AGEN-1884, an Anti-CTLA-4 Antibody, in Advanced Solid Cancers
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This is an open-label, Phase 1, multicenter study to evaluate the safety, PK, and PD of an anti-CTLA-4 human monoclonal antibody (AGEN1884) and to estimate the MTD in subjects with advanced or refractory cancer. The study will consist of a 3+3 dose escalation cohort starting at a near minimally anticipated biologic effect level (MABEL) dose with expansion cohorts at 1 mg/kg and 3 mg/kg..
Study To Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of an Anti-CTLA-4 Human Monoclonal Antibody (AGEN1884), and to Estimate the Maximum Tolerated Dose in Subjects With Advanced or Refractory Cancer
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Ages Eligible for Study:
18 Years and older (Adult, Senior)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Sign 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 subjects with known prior diagnosis and clinical or radiographic evidence of recurrence.
Eastern Cooperative Oncology Group score of 0 or 1.
Life expectancy ≥12 weeks.
Adequate cardiac function (≤New York Heart Association [NYHA] Class II).
Adequate organ function defined as absolute neutrophil count ≥1,500×10^6/L, absolute lymphocyte count ≥500/mm^3, and platelet count ≥100,000×10^6/mm^3. Adequate liver function defined as aspartate aminotransferase and alanine aminotransferase ≤2.5× the upper limit of institutional normal, bilirubin ≤1.5 mg/dL or 25 µmol/L. Adequate renal function defined as blood urea nitrogen and serum creatinine of ≤1.5 mg/dL or 130 µmol/L.
Female subjects of childbearing potential and fertile male subjects 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.
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 monoclonal antibody, such as colitis or pneumonitis requiring treatment with steroids, or has a history of interstitial lung disease.
History of acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or abdominal carcinomatosis.
Primary or secondary immunodeficiency (including immunosuppressive disease, autoimmune disease [including autoimmune endocrinopathies, such as hypothyroidism, and insulin dependent diabetes mellitus], or usage of immunosuppressive medications).
Subjects with a known history of human immunodeficiency virus 1 and 2, human T lymphotropic virus 1, hepatitis B virus, or active hepatitis C virus.
Subjects with a history of connective tissue disorders.
Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study drug:
≤14 days for chemotherapy, targeted small molecule therapy, or radiation therapy. Subjects 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 sponsor approval.
Note: Bisphosphonates and denosumab are permitted medications.
≤28 days for a prior immunotherapy. No prior therapy with check point inhibitors, costimulatory agonists or immunomodulatory agents is allowed.
≤28 days for prior monoclonal antibody used for anticancer therapy with the exception of denosumab.
≤28 days for prior systemic corticosteroid therapy.
≤7 days for immune-suppressive-based treatment for any reason. Note: Use of inhaled or topical corticosteroid use for radiographic procedures is permitted.
Note: The use of physiologic corticosteroid replacement therapy may be approved after consultation with the sponsor.
≤28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational study drugs or devices.
Has not recovered to Grade ≤1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting therapy.
Note: Subjects with Grade ≤2 neuropathy is an exception and may enroll.
Uncontrolled infection or other serious medical illnesses.
History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. Screening corrected QT (QTc) interval > 470 msec is excluded (corrected by Fridericia). If a single QTc is > 470 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is < 470 milliseconds. For subjects with an intraventricular conduction delay (QRS interval > 120 milliseconds), the JTc interval may be used in place of the QTc with sponsor approval. The JTc must be < 340 milliseconds if JTc is used in place of the QTc. Subjects with left bundle branch block are excluded.
Note: QTc prolongation due to pacemaker may enroll if the JTc is normal or with medical monitor approval.
Any medications that are known to prolong the QTc interval.
Any medical conditions that, in the opinion of the investigator, would preclude use of AGEN1884, including AGEN1884 hypersensitivity.
Women who are pregnant or breast-feeding.
Concurrent participation in other investigational drug trials.
Subjects with a history of or active CNS tumors or metastases from non-CNS tumors.