Fc-Engineered Anti-CTLA-4 Monoclonal Antibody in Advanced Cancer

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 as Monotherapy and in Combination With AGEN2034 (Balstilimab), an Anti-PD-1 Monoclonal Antibody, in Subjects With Advanced Cancer

Brief Summary

      This study is an open-label, Phase 1, multicenter study to evaluate the safety, tolerability,
      pharmacokinetics (PK), and pharmacodynamic (PD) profiles of a novel fragment crystallizable
      (Fc)-engineered immunoglobulin G1 anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) human
      monoclonal antibody (botensilimab) monotherapy and in combination with an anti-programmed
      cell death protein-1 (PD-1) antibody (balstilimab), and to assess the maximum tolerated dose
      (MTD) in participants with advanced solid tumors. This study will also determine the
      recommended phase 2 dose (RP2D) of botensilimab monotherapy and in combination with
      balstilimab.
    

Detailed Description

      This Phase 1 study will enroll up to approximately 195 evaluable adult participants with
      refractory cancer (solid tumors) regardless of diagnosis.

      The study will consist of a 3+3 dose escalation. Different dose levels of botensilimab, both
      monotherapy and in combination with balstilimab, will be evaluated in individual cohorts
      based upon dose. Each participant will remain in the cohort of the dose level and schedule
      assigned at study entry. Participants can be replaced for any reason other than a
      dose-limiting toxicity (DLT). Participants will receive treatment for ≤ 2 years or until
      progressive disease, unacceptable toxicity, or any criterion for stopping the study drug or
      withdrawal of trial occurs.

      Additionally, the study is intended to further explore the safety, PK, PD, and clinical
      activity in selected cancer types at dose levels (botensilimab monotherapy and combination
      therapy with balstilimab) determined as potentially effective. Indications of interest
      include, but are not limited to, non-small-cell lung cancer, melanoma, endometrial cancer,
      ovarian cancer, angiosarcoma, colorectal cancer without liver metastases, and fibrolamellar
      carcinoma.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Incidence Of Treatment-emergent Adverse Events (TEAEs)

Secondary Outcome

 Objective Response Rate (ORR) According To Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)

Condition

Advanced Cancer

Intervention

Botensilimab

Study Arms / Comparison Groups

 3-Week Monotherapy
Description:  3+3 Dose escalation: botensilimab, every 3 weeks, starting at dose level 0.1 milligrams/kilogram (mg/kg) up to 4 mg/kg, administered intravenously (IV) for up to 2 years.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

195

Start Date

April 1, 2019

Completion Date

December 2024

Primary Completion Date

December 2024

Eligibility Criteria

        Inclusion Criteria:

        For inclusion in the trial, all of the following inclusion criteria must be fulfilled, as
        no waivers will be permitted:

          1. Provision of signed and dated written informed consent prior to any study specific
             procedures. Participation in pharmacogenomics testing is optional.

          2. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced
             solid tumor for which no standard therapy is available or standard therapy has failed.

          3. Measurable disease on imaging based on RECIST 1.1.

          4. Life expectancy of ≥ 3 months and Eastern Cooperative Oncology Group performance
             status of 0 or 1.

          5. Adequate organ and bone marrow reserve function, as indicated by the following
             laboratory values:

               1. Adequate hematological function, defined as absolute neutrophil count ≥ 1.5 ×
                  10^9/liter (L), platelet count ≥ 100 × 10^9/L, and hemoglobin ≥ 8 grams/deciliter
                  without recent transfusion (defined as a transfusion that has occurred within 2
                  weeks of the hemoglobin measurement).

               2. Adequate liver function, defined as total bilirubin level ≤ 1.5 × institutional
                  upper limit of normal (IULN), aspartate aminotransferase ≤ 2.5 × IULN, and
                  alanine aminotransferase ≤ 2.5 × IULN.

               3. Adequate renal function defined as creatinine ≤ 1.5 × IULN or measured or
                  calculated creatinine clearance ≥ 40 milliliters/minute per institutional
                  standard. Assessment methods should be recorded.

               4. Adequate coagulation, defined as international normalized ratio or prothrombin
                  time ≤ 1.5 × IULN and activated partial thromboplastin time ≤ 1.5 × IULN (unless
                  participant receiving anticoagulant therapy).

          6. No history of prior or concomitant malignancy that requires other active treatment.

          7. Participants must provide a sufficient and adequate formalin-fixed paraffin embedded
             tumor tissue sample (fresh biopsy) collected within 28 days before the first dose from
             a site not previously irradiated and agree to a mandatory on-treatment biopsy if
             clinically feasible.

          8. Female participants 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.

          9. Female participants 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 participant.

         10. Male participants 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 participant.

        Exclusion Criteria:

        For inclusion in the trial, participant 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, radiotherapy, or
             major surgery within 3 weeks 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.

          3. Participants who have received prior CTLA-4 therapy may be enrolled in selected
             indications upon agreement with the Sponsor. Note: Selected expansion cohorts may
             accept prior therapy with anti-CTLA-4 antibody or agent.

          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 trial (including maintenance therapy with another agent, radiation therapy,
             and/or surgical resection).

          6. Known severe (Grade ≥ 3) hypersensitivity reactions to fully human monoclonal
             antibodies, antibody, 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.

          7. Receiving systemic corticosteroid therapy 1 week prior to the first dose of study drug
             or receiving any other form of systemic immunosuppressive medication. Note:
             Corticosteroid use as a premedication for IV contrast allergies/reactions is allowed.
             Participants 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: Participants 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). 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 drug (that is, with use of disease-modifying agents,
             corticosteroids, or immunosuppressive drugs). Note: Participants with autoimmune
             conditions requiring hormone replacement therapy or topical treatments are eligible.

         10. Has had an allogeneic tissue/solid organ transplant, except for corneal transplants.

         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 (that is, 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 trial, interfere with
             the participant's participation for the full duration of the trial, or is not in the
             best interest of the participant 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.

         19. For participants in the colorectal cancer expansion cohort only: current or previous
             evidence of liver metastases as determined by computed tomography, magnetic resonance
             imaging, or biopsy.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Medical Director, 781-674-4265, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03860272

Organization ID

C-800-01


Responsible Party

Sponsor

Study Sponsor

Agenus Inc.


Study Sponsor

Medical Director, Study Director, Agenus Inc.


Verification Date

July 2022