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

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 specificprocedures. Participation in pharmacogenomics testing is optional.

2. Histologically or cytologically confirmed diagnosis of metastatic or locallyadvanced solid tumor for which no standard therapy is available or standard therapyhas failed.

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

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

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

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

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

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

9. Adequate coagulation, defined as international normalized ratio or prothrombintime ≤ 1.5 × IULN and activated partial thromboplastin time ≤ 1.5 × IULN (unless participant receiving anticoagulant therapy) or stable knowncoagulopathy with sponsor approval.

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

11. Female participants of childbearing potential must have a negative serum pregnancytest at screening (within 72 hours of first dose of study medication).Non-childbearing potential is defined as 1 of the following:

12. ≥ 45 years of age and has not had menses for > 1 year and there is noalternative medical cause.

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

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

15. Female participants of childbearing potential must be willing to use highlyeffective contraceptive measures starting with the Screening visit through 90 daysafter last dose of study treatment. For the UK only, highly effective contraceptivemeasures are defined as follows:

16. Combined (estrogen and progesterone containing) hormonal contraceptionassociated with inhibition of ovulation.

• Oral
• Intravaginal
• Transdermal

2. Progesterone-only hormonal contraception associated with inhibition ofovulation.

• Oral
• Injectable
• Implantable

3. Intrauterine device

4. Intrauterine hormone-releasing system

5. Bilateral tubal occlusion

6. Vasectomized partner

7. Sexual abstinence

8. Male participants with a female partner(s) of childbearing potential must agree touse highly effective contraceptive measures throughout the trial starting with theScreening 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 thepregnant partner. Note: Abstinence is acceptable if this is the established andpreferred contraception method for the participant. The following inclusion criteria are in addition to the above criteria. If there arecriteria below that differs from above, the below indication-specific criteria takeprecedence. Additional Inclusion Criteria for Angiosarcoma Cohort

9. Histologically or cytologically confirmed diagnosis of metastatic or locallyadvanced angiosarcoma for which no standard therapy is available or standard therapyhas failed. Additional Inclusion Criteria for the Hepatocellular Cancer (HCC) Cohort

10. Histologically or cytologically confirmed diagnosis or radiological diagnosisfollowing the guidelines from the American Association for the Study of LiverDiseases of metastatic or locally advanced HCC.

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

12. Child-Pugh score of A. Note: Participants on anticoagulant treatment would have anassigned value of 1 point when scoring prothrombin time/international normalizedratio so the overall Child-Pugh score is not adversely affected.

13. Adequate organ and bone marrow reserve function as indicated by the followinglaboratory values:

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

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

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

17. Chronic HBV infection as evidenced by detectable HBV surface antigen or HBVDNA. Participants with chronic HBV infection must be on antiviral therapy andhave HBV DNA < 500 international units/mL.

18. Active or resolved HCV infection as evidenced by detectable HCV RNA orantibody. Additional Inclusion Criteria for the Non-Small Cell Lung Cancer (NSCLC) Cohort

19. Histologically or cytologically confirmed diagnosis of metastatic or locallyadvanced NSCLC for which no standard therapy is available or standard therapy hasfailed:

20. Adenocarcinoma or squamous cell carcinoma at the time of enrollment. If otherhistologies are also present, must be approved by the medical monitor prior tostudy entry.

21. For participants without targetable alterations: Prior treatment with antiPD(L)-1-based therapy.

22. Participants with targetable alterations (for example, estimated glomerularfiltration rate, anaplastic lymphoma kinase, Kirsten rat sarcoma virus-singlepoint mutation with a glycine-to-cysteine substitution at codon 12, reactiveoxygen species, mesenchymal epithelial transition factor receptor, etc.): musthave received or be intolerant of at least one approved targeted therapy. Additional Inclusion Criteria for the Prostate Cancer Cohort

23. Diagnosis of metastatic castrate resistant prostate cancer.

24. Must have demonstrated serologic or radiographic progression on or following themost recent therapy in the setting of castrate-level testosterone (< 50 nanogramsper mL [ng/mL] and/or maintained on medical/surgical castration throughout) asdefined by at least one of the following:

25. 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.

26. Progression by RECIST 1.1.

27. Progression by PCWG3 criteria for bone disease ("2+2" rule) with or without PSAprogression.

28. Must maintain castration status defined as serum testosterone < 50 ng/mL. Must beeither surgically castrate or on luteinizing hormone-releasing hormone analog forthe duration of the study. Additional Inclusion Criteria for Breast Cancer

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

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 studyof an investigational agent and received study therapy or used an investigationdevice within 3 weeks of first dose of current study drug.

2. Received prior systemic cytotoxic chemotherapy, biological therapy, radiotherapy, ormajor surgery within 3 weeks prior to first dose of study drug; for tyrosine kinaseinhibitor or similar within 4 × half-life prior to first dose of study drug. A 1-week washout is permitted for palliative radiation to non-central nervous systemdisease, with Sponsor approval.

3. Participants who have received prior CTLA-4 therapy may be enrolled in selectedindications upon agreement with the Sponsor.

4. Persistent toxicity of NCI CTCAE version 5.0 Grade > 1 severity that is related toprior therapy. Note: Sensory neuropathy, hypothyroidism or alopecia of Grade ≤ 2 areacceptable. Other Grade 2 toxicities of prior treatments that are controlled withmedication (for example, diabetes or hypertension) may be permitted with sponsorapproval.

5. Expected to require any other form of systemic or localized antineoplastic therapywhile on trial (including maintenance therapy with another agent, radiation therapy,and/or surgical resection).

6. History of:

7. Severe (Grade ≥ 3) hypersensitivity reaction to a fully human monoclonalantibodies

8. Immune-related adverse event requiring treatment with systemic steroids for > 7days excluding Grade 1 or 2 rash.

9. Interstitial lung disease or lung disease which may interfere with theassessment of pneumonitis.

10. Uncontrolled asthma (that is, ≥ 3 features of partly controlled asthma)

11. Pneumonitis that has required oral or IV corticosteroids.

12. Receiving systemic corticosteroid therapy 1 week prior to the first dose of studydrug or receiving any other form of systemic immunosuppressive medication. Note:Corticosteroid use as a premedication for IV contrast allergies/reactions isallowed. Participants who are receiving daily corticosteroid replacement therapy arealso an exception to this rule. Daily prednisone at doses of ≤ 7.5 mg or equivalenthydrocortisone dose are examples of permitted replacement therapy. Use of inhaled ortopical corticosteroids is permitted.

13. Brain metastases or leptomeningeal metastases with the following exceptions: Note:Brain metastases which have been treated with either surgical resection orstereotactic radio surgery. These participants must be off steroids ≥ 10 days priorto enrollment for the purpose of managing their brain metastases. Repeat brainimaging following surgical resection or stereotactic radiosurgery is not required iftheir last brain magnetic resonance imaging is within screening window. Note:Untreated isolated brain metastases that are too small for treatment by surgicalresection or stereotactic radiosurgery (that is, 1-2 mm) and/or of uncertainetiology are potentially eligible but must be approved by the sponsor.

14. Active or history of autoimmune disease that requires systemic treatment within 2years of the start of study drug (that is, with use of disease-modifying agents,corticosteroids, or immunosuppressive drugs). Note: Participants with autoimmuneconditions requiring hormone replacement therapy or topical treatments are eligible.

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

16. Active infection requiring systemic treatment.

17. Known history of human immunodeficiency virus type 1 or 2 antibodies.

18. Known active infection with hepatitis B and/or hepatitis C virus.

19. Clinically significant (that is, active) cardiovascular disease: cerebral vascularaccident/stroke or myocardial infarction within 6 months of enrollment, unstableangina, congestive heart failure (New York Heart Association class ≥ II), or seriousuncontrolled cardiac arrhythmia requiring medication.

20. History or current evidence of any condition, therapy, any active infections, orlaboratory abnormality that might confound the results of the trial, interfere withthe participant's participation for the full duration of the trial, or is not in thebest interest of the participant to participate, in the opinion of the treatingInvestigator.

21. Known psychiatric or substance abuse disorder that would interfere with cooperationwith the requirements of the study.

22. Legally incapacitated or has limited legal capacity.

23. Pregnant or breastfeeding.

24. Concurrent malignancy requiring treatment or history of prior malignancy activewithin 2 years prior to the first dose of study treatment. Exceptions: participantswith completely resected prior early-stage basal/squamous cell skin cancer ortreated cervical carcinoma in situ. The following exclusion criteria are in addition to the above criteria. If there arecriteria below that differs from above, the below indication-specific criteria takeprecedence. Additional Exclusion Criteria for the HCC Cohort

25. Received locoregional therapy (for example, transcatheter chemoembolization,radiation, surgery) within 6 weeks or yttrium-90 within 12 weeks.

26. Hepatic encephalopathy within the last 6 months requiring admission or initiation ofor intensification of therapy. Participants taking rifaximin/lactulose asencephalopathy prophylaxis are allowed as long as they have not had clinicallyevident encephalopathy in the past 6 months.

27. Gastro-esophageal varices bleeding in the last 6 months.

28. Ascites requiring paracentesis within the last 3 months. Participants with previousascites that is managed with stable doses of diuretics and have a Child Pugh scoreof A are allowed. Exclusion Criterion Specific for the UK

29. Hypersensitivity to the active ingredient or any other component of theinvestigational medicinal products.