Purpose

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) monotherapy and in combination with a human monoclonal IgG4 antibody (AGEN2034), and to assess the maximum tolerated dose (MTD) in subjects with advanced solid tumors. This study will also determine the RP2D of AGEN1181 monotherapy and in combination with AGEN2034.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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. 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 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 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 measured or calculated creatinine clearance ≥ 40 mL/min per institutional standard. Assessment methods should be recorded.

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 (fresh biopsy) collected within 28 days before the first dose 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/or 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 study drug.

2. Received prior systemic cytotoxic chemotherapy, biological therapy, or major surgery within 3 weeks prior to first dose of study drug. 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 version 5.0 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 IV corticosteroids.

7. Receiving systemic corticosteroid therapy 1 week prior to the first dose of study drug 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 study drug (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.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Randomized
Intervention Model
Single Group Assignment
Intervention Model Description
Dose escalation
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
3-Week Monotherapy
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
Experimental
6-Week Monotherapy
3+3 Dose escalation of AGEN1181, every 6 weeks, starting at dose level 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
Experimental
6-Week Combination Therapy
3+3 Dose escalation of AGEN2034, every 3 weeks, at dose level 3 mg/kg in combination with AGEN1181, every 6 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
  • Drug: AGEN2034
    A fully human monoclonal Anti-PD-1 Antibody
    Other names:
    • Anti-PD-1

Recruiting Locations

The University of Texas Health Science Center at San Antonio
San Antonio, Texas 78229
Contact:
Goodwine Epp
210-450-5798
GOODWINE@uthscsa.edu

More Details

Status
Recruiting
Sponsor
Agenus Inc.

Study Contact

Detailed Description

This Phase 1 study will enroll up to approximately 86 evaluable adult subjects with refractory cancer (solid tumors) regardless of diagnosis. Subjects may be enrolled into the following cohorts:

Cohort 1: AGEN1181 every 3 weeks at 0.1, 0.3, 1, 2, and 4 mg/kg Cohort 2: AGEN1181 every 6 weeks at 1, 2, and 3 mg/kg Cohort 3: AGEN2034 every 2 weeks at 3 mgkg + AGEN1181 every 6 weeks at 0.1, 0.3, 1, 2, and 4 mg/kg

The trial will consist of a 3+3 dose escalation that will evaluate different dose levels of AGEN1181 monotherapy and in combination with AGEN2034. Each subject will stay on the dose level an schedule assigned at trial entry. Subjects can be replaced for any reason other than a DLT. Subjects will receive treatment for ≤ 2 years or until PD, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal of trial occurs.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.