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History of Changes for Study: NCT03860272
Fc-Engineered Anti-CTLA-4 Monoclonal Antibody in Advanced Cancer
Latest version (submitted September 15, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 February 28, 2019 None (earliest Version on record)
2 March 27, 2019 Recruitment Status, Study Status, Contacts/Locations and Oversight
3 April 26, 2019 Contacts/Locations and Study Status
4 May 31, 2019 Contacts/Locations and Study Status
5 September 9, 2019 Outcome Measures, Contacts/Locations, Study Status, Eligibility and Study Description
6 October 8, 2019 Study Status and Contacts/Locations
7 December 17, 2019 Outcome Measures, Arms and Interventions, Study Status, Study Design, Study Description, Eligibility and Study Identification
8 January 22, 2020 Contacts/Locations, Study Status and Conditions
9 April 24, 2020 Study Status and Contacts/Locations
10 May 29, 2020 Study Status and Contacts/Locations
11 September 14, 2020 Study Status, Contacts/Locations, Eligibility and Study Description
12 September 22, 2020 Study Design and Study Status
13 November 25, 2020 Contacts/Locations and Study Status
14 December 14, 2020 Contacts/Locations and Study Status
15 December 28, 2020 Contacts/Locations and Study Status
16 January 21, 2021 Recruitment Status, Study Status, Contacts/Locations, Study Description, Study Design and Study Identification
17 February 4, 2021 Recruitment Status, Study Status and Contacts/Locations
18 February 17, 2021 Contacts/Locations and Study Status
19 July 12, 2021 Contacts/Locations and Study Status
20 November 2, 2021 Study Status and Contacts/Locations
21 January 5, 2022 Study Status and Contacts/Locations
22 February 9, 2022 Study Status and Contacts/Locations
23 March 1, 2022 Contacts/Locations and Study Status
24 March 29, 2022 Arms and Interventions, Outcome Measures, Contacts/Locations, Study Design, Study Description, Study Status, Eligibility and Study Identification
25 April 20, 2022 Contacts/Locations and Study Status
26 April 28, 2022 Contacts/Locations, Study Status, Eligibility, Study Design, Conditions and Study Description
27 June 17, 2022 Contacts/Locations, Study Description, Study Status, Arms and Interventions and Conditions
28 July 25, 2022 Contacts/Locations and Study Status
29 September 7, 2022 Contacts/Locations and Study Status
30 September 15, 2022 Eligibility and Study Status
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Study NCT03860272
Submitted Date:  February 28, 2019 (v1)

Open or close this module Study Identification
Unique Protocol ID: C-800-01
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 in Subjects With Advanced Cancer
Secondary IDs:
Open or close this module Study Status
Record Verification: February 2019
Overall Status: Not yet recruiting
Study Start: March 2019
Primary Completion: March 2022 [Anticipated]
Study Completion: March 2022 [Anticipated]
First Submitted: February 12, 2019
First Submitted that
Met QC Criteria:
February 28, 2019
First Posted: March 1, 2019 [Actual]
Last Update Submitted that
Met QC Criteria:
February 28, 2019
Last Update Posted: March 1, 2019 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Agenus Inc.
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: No
Open or close this module Study Description
Brief Summary: 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), and to assess the maximum tolerated dose (MTD) in subjects with advanced solid tumors. This study will also determine the RP2D of AGEN1181 monotherapy.
Detailed Description:

This Phase 1 study will enroll approximately ≤36 evaluable adult subjects with refractory, advanced cancer (solid tumors) regardless of diagnosis and prior therapies. Subjects who discontinue early for reason other than DLT will be replaced. The biopharmacological properties of the antibody suggest that this proposed dose range will be safe and potentially active. Toxicity will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

The dose escalation phase includes an open-label monotherapy dose escalation consisting of a standard 3+3 dose escalation scheme with the following escalating dose levels and schedules of AGEN1181: 0.1, 0.3, 1, 2, and 4 mg/kg administered every 3 weeks (Table 4 and Figure 1). Each subject will stay on the dose level and schedule assigned at trial entry. Subjects will receive AGEN1181 for ≤2 years or until confirmed PD, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal from the trial occurs.

The treatment phase is divided into 3-week treatment cycles, with associated evaluations and procedures at specific time points. Each 3-week cycle begins with administration of AGEN1181.

Open or close this module Conditions
Conditions: Advanced Cancer
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 1
Interventional Study Model: Single Group Assignment
Dose escalation
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 36 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: 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.
Drug: AGEN1181
an Fc-Engineered Anti-CTLA-4 Monoclonal Antibody
Other Names:
  • Anti-CTLA-4
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Incidence of Adverse Events according to NCI CTCAE version 5.0
[ Time Frame: Screening to 30 days from last dose. ]

AEs, including AESIs, irAE, ADRs, according to NCI CTCAE version 5.0
2. Dose Limiting Toxicity
[ Time Frame: First 28 days of treatment ]

Any Grade 3 or greater drug related toxicity for all dose groups, according to NCI CTCAE version 5.0 with described protocol exceptions.
3. Recommended Phase II Dose (RP2D)
[ Time Frame: First dose to 30 days from last dose. ]

Maximum Tolerated Dose (MTD) based on DLT occurrence at DLT period and all AEs seen during safety period.
Secondary Outcome Measures:
1. Response rate according to RECIST 1.1
[ Time Frame: 12 Weeks from first dose. ]

Unconfirmed response
2. Response rate according to RECIST 1.1
[ Time Frame: Evaluated throughout the protocol up to 2 years. ]

Confirmed Best Overall Response (BOR) in analysis population.
3. Response rate according to RECIST 1.1
[ Time Frame: First observation of documented DP (or death within 12 weeks of last tumor assessment). ]

Duration of Response (DOR)
4. Response rate according to RECIST 1.1
[ Time Frame: 24 Weeks of first dose. ]

Stable Disease (SD) and duration of SD and Disease Control (DCR)
5. Response rate according to RECIST 1.1
[ Time Frame: First treatment administration to first observation of documented disease progression (or death within 12 weeks of last tumor assessment). ]

Progression Free Survival (PFS) time.
6. Overall survival time
[ Time Frame: Up to 1 year after discontinuation. ]

Duration of survival
7. Maximum observed concentration at steady-state (Cmax-ss)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
8. Minimum observed concentration at steady-state (Cmin-ss)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
9. Area under the concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
10. Area under the concentration-time curve from time zero to infinity (AUC(0-∞)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
11. Time to maximum observed concentration (tmax)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
12. Terminal disposition rate constant (λz)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
13. Terminal elimination half-life (t1/2)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
14. Systemic clearance (CL)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
15. Volume of distribution (Vd)
[ Time Frame: Pre-dose through 3 months after last dose. ]

AGEN1181 blood levels measured throughout the study.
16. Evaluate the immunogenicity of AGEN1181 as monotherapy
[ Time Frame: Pre-dose through 3 months after last dose ]

Anti Drug Antibody (ADA) measurements throughout the study.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
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. Diagnosis of 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 ECOG performance status of 0 or 1.
  6. Adequate organ function, as indicated by the following laboratory values:
    1. Adequate hematological function, defined as ANC ≥1.5 x 109/L, platelet count ≥100 x 109/L, and hemoglobin ≥9 g/dL.
    2. Adequate hepatic function, defined as total bilirubin level ≤1.5 x institutional upper limit of normal (IULN), AST ≤2.5 x IULN, ALT ≤2.5 x IULN, and AP ≤2.5 x IULN.
    3. Adequate renal function, defined as calculated creatinine clearance >50 mL/min (calculated using 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 concomitant malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, and in situ cervical cancer that has undergone potentially curative therapy with no evidence of disease recurrence for 5 years since initiation of that therapy.
  8. Sufficient and adequate formalin-fixed tumor tissue sample, preferably from biopsy of tumor lesion either at time of or after diagnosis of advanced or metastatic disease has been made, and 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 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 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-CNS disease, with sponsor approval.
  3. Received prior therapy with an anti-CTLA-4 antibody or drug.
  4. Persistent toxicity of NCI CTCAE grade >1 severity that is related to prior therapy.

    Note: Sensory neuropathy 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 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.
  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 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.
Open or close this module Contacts/Locations
Central Contact Person: Waldo Ortuzar, MD
Telephone: 781-674-4455
Email: Waldo.Ortuzar@Agenusbio.com
Central Contact Backup: Anna Wijatyk, MD
Telephone: 781-674-4635
Email: Anna.Wijatyk@Agenusbio.com
Study Officials: Waldo Ortuzar, MD
Study Director
Agenus Inc.
Locations: United States, Arizona
HonorHealth Research Institute
Scottsdale, Arizona, United States, 85258
Contact:Principal Investigator: Michael Gordon, MD
United States, California
University of Southern California Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
Contact:Principal Investigator: Anthony El-Khoueiry, MD
John Wayne Cancer Institute
Santa Monica, California, United States, 90404
Contact:Principal Investigator: Steven O'Day, MD
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Contact:Principal Investigator: Manuel Hidalgo, MD
United States, Texas
The University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States, 78229
Contact:Principal Investigator: Chethan Ramamurthy, MD
Open or close this module IPDSharing
Plan to Share IPD: No
Open or close this module References
Citations:
Links:
Available IPD/Information:

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