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

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

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

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

• Measurable disease on imaging based on RECIST 1.1, except for prostate cancer.

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

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

∙ 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).

‣ Adequate liver function, defined as total bilirubin level ≤ 1.5 × institutional upper limit of normal (IULN) (except for participants with Gilbert syndrome who must have a total bilirubin level of ≤ 3.0 × IULN), aspartate aminotransferase ≤ 2.5 × IULN, and alanine aminotransferase ≤ 2.5 × IULN.

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

‣ 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) or stable known coagulopathy with sponsor approval.

• A sufficient and adequate formalin-fixed paraffin embedded tumor tissue sample (fresh or archival tumor tissue) collected since last treatment and before the first dose from a site not previously irradiated, if clinically feasible.

• 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:

∙ ≥ 45 years of age and has not had menses for \> 1 year and there is no alternative medical cause.

‣ Amenorrheic for \> 2 years without a hysterectomy and/or oophorectomy and follicle stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation.

‣ Status is post-hysterectomy, -oophorectomy, or -tubal ligation.

• 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. For the UK only, highly effective contraceptive measures are defined as follows:

∙ Combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation.

⁃ Oral

• Intravaginal

• Transdermal

‣ Progesterone-only hormonal contraception associated with inhibition of ovulation.

⁃ Oral

• Injectable

• Implantable

‣ Intrauterine device

‣ Intrauterine hormone-releasing system

‣ Bilateral tubal occlusion

‣ Vasectomized partner

‣ Sexual abstinence

• 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 (which is not considered highly effective); 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.

• The following inclusion criteria are in addition to the above criteria. If there are criteria below that differs from above, the below indication-specific criteria take precedence.

• Additional Inclusion Criteria for Angiosarcoma Cohort

⁃ Histologically or cytologically confirmed diagnosis of metastatic or locally advanced angiosarcoma for which no standard therapy is available or standard therapy has failed.

⁃ Additional Inclusion Criteria for the Hepatocellular Cancer (HCC) Cohort

⁃ Histologically or cytologically confirmed diagnosis or radiological diagnosis following the guidelines from the American Association for the Study of Liver Diseases of metastatic or locally advanced HCC.

⁃ Must have progressed while receiving, or following, programmed death-ligand 1 (PD(L)-1)-based therapy.

⁃ Child-Pugh score of A. Note: Participants on anticoagulant treatment would have an assigned value of 1 point when scoring prothrombin time/international normalized ratio so the overall Child-Pugh score is not adversely affected.

⁃ Adequate organ and bone marrow reserve function as indicated by the following laboratory values:

• Platelet count ≥ 60 × 10\^6/cubic millimeter (mm\^3) and absolute neutrophil count ≥ 1,000 × 10\^6/L are acceptable provided that the investigator assesses these abnormalities as being due to liver disease.

∙ Adequate liver function, defined as aspartate aminotransferase and alanine aminotransferase ≤ 5 × IULN, bilirubin ≤ 2 × IULN.

⁃ Participants are eligible to enroll if they have non-viral-HCC or if they have hepatitis B (HBV), or hepatitis C virus (HCV) related HCC, defined as follows:

• Chronic HBV infection as evidenced by detectable HBV surface antigen or HBV DNA. Participants with chronic HBV infection must be on antiviral therapy and have HBV DNA \< 500 international units/mL.

∙ Active or resolved HCV infection as evidenced by detectable HCV RNA or antibody.

⁃ Additional Inclusion Criteria for the Non-Small Cell Lung Cancer (NSCLC) Cohort

⁃ Histologically or cytologically confirmed diagnosis of metastatic or locally advanced NSCLC for which no standard therapy is available or standard therapy has failed:

• Adenocarcinoma or squamous cell carcinoma at the time of enrollment. If other histologies are also present, must be approved by the medical monitor prior to study entry.

∙ For participants without targetable alterations: Prior treatment with anti PD(L)-1-based therapy.

∙ Participants with targetable alterations (for example, estimated glomerular filtration rate, anaplastic lymphoma kinase, Kirsten rat sarcoma virus-single point mutation with a glycine-to-cysteine substitution at codon 12, reactive oxygen species, mesenchymal epithelial transition factor receptor, etc.): must have received or be intolerant of at least one approved targeted therapy.

⁃ Additional Inclusion Criteria for the Prostate Cancer Cohort

⁃ Diagnosis of metastatic castrate resistant prostate cancer.

⁃ Must have demonstrated serologic or radiographic progression on or following the most recent therapy in the setting of castrate-level testosterone (\< 50 nanograms per mL \[ng/mL\] and/or maintained on medical/surgical castration throughout) as defined by at least one of the following:

• Baseline PSA ≥ 2.0 ng/mL and 2 sequential rises in prostate-specific antigen (PSA) with each rising value being at least 1 week apart.

∙ Progression by RECIST 1.1.

∙ Progression by PCWG3 criteria for bone disease (2+2 rule) with or without PSA progression.

⁃ Must maintain castration status defined as serum testosterone \< 50 ng/mL. Must be either surgically castrate or on luteinizing hormone-releasing hormone analog for the duration of the study.

⁃ Additional Inclusion Criteria for Breast Cancer

⁃ Must have received PD-(L)1 therapy if indicated. Note: Premenopausal participants may continue ongoing ovarian suppression on study. Permitted agents are goserelin, triptorelin or analogs.