A Phase 1/2, Open-Label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics 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
Phase: PHASE1
Conditions: Advanced Solid Cancers, Advanced Solid Cancers Refractory to PD-1 and PD-L1 Therapies
Sponsor: Agenus Inc.

Protocol C-500-01 
Phase 1/2 Study of AGEN1884 in Advanced Tumors 
Amendment 9, 26 November 2019 
Protocol C-500-01
A Phase 1/2, Open-Label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and 
Pharmacodynamics 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 
Sponsor 
Agenus Inc.
3 Forbes Road
Lexington, MA 02421 USA
Phone: 
Fax: 
US toll-free phone: 
Medical Monitor 
 
Agenus Inc.
3 Forbes Road
Lexington, MA 02421
Clinical Trial Protocol Version, 
Date 
Amendment 9, 26 November 2019 
Replaces Clinical Trial Protocol 
Version, Date
Amendment 8, 20 February 2019 
CONFIDENTIAL DOCUMENT 
This document is the confidential property of Agenus Inc. No part of it may be transmitted, 
reproduced, published, or used without the permission of Agenus. 
The study is to be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP) and other applicable regulatory requirements. 
NCT #: NCT02694822

Protocol C-500-01 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 2 
SYNOPSIS ...................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND TERMS ................................................................................ 15 
1. 
STUDY OBJECTIVES ......................................................................................................... 19 
 
Primary Objectives........................................................................................................ 19 
 
Secondary Objectives.................................................................................................... 19 
 
Exploratory Objectives ................................................................................................. 19 
2. 
BACKGROUND .................................................................................................................. 19 
 
Investigational Agent: AGEN1884 ............................................................................... 19 
2.1.1 
Supporting Nonclinical Data..................................................................................... 19 
 
Rationale ....................................................................................................................... 21 
3. 
INVESTIGATIONAL PLAN................................................................................................ 21 
 
Overall Study Design .................................................................................................... 21 
3.1.1 
Safety Review Committee ........................................................................................ 25 
3.1.2 
Dose-Limiting Toxicity Evaluation .......................................................................... 26 
 
Eligibility Criteria ......................................................................................................... 28 
3.2.1 
Inclusion Criteria ...................................................................................................... 28 
3.2.2 
Exclusion Criteria ..................................................................................................... 29 
 
Randomization .............................................................................................................. 32 
 
Blinding......................................................................................................................... 32 
 
Discontinuation of Therapy .......................................................................................... 32 
 
Discontinuation from Study .......................................................................................... 32 
 
Treatment Beyond Disease Progression ....................................................................... 33 
4. 
INVESTIGATIONAL AGENT ............................................................................................. 33 
 
Description of Investigational Agent ............................................................................ 33 
4.1.1 
Dosage and Administration ....................................................................................... 33 
4.1.2 
Dosing Delay Criteria ............................................................................................... 34 
 
Infusion Reactions ........................................................................................................ 35 
 
Management of Immune-Related Adverse Events ....................................................... 37 
4.3.1 
Dermatological irAEs ............................................................................................... 37 
4.3.2 
Gastrointestinal irAEs ............................................................................................... 39 
4.3.3 
Pulmonary irAEs ....................................................................................................... 40 
4.3.4 
Hepatic irAEs ............................................................................................................ 41 
4.3.5 
Endocrine irAEs ........................................................................................................ 42 
4.3.6 
Renal irAEs ............................................................................................................... 44 
4.3.7 
Neurological irAEs ................................................................................................... 45 
 
Adverse Drug Reactions Requiring Treatment Discontinuation or Modifications ....... 45 
4.4.1 
Dose Reductions ....................................................................................................... 45 
4.4.2 
Permanent Treatment Discontinuation ...................................................................... 46 
 
Prior and Concomitant Therapy .................................................................................... 47 
 
Investigational Agent Accountability ............................................................................ 47 

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5. 
STUDY PROCEDURES AND ASSESSMENTS ................................................................ 47 
 
Schedule of Assessments .............................................................................................. 47 
5.1.1 
Screening................................................................................................................... 51 
5.1.2 
Treatment and Evaluation Period .............................................................................. 51 
5.1.3 
End-of-Treatment Visit ............................................................................................. 51 
5.1.4 
Final Safety Visit ....................................................................................................... 51 
5.1.5 
Survival Follow-up ................................................................................................... 51 
 
Demographics and Screening Procedures ..................................................................... 51 
5.2.1 
Demographics and Medical/Cancer History ............................................................. 51 
5.2.2 
Eastern Cooperative Oncology Group Scale ............................................................ 52 
5.2.3 
New York Heart Association Class Evaluation ......................................................... 52 
5.2.4 
Tumor Markers ......................................................................................................... 52 
 
Pharmacokinetic Assessments ...................................................................................... 52 
 
Immunogenicity Assessments ....................................................................................... 53 
 
Exploratory Biomarkers ................................................................................................ 53 
 
Pharmacodynamic Assessments and Biopsy ................................................................ 54 
5.6.1 
Biopsy and Tissue Collection ................................................................................... 54 
5.6.2 
Pharmacogenomics (Optional) .................................................................................. 54 
 
Tumor Assessments ....................................................................................................... 55 
5.7.1 
Response Evaluation Criterion in Solid Tumors ....................................................... 55 
 
Safety Assessments ....................................................................................................... 55 
5.8.1 
Physical Examination................................................................................................ 55 
5.8.2 
Vital Signs ................................................................................................................. 56 
5.8.3 
12-Lead Electrocardiogram ...................................................................................... 56 
5.8.4 
Clinical Laboratory Assessments .............................................................................. 56 
5.8.5 
Concomitant Medications ......................................................................................... 57 
5.8.6 
Adverse Events ......................................................................................................... 57 
 
Relationship to Study Treatment ................................................................................... 60 
 
Pregnancy ...................................................................................................................... 61 
 
Disease Progression or Secondary Cancer or Death ..................................................... 61 
6. 
STATISTICAL CONSIDERATIONS ................................................................................... 62 
 
Sample Size Considerations .......................................................................................... 62 
 
Endpoints ...................................................................................................................... 62 
 
Analysis Sets ................................................................................................................. 63 
 
Analysis Methods.......................................................................................................... 63 
6.4.1 
Safety Analysis.......................................................................................................... 63 
6.4.2 
Efficacy Analysis ...................................................................................................... 64 
 
Statistical Analysis Plan ................................................................................................ 64 
7. 
COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL CONSIDERATIONS, 
AND INFORMED CONSENT..................................................................................................... 64 
 
Compliance with Good Clinical Practice and Ethical Considerations .......................... 64 
8. 
STUDY MANAGEMENT AND MATERIALS ................................................................... 65 
 
Data Recording and Retention of Study Data ............................................................... 65 

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Monitoring, Verification of Data, Audit, and Inspection .............................................. 66 
 
Study Stopping Rules .................................................................................................... 66 
9. 
COMMUNICATION AND PUBLICATION OF RESULTS ............................................... 67 
10. 
REFERENCES ................................................................................................................. 68 
APPENDIX A PROTOCOL LEAD SIGNATURE PAGE ........................................................... 70 
APPENDIX B INVESTIGATOR SIGNATURE PAGE ............................................................... 71 
APPENDIX C EASTERN COOPERATIVE ONCOLOGY GROUP SCORE ............................ 72 
APPENDIX D NEW YORK HEART ASSOCIATION CLASS .................................................. 73 
APPENDIX E RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 
VERSION 1.1) .............................................................................................................................. 74 
APPENDIX F CHILD-PUGH SCORE FOR CIRRHOSIS MORTALITY ................................. 78 
 
 
LIST OF TABLES 
 
Table 1: AGEN1884 Dose Levels and Cohorts .............................................................................24 
Table 2: Infusion Reaction Guidelines ...........................................................................................36 
Table 3: Dermatological irAE Management Algorithm .................................................................38 
Table 4: Gastrointestinal irAEs Management Algorithm ...............................................................39 
Table 5: Pulmonary irAE Management Algorithm ........................................................................40 
Table 6: Hepatic irAE Management Algorithm .............................................................................41 
Table 7: Endocrine irAE Management Algorithm .........................................................................43 
Table 8: Renal irAE Management Algorithm ................................................................................44 
Table 9: Neurological irAE Management Algorithm .....................................................................45 
Table 10: Schedule of Assessments ...............................................................................................48 
Table 11: Additional Pharmacokinetic Sampling Schedule in an Approximate 20 Subject 
Subpopulation ........................................................................................................53 
Table 12: Clinical Laboratory Assessments ...................................................................................57 
 
LIST OF FIGURES 
 
Figure 1: Study Design ..................................................................................................................23 
 

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SYNOPSIS 
Study Title 
Phase 1/2, Open-Label, Multicenter Study to Evaluate the Safety, 
Pharmacokinetics, and Pharmacodynamics 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 
Protocol  
C-500-01 
Number of Study Centers 
Multicenter (US only) 
Clinical Phase 
Phase 1/2 
Study Rationale 
Cytotoxic T lymphocyte–associated protein 4 (CTLA-4) is one of various 
downregulators of immune response, known as an inhibitory checkpoint, and 
blocking it with an anti–CTLA-4 antibody has been demonstrated to enhance 
immune responsiveness by inhibiting downregulation of T-cell activation. An 
immunoglobulin G1 (IgG1) anti–CTLA-4 antibody has demonstrated robust 
clinical efficacy, and has received approval in the United States for the treatment 
of metastatic melanoma, and in Europe for previously treated metastatic 
melanoma.  
The clinical efficacy associated with blockade of CTLA-4 has also been 
associated with toxicity as the result of immune activation. Moreover, only a 
subset of patients, even among melanoma patients, will respond to CTLA-4 
blockade alone. The combination of CTLA-4 blockade with blockade of the 
PD-1/PD-L1 (programmed cell death protein 1/programmed cell death protein 1 
ligand 1) pathway was recently shown to be more effective than targeting either 
pathway alone, but still had substantial side effects suggestive primarily of 
toxicity from CTLA-4 blockade. Moreover, substantial clinical activity has been 
observed when PD-1/PD-L1 inhibition and CTLA-4 inhibition are combined 
sequentially. Although the half-life of nivolumab is 17-25 days, its occupancy of 
PD-1 on circulating T cells has a mean plateau of 72% for at least 59 days, with 
PD-1 blockade persisting even with undetectable serum nivolumab 
concentrations ; therefore, substantial inhibition of PD-1 would be expected to 
continue in the PD-l/PD-L1 cohorts at the time of AGEN1884 treatment 
initiation. The results of this single-agent study will inform the further 
development of AGEN1884. 
Combining a CTLA-4 inhibitor such as AGEN1884 with PD-1 blockade or other 
immunotherapies therefore remains an attractive goal in immuno-oncology. 
Alternate combination approaches to the development of AGEN1884 may 
ameliorate the side effects of CTLA-4 blockade while focusing immune 
stimulation to the benefit of patients with tumor types for which immunotherapy 
does not currently work, and patients with melanoma who cannot tolerate 
CTLA-4 blockade with the approved antibody as currently administered. The 
present study will seek to define the safety and maximum tolerated dose (MTD) 
of single-agent AGEN1884, and include expansion of enrollment at the MTD or 
maximum planned dose level to further explore the activity of AGEN1884 
monotherapy in subjects with advanced or refractory cancer, including those 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). 

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The Phase 1 portion of the study also included expansion of enrollment at 
1 mg/kg and 3 mg/kg to further explore the activity of AGEN1884 as a 
monotherapy. 
In Phase 2, subjects who have received previous treatment with 
immunotherapeutic agents (except those who received previous treatment with 
anti–CTLA-4 agents) will be allowed to enroll in order to better understand the 
safety of sequential treatment with AGEN1884 in what is becoming a common 
clinical practice due to the approval of multiple PD-1– and PD-L1–targeting 
agents. 
Study Objectives 
Primary Objectives 
 To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of 
AGEN1884 in subjects with advanced or metastatic cancer (solid tumors or 
lymphoma), including but not limited to carcinoma, sarcoma, or melanoma 
(Phase 1); and to evaluate the safety and tolerability of AGEN1884 in 
subjects who have progressed during treatment with a PD-1/PD-L1 
inhibitor as their most recent therapy (Phase 2).  
 To characterize AGEN1884 pharmacokinetics (PK). 
Secondary Objectives 
 To evaluate the preliminary efficacy of AGEN1884 by assessing objective 
response rate (ORR), disease control rate (DCR), and duration of response 
(DOR) per Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1. 
 To evaluate the preliminary efficacy of AGEN1884 by assessing 
progression-free survival (PFS) and overall survival (OS). 
Exploratory Objectives 
 To explore biomarkers that may predict pharmacologic activity or response 
to AGEN1884. 
 To characterize the effect of AGEN1884 on tumor tissue obtained post-
treatment, if available. 
Study Population 
The population in this Phase 1/2 study will include subjects ≥18 years old with a 
histological or cytological diagnosis of relapsed or refractory lymphoma or solid 
cancer, including carcinoma, sarcoma, or melanoma, that is considered incurable 
and without therapies with established benefit. The Phase 2 population will 
include subjects 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) with a subpopulation to include  approximately 
20 subjects with advanced hepatocellular carcinoma (HCC) and 40 non-HCC 
subjects.  
Subjects will be excluded if they have had a previous severe hypersensitivity 
reaction to another fully human monoclonal antibody, history of primary of 
secondary immunodeficiency or autoimmunity, or received anticancer 
medications or other investigational drugs within protocol-defined intervals 
before the first administration of study drug. 
Number of Subjects, 
Accrual, and Study 
Duration 
Overall, approximately 100 subjects will be enrolled in Phase 1 and Phase 2. In 
Phase 2, up to 60 of these subjects must have experienced progression with a 
PD-1/PD-L1 inhibitor as their most recent therapy (2-6 weeks prior to first dose 
of study drug). Approximately 20 subjects in Phase 2 will have advanced HCC. 

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Study duration will be approximately 5 years (including enrollment and follow-
up). 
Study Design and Dosing 
This is an open-label, Phase 1/2, multicenter study to evaluate the safety, PK, 
pharmacodynamics, and activity of an anti–CTLA-4 human monoclonal 
antibody (AGEN1884).  
The Phase 1 portion of the study is completed. It enrolled adult subjects with 
refractory, advanced cancer. The 3+3 dose escalation evaluated AGEN1884 at 
0.1, 0.3, 1, 3, and 6 mg/kg dose levels. It also included an expansion phase at 
1 mg/kg and 3 mg/kg. Dose levels >6 mg/kg were not planned. The 
biopharmacological properties of the antibody indicated that this dose escalation 
plan would include evaluation of doses within a safe and clinically active range. 
Dose escalation continued until the MTD was reached or the maximum planned 
dose level (6 mg/kg) was shown to be safe (i.e., passes DLT evaluation). The 
MTD was defined as the dose below which 2 DLTs are observed among 
3 subjects treated at a given dose level. 
Based on data from the Phase 1 dose escalation, 1 mg/kg was chosen as the 
starting dose in Phase 2. Phase 2 consists of approximately 40 subjects 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). For this phase: 
 
Approximately 20 subjects with advanced HCC will be enrolled. 
 
The enrollment of non-HCC will be approximately 40 subjects. 
Note: additional subjects may be enrolled to either the HCC or non-HCC 
populations as necessary to ensure that 20 subjects are evaluable for the 
additional PK evaluation (i.e., 3 additional timepoints, see Section 5.3). 
Expanded PK/anti-drug antibody (ADA) and safety data will be analyzed to plan 
future development of combination therapies. 
Subjects who have received prior therapy with cancer vaccines or oncolytic viral 
therapy will be allowed to enroll on this study. 
Subjects will be evaluated for immune correlates, PK, pharmacodynamics, 
disease response, and safety, as determined through adverse events, vital signs, 
physical examination, clinical laboratory tests, and imaging. 
Study Drug 
AGEN1884 is a novel, fully human monoclonal immunoglobulin G1 antibody 
designed to block CTLA-4. 
Dosage and Administration 
AGEN1884 will be administered intravenously (IV) for each cycle (3 weeks) as a 
60-min (-10/+20 min) infusion. Infusions will be followed immediately by a 
15-min saline flush of the IV line. 
In Phase 1, subjects will receive AGEN1884 at 0.1, 0.3, 1, 3, and 6 mg/kg dose 
levels in a 3+3 dose escalation design. Subjects in Phase 2 will begin treatment at 
the 1 mg/kg dose level.   
Duration of cycles: cycles are 3 weeks for the first 4 cycles. 
For the subsequent cycles (Cycle 5 and onward): At the 12-week evaluation 
timepoint, subjects may continue to receive AGEN1884 every 3, 6, or 12 weeks 
(± 7 days) for a maximum duration of 1 year of treatment, provided they were 
not evaluated with PD and were tolerating the study drug. The appropriate 
schedule will be based on discussion with the medical monitor. Subjects who 

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progressed yet still have clinical benefit from treatment may continue on 
treatment following discussion with, and approval of, the medical monitor. 

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Inclusion and Exclusion 
Criteria 
Inclusion Criteria 
Subjects must meet all of the following 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 PD-1/PD-L1 naïve and those 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).  
 
For subjects in Phase 2 with HCC: 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 being due to liver disease. 
9. Adequate liver function, defined as aspartate aminotransferase (AST) 
and alanine aminotransferase (ALT) ≤2.5× institutional upper limit of 
normal (ULN), and bilirubin ≤1.5 ULN.  
For subjects in Phase 2 with HCC: AST and ALT ≤5 × ULN, 
bilirubin ≤2  × 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. 

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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 (Phase 2), 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-

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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 
safety review committee, 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-grades 
(≤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) ≤7days 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 the 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 (i.e., >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 electrocardiogram (ECG) that, in 
the investigator’s opinion, is clinically meaningful.  

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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 at screening (defined as 2 brain images, both of which 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:  
a. 
Recent encephalopathy episodes in the last 6 months.   
b. Recent (within the last 3 months) gastro-esophageal varices 
bleeding  
c. 
Subject whose tumors have cardiac involvement, as 
determined by imaging. 
Pharmacodynamics 
Blood samples will be collected to measure proteins and markers of 
inflammation or immune modulation. Plasma will be derived from whole blood 
samples and used for immune cell population profiling and DNA/ribonucleic 
acid (RNA) sequencing. 
Pharmacokinetics and 
Immunogenicity 
AGEN1884 PK will be characterized and potential impact of ADA on PK 
profiles will be assessed.  
AGEN1884 immunogenicity will be evaluated with serum ADA monitoring. 
Efficacy 
Disease assessments will be performed based on RECIST Version 1.1.  Disease 
response assessments by RECIST to be performed at Study Week 6, Week 12 
and Q6w for subjects assigned to 3- or 6-w treatment schedule, or Q12w for 
subjects assigned to 12-w treatment schedule until off-disease response 
evaluation criteria are met. 
Safety 
Subjects will be followed for safety and adverse events for the duration of the 
study and for ≤90 days after the last dose of investigational agent. Safety will be 
evaluated through adverse events (per National Cancer Institute Common 
Terminology Criteria for Adverse Events v. 5), physical examinations, vital 
signs, 12-lead ECG, clinical laboratory assessments, and lymphocyte subset 
measurements. 

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Endpoints 
Primary Endpoints 
 Safety and tolerability will be assessed by monitoring the frequency, 
duration, and severity of drug-related adverse events; by completing 
physical examinations; by evaluating changes in vital signs and ECG; 
through clinical evaluations; and laboratory blood and urine sample 
evaluations. 
 PK parameters to be estimated and reported may include, but may not be 
limited to, maximum drug concentration at steady-state (Cmax-ss), minimum  
drug concentration at steady state (Cmin-ss), area under the drug 
concentration-time curve within time span t1 to t2 at steady-state 
(AUC(t1-t2)-ss), area under the drug concentration-time curve from time of 
dosing to time of last observation (AUC(0-t)), area under the drug 
concentration-time curve from time of dosing extrapolated to infinity 
(AUC(0-∞)), time to reach maximum drug concentration (tmax), terminal 
elimination rate constant (λz), terminal elimination half-life (t½), systemic 
clearance (CL), and volume of distribution (Vd). 
Secondary Endpoints 
 Objective response rate, (ORR), defined as the percentage of subjects 
having CR or PR, as determined by radiographic disease assessments per 
RECIST 1.1. 
 Disease control rate (DCR) will include subjects that have best overall 
response (BOR) of CR, PR and SD for at least 12 weeks. 
 Progression-free survival (PFS), defined as the interval from the date of first 
dose of investigational agent until the earliest date of disease progression 
(PD), as determined by investigator assessment of objective radiographic 
disease assessments per RECIST 1.1, or death due to any cause if occurring 
sooner than progression. 
 Duration of response, (DOR), defined as the interval from the date 
measurement criteria are met for CR or PR (whichever is first recorded) 
until the earliest date of disease progression, as determined by investigator 
assessment of objective radiographic disease assessments per RECIST 1.1, 
or death due to any cause if occurring sooner than progression. Only 
subjects who achieve an initial response will be evaluated for DOR. 
 Overall survival (OS), defined as the interval from the date of first dose of 
investigational agent until the date of death. 
 The pharmacologically active dose of AGEN1884, determined through 
clinical signs of drug activity, surrogate markers, or pharmacodynamic 
studies, including but not limited to the presence of immune-related adverse 
events. 
Exploratory Endpoints 
 Other biomarker effects and outcome predictors for AGEN1884 in 
peripheral blood and/or tumor tissue will be evaluated as exploratory 
analyses. 
Statistical Considerations 
Overall, there will be approximately 100 subjects enrolled in Phase 1 and Phase 
2 of this study. After safety is established in the 1 mg/kg and 3 mg/kg cohorts, 
additional subjects will be enrolled into those dose levels to support the 
objectives and expand the number of correlates available for evaluation. The 
Phase 2 population will include up to 60 subjects 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) with a 
subpopulation to include approximately 20 subjects with advanced HCC and 
approximately 40 non-HCC subjects. 

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The sample size is not based on inferential statistics. 
Statistical Analyses 
Descriptive statistics of safety, efficacy, PK, and pharmacodynamic parameters 
will be provided by dose level, study cohort, and study phase. 
Both noncompartmental (NCA) and compartmental modeling (e.g., population 
pharmacokinetics [PopPK]) techniques will be used to analyze the PK. 

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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Term 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody(ies) 
ADCC 
antibody-dependent cellular cytotoxicity 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
AFP 
alpha-fetoprotein 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APC 
antigen-presenting cell 
aPTT 
partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the drug concentration-time curve 
AUC(0-∞) 
area under the drug concentration-time curve from time of 
dosing extrapolated to infinity 
AUC(0-t) 
area under the drug concentration-time curve from time of 
dosing to time of last observation 
AUC(τ1-τ2)-ss 
area under the drug concentration-time curve within time span 
t1 to t2 at steady-state 
BOR 
best overall response 
C 
Celsius or cycle 
CA-125 
cancer antigen 125 
CL 
systemic clearance 
Cmax-ss 
maximum drug concentration at steady-state 
Cmin-ss 
minimum drug concentration at steady-state 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events Version 5 
CTLA-4 
cytotoxic T lymphocyte–associated protein 4 

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Abbreviation 
Term 
D 
day 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
EBUS 
endobronchial ultrasound 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
Fc 
fragment crystallizable 
FcγR 
fragment-crystallizable gamma receptor  
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyltransferase 
GLP 
Good Laboratory Practice 
h 
hour(s) 
HCC 
hepatocellular carcinoma 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG1 
immunoglobulin G1 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
LFT 
liver function test 
LLN 
lower limit of normal 
λz 
terminal elimination rate constant 
MABEL 
minimally anticipated biologic effect level 
mol 
micromolar 

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Abbreviation 
Term 
MRI 
magnetic resonance imaging 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NSAID 
nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death protein 1 ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PGx 
pharmacogenomics 
PK 
pharmacokinetic(s) 
PO 
per os (orally) 
PopPK 
population pharmacokinetic(s) 
PR 
partial response 
PT 
prothrombin time 
Q 
every 
QTc 
corrected QT 
RECIST 
Response Evaluation Criteria in Solid Tumors Version 1.1 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease  
SRC 
Safety Review Committee 
t1/2 
terminal elimination half-life 
T4 
thyroxine 
TCR 
T-cell receptor  

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Abbreviation 
Term 
tmax 
time to reach maximum drug concentration 
Tregs 
regulatory T cells 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal  
Vd 
volume of distribution  
W 
week 
WBC 
white blood cell 
 
 

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1. 
Study Objectives 
 
Primary Objectives 
 To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of AGEN1884 in 
subjects with advanced or metastatic cancer (solid tumors or lymphoma), including but 
not limited to carcinoma, sarcoma, or melanoma (Phase 1); and to evaluate the safety and 
tolerability of AGEN1884 in subjects who have progressed during treatment with a PD-
1/PD-L1 (programmed cell death protein 1/PD-1 ligand 1) inhibitor as their most recent 
therapy (Phase 2).  
 To characterize AGEN1884 pharmacokinetics (PK). 
 
Secondary Objectives 
 To evaluate the preliminary efficacy of AGEN1884 by assessing objective response rate 
(ORR), disease control rate (DCR), and duration of response (DOR) per Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. 
 To evaluate the preliminary efficacy of AGEN1884 by assessing progression-free 
survival (PFS) and overall survival (OS). 
 
Exploratory Objectives  
 To explore biomarkers that may predict pharmacologic activity or response to 
AGEN1884. 
 To characterize the effect of AGEN1884 on tumor tissue obtained post-treatment, if 
available. 
2. 
Background 
 
Investigational Agent: AGEN1884 
AGEN1884 is a novel, fully human monoclonal immunoglobulin G1 (IgG1) antibody designed 
to block cytotoxic T lymphocyte–associated protein 4 (CTLA-4), a key negative regulator of T-
cell responses. Blocking CTLA-4 with an antibody enhances antitumor immune responsiveness 
by inhibiting the downregulation of T-cell activation. In this first-in-human trial, AGEN1884 will 
be evaluated as monotherapy in subjects with advanced and/or refractory malignancies, including 
those who have progressed during treatment with a PD-1/PD-L1 inhibitor as their most recent 
therapy. 
2.1.1 Supporting Nonclinical Data 
AGEN1884 selectively binds with high affinity to human CTLA-4 and cross-reacts with 
cynomolgus monkey (Macaca fascicularis) CTLA-4. However, AGEN1884 does not cross-react 
with rodent CTLA-4 or CTLA-4–related members of the CD28 superfamily. AGEN1884 
potently blocks the interaction of CTLA-4 with CD80 and CD86, resulting in increased levels of 
interleukin 2 from T-cell receptor (TCR)–activated T cells cultured from peripheral blood 
mononuclear cells (PBMCs). By contrast, when soluble AGEN1884 is added to human PBMCs 
or whole blood in the absence of TCR activation, cytokines are not induced. Cytokine production 
in the absence of TCR stimulation would be predictive of cytokine release syndrome in vivo. 
Importantly, activated T cells cultured in the presence of AGEN1884 showed no evidence of 
reduced cytokine production, thereby excluding any agonistic inhibitory signals delivered by this 

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antibody. Consistent with its ability to engage cynomolgus monkey CTLA-4, AGEN1884 
enhanced T cell–dependent antibody responses in animals immunized with a hepatitis B vaccine.  
CTLA-4 is also expressed by regulatory T cells (Tregs), which can impair tumor immunity by 
multiple suppressive mechanisms (Wing et al., 2008; Zou, 2006). One such mechanism involves 
Treg-expressed CTLA-4 mediating the physical removal of CD80 and CD86 from the surface of 
activated antigen-presenting cells (APCs) by a process termed trans-endocytosis, which can 
attenuate the immune-stimulatory potential of APCs (Qureshi et al.). Emerging clinical and 
preclinical study data support a secondary mechanism of action for anti–CTLA-4 antagonist 
antibodies involving the deletion of Tregs (Bulliard et al., 2013; Marabelle et al., 2013; Romano 
et al., 2015; Selby et al., 2013; Simpson et al., 2013). This mechanism involves the co-binding of 
anti–CTLA-4 antibodies to Tregs located within the tumor and fragment-crystallizable gamma 
receptor (FcγR)–expressing effector cells (e.g., natural killer or myeloid cells), resulting in 
antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis. 
The elimination of tumor-associated Tregs, which contribute to tumor immunity by dampening 
the activation of effector T cell to tumor-associated antigens, is considered to be a major obstacle 
in achieving effective antitumor immunity during immunotherapy (Zou, 2006). Consistent with 
an IgG1 fragment crystallizable (Fc) region, AGEN1884 can bind to FcγRs expressed by 
effector immune cell populations and mediate ADCC activity against target cells expressing high 
levels of CTLA-4. Also consistent with its IgG1Fc region, AGEN1884 showed in vitro 
evidence of complement-dependent cytotoxicity toward CTLA-4–expressing target cells. 
AGEN1884 PK studies have been conducted in cynomolgus monkeys following both single and 
repeated intravenous (IV) administration. AGEN1884 has a biphasic disposition with a terminal 
elimination half-life (t1/2) of between 8 and 20 days. Exposure (maximum drug concentration at 
steady-state [Cmax-ss] and area under the drug concentration-time curve [AUC]) increased in an 
approximately dosage-proportional manner. No gender difference was noted for plasma drug 
exposure (Cmax-ss or AUC). Accumulation was observed, as exposure was approximately twice as 
high after multiple weekly administrations. 
Repeated-administration IV toxicology studies have been conducted in cynomolgus monkeys, 
including a 1-month Good Laboratory Practice (GLP) study. In both studies, AGEN1884 was 
administered by a slow IV bolus once weekly (days 1, 8, 15, 22, and 29) at dosages of 0 
(vehicle), 5, 30, and 100 mg/kg AGEN1884. No evidence of any toxicity was observed after a 
thorough examination of in-life, clinical pathology (including cytokines), flow cytometry, and 
macroscopic and histopathological examinations. A GLP tissue cross-reactivity study with 
human tissues indicated binding to plasma membranes of mononuclear cells in a number of 
tissues. 
The maximum recommended starting dose (MRSD) was based on the MRSD derived from the 
minimally anticipated biological effect level (MABEL). The proposed starting dose for this study 
is 0.1 mg/kg of AGEN1884, which is based on in vitro pharmacology and in vivo PK and 
toxicology studies. This dosage is higher than the calculated MABEL of 0.042 mg/kg, but is 
believed to represent a safe starting dosage that will provide improved opportunity for 
pharmacological activity in Phase 1 subjects. Please refer to the Investigator’s Brochure for 
further details. 

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Rationale 
CTLA-4 is one of various down regulators of the immune response, known as an inhibitory 
checkpoint, and blocking it with an anti–CTLA-4 antibody has been demonstrated to enhance 
immune responsiveness by inhibiting downregulation of T-cell activation. An IgG1 anti–CTLA-4 
antibody has demonstrated robust clinical efficacy, and has received approval in the United 
States for the treatment of metastatic melanoma, and in Europe for previously treated metastatic 
melanoma (Page et al.m 2013).  
The clinical efficacy associated with blockade of CTLA-4 has also been associated with toxicity 
as the result of immune activation. Moreover, only a select group of patients, even among 
melanoma patients, will respond to CTLA-4 blockade alone (Page et al., 2013). The combination 
of CTLA-4 blockade with PD-1 blockade was recently shown to be more effective than targeting 
either pathway alone, but still had substantial side effects suggestive primarily of toxicity from 
CTLA-4 blockade (Larkin et al., 2015). Combining a CTLA-4 inhibitor such as AGEN1884 with 
PD-1 blockade or other immunotherapies therefore remains an attractive goal in immuno-
oncology. Alternate combination approaches to the development of AGEN1884 may ameliorate 
the side effects of CTLA-4 blockade while focusing immune stimulation to the benefit of 
patients with tumor types for which immunotherapy does not currently work, and patients with 
melanoma who cannot tolerate CTLA-4 blockade with the approved antibody as currently 
administered.  
The present study will seek to define the safety and maximum tolerated dose (MTD) of single-
agent AGEN1884, and include expansion of enrollment at the MTD or maximum planned dose 
level to further explore the activity of AGEN1884 monotherapy in subjects with advanced or 
refractory cancer, including those 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). The Phase 2 portion of the study will also include expansion of enrollment at 
1 mg/kg and 3 mg/kg to further explore the activity of AGEN1884 as a monotherapy. In the 
expansion phase, subjects who have received previous treatment with immunotherapeutic agents 
(except those who received previous treatment with anti–CTLA-4 agents) will be allowed to 
enroll in order to better understand the safety of sequential treatment with AGEN1884 in what is 
becoming a common clinical practice due to the approval of multiple PD-1– and PD-L1–
targeting agents.  
Moreover, substantial clinical activity has been observed when PD-1/PD-L1 inhibition and 
CTLA-4 inhibition are combined sequentially (Weber et al., 2016). Although the half-life of 
nivolumab is 17-25 days (Bristol-Meyers Squibb, 2013), its occupancy of PD-1 on circulating T 
cells has a mean plateau of 72% for at least 59 days, with PD-1 blockade persisting even with 
undetectable serum nivolumab concentrations (Brahmer et al., 2010); therefore, substantial 
inhibition of PD-1 would be expected to continue in the PD-l/PD-L1 cohorts at the time of 
AGEN1884 treatment initiation. The results of this single-agent study will inform the further 
development of AGEN1884. 
3. 
Investigational Plan 
 
Overall Study Design 
This is an open-label, Phase 1/2, multicenter study to evaluate the safety, PK, and 
pharmacodynamics, and activity of an anti–CTLA-4 human monoclonal antibody (AGEN1884) 

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in subjects with advanced or refractory cancer. The Phase 1 portion of the study has been 
completed and contained a 3+3 dose escalation phase evaluating AGEN1884 at 0.1, 0.3, 1, 3, and 
6 mg/kg dose levels, and an expansion phase at 1 mg/kg and 3 mg/kg. Dose levels >6mg/kg were 
not planned.  
The Phase 2 portion of the study includes subjects 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). The dose for the Phase 2 portion of the study was based on clinical 
data from the Phase 1 portion evaluating AGEN1884 as monotherapy. At the time of this 
amendment, based on data from the Phase 1 dose escalation, 1 mg/kg was chosen as the starting 
dose for Phase 2. 
The study design is depicted in Figure 1. 

Protocol C-500-01 
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Figure 1: Study Design 
 
 
*  Additional subjects may be enrolled in Phase 2 to either the HCC or non-HCC populations as necessary to ensure that 20 subjects are evaluable for additional 
PK assessments (i.e., 3 additional timepoints, see Section 5.3).
Up to 60* subjects 
diagnosed with solid 
tumors, who 
progressed on prior 
PD-1/L1 therapy: 
 
Approximately 
20 subjects 
with HCC 
 
 
Approximately 
40 subjects 
with non-HCC 
 

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AGEN1884 will be administered on Day 1 of each 3-week cycle for 4 cycles. At a 12-week 
evaluation timepoint (based on 2 scans of tumor assessment), subjects may continue to receive 
AGEN1884 every 3, 6, or 12 weeks (± 7-days), for a maximum duration of 1 year of treatment, 
provided they were not diagnosed with disease progression and were tolerating the study drug. 
The appropriate schedule will be based on discussion with the medical monitor. Subjects who 
progressed during the treatment period, yet still have clinical benefit from treatment, may 
continue treatment post-progression with the medical monitor’s approval. The dosing schedule 
for these subjects should be determined based on discussion with the medical monitor. 
Phase 1 
The Phase 1 portion of the study was to enroll overall approximately 40 adult subjects with 
refractory, advanced cancer (solid tumors or lymphoma), including those 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). The 3+3 dose escalation started at 
0.1 mg/kg, as shown in Table 1. (Dose levels beyond 6 mg/kg are not currently planned.) The 
bio-pharmacological properties of the antibody suggested that this dose escalation plan would 
include evaluation of doses within a safe and clinically active range. Dose escalation continued 
until the MTD was reached or the maximum planned dose level (6 mg/kg) was shown to be safe 
after cohort expansion occurred at the 1 mg/kg and 3 mg/kg dose levels. The MTD is defined as 
the dose below which 2 DLTs are observed (see Section 3.1.2.2 for definition of DLTs).  
The cohorts and dose levels are shown in Table 1. Information about stopping rules for toxicity is 
provided in Section 3.1.2.3. 
Table 1: AGEN1884 Dose Levels and Cohorts 
Dose Level 
Cohort 
AGEN1884 Dose 
(mg/kg) 
Study Phase 
Number of 
Subjects 
Phase 1 
1 (starting dose) 
0.1 
Dose escalation  
3-6 
2 
0.3 
Dose escalation 
3-6 
3 
1 
Dose escalation and expansion (a) 
10 
4 
3 
Dose escalation and expansion (a) 
10 
5 
6 
Dose escalation 
3-6 
Phase 2 
 
1 
Subjects who progressed on a PD-1/PD-L1 
inhibitor as last prior therapy (b) 
Up to 60 (c) 
DLT: dose-limiting toxicity; HCC: hepatocellular carcinoma; PD-1: programmed cell death protein 1; PD-L1: ligand 1 of 
programmed cell death protein 1. 
a  Includes 3-6 subjects for DLT evaluation plus additional subjects to achieve up to 10 evaluable subjects in the cohort. 
b  Includes subjects 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). Includes subjects in Phase 2 with HCC 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). Of the 40 subjects in this cohort at the 1.0 mg/kg dose level: 1) Approximately 20 subjects diagnosed with HCC 
will be enrolled; 2) The enrollment of non-HCC will be approximately 40 subjects. 
c Additional subjects may be enrolled to either the HCC or non-HCC populations as necessary to ensure that 20 subjects are 
evaluable for additional PK evaluation (i.e., 3 additional timepoints, see Section 5.3). 

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The DLT observation period was defined as 28 days from initial administration of AGEN1884. 
Based on experience with other anti–CTLA-4 antibodies, this allowed for infusion-related 
toxicities and other early onset immune-related toxicities, such as skin-related adverse events, to 
be observed during the DLT observation period without unnecessarily prolonging the observation 
period. Additionally, some immune-related toxicities from CTLA-4 inhibition were likely to 
occur later in therapy than 42 days (Weber et al., 2013), the last day before dose number 3 would 
be due for subjects on this study. Therefore, late toxicities were evaluated by the Safety Review 
Committee (SRC) per Section 3.1.1 to ensure that related toxicities are still considered in DLT 
review even if they fall outside of the observation period.  
Once the 1 mg/kg and 3 mg/kg dosages were declared safe, these cohorts were expanded to 
include overall 10 evaluable subjects in each cohort before enrolling subjects into the 6 mg/kg 
dose cohort. Dose escalation continued until the MTD was reached, or the maximum planned 
dose level (6 mg/kg) was shown to be safe after cohort expansion occurred at the 1 mg/kg and 
3 mg/kg dose levels. The expansion cohorts allowed collection of additional PK/anti-drug 
antibody (ADA) and safety data, which will be used to plan development of combination 
(AGEN1884 plus drug[s]) strategies. As several anti–PD-1 and anti–PD-L1 products are already 
commercially available, many subjects receive these therapies as standard of care, therefore 
subjects who previously received these therapies were allowed to enroll in these expansion 
cohorts to help to better understand the safety of sequential treatment with AGEN1884. 
Disease response assessments by RECIST was to be performed at Study Week 6, Week 12 and 
Q6w for subjects assigned to 3- or 6-w treatment schedule, or Q12w for subjects assigned to 
12-w treatment schedule until off-disease response evaluation criteria are met.   
Phase 2 
Up to 60 subjects will be enrolled at the recommended Phase 2 dose of 1.0 mg/kg. Phase 2 
consists of subjects 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). 
For this phase: 
 Approximately 20 subjects with advanced HCC will be enrolled. 
 The enrollment of non-HCC will be approximately 40 subjects. 
Note: additional subjects may be enrolled to either the HCC or non-HCC populations as 
necessary to ensure that 20 subjects are evaluable for the purpose of the additional PK 
evaluation (i.e. 3 additional timepoints, see Section 5.3). 
Disease response assessments by RECIST to be performed at Study Week 6, Week 12 and Q6w 
for subjects assigned to 3- or 6-w treatment schedule, or Q12w for subjects assigned to 12-w 
treatment schedule until off-disease response evaluation criteria are met.   
Subjects in both phases were evaluated for PK, PD, disease response, and safety, as determined 
through physical examination, vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory 
tests, cytokine and lymphocyte subset measurements, and adverse events (Table 10). 
3.1.1 Safety Review Committee 
Study safety review will be presided over by the SRC, composed of the clinical investigators and 
medical monitor/study sponsor. The SRC will be convened regularly, including at the end of a 
cohort, once the protocol-defined criteria for dose escalation are met, to review all available 

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subject safety data in advance of providing formal notification to investigators that they may 
proceed to enroll subjects in the escalated dose cohort. The SRC will also be convened to 
evaluate all subjects on study when ≥2 adverse events are noted that are possible DLTs on a dose 
level and/or discuss additional toxicities that may warrant dose de-escalation, as described in 
Section 3.1.2.3. In Phase 2, the SRC will continue to meet at a frequency specified in the Safety 
Review Charter. 
3.1.2 Dose-Limiting Toxicity Evaluation 
3.1.2.1 Dose Escalation Procedures in Phase 1 
The initial starting dose was 0.1 mg/kg and the first subject was enrolled to confirm safety at this 
level, which is near the MABEL dose. A minimum of 3 subjects were to be enrolled in each 
cohort. The first 2 subjects in each dosing cohort were to be enrolled ≥24 hours apart, and 
enrollment of the second subject did not proceed unless the first subject tolerated the therapy 
without DLT within the first 24 hours following the start of the infusion of the first subject. Each 
subject was observed for a DLT observation period of 28 days from initiation of AGEN1884 
treatment, and 3 subjects must have been able to receive and tolerate the first 2 doses of 
AGEN1884 without DLTs during this observation period before the next cohort began 
enrollment. The dose was to be escalated if 0 of the first 3 evaluable subjects enrolled had a DLT. 
If 1 of the first 3 evaluable subjects enrolled had a DLT, then the cohort was to be expanded to 
include 3 additional evaluable subjects; if no DLT occurred in the additional 3 subjects, then the 
dose was to be escalated. If a DLT occurred in ≥2 subjects in the total cohort, the MTD was 
deemed to be exceeded, and the prior dose level was evaluated to determine the MTD by 
increasing enrollment to 6 subjects. If the prior dose level was already deemed to be safe and 
enrolled 6 subjects, then it was defined as the MTD. Alternate dosing schedules of AGEN1884 
could have been explored depending on PK, pharmacodynamics, and safety results. 
If 0.1 mg/kg exceeded the MTD (i.e., does not pass DLT evaluation), the sponsor and 
investigators considered alternate dose schedules (e.g., every 4 weeks) based on available safety, 
PK, and pharmacodynamics data. If an alternate schedule was tested and determined to be safe, 
re-escalation of AGEN1884 proceeded according to Table 1.  
Additional subjects were enrolled in a cohort to achieve the minimum of 3 evaluable subjects at 
each dose level. Subjects who dropped out or who had dose interruptions/reductions that resulted 
in a subject being non-evaluable for DLTs were considered non-evaluable. Dose modifications in 
the DLT period due to any related toxicity were considered a DLT. Subjects who experienced a 
DLT during the dose-escalation portion of the study were discontinued from study drug. 
Intrasubject dose escalation was not permitted.  
When accrual for the 3 mg/kg dose cohort was paused for safety assessment and DLT 
observation, expansion of the 1 mg/kg cohort began to enroll a total of 10 evaluable subjects.  
Once 3 mg/kg was determined to be safe by the SRC, the 3 mg/kg dose cohort was expanded to 
enroll a total of 10 evaluable subjects; backfilling into the 1 mg/kg dose cohort was paused 
during this time. If the 1 mg/kg dose cohort did not reach 10 subjects, additional subjects were 
enrolled in the 1 mg/kg cohort after 10 evaluable subjects were enrolled in the 3 mg/kg cohort. 
Once 1 mg/kg and 3 mg/kg cohorts completed expansion and had each enrolled 10 evaluable 
subjects, dose escalation resumed at 6 mg/kg, according to the protocol. If any of the first 3 

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evaluable subjects enrolled at the maximum planned dose of 6 mg/kg experienced DLT, an 
additional 3 subjects were enrolled for a total of 6 subjects at the maximum planned dose. 
3.1.2.2 Definition of Dose-Limiting Toxicity  
With exceptions discussed below, a DLT is defined as a grade ≥3 adverse drug reaction (ADR), 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5, occurring in the DLT evaluation period (i.e., 28 days after the initial 
administration of AGEN1884) in subjects enrolled in the phase 1 dose escalation.   
The SRC recognizes that in the absence of prior human experience with AGEN1884, a 
conservative approach should be adopted in ascribing the relevance of the treatment-related 
toxicity to drug. Treatment-emergent serious adverse events (SAEs) will be ascribed as related to 
drug except in cases in which a clear relationship to the underlying disease or recognized 
comorbidities are evident. For this trial, the MTD is defined as the highest dose at which <2 of 6 
subjects experience a DLT.  
A DLT is specifically defined as any one of the following:  
 Grade ≥2 uveitis, eye pain, or blurred vision that does not respond to topical therapy. 
 Any grade ≥3 toxicity that is possibly, probably, or definitely related to AGEN1884 
occurring during the DLT evaluation period (28 days after initial administration of 
AGEN1884), except for any of the following:  
 Grade 3 infusion-related reaction resolving within 6 hours of dosing and controlled 
with medical management. 
 Transient (≤6 hours) grade 3 flu-like symptoms or fever, which are controlled with 
medical management. 
 Transient (≤24 hours) grade 3 fatigue, local reactions, headache, nausea, or emesis that 
resolves to grade ≤1.  
 Grade 3 diarrhea, skin toxicity, or liver function test (LFT), (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], or gamma glutamyltransferase [GGT]) 
increase that resolves to grade ≤1 within 7 days after medical management 
(e.g., immunosuppressant treatment) has been initiated. 
 Single laboratory values out of normal range that are unlikely related to trial treatment 
according to the investigator, do not have any clinical correlate, and resolve to grade ≤1 
within 7 days with adequate medical management. 
 Tumor flare phenomenon, defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor. 
Subjects who do not complete the DLT observation period and do not receive 2 doses of 
AGEN1884 during the DLT observation period for reasons other than a DLT will be replaced. 
3.1.2.3 Stopping Rules in Phase 1 for Enrollment Based on Toxicities 
 If 2 or more DLTs occur at Dose Level 1 (0.1 mg/kg), then study enrollment will stop and 
evaluation of biologic and clinical activity will be completed for Dose Level 1. If there is a 
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enrolled subjects, then Agenus will redesign the study with new dose levels and potentially a 
new dose frequency, both of which would be intended to decrease the dose intensity on study, 
and approach the Food and Drug Administration (FDA) for guidance before activating such a 
redesigned study. 
 The SRC will meet to review the dose cohort under evaluation as well as safety of the full 
cohort under evaluation. Should ≥2 subjects on any dose level experience toxicities that meet 
DLT criteria but occur after the DLT evaluation period, enrollment will be held and the 
occurrences would be thoroughly evaluated by the SRC. Should these events be consistent 
with DLTs, for instance, from immune-related toxicities, they will be evaluated for 
relatedness to AGEN1884. The SRC will evaluate the events and de-escalate the dose level 
due to immune-related adverse events meeting DLT criteria that occur beyond the DLT 
evaluation period. 
 
Eligibility Criteria 
3.2.1 Inclusion Criteria 
Subjects must meet all of the following 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 PD-1/PD-L1 naïve and those 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). 
  
For subjects in Phase 2 with HCC: 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 (Appendix C). 
5. Subjects in Phase 2 with HCC should have a Child-Pugh score of A or B7 with no 
encephalopathy or ascites (Appendix F). 
6. Life expectancy ≥12 weeks. 
7. Adequate cardiac function (New York Heart Association [NYHA] class ≤II)  
(Appendix D ). 
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 

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≥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 ULN.  
For subjects in Phase 2 with HCC: AST and ALT ≤5 × ULN, bilirubin ≤2 × 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 (Phase 2) , 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 (See Section 5.6.1 for details). 
3.2.2 Exclusion Criteria 
Subjects are ineligible to enroll in this study if they fulfill any of the following 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. 

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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. 

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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 at screening (defined as 2 
brain images, both of which 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:  
a. Recent encephalopathy episodes in the last 6 months.   
b. Recent (within the last 3 months) gastro-esophageal varices bleeding. 
c. Subject whose tumors have cardiac involvement, as determined by imaging. 

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Randomization 
No randomization to treatment assignments will be performed in this study. 
 
Blinding 
The study will be open label; no blinding will be performed. 
 
Discontinuation of Therapy 
Treatment with AGEN1884 should be discontinued if 1 of the following primary reasons occur: 
 Unacceptable toxicity (based on the investigator’s clinical decision that the subject is 
unable to tolerate therapy). 
 Adverse event 
 Radiographic progression of disease (compared to baseline assessment). Disease 
progression is defined as progression confirmed by a second, consecutive assessment ≥6 
weeks apart. 
Note: If subject with evaluation of disease progression is having clinical benefit despite 
the progression, treatment may continue following discussion with, and approval of the 
medical monitor. 
 Investigator decision 
 Clinical progression of disease 
 Protocol deviation 
 Subject completed treatment 
 Investigator decision 
 Subject noncompliance with protocol for nonmedical reasons 
Subjects who discontinue therapy prior to progression should continue to be followed for 
response and complete disease assessments every 12 weeks according to standard of care for up 
to 2 years from first AGEN1884 administration. Subjects will be followed for safety ≥90 days 
following the last administration of investigational agent, as described in Section 5.8. 
 
Discontinuation from Study 
Subjects should be discontinued from the study for 1 of the following primary reasons: 
 Withdrawal of consent 
 Lost to Follow-up 
 Death 
 Subject noncompliance with protocol  
 Administrative study closure 
 Completed study 

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Treatment Beyond Disease Progression   
Subjects will be permitted, with the Sponsor’s approval, to continue with treatment beyond 
initial RECIST 1.1 defined PD as long as they meet the following criteria:  
 Investigator-assessed clinical benefit from the treatment;  
 Subject is clinically stable;  
 Subject is tolerating study drug; and  
 There is agreement with the sponsor.  
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. The following 
criteria need to be taken into consideration:  
 Absence of clinical symptoms and signs (including worsening of laboratory values) 
indicating disease progression.  
 No decline in ECOG performance status.  
 Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention.  
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden from time of initial progression (including all 
target lesions and new measurable lesions).  
Imaging is required every 6 weeks (± 3 days) for those subjects with confirmed PD who remain 
on AGEN1884 until treatment is discontinued. 
4. 
Investigational Agent 
 
Description of Investigational Agent 
AGEN1884 is a novel, fully human monoclonal IgG1 antibody designed to block CTLA-4. It 
will be supplied as 50 mg per vial. AGEN1884 should be stored in a refrigerator at 2°C to 8°C. 
4.1.1 Dosage and Administration 
AGEN1884 will be administered intravenously (IV) for each cycle (3 weeks) as a 60-min 
(-10/+20 min) infusion. Infusions will be followed immediately by a 15-min saline flush of the 
IV line. 
Treatment will be administered every 3 weeks for the first 4 cycles.  
At the 12-week evaluation timepoint, subjects may continue to receive AGEN1884 every 3, 6, or 
12 weeks (± 7 days) for a maximum duration of 1 year of treatment, provided they were not 
diagnosed with PD and were tolerating the study drug. The appropriate schedule will be based on 
discussion with the medical monitor. Subjects who progressed yet still have clinical benefit from 
treatment may continue on treatment following discussion with, and approval of, the medical 
monitor.  For detailed criteria and consideration for treatment post-progression, refer to Section 
3.7.  Dosing is described in Table 1. 
Please refer to the Pharmacy Manual for further instructions on AGEN1884 dosage and 
administration. 

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4.1.2 Dosing Delay Criteria  
Prior to every AGEN1884 administration, laboratory values will be reviewed. AGEN1884 
administration will be delayed for the following adverse events (AEs), if the following AEs 
occur on the day of planned AGEN1884 dosing: 
 Either febrile neutropenia or neutropenia <500 cells/mm³ for >1 week despite the use of 
growth factors. 
 Any grade ≥2, non-skin, drug-related AE except for fatigue and laboratory abnormalities 
 Any grade 3 drug-related laboratory abnormality (except lymphopenia, AST, ALT, total 
bilirubin, or asymptomatic lipase or amylase). 
o Grade 3 lymphopenia does not require a dose delay. 
o If the subject has a baseline AST, ALT, or total bilirubin that is within normal 
limits, dosing should be delayed for drug-related grade ≥2 toxicity.  
o If the subject has a baseline AST, ALT, or total bilirubin within the grade 1 
toxicity range, dosing should be delayed for drug-related grade ≥3 toxicity.  
o Any grade 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay.  
 Any grade 3, skin, drug-related AE.  
 Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
 For subjects in Phase 2 with HCC and an elevated baseline liver function test:  
Dose delay for the following:  
- 
Baseline AST, ALT < 2 x ULN with an increase to ≥ 5 x ULN   
- 
Baseline AST, ALT ≥ 2 x ULN with an increase to >3 x the baseline level 
- 
Elevations of AST, ALT ≥500 IU/L or 20 x ULN regardless of baseline level 
- 
Baseline total bilirubin ≤ 1.5 x ULN and increase to ≥ 2 x ULN   
- 
Baseline total bilirubin >1.5 x ULN and increase to ≥ 2 x baseline level 
- 
Elevations of total bilirubin ≥3x ULN regardless of baseline level 
Permanently discontinue for  
- 
Elevations of ALT ≥20 x ULN regardless of baseline level  
- 
Clinical Hepatic Decompensation regardless of lab values as follows: 
o New onset clinical ascites  
o Upper gastrointestinal bleeding due to portal hypertension  
o Encephalopathy  
o Coagulopathy due to liver disease  
o Worsening Child-Pugh score to 9 

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Subjects in Phase 2 with HCC will be followed closely and the appropriate course of action 
(including but not limited to hospitalization and/or consultation with a hepatologist) will be 
implemented as clinically indicated. In addition, other common causes of hepatic dysfunction 
should be ruled out; if a diagnoses of autoimmune hepatitis (AIH) is made, see Table 6 for 
additional management guidelines. 
 
Infusion Reactions 
Subjects receiving AGEN1884 should be monitored for infusion reactions. This includes the 
measurement of vital signs for ≥1 hour after infusion, defined as 1 hour after the completion of 
the 60-minute infusion of AGEN1884 and the 15-minute flush that follows the infusion. Subjects 
will remain in the clinic under close supervision for the duration of this monitoring period. 
Subjects with mild or moderate infusion reactions may receive AGEN1884 with close 
monitoring. Premedication with an antipyretic or antihistamine may be considered. For severe 
infusion reactions, AGEN1884 infusion must be discontinued, and appropriate medical therapy 
should be administered. 
Subjects who do not experience any grade ≥1 infusion-related toxicity during or after the 
infusion may be released from monitoring after 1 hour if they are otherwise stable. Subjects with 
any infusion-related toxicity must be managed as per the guidelines below, and monitoring will 
continue until any infusion-related toxicity has abated to grade <1 and ≥1 hour has passed from 
the completion of the entire infusion and flush. Before leaving the study site, all subjects will be 
given information on infusion-related toxicity per institutional guidelines. This will include 
instructions on when and how to return for immune-mediated toxicities associated with CTLA-4 
blockade. 
If mild or moderate infusion reaction occurs, the infusion should be interrupted, and supportive 
care should be administered until the symptoms resolve, per treating clinician. 
Management guidelines for infusion reactions will be provided to the investigators at each site 
(Table 2). 
 

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Table 2: Infusion Reaction Guidelines 
CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dose 
Administration 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated. 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable in 
the opinion of the investigator. 
None. 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment  
(e.g., antihistamines, 
nonsteroidal anti-
inflammatory drugs 
[NSAIDs], narcotics, IV 
fluids); prophylactic 
medications indicated for ≤24 
hours. 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may include but 
is not limited to the following: 
 IV fluids 
 Antihistamines 
 NSAIDS 
 Acetaminophen 
 Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable in 
the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate. Otherwise, dose administration 
will be held until symptoms resolve, and the subject 
should be premedicated for the next scheduled dose. 
Subjects who develop grade 2 toxicity despite adequate 
premedication should be permanently discontinued 
from further study drug administration. 
Subject may be 
premedicated 1.5 h 
(± 30 min) prior to infusion 
with the following: 
 Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine). 
 Acetaminophen 500-
1000 mg PO (or 
equivalent dose of 
antipyretic). 
Grade 3 or 4 
 
Grade 3 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates). 
 
Grade 4 
Life-threatening; pressor or 
ventilatory support indicated. 
Stop infusion. 
Additional appropriate medical therapy may include but 
is not limited to: 
 IV fluids 
 Antihistamines 
 NSAIDs 
 Acetaminophen 
 Narcotics 
 Oxygen 
 Pressors 
 Corticosteroid 
 Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable in 
the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further study 
drug administration. 
No subsequent dosing.  
CTCAE: Common Terminology Criteria for Adverse Events; h: hour; IV: intravenous; min: minute; NSAID: nonsteroidal anti-
inflammatory drug, PO: orally. 

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Management of Immune-Related Adverse Events 
Immuno-oncology agents such as AGEN1884 are associated with immune-related adverse events 
(irAEs). Early recognition and management of irAEs may mitigate severe toxicity. Investigators 
should also monitor subjects closely for potential irAEs, which may manifest after weeks of 
treatment, at the earliest. Such events may consist of persistent rash, diarrhea, colitis, 
autoimmune hepatitis, pneumonitis, encephalitis, arthritis, glomerulonephritis, cardiomyopathy, 
or uveitis and other inflammatory eye conditions.  
Management algorithms have been developed to assist investigators in assessing and managing 
the following groups of irAEs: gastrointestinal, pulmonary, dermatological, renal, hepatic, 
neurological, and endocrine, among others. 
Adverse events (both non-serious and serious) associated with drug exposure and consistent with 
an immune phenomenon may represent an immunologic etiology. These irAEs may be predicted 
based on the nature of the study drugs, their mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action. An irAE can occur shortly after the 
first dose or several months after the last dose of treatment. Particular attention should be paid to 
AEs that may be suggestive of potential irAEs, as outlined below. 
4.3.1 Dermatological irAEs 
Rule out non-inflammatory causes. If a non-inflammatory cause is identified, treat accordingly 
and continue therapy per protocol (Table 3). 
 
 

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Table 3: Dermatological irAE Management Algorithm  
Dermatological irAEs 
CTCAE Grade of Rash 
Management 
Follow-Up 
Grade 1-2 
Covering ≤30% body surface 
area 
 Symptomatic therapy (e.g., 
antihistamines, topical 
corticosteroids). 
 Continue AGEN1884 therapy 
per protocol. 
 If persists >1 to 2 weeks or recurs: 
Consider skin biopsy. 
 Delay AGEN1884 therapy. 
 Consider 0.5-1 mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving, taper 
corticosteroids over ≥1 month; consider 
prophylactic antibiotics for opportunistic 
infections; and resume AGEN1884 
therapy per protocol. 
 If worsens: Treat as grade 3-4. 
Grade 3-4 
Covering >30% body surface 
area; life-threatening 
consequences 
 Delay or discontinue 
AGEN1884 therapy per 
protocol. 
 Consider skin biopsy. 
 Dermatology consult  
 1-2 mg/kg/day 
methylprednisolone IV or IV 
equivalent. 
 If improves to grade 1: Taper 
corticosteroids over ≥1 month; add 
prophylactic antibiotics for opportunistic 
infections. 
 Resume AGEN1884 therapy per 
protocol. 
CTCAE: Common Terminology Criteria for Adverse Events; irAE: immune-related adverse event; IV: intravenous; kg: 
kilogram; mg: milligram 
 
 
 

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4.3.2 Gastrointestinal irAEs 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy. Opiates/narcotics may mask symptoms of perforation. Infliximab should not be 
used in cases of perforation or sepsis (Table 4). 
Table 4: Gastrointestinal irAEs Management Algorithm 
Gastrointestinal irAEs 
CTCAE Grade of 
Diarrhea/Colitis 
Management 
Follow-Up 
Grade 1 
Diarrhea: <4 stools/day over 
baseline. 
Colitis: asymptomatic. 
 Continue AGEN1884 
therapy per protocol. 
 Symptomatic treatment. 
 Close monitoring for worsening 
symptoms. 
 Educate subject to report worsening 
immediately. 
 Consider symptomatic treatment 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide. 
 If worsens: Treat as grade 2 or 3-4. 
Grade 2 
Diarrhea: 4-6 stools per day 
over baseline; IV fluids 
indicated <24 h; not interfering 
with activities of daily living 
(ADL). 
Colitis: abdominal pain; blood 
in stool.  
 Delay AGEN1884 therapy 
per protocol. 
 Symptomatic treatment. 
 If improves to grade 1: Resume 
AGEN1884 therapy per protocol. 
 If persists >5 to 7 days or recurs:  
0.5-1 mg/kg/day methylprednisolone 
or equivalent. 
 When symptoms improve to grade 1, 
taper corticosteroids over ≥1 month; 
consider prophylactic antibiotics for 
opportunistic infections; resume 
AGEN1884 therapy per protocol. 
 If worsens or persists >3 to 5 days 
with oral corticosteroids: Treat as 
grade 3-4. 
Grade 3-4 
Diarrhea (grade 3): ≥7 stools 
per day over baseline; 
incontinence; IV fluids ≥24 h; 
interfering with ADL. 
Colitis (grade 3): severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs. 
Grade 4: life-threatening, 
perforation 
 Discontinue AGEN1884 
therapy per protocol. 
 1-2 mg/kg/day 
methylprednisolone IV or 
equivalent. 
 Add prophylactic antibiotics 
for opportunistic infections. 
 Consider lower endoscopy. 
 If improves: Continue corticosteroids 
until grade 1, then taper over ≥1 
month. 
 If persists >3 to 5 days, or recurs 
after improvement: Add infliximab 5 
mg/kg (if no contraindication).  
 Note: Infliximab should not be used in 
cases of perforation or sepsis. 
ADL: activities of daily living; CTCAE: Common Terminology Criteria for Adverse Events; h: hour; irAE: immune-related 
adverse event; IV: intravenous; kg: kilogram; mg: milligram. 

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4.3.3 Pulmonary irAEs 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol. Evaluate with imaging and pulmonary consultation (Table 5). 
Table 5: Pulmonary irAE Management Algorithm  
Pulmonary irAEs 
CTCAE Grade of Pneumonitis 
Management 
Follow-Up 
Grade 1 
Radiographic changes only. 
 Consider delay of AGEN1884 
therapy per protocol. 
 Monitor for symptoms every 
2-3 days. 
 Consider pulmonary and 
infectious disease consults. 
 Re-image every ≥3 weeks. 
 If worsens: Treat as grade 2 or grade  
3-4. 
Grade 2 
Mild to moderate new 
symptoms 
 Delay AGEN1884 therapy per 
protocol. 
 Pulmonary and infectious 
disease consults. 
 Monitor symptoms daily; 
consider hospitalization. 
 1 mg/kg/day 
methylprednisolone IV or oral 
equivalent. 
 Consider bronchoscopy, lung 
biopsy. 
 Re-image every 1-3 days. 
 If improves: When symptoms return to 
near baseline, taper corticosteroids over 
≥1 month, then resume AGEN1884 
therapy per protocol, and consider 
prophylactic antibiotics. 
 If not improving after 2 weeks or 
worsening: Treat as grade 3-4. 
Grade 3-4 
Severe new symptoms; new/ 
worsening hypoxia; life-
threatening. 
 Discontinue AGEN1884 
therapy per protocol. 
 Hospitalize. 
 Pulmonary and infectious 
disease consults. 
 2-4 mg/kg/day 
methylprednisolone IV or IV 
equivalent. 
 Add prophylactic antibiotics 
for opportunistic infections. 
 Consider bronchoscopy, lung 
biopsy. 
 If improves to baseline: Taper 
corticosteroids over ≥6 weeks. 
 If not improving after 48 hours or 
worsening: Add additional 
immunosuppression (e.g., infliximab, 
cyclophosphamide, IV immunoglobulin, 
mycophenolate mofetil). 
CTCAE: Common Terminology Criteria for Adverse Events; irAE: immune-related adverse event; IV: intravenous; kg: 
kilogram; mg: milligram 
 
 

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4.3.4 Hepatic irAEs 
Rule out non-inflammatory causes (e.g., alcohol use, acute viral hepatitis, flare up from chronic 
hepatitis, co-infection [e.g., with hepatitis D], etc.). If a non-inflammatory cause is identified, treat 
accordingly and continue therapy per protocol. Consider imaging for obstruction and a 
hepatologist consult (Table 6). 
Table 6: Hepatic irAE Management Algorithm  
Hepatic irAEs
CTCAE Grade of  
Liver Test Elevation 
Management
Follow-Up
Grade 1 
AST or ALT >ULN to 3 x ULN 
and/or total bilirubin >ULN to 1.5 x 
ULN. 
 Continue AGEN1884 therapy per 
protocol. 
 Continue liver function tests (LFT) 
monitoring per protocol. 
 If worsens: Treat as grade 2 or grade 3-4. 
Grade 2 
AST or ALT >3 to ≤5 x ULN and/or 
total bilirubin >1.5 to  
≤3 x ULN. 
 
If subject has concurrent AST or 
ALT >3 x ULN and total bilirubin 
>2 x ULN, discontinue AGEN1884 
therapy per protocol (Hy’s Law) 
 Delay AGEN1884 therapy per 
protocol. 
 Increase frequency of monitoring 
to every 3 days. 
 
 If returns to baseline: Resume routine 
monitoring; resume AGEN1884 therapy per 
protocol. 
 If elevations persist >5 to 7 days or 
worsen: 0.5-1 mg/kg/day 
methylprednisolone IV or oral equivalent. 
When LFT returns to grade 1 or baseline, 
taper corticosteroids over ≥1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
AGEN1884 therapy per protocol. 
Grade 3-4 
AST or ALT >5 x ULN and/or total 
bilirubin >3 x ULN. 
 Permanently discontinue 
AGEN1884 therapy per protocol. 
 Increase frequency of monitoring 
to every 1-2 days. 
 1-2 mg/kg/day 
methylprednisolone IV or oral 
equivalent.* 
 Add prophylactic antibiotics for 
opportunistic infections. 
 Consult gastroenterology. 
 Consider obtaining MRI/CT scan 
of liver and liver biopsy if 
clinically warranted. 
 If returns to grade 2: Taper corticosteroids 
around 4 to 6 weeks. 
 If does not improve in >3 to 5 days, 
worsens, or rebounds: Add mycophenolate 
mofetil 1 g twice daily. If no response within 
an additional 3-5 days, consider other 
immunosuppressants per local guidelines. 

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Hepatic irAEs
CTCAE Grade of  
Liver Test Elevation 
Management
Follow-Up
For subjects in Phase 2 with HCC 
and elevated baseline LFT  
Dose delay for the following: 
Baseline AST, ALT < 2 x ULN with 
an increase to ≥ 5 x ULN   
Baseline AST, ALT ≥ 2 x ULN with 
an increase to >3 x the baseline level 
Elevations of AST, ALT ≥500 IU/L 
or 20 x ULN regardless of baseline 
level 
Baseline total bilirubin ≤ 1.5 x ULN 
and increase to ≥ 2 x ULN   
Baseline total bilirubin >1.5 x ULN 
and increase to ≥ 2 x baseline level 
Elevations of total bilirubin ≥3x 
ULN regardless of baseline level 
 
 Dose delay or discontinue 
AGEN1884 therapy.  
 1-2 mg/kg/day 
methylprednisolone IV or oral 
equivalent.* 
 Consider hepatologist consult 
 Increase frequency of monitoring 
to every 3 days 
 If returns to grade <1 or baseline level 
within 1 week then taper corticosteroids 
over ≥ 1 month  
 If symptoms and laboratory resolve to grade 
≤1 or baseline levels and steroids have been 
tapered to a prednisone level ≤ 10mg/day or 
equivalent for at least a week, may consider 
resuming AGEN1884 
 If does not improve in >3 to 5 days, 
worsens, or rebounds: Add mycophenolate 
mofetil 1 g twice daily. If no response within 
an additional 3-5 days, consider other 
immunosuppressants per local guidelines 
and hepatologist consult. Also, permanently 
discontinue. 
 If symptoms and laboratory do not resolve to 
grade ≤1 or baseline levels within 3 weeks or  
steroids cannot be tapered to a prednisone 
level ≤ 10 mg/day or equivalent within 
9 weeks, AGEN1884 must be permanently 
discontinued.   
 All cases considered for re-treatment 
should be discussed with the medical 
monitor 
* The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CT: computed tomography; CTCAE: Common Terminology 
Criteria for Adverse Events; HCC: hepatocellular carcinoma; irAE: immune-related adverse event; IV: intravenous; kg: 
kilogram; LFT: liver function test; mg: milligram; MRI: magnetic resonance imaging; ULN: upper limit of institutional 
normal. 
4.3.5 Endocrine irAEs 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol. Consider visual field testing, endocrinology consultation, and 
imaging (Table 7). 

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Table 7: Endocrine irAE Management Algorithm  
Endocrine irAEs 
Endocrine Disorder 
Management 
Follow-Up 
Asymptomatic TSH 
abnormality 
 Continue AGEN1884 therapy per protocol. 
 If TSH <0.5 x lower limit of normal (LLN) or TSH >2 x ULN, or 
consistently out of range in 2 subsequent measurements: Include free 
thyroxine (T4) at subsequent cycles as clinically indicated; consider 
endocrinology consult. 
Symptomatic endocrinopathy 
 Evaluate endocrine function. 
 Consider pituitary scan. 
 Symptomatic with abnormal 
lab/pituitary scan: Delay 
AGEN1884 therapy per 
protocol; 1-2 mg/kg/day 
methylprednisolone IV or oral 
equivalent; initiate 
appropriate hormone therapy. 
 No abnormal lab/pituitary 
MRI scan but symptoms 
persist: Repeat labs in 1-3 
weeks, MRI in 1 month. 
 If improves (with or without hormone 
replacement): Taper corticosteroids 
over ≥1 month and consider 
prophylactic antibiotics for 
opportunistic infections. 
 Resume AGEN1884 therapy per 
protocol. 
 Subjects with adrenal insufficiency may 
need to continue corticosteroids with 
mineralocorticoid component. 
Suspicion of adrenal crisis 
(e.g., severe dehydration, 
hypotension, shock out of 
proportion to current illness) 
 Delay or discontinue AGEN1884 therapy per protocol. 
 Rule out sepsis. 
 Stress dose of IV corticosteroids with mineralocorticoid activity. 
 IV fluids. 
 Consult endocrinologist. 
 If adrenal crisis ruled out, treat as above for symptomatic endocrinopathy. 
irAE: immune-related adverse event; IV: intravenous; kg: kilogram; LLN: lower limit of normal; mg: milligram; MRI: 
magnetic resonance imaging; TSH: thyroid stimulating hormone; ULN: upper limit of normal. 
 

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4.3.6 Renal irAEs 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol (Table 8). 
Table 8: Renal irAE Management Algorithm  
Renal irAEs 
CTCAE Grade of  
Creatinine Elevation 
Management 
Follow-Up 
Grade 1 
Creatinine >ULN and >baseline 
but ≤1.5 x baseline 
 Continue AGEN1884 
therapy per protocol. 
 Monitor creatinine weekly. 
 If returns to baseline: Resume routine 
creatinine monitoring per protocol. 
 If worsens: Treat as grade 2 or grade  
3-4. 
Grade 2-3 
Creatinine >1.5 x baseline to  
≤6 x ULN 
 Delay AGEN1884 therapy 
per protocol. 
 Monitor creatinine every 2-
3 days. 
 0.5-1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent. 
 Consider renal biopsy 
 If returns to grade 1: Taper 
corticosteroids over ≥1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and resume 
AGEN1884 therapy and routine 
creatinine monitoring per protocol. 
 If elevations persist > 7 days or 
worsen: Treat as grade 4. 
Grade 4 
Creatinine >6 x ULN 
 Discontinue AGEN1884 
therapy per protocol. 
 Monitor creatinine daily. 
 1.0-2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent. 
 Consult nephrologist. 
 Consider renal biopsy. 
 If returns to grade 1: Taper 
corticosteroids over ≥1 month and add 
prophylactic antibiotics for 
opportunistic infections. 
CTCAE: Common Terminology Criteria for Adverse Events; irAE: immune-related adverse event; IV: intravenous; kg: 
kilogram; mg: milligram; ULN: upper limit of normal. 
 
 
 

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4.3.7 Neurological irAEs 
Rule out non-inflammatory causes. If a non-inflammatory cause is identified, treat accordingly 
and continue therapy per protocol (Table 9).  
Table 9: Neurological irAE Management Algorithm  
Neurological irAEs 
CTCAE Grade of  
Neurological Toxicity 
Management 
Follow-Up 
Grade 1 
Asymptomatic or mild symptoms; 
intervention not indicated. 
 Continue AGEN1884 
therapy per protocol. 
 Continue to monitor subject.  
 If worsens: Treat as grade 2 or grade  
3-4. 
Grade 2 
Moderate symptoms; limiting 
instrumental ADL. 
 Delay AGEN1884 therapy 
per protocol. 
 Treat symptoms per local 
guidelines. 
 Consider 0.5-1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent. 
 If returns to baseline: Resume 
AGEN1884 therapy per protocol. 
 If worsens: Treat as grade 3-4. 
Grade 3-4 
Severe symptoms; limiting self-
care ADL; life-threatening. 
 Discontinue AGEN1884 
therapy per protocol. 
 Obtain neurology consult. 
 Treat symptoms per local 
guidelines. 
 1.0-2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent. 
 Add prophylactic 
antibiotics for opportunistic 
infections. 
 If improves to grade 2: Taper 
corticosteroids over ≥1 month. 
 If worsens or atypical presentation: 
Consider IV immunoglobulin or other 
immunosuppressive therapies per local 
guidelines. 
ADL: activities of daily living; CTCAE: Common Terminology Criteria for Adverse Events; irAE: immune-related adverse event; 
IV: intravenous; kg: kilogram; mg: milligram. 
 
Adverse Drug Reactions Requiring Treatment Discontinuation or Modifications 
An ADR is defined as all noxious and unintended responses to a medicinal product, related to 
any dose. A causal relationship between the medicinal product and an AE is deemed at least a 
reasonable possibility if the relationship cannot be ruled out by another cause. 
4.4.1 Dose Reductions 
No dose reductions are allowed. Each subject will stay on the regimen dose levels assigned in 
the trial unless treatment needs to be stopped. Dose reductions or dose escalations of AGEN1884 
are not permitted. 

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4.4.2 Permanent Treatment Discontinuation 
The following ADRs require permanent treatment discontinuation of AGEN1884: 
Any grade 4 ADRs except for single laboratory values out of normal range that are unlikely 
related to trial treatment as assessed by the investigator, do not have any clinical correlate, and 
resolve within 7 days with adequate medical management. 
Any grade 3 ADRs except for any of the following:  
 
Transient (≤6 hours) grade 3 flu-like symptoms or fever, which are controlled with 
medical management. 
 
Transient (≤24 hours) grade 3 fatigue, local reactions, headache, nausea, or emesis that 
resolves to grade ≤1. 
 
Single laboratory values out of normal range (excluding grade ≤3 liver function test 
increase) that are unlikely related to trial treatment according to the investigator; do not 
have any clinical correlate; and resolve to grade ≤1 within 7 days with adequate medical 
management. 
 
Tumor flare phenomenon, defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor. 
 
Any grade ≥3 drug-related amylase or lipase abnormality that is not associated with 
symptoms, or clinical manifestations of pancreatitis does not require dose delay. The 
trial medical monitor should be consulted for such grade ≥3 amylase or lipase 
abnormalities. 
 
Increases in ECOG performance status to ≥3 that do not resolve to ≤2 by Day 14 of the 
following cycle (infusions should not be given on the following cycle if ECOG 
performance status is ≥3 on day of study drug administration). 
 
Any grade 2 ADR should be managed as follows: 
 If a grade 2 ADR resolves to grade ≤1 by the last day of the current cycle, trial treatment 
may continue. 
 If a grade 2 ADR does not resolve to grade ≤1 by the last day of the current cycle, 
infusions should not be administered during the following cycle. If, at the end of the 
following cycle, the event has not resolved to grade 1, the subject should permanently 
discontinue treatment with AGEN1884. 
 For grade 2 ADRs related to hormone insufficiencies that can be managed by 
replacement therapy, up to 2 subsequent doses may be omitted. 
 Upon the second occurrence of the same grade 2 ADR (except for hormone 
insufficiencies that can be managed by replacement therapy) in the same subject, 
treatment with AGEN1884 should be permanently discontinued. 

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Subjects who received systemic corticosteroids for management of any drug-related toxicity 
must be off corticosteroids or have tapered down to an equivalent dose of prednisone ≤10 
mg/day for study treatment to be resumed. 
All infusion-related and hypersensitivity reactions (grades 1-4) should be handled according to 
the guidelines in Table 2. 
Subjects in Phase 2 with HCC will be discontinued for any of the following reasons: 
 
New onset clinical ascites 
 
Upper gastrointestinal bleeding due to portal hypertension 
 
Encephalopathy 
 
Coagulopathy secondary to liver disease 
 
Worsening Child-Pugh score to 9 
 
ALT, AST elevations ≥20 x ULN 
 
 
Prior and Concomitant Therapy 
Before first administration of study drug, subjects must not have received anticancer medications 
or investigational drugs within the intervals defined in Section 3.2.2, exclusion criterion #7. 
Subjects will not be permitted to receive any other anticancer-related therapy during the study. 
 
Investigational Agent Accountability 
International regulatory agencies require accounting for the disposition of all investigational 
product received by each investigative site. Information on investigational product disposition 
required by law consists of the date received, date administered, quantity administered, and the 
subject to whom the investigational product was administered. The principal investigator (or 
designee, as specified in the Delegation of Authority Log) is responsible for accounting for all 
unused investigational product and all used investigational product containers. Investigational 
product may not be given to non–study participants under any circumstances.  
Supplies will be shipped to the investigative site at appropriate intervals, depending on subject 
accrual. The site will use either the Investigational Product Dispensing Form provided by Agenus 
or a similar standard form approved by Agenus to document investigational drug disposition. 
This form must be maintained either in the pharmacy or in another area approved by the Agenus 
monitor. The monitor will review investigational product accountability during routine 
monitoring visits.  
At the termination of the study, a final investigational product accountability review and 
reconciliation must be completed, and any discrepancies must be investigated and their 
resolution documented. 
5. 
Study Procedures and Assessments 
 
Schedule of Assessments 
The schedule of assessments is provided in Table 10. 
 

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Table 10: Schedule of Assessments 
 
Screening
Treatment and Evaluation 
Disease 
Assessments
End of 
Treatment 
Visit 
Final 
Safety 
Visit 
Survival 
F/U 
Study Week 
 
1 
2 
 
4 
 
 
7 
 
 
10 
 
12 
Q3, 6, and 
12W after 
Week 12 
After disc. of 
treatment 
28 days after 
last dose 
90 days 
after last 
dose 
Every 12 
weeks until 
death or 
for up to 2 
years 
Visit Window 
(days) 
Within 28 d 
of first dose
 
± 2 
 
± 3 
 
 
± 3 
 
 
± 7 
 
± 2 
± 7 
± 7 
± 7 
± 7 
± 14 
Assessment 
D1
C1 
D8
C1 
D1
C2 
D1
C3 
 
 
D1
C4 
 
D15
C4 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
criteria
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA class 
evaluation
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
biopsies/archival 
tissue collection b
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG c 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Performance status 
(ECOG)
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Physical examination
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
MRI or CT disease 
assessment by 
RECIST d
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
X d 
X 
X 
X 
 
AGEN1884 
administration e
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Serum chemistry f 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Endocrine function 
tests (free T4, TSH 
and ACTH) f
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Hematology f 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Tumor marker 
assessment g
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Urinalysis f 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Coagulation f 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 

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Screening
Treatment and Evaluation 
Disease 
Assessments
End of 
Treatment 
Visit 
Final 
Safety 
Visit 
Survival 
F/U 
Study Week 
 
1 
2 
 
4 
 
 
7 
 
 
10 
 
12 
Q3, 6, and 
12W after 
Week 12 
After disc. of 
treatment 
28 days after 
last dose 
90 days 
after last 
dose 
Every 12 
weeks until 
death or 
for up to 2 
years 
Visit Window 
(days) 
Within 28 d 
of first dose
 
± 2 
 
± 3 
 
 
± 3 
 
 
± 7 
 
± 2 
± 7 
± 7 
± 7 
± 7 
± 14 
Assessment 
D1
C1 
D8
C1 
D1
C2 
D1
C3 
 
 
D1
C4 
 
D15
C4 
 
 
 
 
Adverse events 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy test h 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
Concomitant 
medications
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
Vital signs i 
X 
X i 
X 
 
X i 
 
 
X i 
 
 
X i 
 
X 
X i 
X 
X 
X 
 
Evaluation of DLTs 
(phase 1 dose 
escalation only)
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx (whole blood) j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
serum PK and/or  
ADA k
 
X  
X 
 
X  
 
 
X  
 
 
X  
 
X 
 
 
X 
X 
 
Survival follow-up 
and initiation of 
subsequent therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ACTH: adrenocorticotropic hormone; ADA: anti-drug antibody(ies); AFP: alpha-fetoprotein; C: cycle; CA-125: cancer antigen 125; CR: complete response; CT: computed 
tomography; D: day; disc: discontinuation; DLT: dose-limiting toxicity; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; F/U: follow-up; FFPE: formalin-
fixed paraffin-embedded; HCC: hepatocellular carcinoma; IV: intravenous; MRI: magnetic resonance imaging; NYHA: New York Heart Association; PGx: pharmacogenomics; 
PK: pharmacokinetic(s); PR: partial response; Q: every; RECIST: Response Evaluation Criteria in Solid Tumors Version 1.1; SD: stable disease; T4: thyroxine; TSH: thyroid 
stimulating hormone; W: week. 
a. 
All prior cancer treatments collected as part of medical history. 
b. 
Biomarker assessment will be performed on the most recent FFPE biopsy of a tumor lesion, 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. An optional tumor biopsy 
will be collected at Cycle 3, Day 1 (-3/+1 day), if clinically feasible, to assess pharmacodynamic effects of the drug. 
c. 
12-lead ECG to be recorded at screening (within 7 d of first treatment dose) any time during visit as long as within protocol window. Day 1 of Cycles 1 and 2 to be recorded  
1 h ± 30 min following flush of infusion line. Other ECGs to be ordered as clinically indicated by treating physician.   
d. 
Disease response assessments by RECIST to be performed at Study Week 6, Week 12 and Q6w for subjects assigned to 3- or 6-w treatment schedule, or Q12w for subjects 
assigned to 12-w treatment schedule until off-disease response evaluation criteria are met.   

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e. 
AGEN1884 to be administered IV over 60 (-10/+20) min. Subjects with SD, PR, or CR at 12-w evaluation timepoint may continue receiving AGEN1884 every 3, 6, or 12 w 
(± 7 d) beginning at Study Week 12 for ≤1 year provided they are tolerating study drug. The appropriate schedule will be based on discussion with medical monitor to confirm 
that proposed schedule is in subject’s best interest. 
f. 
For screening, laboratory assessments to be completed within 7 d prior to first AGEN1884 administration. Prior to every AGEN1884 administration, laboratory values to be 
reviewed (with the exception of endocrine function tests). Delay AGEN1884 if any dosing delay criteria are met according to Section 4.1.2.  
g. 
For tumors with known markers (e.g., AFP for HCC, CA-125 for ovarian cancer, etc.), samples to evaluate tumor marker levels at sites at screening and at each tumor 
assessment. 
h. 
Women of childbearing potential only. Serum pregnancy test to be performed at screening (within 7 d of first AGEN1884 treatment); urine pregnancy tests to be performed at 
subsequent visits. 
i. 
Vital sign measurements to be collected within 30 min prior to administration, every 30 (± 10) min during the 60-min AGEN1884 infusion, including at end of 15-min flush 
of infusion line (± 15 min). This equates to 4 sets of vitals over the course of a 60-min infusion and flush, including pre-administration vitals. A final set of vitals will be 
collected 1 h (± 15 min) following flush of infusion line, unless otherwise indicated. 
j. 
Blood sample for PGx is collected only if an optional PGx consent is signed. 
k. 
For Cycles 1, 2, 3, 4, 5, 8, 12, and 16, blood samples for serum PK and ADA analyses to be collected on Day 1 predose (within 1 h predose). For Cycles 1 and 4, a blood 
sample for serum PK analysis is to be collected on Day 1 at 2 (±0.25) h post start of AGEN1884 infusion. The 2 h postdose PK sample should never be taken during any study 
drug infusion, but within 1 h following end of the infusion (for those study drug infusions that go longer than the protocol recommended durations). A blood sample for serum 
PK analysis will also be collected at Cycle 1 Day 8 (168 ±4 h post start of AGEN1884 infusion).Blood samples for serum PK and ADA analyses are to be collected at the End 
of Treatment Visit and the Final Safety Visit. See Table 11 for additional PK sampling in an approximate 20 subject subpopulation. 
 

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5.1.1 Screening 
Subjects will undergo screening assessments specified in the schedule of assessments (Table 10) 
within 28 days prior to the first dose of AGEN1884. Laboratory assessments (including serum 
pregnancy) and ECG should be performed within 7 days prior to first treatment dose of 
AGEN1884. 
Subjects who fulfill all of the inclusion criteria and none of the exclusion criteria will be enrolled 
into the study. Subjects who do not meet the inclusion and exclusion criteria will be considered 
screen fails, and their demographic information and reason for screen failure should be 
documented. 
5.1.2 Treatment and Evaluation Period 
Subjects will be treated as described in the schedule of assessments (Table 10) and evaluated for 
pharmacodynamics, PK, immune correlates, disease response, and safety. If a subject 
discontinues for reasons other than PD, tumor assessments will continue until PD occurs or other 
criteria for discontinuation are met. 
5.1.3 End-of-Treatment Visit 
The End-of-Treatment Visit should occur at the time study drug is discontinued for any reason. 
The End-of-Treatment Visit occurs 28 days from the last dose of study treatment. 
5.1.4 Final Safety Visit 
The mandatory Safety Follow-Up Visit should be conducted for all subjects approximately 
90 days after the last dose of study drug or before the initiation of a new antineoplastic treatment, 
whichever comes first. Subjects with an AE of Grade >1 will be further followed until the 
resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever 
occurs first. Subjects with an ADR ongoing at the Safety Follow-up Visit must be followed up 
until the ADR resolves, becomes stable, or is considered not clinically significant by the 
investigator. 
5.1.5 Survival Follow-up 
Subjects who discontinue study treatment will be followed for survival by phone contact every 3 
months. Survival follow-up will continue until death, for up to 2 years, or until study closure.  
Subjects will also be followed for initiation of another cancer therapy. 
If a subject withdraws from the interventional portion of a study and does not consent to 
continued follow-up of associated clinical outcome information, the investigator will not access 
for purposes related to the study the subject’s medical record or other confidential records 
requiring the subject’s consent. However, investigators will consult public records, such as 
obituaries and the Social Security index to establish survival status. 
 
Demographics and Screening Procedures 
5.2.1 Demographics and Medical/Cancer History 
The subject’s date of birth, gender, race, and ethnicity are to be documented. 
A full medical history is to be documented during the screening visit by the investigator or 
designated participating physician and may include medical notes documented by a referring 

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physician in the subject’s medical record. The medical history is to include any current active 
diagnoses and any previously treated illnesses, including the approximate date of onset (at 
minimum indicate the year or approximate year) and date of resolution if applicable, and 
description of any prior surgeries. The body systems to be reviewed and any concurrent or past 
diagnoses documented include but are not limited to: eyes, ears, nose, and throat; respiratory; 
cardiovascular; gastrointestinal; musculoskeletal; neurological; endocrine/metabolic; 
hematologic/lymphatic; dermatological; genitourinary; psychiatric; and allergies.  
Baseline information about the malignancy, including type of cancer, date of diagnosis, and prior 
treatments, will also be collected. 
5.2.2 Eastern Cooperative Oncology Group Scale 
Subjects will be graded according to ECOG performance status score (Appendix C). 
5.2.3 New York Heart Association Class Evaluation 
The NYHA class will be evaluated at screening (Appendix D ). 
5.2.4 Tumor Markers  
For tumors with known markers (e.g., alpha-fetoprotein [AFP] for HCC, cancer antigen 125 
[CA-125] for ovarian cancer, etc.), samples to evaluate levels of tumor markers will be obtained 
at screening and at each tumor assessment. 
 
Pharmacokinetic Assessments 
Serum AGEN1884 concentrations will be determined by validated methods. PK parameters to be 
estimated and reported may include, but may not be limited to, maximum observed drug 
concentration at steady-state (Cmax-ss), minimum observed drug concentration at 
steady-state (Cmin-ss), area under the drug concentration-time curve within time span t1 to t2 at 
steady-state (AUC(t1-t2)-ss), area under the drug concentration-time curve from time of dosing to 
time of last observation (AUC(0-t)), area under the drug concentration-time curve from time of 
dosing extrapolated to infinity (AUC(0-∞)), time to reach maximum drug concentration (tmax), 
terminal elimination rate constant (λz), terminal elimination half-life (t½), systemic clearance 
(CL), and volume of distribution (Vd). PK parameters will be summarized using descriptive 
statistics. Individual as well as summary drug concentration-time profiles will be depicted. 
Unresolved missing data may be imputed when analysis integrity is affected. The conservative 
principle will be used for data imputation. Both noncompartmental (NCA) and compartmental 
modeling (e.g., population pharmacokinetics [PopPK]) techniques will be used to analyze the 
pharmacokinetics.  Sampling times for all subjects are shown in Table 10. 
In addition to the PK sampling times for the general population shown in Table 10, a subgroup of 
approximately 20 subjects will have samples taken at 3 additional timepoints shown in Table 11. 

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Table 11: Additional Pharmacokinetic Sampling Schedule in an Approximate 20 Subject 
Subpopulation 
Cycle 
Sampling Times 
Cycle 1 
D3 (48±4 h) 
Cycle 4 
D3 (48±4 h); D8 (168±4 h). 
Blood samples collected Days 3 and 8 at 48±4 h and 168±4 h, respectively, after the start of the infusion. 
Unresolved missing data may be imputed when analysis integrity is affected. The conservative 
principle will be used for data imputation. 
 
Immunogenicity Assessments 
Serum AGEN1884 ADA monitoring will be conducted via blood serum samples collected prior 
to drug administration, throughout the entire course of drug administration, and at the final safety 
visit. Sampling times are shown in Table 10. 
 
Exploratory Biomarkers 
To better understand the pharmacodynamics of AGEN1884, a correlation with additional 
biomarkers may be necessary, this includes but may not be limited to whole blood, plasma, and 
serum samples for exploratory biomarker analysis according to the schedule of assessments 
(Table 10) as well as tumor tissue collected at screening and an optional on-treatment biopsy. 
Within this trial, additional biomarker assessments that might be correlated with safety, response, 
or resistance to treatment beyond those listed (e.g., monitoring inflammatory or immune 
markers, measuring specific cell populations, or measuring cell surface markers by flow 
cytometry, immunoblot, mass spectroscopy, immunoassay, tumor markers, or correlations 
between drug exposure and/or response including tumor mutational burden and other variations 
in deoxyribonucleic acid [DNA] or in ribonucleic acid [RNA] [pharmacogenomics]) may be 
evaluated at the discretion of the Sponsor using excess PD, PK, whole blood, plasma, serum, or 
biopsy samples. Participation in pharmacogenomics (PGx) studies involving the analysis of DNA 
and/or RNA is optional and requires separate informed consent (Section 7.1). 
Ongoing research may lead to the identification of new important markers related to anti-CTLA4 
therapies and/or safety in a near future; therefore, each subject will also be asked whether any 
remaining tumor tissue or blood-derived samples can be stored at a central repository and can be 
used for future exploratory research on the drug and / or disease-related aspects. A subject’s 
consent to the use of any remaining samples for such future exploratory research shall be 
optional and shall not affect the subject’s participation in the current trial. After analysis by the 
Sponsor or its designee, samples will be maintained for up to 5 years following completion of the 
study and will then be destroyed unless the subject withdraws consent or requests that his/her 
sample/results be destroyed. During this 5 year period, samples may be reanalyzed by the 
Sponsor or its designee, collaborator, or partner. 

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Pharmacodynamic Assessments and Biopsy 
5.6.1 Biopsy and Tissue Collection 
Tumor tissue for biomarker analysis from a biopsy of a tumor lesion not previously irradiated 
must be available for biomarker assessments. Biomarker assessment will be performed on the 
most recent FFPE biopsy of a tumor lesion, 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. An optional 
tumor biopsy will be collected at Cycle 3, Day 1 (-3/+1 day), if clinically feasible, to assess 
pharmacodynamic effects of the drug. 
Tissue from needle or excisional biopsy or from resection is required. 
Preferably, an FFPE tumor tissue block should be provided. If the tumor-containing FFPE tissue 
block is not available, 25 sections (slides) ≤ 1 month old should be provided; ≥ 15 slides are 
required. If no tumor tissue is available, a fresh biopsy will be required, if clinically feasible.  
Fine needle aspirates, endobronchial ultrasound (EBUS) or cell blocks are not acceptable. 
If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred 
to obtain a new baseline scan. Biopsy of lesions on study should be limited to non-target lesions 
or new lesions if their pathologic etiology is ambiguous.  
Tissue processing: The cancer tissues should be fixed in 10% neutral buffered formalin, paraffin 
embedded, and routinely processed for histological evaluation. Formalin substitutes are not 
suited as fixative.  
Provision of samples:  
1. Priority: tumor containing FFPE tissue block;  
2. Priority: if the tumor containing FFPE tissue block cannot be provided in total, sections 
from this block should be provided that are freshly cut (within the last month), 5 µm 
thick, and mounted on SuperFrost Plus microscope slides. Preferably, 25 slides should be 
provided; if not possible, a minimum of 15 slides are required. The SuperFrost Plus 
microscope slides and slide containers will be provided by the central lab.  
Sample shipment: The tumor blocks and freshly prepared slides should be sent with the next 
shipment to the central lab.  
Sample storage: At the central laboratory, the FFPE tissue blocks shall be stored at room 
temperature in the dark and the FFPE tumor slides shall be kept in sealed containers at 2°C to 
8°C. 
For additional details and instructions regarding tissue requirements, collection, storage and 
shipment, refer to the study Laboratory Manual. 
5.6.2 Pharmacogenomics (Optional) 
The sponsor may conduct research on DNA (blood)  or tumor tissue specimens collected during 
this trial. This research may include genetic analysis (DNA) and gene expression profiling 
(RNA). Such research is for pharmacogenomic testing to address emergent questions not 
described elsewhere in the protocol (as part of the main trial) and will only be conducted on 

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specimens from appropriately consented subjects. The overarching goal is to develop safer, more 
effective drugs. 
Germline (inherited) variants will be investigated in DNA extracted from the whole blood. For 
this purpose, an additional 4 mL of whole blood (PGx sample) will be collected at screening. 
Additionally, tumor biopsy samples may be used for the extraction of DNA to study tumor 
genetics (somatic variations). Participation is optional for subjects being recruited at sites whose 
IEC/IRB has approved PGx assessments and a PGx informed consent form (ICF) (optional) is 
signed (Section 7.1). 
All samples collected during the trial will be kept confidential. For this purpose, the samples will 
be given a label connected with a code assigned at the start of the Main Study (coded trial subject 
number). Outside the study center, no one will be able to link the subject’s identity to the subject 
number. The link between the subject’s identity and the subject number will only be known by a 
limited number of authorized personnel. Information about race, ethnicity, sex, medical history, 
etc., may be available to scientists studying the PGx blood samples. Such information might be 
important for research or public health purposes. Genomic analysis results will not be reported 
back to the sites. 
Participation in PGx portion of the trial is optional and requires separate informed consent. 
Participation in the PGx portion of the trial will not affect participation in the trial. Subjects may 
withdraw consent from PGx portion of the trial without withdrawing from the trial. Consent and 
withdrawal of consent (if applicable) for PGx assessments will be documented in the eCRF. 
 
Tumor Assessments 
5.7.1 Response Evaluation Criterion in Solid Tumors  
Primary disease assessments will be performed based on RECIST Version 1.1 (Appendix E). 
Disease response assessments by RECIST to be performed at Study Week 6, Week 12 and Q6w 
for subjects assigned to 3- or 6-w treatment schedule, or Q12w for subjects assigned to 12-w 
treatment schedule until off-disease response evaluation criteria are met. 
Assessment of tumor size (by magnetic resonance imaging [MRI] or computed tomography [CT] 
scan) will be performed as specified in the schedule of assessments (Table 10) until disease 
progression is determined by RECIST or other off–tumor evaluation criteria are met. The same 
modality should be used for each subject through the course of his or her disease evaluation. 
Treatment cycles may become out of sync with tumor assessments if a delay in therapy is 
indicated; however, in this event, tumor assessments will remain on the original schedule.  
Subjects who discontinue study drug for a reason other than disease progression will continue to 
be assessed for their disease status per the schedule of events and should continue to have tumor 
assessments every 6 weeks, or per disease-specific schedule, until further disease progression 
(additional 10% from first PD observation), death, or the end of the study. 
 
Safety Assessments 
5.8.1 Physical Examination 
Physical examinations are to be completed by the investigator or designated participating 
physician as indicated in the schedule of assessments (Table 10). The minimum body systems to 
be examined for any abnormalities and symptoms include: general appearance; skin; lymphatic; 

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head, eyes, ears, nose, throat; extremities; respiratory; cardiovascular; abdominal; 
musculoskeletal; and neurological. 
5.8.2 Vital Signs 
Vital signs will be measured at all visits indicated in the schedule of assessments (Table 10) and 
documented in the medical record. Measurements to be reported are temperature in Celsius or 
Fahrenheit, pulse (beats per minute), respiratory rate (breaths per minute), oxygen saturation, and 
blood pressure.  
Vital sign measurements will be collected within 30 minutes prior to study drug administration, 
and every 30 (± 10) minutes during the 60-minute AGEN1884 infusion, including at the end of 
the 15-minute flush of the infusion line (± 15 minutes). This would equate to 4 sets of vitals over 
the course of a 60-minute infusion and flush, including the pre-administration vitals. A final set 
of vitals will be collected 1 hour (± 15 minutes) following the flush of the infusion line, unless 
otherwise indicated. 
Because AGEN1884 is administered based on subject body weight, weight will be collected 
before each dose of AGEN1884 to confirm the administered dose. The subject’s weight at the 
Week 1 (Cycle 1, Day 1) visit should be used for dosing calculations unless there is a >10% 
change in body weight. Dose adjustments for each cycle are only needed for a >10% change in 
weight. 
5.8.3 12-Lead Electrocardiogram 
A 12-lead ECG will be recorded as indicated in the schedule of assessments (Table 10). The 
corrected QT (QTc) interval will be calculated using Fridericia’s formula.   
5.8.4 Clinical Laboratory Assessments 
Blood samples will be collected and submitted to the institution’s local laboratory according to 
the institution’s standard procedures.  
Standard laboratory procedures and institutional guidelines will be followed to analyze and 
report findings for hematology, coagulation times, and serum biochemistry.  
Normal ranges with the units of measure for all required parameters will be provided to the study 
sponsor by the local laboratory conducting the clinical laboratory analysis. All results may be 
reported in conventional units if this is the typical clinic report method for the local laboratory; 
otherwise, the International System of units may be used. 
A listing of clinical laboratory assessments to be performed is provided in Table 12. 

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Table 12: Clinical Laboratory Assessments 
Hematology 
Red blood cell count 
Platelets 
Hematocrit 
Hemoglobin 
WBC count 
WBC differentials and absolute counts: 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Serum biochemistry 
Albumin 
Alkaline phosphatase 
Aspartate amino transferase 
Alanine amino transferase 
Total bilirubin 
Blood urea nitrogen 
Glucose 
Creatinine 
Potassium  
Sodium 
Lactate dehydrogenase 
Endocrine function tests 
Free thyroxine (T4) 
Thyroid-stimulating hormone 
Adrenocorticotropic hormone 
Urinalysis 
Red blood cells 
WBCs 
Protein 
Coagulation 
Prothrombin time 
INR 
Partial thromboplastin time 
Tumor markers 
Tumors with known markers, such as alpha-fetoprotein for HCC and cancer 
antigen 125 for ovarian cancer
Other 
Serum and urine pregnancy tests (for women of childbearing potential only) 
PGx
HCC: hepatocellular carcinoma; INR: International Normalized Ratio; PGx: pharmacogenomics; WBC: white blood 
cell. 
5.8.5 Concomitant Medications 
Concomitant medications will be recorded from date of signing of the informed consent through 
90 days after the last study drug administration. 
5.8.6 Adverse Events 
5.8.6.1 Definitions 
5.8.6.1.1 Adverse Event 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding that is deemed clinically significant), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  

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Examples include: 
 
Any clinically significant worsening of a pre-existing condition (e.g., an increase in 
severity or frequency of pre-existing abnormality or disorder). 
 
Any illness, injury, or accident, including those that appear unrelated to study treatment. 
 
Extensions or exacerbations or symptomatology. 
 
Clinically significant abnormalities in clinical laboratory, physiological testing, or 
physical examination. 
5.8.6.1.2 Immune-Related Adverse Events 
Blocking CTLA-4 function may permit the emergence of immune-mediated AEs that result in 
clinical syndromes resembling autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, 
hepatitis, and hypopituitarism were drug-related, presumptive immune-related events noted in 
previous studies of anti–CTLA-4 agents. 
For the purposes of this study, an irAE is defined as an adverse event of unknown etiology, 
associated with drug exposure, and is consistent with an immune phenomenon. Efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes prior to 
labeling an adverse event an irAE. Serological, immunological, and histological (biopsy) data 
should be used to support the diagnosis of an immune-mediated toxicity.  
5.8.6.1.3 Adverse Drug Reaction 
An ADR is defined as all noxious and unintended responses to a medicinal product, related to 
any dose. A causal relationship between the medicinal product and an AE is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
5.8.6.1.4 Unexpected Adverse Drug Reaction 
An unexpected ADR is an ADR whose nature or severity is not consistent with the applicable 
product information (e.g., Investigator Brochure). The ADRs that are more specific or more 
severe than described in the Investigator Brochure should also be considered unexpected. 
5.8.6.1.5 Serious Adverse Event 
An SAE in a clinical trial is defined as any untoward medical occurrence that at any dose, in the 
view of either the investigator or sponsor: 
 
Results in death. 
 
Is life-threatening (the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe). 
 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 
Is a congenital anomaly/birth defect. 
 
Any event that does not meet the above criteria, but when based on appropriate medical 
judgment, may require medical or surgical intervention to prevent one of the outcomes 
listed above, e.g., allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in in-patient 
hospitalization; development of drug abuse or drug dependency. 

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5.8.6.2 Recording and Reporting 
5.8.6.2.1 Adverse Events 
Subjects will be assessed for any AEs (non-serious or serious) from the date of consent until 90 
days after the last study treatment. Any non-serious AEs identified during this time period will be 
followed until resolution or stabilization or only until the discontinuation from the study 
evaluation period if the event is not resolved at the conclusion of the study. The dates of onset 
and resolution for each AE will be recorded in the subject file. All AEs will be evaluated for 
duration, intensity, and attribution (relationship) to the investigational agent(s). All AEs (serious 
and non-serious) and laboratory abnormalities should be assessed for significance by the 
investigator, with consideration for the subject’s overall medical history and concomitant 
medication profile. 
If there is a change from baseline in a laboratory value, physical examination finding, vital sign, 
or medical finding, and the change is considered by the investigator to be clinically significant, 
the event must be recorded as an AE. 
All AEs regardless of causality or seriousness must be recorded on the electronic case report 
form (eCRF). The frequency, grade, and nature of irAEs must be recorded. 
5.8.6.2.2 Serious Adverse Events 
All AEs that meet the SAE criteria, occurring from the date of consent, must be recorded on the 
AE pages of the eCRF and reported by facsimile to Agenus/PrimeVigilance within 24 hours of 
obtaining knowledge of the event. The facsimile report should include all available information 
requested on the SAE Report Form.  
Email: 
 
Facsimile: 
 
The SAE Report Form will include data surrounding the event, e.g., the nature of the 
symptom(s), time of onset in relation to initiation of therapy, duration, intensity, and whether or 
not therapy was interrupted or discontinued. The investigator’s assessment of the probable cause 
of the event will also be included. In addition, relevant medical history, concomitant 
medications, laboratory and diagnostic tests reports, and procedures, as well as all pertinent 
medical information related to the event, will also be collected. 
PrimeVigilance will forward SAE queries directly to the investigator requesting incomplete or 
missing information. It is the investigator’s responsibility to be diligent in providing this 
information back to PrimeVigilance as soon as it is available. Initial reports of SAEs should 
never be left on telephone voicemails. Always fax SAE Report Forms and follow up with a 
telephone call if needed.  
If you have any safety-related questions or need to report an SAE, please email: 
 
For reported deaths, the investigator should supply the sponsor and the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) with any additional requested information 
(e.g., autopsy results, hospital discharge reports, and/or certificates of death) and should be sent 
as soon as they become available. Any additional information, if collected, will be reported to the 
sponsor as a follow-up to the initial report. 

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All SAEs will be followed until the event has resolved or stabilized, regardless of causality. 
It is the responsibility of the principal investigator to report SAEs to their IRB. The investigator 
should also comply with the applicable regulatory requirement(s) related to the reporting of 
unexpected serious ADRs to the regulatory authority(ies) and the IRB/IEC. 
Deaths occurring during the AE reportable time frame should be reported as SAEs and recorded 
on the eCRF. The underlying event that resulted in death should be recorded as the verbatim 
term, with “death” recorded as the outcome of the event. 
5.8.6.3 Adverse Events of Special Interest  
In the event of a non-serious adverse events of special interest (AESI), the investigator must 
complete the AESI report form and send it to the Sponsor/designee immediately, within 24 hours. 
Names, addresses, and telephone and fax numbers for AESI reporting will be included on the 
report form. Serious AESIs must be reported in an expedited manner as SAEs, as outlined above. 
5.8.6.4 Severity of Adverse Events  
Each AE is to be classified and graded according to NCI CTCAE Version 5, publication date 
27 November 2017 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf). 
If no CTCAE grading is applicable, the severity of an AE is graded as follows: 
 Mild (grade 1): The event causes discomfort without disruption of normal daily 
activities. 
 Moderate (grade 2): The event causes discomfort that affects normal daily activities. 
 Severe (grade 3): The event makes the subject unable to perform normal daily 
activities or significantly affects his/her clinical status. 
 Potentially life-threatening/life-threatening (grade 4): An SAE Report Form must 
be completed for each grade 4 AE.  
 An event that results in death is considered a grade 5 AE, meets the definition of an 
SAE, and must have an SAE Report Form completed for the event. 
Note: All subjects who have a grade 3 or 4 AE may be considered for discontinuation from 
treatment by the principal investigator and after consultation with the medical monitor. 
 
Relationship to Study Treatment 
The relationship of an AE to the investigational agent will be recorded on eCRF and defined as 
“unrelated,” “unlikely,” “possible,” “probable,” or “highly probable/definite.”  
 Unrelated: The event is definitely not associated with study drug administration, but is 
judged clearly and incontrovertibly due to causes other than the study drug. 
 Unlikely: An event that follows such a temporal sequence from administration of the 
study drug that a relationship is not likely, and is likely to be due to cause such as (known 
characteristics of) the subject’s clinical state or other treatment. 

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 Possible: An event that follows a reasonable temporal sequence from administration of 
the study drug, but that may be due to another cause. 
 Probable: An event that follows a reasonable temporal sequence from administration of 
the study drug, and that is not easily explained by another cause such as known 
characteristics of the subject’s clinical state or other treatment. 
 Highly probable/definite: An event that follows an established temporal sequence from 
administration of the study drug, the re-challenge is positive, or there is a reoccurring 
pattern of characteristics during onset and cessation of event. 
 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method. When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
within 90 days of the last dose of study drug, the following procedures should be followed in 
order to ensure subject safety: 
 The study drug must be discontinued immediately (female subjects only). 
 The investigator must complete and submit the Agenus Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
 A serum pregnancy test must be performed to confirm the urine pregnancy test result.  
If a negative serum test does not confirm the urine pregnancy test result, then: 
o 
The investigator will use his or her expert judgment, based on an assessment of 
the potential benefit/risk to the subject, to determine whether it is in the subject's 
best interest to resume study drug and continue participation in the study. 
o The final safety visit evaluations must be performed. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation. Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit. Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee. Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor’s study drug to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later. Refer to the 
Agenus Study Operational Guide for Completing the Clinical Trial Pregnancy Form. 
Note: Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
 
Disease Progression or Secondary Cancer or Death 
For the purpose of this protocol, disease progression events should not be reported as a 
nonserious AE or SAE unless the criteria for an SAE are met (Section 5.8.6.1.5). If the event 
meets SAE criteria, a specific verbatim SAE term is to be reported (e.g., brain metastases). 
Details of how the event manifested should be provided in a narrative format and submitted with 

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the Agenus SAE Report Form. An appropriate verbatim term that describes the subject diagnosis 
should be provided in the Agenus SAE Report form. The verbatim terms “disease progression” 
or “disease recurrence” should be avoided; if used, it will be queried for a request for an 
appropriate term with supportive details for the event. 
Changes in any medical condition of a subject, including the diagnosis of a secondary cancer or a 
clinically significant change of medical status, should be reported as an AE on the appropriate 
eCRF and should be reported as an SAE only if the event meets SAE criteria. 
Deaths occurring during the AE reportable time frame (within 90 days of study drug) should be 
reported as SAEs and recorded on the Agenus SAE Report Form. The underlying event that 
resulted in death should be recorded as the verbatim term, with “death” recorded as the outcome 
of the event. 
6. 
Statistical Considerations 
This section outlines the core elements of the planned statistical summaries and analyses for the 
data collected in this study. Detailed methodology for summary and statistical analyses of the 
data collected in this study will be documented in a statistical analysis plan (SAP), which will be 
maintained by the sponsor. The SAP may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be reflected 
in a protocol amendment. If, after the data are locked, changes are made to the SAP, then these 
deviations to the plan will be documented, in the clinical study report. 
 
Sample Size Considerations 
Overall, approximately 90 subjects will be enrolled in Phase 1 and Phase 2 of this study. After 
safety is established in the 1 mg/kg and 3 mg/kg cohorts, additional subjects will be enrolled into 
these dose cohorts (target size of 10 subjects per cohort) to support the objectives and expand the 
number of correlates available for evaluation.  
The Phase 2 population will include approximately 40 subjects 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) with a subpopulation to include approximately 
20 subjects with advanced HCC. 
These sample sizes are not based on inferential statistics. 
 
Endpoints 
6.2.1.1 Primary Endpoints 
 Safety and tolerability will be assessed by monitoring the frequency, duration, and 
severity of drug-related AEs; by completing physical examinations; by evaluating 
changes in vital signs and ECG; through clinical examinations; and laboratory blood and 
urine sample evaluations. 
 PK parameters to be estimated and reported may include, but may not be limited to, 
Cmax-ss, Cmin-ss, AUC(t1-t2)-ss, AUC(0-t), AUC(0-∞), tmax, λz, t½, CL, and Vd. PK parameters 
will be summarized using descriptive statistics. Individual as well as summary 
concentration-time profiles will be depicted. Both NCA and compartmental modeling 
(e.g., PopPK) techniques will be used to analyze the pharmacokinetics. 

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6.2.1.2 Secondary Endpoints 
 Objective response rate, (ORR), defined as the percentage of subjects having CR or PR, 
as determined by radiographic disease assessments per RECIST 1.1. 
 Disease control rate (DCR) will include subjects that have best overall response (BOR) of 
CR, PR and SD for at least 12 weeks. 
 Progression-free survival (PFS), defined as the interval from the date of first dose of 
investigational agent until the earliest date of disease progression, as determined by 
investigator assessment of objective radiographic disease assessments per RECIST 1,1, or 
death due to any cause if occurring sooner than progression. 
 Duration of response, (DOR), defined as the interval from the date measurement criteria 
are met for CR or PR (whichever is first recorded) until the earliest date of disease 
progression, as determined by investigator assessment of objective radiographic disease 
assessments per RECIST 1.1, or death due to any cause if occurring sooner than 
progression. Only subjects who achieve an initial response will be evaluated for DOR. 
 Overall survival (OS), defined as the interval from the date of first dose of investigational 
agent until the date of death. 
 The pharmacologically active dose of AGEN1884, determined through clinical signs of 
drug activity, surrogate markers, and pharmacodynamic studies, including but not limited 
to the presence of irAEs. 
6.2.1.3 Exploratory Endpoints 
 Other biomarker effects and outcome predictors of AGEN1884 in peripheral blood and 
tumor tissue will be evaluated as exploratory analyses. 
 
Analysis Sets 
The following analysis sets will be evaluated: 
 DLT evaluable analysis set: 
o All subjects within the dose escalation cohorts who received ≥2 doses of 
AGEN1884 at their assigned dose level and completed the DLT evaluation period 
of 28 days, or all subjects within the dose escalation cohorts who received ≥1 
dose of AGEN1884 and experienced a DLT. 
 Safety analysis set: 
o All subjects who have received ≥1 dose of AGEN1884. 
 Efficacy analysis set:  
o Subjects who have received ≥2 doses of AGEN1884 at the assigned dose level. 
 
Analysis Methods 
6.4.1 Safety Analysis 
Descriptive statistics of safety parameters will be provided in the full safety analysis set, by dose 
level, and study cohort. Safety parameters include the following:  

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 AEs (all AEs and irAEs, subsets of related, serious, severe, and fatal events). In addition, 
the number and percentage of subjects who discontinue treatment due to an AE will be 
provided, together with the number and percentage of subjects who die due to an AE. 
 Laboratory evaluations. 
 Vital signs. 
6.4.2 Efficacy Analysis 
Efficacy endpoints will be measured in the safety analysis set. As an exploratory analysis, similar 
calculations will be performed on the efficacy analysis set.   
6.4.2.1 Progression-Free Survival 
Subjects who are alive and have not progressed at the time of analysis will be censored at the 
time of the last clinical assessment noted to be free of progression. The distribution of PFS times, 
including median PFS time and PFS rates, will be estimated in a pooled manner and by each 
dose level and study cohort using the Kaplan-Meier method with 95% confidence intervals. 
Dates of progression will be based on RECIST 1.1.  
6.4.2.2 Overall Survival 
Subjects who have not died at the time of analysis will be censored at the time of last known 
alive. The distribution of survival times, including median survival time and survival rates, will 
be estimated in a pooled manner and by each dose level and study cohort using the Kaplan-Meier 
method with 95% confidence intervals.  
6.4.2.3 Objective Response Rate 
Descriptive statistics (number and frequency) of response rates will be presented in a pooled 
manner and by dose of AGEN1884 and cohort. Disease responses will be defined based on 
RECIST 1.1. 
6.4.2.4 Duration of Response 
Descriptive statistics (median, minimum, maximum, number of applicable subjects) of disease 
response durations will be presented in a pooled manner and by dose of AGEN1884 and cohort. 
Disease responses will be defined based on RECIST 1.1.  
 
Statistical Analysis Plan 
A statistical analysis plan (SAP) for the study will be created as a separate document. General 
considerations with regard to statistical methods, as well as specific plans for the analysis of 
efficacy and safety will be detailed in the SAP. 
7. 
Compliance with Good Clinical Practice, Ethical Considerations, and Informed 
Consent 
 
Compliance with Good Clinical Practice and Ethical Considerations 
This study must be conducted in compliance with the IRB/IEC informed consent regulation, and 
the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. 
In addition, all local regulatory requirements will be adhered to, in particular those which afford 
greater protection to the safety of the trial participants. 

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This study will be conducted according to the current revision of the Declaration of Helsinki 
(Revised 64th WMA General Assembly, Fortaleza, Brazil, October 2013) and with local laws 
and regulations relevant to the use of new therapeutic agents in the country of conduct. 
Before initiating a trial, the investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the trial protocol/amendment(s), written ICF, 
subject recruitment procedures (e.g., advertisements), and written information to be provided to 
subjects. Subjects may also sign a separate, optional section of the ICF, related to 
pharmacogenomic analysis, which refers to extraction and analysis of DNA from blood and/or 
tumor biopsy to better understand how gene(s) may affect the efficacy of AGEN1884. 
Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
subjects.  
The investigator, or a person designated by the investigator, will explain the benefits and risks of 
participation in the study to each subject or the subject’s legally acceptable representative in the 
presence of an impartial witness and obtain written informed consent prior to the subject entering 
the study (before initiation of non-routine tests and administration of study drug).  
Agenus will provide the site with a sample ICF, which may be modified according to local 
regulations or requirements. The final ICF must be agreed to by Agenus and the IRB/IEC and 
must contain all elements in the sample form in language readily understood by the subject. The 
investigator will retain each subject’s original ICF, signed and dated by the subject or by the 
subject’s legally acceptable representative, and by the person who conducted the informed 
consent discussion, with a copy provided to the subject. 
Participation in the pharmacogenomics portion of the trial is optional. Participation in the 
pharmacogenomics portion of the trial will not affect participation in the trial. Subjects may 
withdraw consent from pharmacogenomics portion of the trial without withdrawing from the 
trial. The results of pharmacogenomics testing will not be made available to the subjects. 
Specimens that may be used for pharmacogenomics testing include: blood and tumor specimens 
collected during this trial.  
The investigator or qualified designee will explain the optional pharmacogenomics assessment 
portion of the consent to the patient, answer all his/her questions, and obtain optional written 
informed consent before performing any procedure related to pharmacogenomics assessment.  
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the sponsor or designee and be submitted again to the IEC/IRB for 
review and favorable opinion. The agreed upon, revised information will be provided to each 
subject in the trial for signing and dating. The investigator will explain the changes to the 
previous version. 
8. 
Study Management and Materials 
 
Data Recording and Retention of Study Data 
In compliance with GCP, the medical records/medical notes, etc., should be clearly marked and 
permit easy identification of participation by a subject in the specified clinical trial. 

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The investigator is to record all data with respect to protocol procedures, drug administration, 
laboratory data, safety data and efficacy ratings on the study eCRFs.  
The principal investigator must, as a minimum, sign the final eCRF pages to attest to the 
accuracy and completeness of all data. 
All corrections on source documents must be made in a way that does not obscure the original 
entry. The correct data must be inserted, dated, and initialed/authorized by study personnel. If the 
reason for the change is not obvious, a reason should be provided. 
If the investigator relocates or retires, or otherwise withdraws his/her responsibility for 
maintenance and retention, Agenus must be notified (preferably in writing) so that adequate 
provision can be made with regard to the trial documents. 
Trial documents should be retained until ≥2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications in 
an ICH region, or ≥2 years have elapsed since the formal discontinuation of clinical development 
of AGEN1884 by Agenus. These documents should be retained for a longer period, however, if 
required by the applicable regulatory requirements or by an agreement with Agenus. Agenus will 
inform the investigator in writing as to when these documents no longer need to be retained. 
 
Monitoring, Verification of Data, Audit, and Inspection 
An Agenus monitor, or appointed agent, will perform monitoring in the form of on-site visits, 
telephone calls, and regular review of the eCRFs at a frequency sufficient to inspect: study 
progress; subject enrollment/screening; compliance with protocol procedures; informed consent 
procedure; completeness and accuracy of data entered on the eCRFs; verification of data against 
original source documents; storage and accountability of investigational product; archiving of 
study documentation; and occurrence of AEs. Adequate time and workspace for these visits must 
be made available by the investigator and his/her study personnel. Periodically some/all of the 
facilities used in the trial (e.g., laboratory) may be reviewed or inspected by the IRB/IEC and/or 
regulatory authorities.  
The investigator is to ensure that the trial participants are aware of and consent that personal 
information may be reviewed during the data verification process as part of the 
monitoring/auditing by properly authorized agents of Agenus or subject to inspection by 
regulatory authorities. In addition, participation and personal information is treated as strictly 
confidential to the extent the applicable law permits and not publicly available. The audit or 
inspection may include, for example, a review of all source documents (medical records), drug 
records, original clinical medical notes, and some or all of the facilities used in the trial. 
The investigator agrees by written consent to this protocol to fully cooperate with compliance 
checks by allowing access for authorized persons to all study documents. 
 
Study Stopping Rules 
Premature termination of the clinical trial may occur because of a regulatory authority decision, 
change of the IRB/IEC, or drug safety problems, at the discretion of the sponsor. In addition, 
Agenus retains the right to discontinue development of AGEN1884.  
Recruitment at a center may be stopped for reason that may include low recruitment, protocol 
violation, or inadequate data recording quality control and quality assurance. 

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9. 
Communication and Publication of Results 
The investigators and Agenus acknowledge that this study is part of a multicenter research study. 
Any publication (or presentation) of the data collected from this trial will be considered a joint 
publication by the investigators and the appropriate Agenus personnel. Authorship will be 
determined by mutual agreement between Agenus personnel and the principal investigators of 
the study. Agenus retains the right to the initial publication or presentation of the results by the 
study group. Following joint publication (or at such early time as Agenus decides), each principal 
investigator may request, in writing, the opportunity to publish or present site-specific data in 
accordance with the terms set forth in the Clinical Trial Agreement between Agenus and such 
principal investigator. 
 
 

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10. 
References 
Brahmer, J.R., Drake, C.G., Wollner, I., Powderly, J.D., Picus, J., Sharfman, W.H., Stankevich, 
E., Pons, A., Salay, T.M., McMiller, T.L., et al. (2010). Phase I study of single-agent anti-
programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, 
pharmacodynamics, and immunologic correlates. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 28, 3167-3175. 
Bristol-MeyersSquibb (2013). Investigator Brochure for nivolumab BMS-936558 MDX1106, 
version 12, pp. 1-131. 
Bulliard, Y., Jolicoeur, R., Windman, M., Rue, S.M., Ettenberg, S., Knee, D.A., Wilson, N.S., 
Dranoff, G., and Brogdon, J.L. (2013). Activating Fc gamma receptors contribute to the 
antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med 210, 1685-
1693. 
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.J., Cowey, C.L., Lao, C.D., Schadendorf, 
D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015). Combined Nivolumab and Ipilimumab 
or Monotherapy in Untreated Melanoma. N Engl J Med 373, 23-34. 
Marabelle, A., Kohrt, H., Sagiv-Barfi, I., Ajami, B., Axtell, R.C., Zhou, G., Rajapaksa, R., Green, 
M.R., Torchia, J., Brody, J., et al. (2013). Depleting tumor-specific Tregs at a single site 
eradicates disseminated tumors. J Clin Invest 123, 2447-2463. 
Page, D.B., Postow, M.A., Callahan, M.K., and Wolchok, J.D. (2013). Checkpoint modulation in 
melanoma: an update on ipilimumab and future directions. Curr Oncol Rep 15, 500-508. 
Qureshi, O.S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E.M., Baker, J., 
Jeffery, L.E., Kaur, S., Briggs, Z., et al. (2011). Trans-endocytosis of CD80 and CD86: a 
molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600-603. 
Romano, E., Kusio-Kobialka, M., Foukas, P.G., Baumgaertner, P., Meyer, C., Ballabeni, P., 
Michielin, O., Weide, B., Romero, P., and Speiser, D.E. (2015). Ipilimumab-dependent cell-
mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma 
patients. Proc Natl Acad Sci U S A 112, 6140-6145. 
Selby, M.J., Engelhardt, J.J., Quigley, M., Henning, K.A., Chen, T., Srinivasan, M., and Korman, 
A.J. (2013). Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through 
reduction of intratumoral regulatory T cells. Cancer Immunol Res 1, 32-42. 
Simpson, T.R., Li, F., Montalvo-Ortiz, W., Sepulveda, M.A., Bergerhoff, K., Arce, F., Roddie, C., 
Henry, J.Y., Yagita, H., Wolchok, J.D., et al. (2013). Fc-dependent depletion of tumor-infiltrating 
regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 
210, 1695-1710. 
Weber, J.S., Gibney, G., Sullivan, R.J., Sosman, J.A., Slingluff, C.L., Jr., Lawrence, D.P., Logan, 
T.F., Schuchter, L.M., Nair, S., Fecher, L., et al. (2016). Sequential administration of nivolumab 
and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an 
open-label, randomised, phase 2 trial. Lancet Oncol 17, 943-955. 
Weber, J.S., Dummer, R., de Pril, V., Lebbe, C., Hodi, F.S., and Investigators, M.D.X. (2013). 
Patterns of onset and resolution of immune-related adverse events of special interest with 

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ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. 
Cancer 119, 1675-1682. 
Weber, J.S., Kahler, K.C., and Hauschild, A. (2012). Management of immune-related adverse 
events and kinetics of response with ipilimumab. J Clin Oncol 30, 2691-2697. 
Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., 
and Sakaguchi, S. (2008). CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 
271-275. 
Zou, W. (2006). Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6, 
295-307. 
 
 
 

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Appendix A Protocol Lead Signature Page 
 
Title 
A Phase 1/2, Open-Label, Multicenter Study to Evaluate the 
Safety, Pharmacokinetics, and Pharmacodynamics 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 
Clinical Trial Version/Date 
Amendment 9, 26 November 2019 
 
I approve the design of the clinical trial. 
 
 
_____________________________________ 
___________________________ 
Signature 
Date of Signature 
 
Name, academic degree
 
Function
 
Institution
Agenus Inc.
Address
3 Forbes Road, Lexington, MA 02421, USA
E-mail address
 
Phone
 
 
 
 

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Appendix B Investigator Signature Page 
 
INVESTIGATOR SIGNATURE PAGE 
Trial Title 
A Phase 1/2, Open-Label, Multicenter Study to Evaluate the 
Safety, Pharmacokinetics, and Pharmacodynamics 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
Clinical Trial Protocol / Date 
Amendment 9, TBD 2019
 
No party involved in the conduct of this study will modify this protocol without obtaining 
Agenus’ agreement. The party initiating a modification will confirm it in writing. Agenus will 
submit protocol amendments to the appropriate worldwide regulatory authorities.  
This study will be performed in accordance with appropriate federal or national regulations and 
ICH-GCP guidelines.  
Contact information will be provided to sites in the Investigator’s Binder and site-specific 
documents. If necessary, contact the telephone numbers for specific adverse event reporting 
information in your country. The event must also be reported in writing within 48 hours of 
occurrence.  
Institutional Review Board (IRB) and/or Independent Ethics Committee (IEC) must be notified 
of drug-related events according to the federal or national regulations. 
I agree to conduct this study in accordance with this protocol and comply with all regulatory 
requirements as set forth in this protocol, appropriate federal or national regulations, and ICH-
GCP guidelines. I also verify that I am the person responsible for the medical decisions at the 
site.  
 
________________________________________ 
______________________  
Principal Investigator: Name 
 
 
 
Date 
 
 
________________________________________ 
Principal Investigator: Signature 
 
 
 
 
 
 
 
 
 

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Appendix C Eastern Cooperative Oncology Group Score 
 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house or office work.  
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of working hours. Symptomatic, but in 
bed <50% of the day. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
working hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead 
 
 

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Appendix D New York Heart Association Class 
 
I 
Patients have cardiac disease but without the resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea or anginal pain. 
II 
Patients have cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
III 
Patients have cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea or anginal pain. 
IV 
Patients have cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased. 
 
 

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Appendix E Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) 
Measurability of tumor at baseline  
Definitions: At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows:  
Measurable Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of:  
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).  
 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. See also notes below on ‘Baseline documentation of target and non-
target lesions’ for information on lymph node measurement. 
Non-measurable: All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Bone lesions:  
 Bone scan, positron emission tomography (PET) scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions.  
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.  
 Blastic bone lesions are non-measurable.  
Cystic lesions:  
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts.  
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 

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noncystic lesions are present in the same subject, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment:  
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
Baseline documentation of ‘target’ and ‘non-target’ lesions  
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where subjects have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but <15 mm) 
should be considered non-target lesions. Nodes that have a short axis <10 mm are considered 
non-pathological and should not be recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.  
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 

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the same organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
 
Tumor response evaluation 
 
Evaluation of target lesions  
 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10mm. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression).  
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of non-target lesions  
 Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10mm short 
axis). 
 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.  
 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.  
 Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: 
the appearance of one or more new lesions is also considered progression). 
 

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Amendment 9, 26 November 2019 
 
 
 
Confidential 
 
Page 78 of 78 
  
Appendix F Child-Pugh Score for Cirrhosis Mortality 
Factor 
1 point 
2 points 
3 points 
Total bilirubin 
<2 mg/dl or 
34 mol/L 
2-3 mg/dl or 
34-51 mol/L 
>3 mg/dl or 
51 mol/L 
Serum albumin 
>3.5 g/dl 
2.8-3.5 g/dl 
<2.8 g/dl 
PT-INR 
< 1.7 
1.7- 2.2 
>2.2 
Ascites  
Absent 
Slight 
Moderate 
Hepatic encephalopathy 
None 
Grade 1-2 
Grade 3-4 
Total points 
5-6 
7-9 
10-15 
Class 
A 
B 
C 
INR: international normalized ratio; PT: prothrombin time.