This is an open-label, Phase 1/2, multicenter study to evaluate the safety, PK, and PD of an
anti-CTLA-4 human monoclonal antibody (AGEN1884) in subjects with advanced or refractory
cancer and in subjects who have progressed during treatment with a PD-1/PD-L1 inhibitor as
their most recent therapy.
The phase 1 portion of the study has been completed; It enrolled adult subjects with
refractory, advanced cancer in a 3+3 dose escalation cohort.
The phase 2 portion consists of up to 60 patients who have 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).
Inclusion Criteria:
1. Written informed consent.
2. ≥18 years of age.
3. 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. For Phase 2 only: Subjects 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 subjects with histological diagnoses of 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).
4. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
5. Subjects in Phase 2 with HCC should have a Child-Pugh score of A or B7 with no
encephalopathy or ascites.
6. Life expectancy ≥12 weeks.
7. Adequate cardiac function (New York Heart Association [NYHA] class ≤II).
8. Adequate organ function, defined as absolute neutrophil count (ANC) ≥1,500×106/L,
absolute lymphocyte count ≥500/mm3, hemoglobin ≥8.0 g/dL, and platelet count
≥100,000×106/mm3 without blood growth factors or without transfusions within 1 week of
first dose.
For subjects in Phase 2 with HCC: Platelet count ≥60×106/mm3 and ANC ≥1,000×106/L are
acceptable provided that the principal investigator assesses these abnormalities as
due to liver disease.
9. Adequate liver function, defined as AST and ALT ≤2.5× institutional upper limit of
normal (ULN), and bilirubin ≤1.5 mg/dL × ULN.
For subjects in Phase 2 with HCC: AST and ALT ≤5 × ULN, bilirubin ≤2 mg/dL × ULN, and
albumin ≥ 2.8 mg/dL.
10. Adequate renal function, defined as estimated creatinine clearance ≥50 mL/min
according to Cockcroft-Gault formula, or measured 24-hour creatinine clearance (or
local institutional standard method).
11. Adequate coagulation defined by international normalized ratio (INR) or prothrombin
time (PT) ≤ 1.5 x ULN (unless the patient is receiving anticoagulant therapy); and
activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (unless the subject is
receiving anticoagulant therapy). Subjects in Phase 2 with HCC can have an INR ≤2.3 x
ULN.
Note: Subjects 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.
12. 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. Note: Abstinence is acceptable
if this is the established and preferred contraception for the subject.
13. In the expansion phase, all subjects 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.
Exclusion Criteria
1. Other malignancies treated within the last 5 years, except in situ cervix carcinoma or
non-melanoma skin cancer.
2. Other form(s) of antineoplastic therapy anticipated during the period of the study.
3. 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.
4. History of interstitial lung disease.
5. Primary or secondary immunodeficiency, including immunosuppressive disease, autoimmune
disease (including autoimmune endocrinopathies), or usage of immunosuppressive
medications.
Note: Subjects with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid
disease not requiring immunosuppressive treatment are eligible. Subjects with Type 2
diabetes mellitus are allowed.
6. Subjects with a known history of human immunodeficiency virus 1 and 2, human T
lymphotropic virus 1.
Subjects in Phase 2 with HCC: Subjects with active hepatitis B infection who are
receiving effective antiviral therapy are permitted. Subjects with active hepatitis C
infection are allowed (antiviral therapy not required).
7. 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. 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
medical monitor approval.
Note: Bisphosphonates and denosumab are permitted medications. b. ≤14 days for prior
immunotherapy. Subjects 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
SRC, subjects will be allowed to enroll in dose-level expansion cohorts if they have
received other non-CTLA-4 targeting immunotherapies.
c. Subjects 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 subject 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 subjects 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).
f. ≤7 days for immunosuppressive-based treatment for any reason, with the
exceptions noted above for prior corticosteroid treatment (exclusion criterion
d).
g. ≤21 days or 5 half-lives before first dose of study treatment for all other
investigational study drugs or devices. For investigational agents with long
half- lives (e.g., >5 days), enrollment before the fifth half-life requires
medical monitor approval.
h. For subjects in Phase 2 with HCC < 6 weeks for prior locoregional therapy to
the liver e.g., transcatheter chemoembolization (TACE), radiation, surgery, or
radioembolization.
8. 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 and alopecia are an exception and may enroll.
9. Uncontrolled infection or other serious medical illnesses.
10. History or presence of an abnormal ECG that, in the investigator's opinion, is
clinically meaningful.
11. Any medical conditions that, in the opinion of the investigator, would preclude use of
AGEN1884, including AGEN1884 hypersensitivity.
12. Women who are pregnant or breastfeeding.
13. Concurrent participation in other investigational drug trials.
14. Has a 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 are obtained after
treatment to the brain metastases. These imaging scans should both be 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.
For individuals who received steroids as part of brain metastases treatment, steroids
must be discontinued ≥ 7 days prior to first dose of study drug.
15. For subjects in Phase 2 with HCC, the following exclusions also apply:
1. Recent encephalopathy episodes in the last 6 months.
2. Recent (within the last 6 months) gastro-esophageal varices bleeding.
3. Subject whose tumors have cardiac involvement, as determined by imaging.
