-lead electrocardiogram, Eastern Cooperative Oncology Group (ECOG) performance status, and clinical laboratory assessments for all dose groups


Secondary Outcome Measures :
  1. 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 and AGEN1181

  2. 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 and AGEN1181

  3. 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 and AGEN1181

  4. 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 and AGEN1181

  5. 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 and AGEN1181

  6. Time to maximum observed concentration (tmax) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373 and AGEN1181

  7. Terminal disposition rate constant (λz) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373 and AGEN1181

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

  9. Systemic clearance (CL) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373 and AGEN1181

  10. Volume of distribution (Vd) [ Time Frame: Day 1 of dosing through 90 days from the last dose ]
    PK Profile of AGEN2373 and AGEN1181

  11. Immunogenicity of AGEN2373 [ Time Frame: Pre-dose through 3 months after the last dose ]
    ADA Profile of AGEN2373 and AGEN1181

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

  13. 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

  14. Disease Control Rate (DCR) [ Time Frame: 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

  15. 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



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 signed, dated, and written informed consent prior to any study specific procedures. Participation in pharmacogenomics testing is optional.
  2. ≥ 18 years of age.
  3. Histologically or cytologically confirmed diagnosis of a solid tumor that is currently metastatic or locally advanced 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 and bone marrow reserve function, as indicated by the following laboratory values:

    • Adequate hematological function, defined as absolute neutrophil count ≥ 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)
    • Adequate liver function, defined as total bilirubin level ≤ 1.5 × upper limit of normal (ULN), aspartate aminotransferase ≤2.5 × ULN, and alanine aminotransferase ≤ 2.5 × ULN, albumin ≥ 3 g/dL, and alkaline phosphatase ≤ 2.5 × ULN or ≤ 5 × ULN for patients with liver metastases
    • Adequate renal function defined as creatinine ≤ 1.5 × ULN OR measured or calculated creatinine clearance ≥ 40 mL/minute per institutional standard. Assessment methods should be recorded
    • Adequate coagulation, defined as international normalized ratio or prothrombin time ≤ 1.5 × ULN and activated partial thromboplastin time ≤ 1.5 × ULN (unless patient is receiving anticoagulant therapy)
  7. Patients with a history of prior malignancy are eligible if treatment was completed ≥ 2 years prior to the first dose of study treatment and the patient has no evidence of disease.
  8. Patients must provide a sufficient and adequate formalin-fixed paraffin-embedded 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 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:

    • ≥ 45 years of age and has not had menses for > 1 year
    • Amenorrheic for > 2 years without a hysterectomy and oophorectomy and follicle-stimulating hormone value in the postmenopausal range upon prestudy (screening) evaluation
    • Status is post-hysterectomy, -bilateral 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 method for the patient.

  11. Male patients with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study 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.

Specific Melanoma Criteria:

Note: these specific criteria below are in addition to the general criteria above.

Inclusion:

  1. Histological confirmation of cutaneous melanoma.
  2. Progression on or within 24 weeks of stopping treatment with a PD-1/PD-L1 confirmed per Society for Immunotherapy of Cancer (SITC).
  3. Patients with BRAF V600-positive tumor(s) should also have received prior treatment with a BRAF inhibitor (alone or in combination with a MEK inhibitor) or have declined targeted therapy.

Note: Patients with BRAF V600-positive tumors with no clinically significant tumor-related symptoms nor evidence of rapidly progressive disease are not required to be treated with a BRAF inhibitor (alone or in combination with a MEK inhibitor) based on Investigator's decision.

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 study treatment.
  2. Received prior systemic cytotoxic chemotherapy, biological therapy, radiotherapy, or major surgery outside of the acceptable washout period 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.

    The following washout windows are acceptable from prior treatments, i.e. patients with time periods less than the following should be excluded:

    • Cytotoxic agent ≥ 3 weeks is acceptable (i.e. < 3 weeks should be excluded)
    • Monoclonal antibodies ≥ 4 weeks is acceptable (i.e. < 4 weeks should be excluded)
    • Proteasome inhibitors or corticosteroids ≥ 2 weeks is acceptable (i.e. < 2 weeks should be excluded)
    • Small molecule/tyrosine kinase inhibitor within 14 days or less than 5 circulating half-lives of investigational drug
    • Having a previous SARS-CoV-2 vaccine > 7 days before administration. For vaccines requiring more than 1 dose, the full series should be completed prior to Cycle 1 Day 1, when feasible, and when the delay in initiation of study treatment would not put the study patients at risk
  3. Patients who have received prior anti-CD137 therapy may be enrolled upon agreement with the Sponsor.
  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 are acceptable.

  5. Expected to require any other form of systemic or localized antineoplastic therapy while on study (including maintenance therapy with another agent, radiation therapy, and/or surgical resection).
  6. Known severe (Grade ≥ 3) hypersensitivity reactions to fully human monoclonal antibodies, 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. (i.e. ≥ 3 features of partly controlled asthma or pneumonitis that has required oral or intravenous [IV] corticosteroids).
  7. Receiving systemic corticosteroid therapy per Exclusion Criterion #2, or 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 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 study medication.

  9. Active or history of autoimmune disease that requires systemic treatment within 2 years of the start of study treatment (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).

    Note: Patients with autoimmune conditions requiring hormone replacement therapy or topical treatment are eligible.

  10. Has had an allogeneic tissue/solid organ transplant except for corneal transplantation.
  11. Active infection requiring treatment.
  12. Active infection with HIV and CD4+ T-cell count <350/μL. Patients not on established antiretroviral therapy for at least 4 weeks and having a detectable HIV viral load. Testing is not required for eligibility.
  13. Active infection with hepatitis B (surface antigen); or infection with hepatitis C, defined by a detectable viral load. Testing is not required for eligibility.
  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 study, interfere with the patient's participation for the full duration of the study, 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 study.
  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, Inc. Clinical Trial Information 781-674-4265 clinicaltrialinfo@Agenusbio.com

Locations
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United States, California
University of Southern California Norris Comprehensive Cancer Center/ Hoag Recruiting
Los Angeles, California, United States, 90033
Contact: Xiomara Menendez    323-865-0212    Xiomara.Menendez@med.usc.edu   
Contact: Lorraine Martinez       Lorraine.Martinez@med.usc.edu   
Principal Investigator: Anthony El-Khoueiry, MD         
United States, New Jersey
Atlantic Health System Recruiting
Morristown, New Jersey, United States, 07960
Contact: Atlantic Health System    973-971-7960      
Principal Investigator: Eric D Whitman, MD         
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, Oregon
Providence Cancer Institute Recruiting
Portland, Oregon, United States, 97213
Contact: Providence Cancer Institute    503-215-2614    CanClinRsrchStudies@providence.org   
Principal Investigator: Matthew Taylor, 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: Cynthia Deleon    210-580-9521    cdeleon@nextoncology.com   
Principal Investigator: Anthony Tolcher, MD         
Sponsors and Collaborators
Agenus Inc.
Investigators
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Study Director: Medical Monitor 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: May 3, 2022
Last Verified: May 2022

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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.:
Combination Therapy
Anti-CD137
Anti-CTLA-4
Single Agent
Monotherapy
Melanoma
Cutaneous Melanoma
Solid Tumors
Advanced Cancer
Open-Label
Dose Escalation
4-1BB
Additional relevant MeSH terms:
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Neoplasms