AGEN1884, an Anti-CTLA-4 Human Monoclonal Antibody in Participants With Advanced or Refractory Cancer and Who Have Progressed With PD-1/PD-L1 Inhibitor as Their Most Recent Therapy

NCT02694822 | Completed Phase 1 Results FDA Drug

• 1 other identifier: C-500-01
• Study Type: interventional
• Target: 89
• Locations: 1 country
• Sites: 11

Brief Summary

This is an open-label, Phase 1/2, multicenter study to evaluate the safety, pharmacokinetics, and pharmacodynamics of an anti-cytotoxic T lymphocyte-associated protein-4 (CTLA-4) human monoclonal antibody (zalifrelimab) in participants with advanced or refractory cancer and in participants who have progressed during treatment with a programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitor as their most recent therapy. The phase 1 portion of the study has been completed; it enrolled adult participants with refractory, advanced cancer in a 3+3 dose escalation cohort. The phase 2 portion consisted of 51 participants who progressed during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug).

Conditions

Advanced Solid Cancers; Advanced Solid Cancers Refractory to PD-1 and PD-L1 Therapies

Outcome Measures

Primary Outcomes (4)

• Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) of Zalifrelimab

  A DLT was defined as a Grade ≥3 adverse drug reaction (ADR), according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5, occurring in the DLT evaluation period (28 days after the initial administration of zalifrelimab). An ADR was defined as all noxious and unintended responses to a medicinal product, related to any dose.

  Up to 28 days

• Phase 1 and Phase 2: Number of Participants Experiencing Any Treatment-related Adverse Events

  An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. A treatment-related AE was one in which a causal relationship between the medicinal product and the AE was at least a reasonable possibility and could not be ruled out. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.

  Up to 6 years

• Phase 1: Maximum Drug Concentration (Cmax) of Zalifrelimab

  Blood samples were collected at designated timepoints to characterize Cmax of serum zalifrelimab following IV infusion in participants with metastatic or locally advanced solid tumors. Data reported as micrograms/milliliter (ug/mL).

  Day 1 of Cycle 1 (21 days/cycle)

• Phase 1: Area Under the Drug Concentration-time Curve From 0 to 21 Days (AUC0-21d) of Zalifrelimab

  Blood samples were collected at designated timepoints to characterize AUC0-21d of serum zalifrelimab following IV infusion in participants with metastatic or locally advanced solid tumors. Data reported as hour times ug/mL (hour\*ug/mL).

  Day 1 of Cycle 1 (21 days/cycle)

Secondary Outcomes (7)

• Phase 1 and Phase 2: Objective Response Rate (ORR)

  Up to 6 years

• Phase 1 and Phase 2: Disease Control Rate (DCR)

  Up to 6 years

• Phase 1 and Phase 2: Duration of Response (DOR)

  Up to 6 years

• Phase 1: Progression-free Survival (PFS)

  Up to 6 years

• Phase 2: PFS

  Up to 6 years

Study Arms (1)

Zalifrelimab

EXPERIMENTAL

Participants received zalifrelimab intravenously.

Drug: Zalifrelimab

Interventions

Zalifrelimab DRUG

An anti-CTLA-4 monoclonal antibody.

Also known as: AGEN1884

Zalifrelimab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent.
• ≥18 years of age.
• Histological or cytological diagnosis of solid cancer or lymphoma that is considered incurable and without therapies with established benefit. Biopsy is not necessary for participants with known prior diagnosis, and clinical or radiographic evidence of recurrence. For Phase 2 only: Participants who experienced documented disease progression during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug). This cohort includes participants with histological diagnoses of hepatocellular carcinoma (HCC) (not including atypical histology such as cholangiocarcinoma mix or fibrolamellar hepatocellular carcinoma) who experienced documented disease progression during treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug).
• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
• Participants in Phase 2 with HCC should have a Child-Pugh score of A or B7 with no encephalopathy or ascites.
• Life expectancy ≥12 weeks.
• Adequate cardiac function (New York Heart Association \[NYHA\] class ≤II).
• Adequate organ function, defined as absolute neutrophil count (ANC) ≥1,500×10\^6/liter (L), absolute lymphocyte count ≥500/cubic millimeters (mm\^3), hemoglobin ≥8.0 grams/deciliter (g/dL), and platelet count ≥100,000×10\^6/mm\^3 without blood growth factors or without transfusions within 1 week of first dose. For participants in Phase 2 with HCC: Platelet count ≥60×10\^6/mm\^3 and ANC ≥1,000×10\^6/L are acceptable provided that the principal investigator assesses these abnormalities as due to liver disease.
• Adequate liver function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5× institutional upper limit of normal (ULN), and bilirubin ≤1.5 milligrams/deciliter (mg/dL) × ULN. For participants in Phase 2 with HCC: AST and ALT ≤5 × ULN, bilirubin ≤2 mg/dL × ULN, and albumin ≥2.8 mg/dL.
• Adequate renal function, defined as estimated creatinine clearance ≥50 milliliters/minute according to Cockcroft-Gault formula, or measured 24-hour creatinine clearance (or local institutional standard method).
• Adequate coagulation defined by international normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN (unless the participant is receiving anticoagulant therapy); and activated partial thromboplastin time ≤1.5× ULN (unless the participant is receiving anticoagulant therapy). Participants in Phase 2 with HCC can have an INR ≤2.3× ULN. Note: Participants in Phase 2 with HCC and on anticoagulant treatment would have an assigned value of 1 point when scoring PT/INR so the overall Child-Pugh score is not adversely affected.
• Female participants of childbearing potential and fertile male participants must agree to use adequate contraception or abstain from sexual activity from the time of consent through 90 days after the end of study drug. Adequate contraception includes condoms with contraceptive foam; oral, implantable, or injectable contraceptives; contraceptive patch; intrauterine device; diaphragm with spermicidal gel; or a sexual partner who is surgically sterilized or postmenopausal. Note: Abstinence is acceptable if this is the established and preferred contraception for the participant.
• In the expansion phase, all participants must provide a sufficient and adequate formalin-fixed paraffin embedded (FFPE) tumor tissue sample preferably collected after progression on the last therapy and/or collected at screening, if clinically feasible. If a recent biopsy is not available, an archival FFPE sample should be provided from a site not previously irradiated. If no tumor tissue is available, a fresh biopsy will be required if clinically feasible.

You may not qualify if:

• Other malignancies treated within the last 5 years, except in situ cervix carcinoma or non-melanoma skin cancer.
• Other form(s) of antineoplastic therapy anticipated during the period of the study.
• Previous severe hypersensitivity reaction to another fully human monoclonal antibody or severe reaction to immuno-oncology agents, such as colitis or pneumonitis requiring treatment with steroids.
• History of interstitial lung disease.
• Primary or secondary immunodeficiency, including immunosuppressive disease, autoimmune disease (including autoimmune endocrinopathies), or usage of immunosuppressive medications.
• Note: Participants with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible. Participants with Type 2 diabetes mellitus are allowed.
• Participants with a known history of human immunodeficiency virus 1 and 2, human T lymphotropic virus 1.
• Participants in Phase 2 with HCC: Participants with active hepatitis B infection who are receiving effective antiviral therapy are permitted. Participants with active hepatitis C infection are allowed (antiviral therapy not required).
• Administration of anticancer medications or investigational drugs within the following intervals before the first administration of study drug: a. ≤14 days for chemotherapy, targeted small molecule therapy, or radiation therapy. Participants must also not have had radiation pneumonitis as a result of treatment and cannot participate in the study if they are on chronic corticosteroids for radiation pneumonitis. A 1-week washout is permitted for palliative radiation to non-central nervous system (CNS) disease, with medical monitor approval.
• Note: Bisphosphonates and denosumab are permitted medications. b. ≤14 days for prior immunotherapy. Participants in the dose escalation cohorts are excluded if they have received prior checkpoint inhibitors, costimulatory agonists, or immune modulating therapy except as described below. Once a dose level is determined to be safe by the safety review committee, participants will be allowed to enroll in dose-level expansion cohorts if they have received other non-CTLA-4 targeting immunotherapies.
• c. Participants enrolling in Phase 2 must have cancer that has progressed after prior treatment with an approved or investigational PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug). The minimum requirement of 2 weeks (14 days) from prior anti-PD-1/PD-L1 therapy is to allow resolution of any lower-grade (≤2) adverse events observed with the therapy. If the investigator feels the participant has tolerated prior anti-PD-1/PD-L1 therapy well, then treatment with study agent may begin sooner.
• d. ≤7 days for prior corticosteroid treatment, with the following exceptions:
• Use of an inhaled or topical corticosteroid is permitted.
• Corticosteroid premedication for radiographic imaging for dye allergies is permitted.
• Use of physiologic corticosteroid replacement therapy may be approved after consultation with the medical monitor. e. ≤21 days for prior monoclonal antibody used for anticancer therapy, with the exception of denosumab. This does not apply to participants being enrolled in Phase 2, who have received a PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose of study drug; see above).

Sponsors & Collaborators

• Agenus Inc.: lead

Study Sites (11)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Rocky Mountain Cancer Center

Denver, Colorado, 80218, United States

Location

University of Miami Miller School of Medicine

Miami, Florida, 33136, United States

Location

Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, 60611, United States

Location

Ochsner Cancer Institute

New Orleans, Louisiana, 70121, United States

Location

Atlantic Health System/Morristown Medical Center

Morristown, New Jersey, 07962, United States

Location

Levine Cancer Institute

Charlotte, North Carolina, 28204, United States

Location

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Texas Oncology - Austin Midtown

Austin, Texas, 78705, United States

Location

Texas Oncology, Tyler Texas

Tyler, Texas, 75702, United States

Location

Results Point of Contact

• Title: Clinical Trial Information
• Organization: Agenus, Inc.

clinicaltrialinfo@Agenusbio.com

1-781-674-4265

Study Officials

• Medical Director

  Agenus Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2016
• First Posted: March 1, 2016
• Study Start: April 1, 2016
• Primary Completion: March 30, 2022
• Study Completion: March 31, 2022
• Last Updated: March 17, 2025
• Results First Posted: March 17, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (11)