Conditions: Metastatic Cancer Solid Tumor Lymphoma
Keywords: Locally advanced/unresectable Metastatic solid tumor Lymphoma Anti-TIM-3 TIM-3 TIM3
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This was the first study to test Sym023 in humans. The primary purpose of this study was to see if Sym023 is safe and tolerable for patients with locally advanced/unresectable or metastatic solid tumor malignancies or lymphomas that are refractory to available therapy or for which no standard therapy is available.

Detailed description:
This study evaluated the preliminary safety, tolerability, and dose-limiting toxicities (DLTs) of Sym023, a recombinant, fully human, anti-T-cell immunoglobulin and mucin-domain containing-3 (anti-TIM-3) monoclonal antibody (mAb). The goal was to establish the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of sequential escalating doses of Sym023 when administered once every 2 weeks (Q2W) by intravenous (IV) infusion to patient cohorts with locally advanced/unresectable or metastatic solid tumor malignancies or lymphomas that are refractory to available therapy or for which no standard therapy is available. If an MTD was not identified, a maximum administered dose (MAD) was to be determined. Sym023 was given to patients in escalating dose cohorts; each patient was given one fixed dose level.

Arms:
arm 1: Sym023 was administered at a dose of 0.03 mg/kg by intravenous infusion arm 2: Sym023 was administered at a dose of 0.1 mg/kg by intravenous infusion arm 3: Sym023 was administered at a dose of 0.3 mg/kg by intravenous infusion arm 4: Sym023 was administered at a dose of 1.0 mg/kg by intravenous infusion arm 5: Sym023 was administered at a dose of 3.0 mg/kg by intravenous infusion arm 6: Sym023 was administered at a dose of 10.0 mg/kg by intravenous infusion arm 7: Sym023 was administered at a dose of 20.0 mg/kg by intravenous infusion

Interventions: intervention 1: Sym023
Intervention descriptions: intervention 1: Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.

Protocol document:
Prot_000.pdf: 


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Trial ID: Sym023-01 
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Sponsor Declarations 
This confidential document is the property of Symphogen A/S. No unpublished information 
contained herein may be passed on, reproduced, published or used without prior written approval 
from Symphogen A/S. Access to this document must be restricted to relevant parties. 
The trial will be conducted in compliance with this clinical trial protocol, International Council 
for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use 
E6(R2): Guideline for Good Clinical Practice (GCP) (EMA/CHMP/ICH/135/1995), the 
Declaration of Helsinki, and applicable regulations. 
The Sponsor has appointed a Coordinating Investigator for the trial. This Coordinating 
Investigator will provide input to the trial design and act as overall coordinator for Investigators 
across all sites. The Coordinating Investigator will furthermore sign off the Clinical Trial Report 
on behalf of all Investigators. 
Lists of Investigators responsible for conducting the trial, medically qualified physicians 
responsible for all site-related medical decisions (if other than the Investigators), monitors, 
clinical laboratories, and other medical and/or technical departments and/or institutions involved 
in the trial are provided as separate documents. 
 
 


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Principal Investigator Signature Page 
 
I, the undersigned, am responsible for the conduct of the trial at this site and agree: 
• To assume responsibility for the proper conduct of the clinical trial at this Investigational 
Site 
• Not to implement any changes to the clinical trial protocol without agreement from the 
Sponsor and prior review and written approval from the appropriate Health Authority (as 
indicated) and the Institutional Review Board/ Ethics Committee, except where necessary 
to eliminate an immediate hazard to the patients 
• That I am aware of, and will comply with “Good Clinical Practice” (ICH E6(R2) GCP) 
(EMA/CHMP/ICH/135/1995), the Declaration of Helsinki, and all applicable regulatory 
requirements 
• That all site staff to which I have delegated tasks for this clinical trial, are appropriately 
selected and adequately informed about the investigational product(s) and of their trial-
related duties and functions as described in the clinical trial protocol 
 
 
________________________________  
____________________ 
Signature  
 
 
 
 
 
 
 
 
Date of Signature 
 
Name: ______________________________________ 
 
Academic Degree: ____________________________ 
 
Function: ___________________________________ 
 
Institution: __________________________________ 
 
 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND EXPANDED TERMS .........................................................10 
1 
SYNOPSIS .............................................................................................................................17 
2 
SCIENTIFIC BACKGROUND AND RATIONALE ...........................................................31 
2.1 
Background ........................................................................................................................31 
2.1.1 
Tumor Malignancies ........................................................................................................31 
2.1.2 
Overview of the Target: TIM-3 .......................................................................................31 
2.1.3 
Overview of the Product: Sym023 ..................................................................................32 
2.2 
Summary of Nonclinical Studies .......................................................................................32 
2.2.1 
Nonclinical Pharmacology Studies ..................................................................................32 
2.2.2 
Nonclinical Toxicology Studies ......................................................................................33 
2.3 
Clinical Experience ............................................................................................................34 
2.3.1 
Clinical Experience with Agents Related to Sym023 .....................................................34 
2.3.1.1 
Clinical Evidence of Activity in Malignant Diseases ...................................................34 
2.3.1.2 
Safety and Tolerability of anti-TIM-3 mAbs ................................................................34 
2.3.1.3 
Patient Selection for Treatment with Sym023 ..............................................................35 
2.3.1.4 
Potential Pharmacodynamic Biomarkers ......................................................................35 
2.3.2 
Clinical Experience with Sym023 ...................................................................................35 
2.4 
Trial Rationale ...................................................................................................................36 
2.5 
Dose Rationale ...................................................................................................................36 
2.6 
Overall Benefits/Risk .........................................................................................................37 
3 
TRIAL OBJECTIVES AND DESIGN SUMMARY ............................................................39 
3.1 
Objectives: Sym023 (anti-TIM-3) Dose-Escalation ..........................................................39 
3.1.1 
Primary Objective ............................................................................................................39 
3.1.2 
Secondary Objectives ......................................................................................................39 
3.1.3 
Exploratory Objectives ....................................................................................................39 
3.2 
Trial Design Summary .......................................................................................................39 
4 
PATIENT NUMBER AND SELECTION CRITERIA .........................................................45 
4.1 
Number of Patients ............................................................................................................45 
4.1.1 
Investigational Sites .........................................................................................................45 
4.1.2 
Number of Patients ..........................................................................................................45 
4.2 
Criteria for Inclusion ..........................................................................................................46 
4.3 
Criteria for Exclusion .........................................................................................................46 
4.3.1 
Patients to be Excluded ...................................................................................................47 
4.3.2 
Drugs and Other Treatments to be Excluded ..................................................................50 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................53 
5.1 
Sym023 ..............................................................................................................................53 
5.1.1 
Formulation Excipients ...................................................................................................53 
5.2 
Storage and Handling of IMP ............................................................................................53 
5.3 
Stability of IMP..................................................................................................................53 
5.4 
Labeling of IMP .................................................................................................................54 
5.5 
Packaging of IMP ..............................................................................................................54 
5.6 
Administration of IMP .......................................................................................................54 
5.7 
Dose Calculation ................................................................................................................54 
5.8 
Dose Preparation ................................................................................................................54 


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5.9 
Accountability ....................................................................................................................55 
5.10 
Disposition of Used IMP ...................................................................................................55 
5.11 
Unused IMP .......................................................................................................................55 
5.12 
Destruction of IMP ............................................................................................................55 
6 
EXPERIMENTAL PLAN .....................................................................................................56 
6.1 
Design Elements ................................................................................................................56 
6.2 
Projected Recruitment Period and Duration of this Trial ..................................................56 
6.3 
Cohort Management...........................................................................................................56 
6.3.1 
Patient Screening and Dose Cohort Assignment .............................................................56 
6.3.1.1 
Screening of Potential Patients .....................................................................................56 
6.3.1.2 
Submission of Patient Enrollment Documentation .......................................................57 
6.3.1.3 
Patient Identification Code Assignment........................................................................57 
6.3.1.4 
Screen Failures ..............................................................................................................57 
6.3.2 
Cohort Closure .................................................................................................................58 
6.4 
Requirements for Patient Observation ...............................................................................58 
6.5 
Drug Treatment Regimen ..................................................................................................58 
6.5.1 
Study Start Day ................................................................................................................58 
6.5.2 
Patient Availability ..........................................................................................................58 
6.5.3 
Therapy with Study Drug ................................................................................................59 
6.5.3.1 
Doses to be Administered .............................................................................................59 
6.5.3.1.1 
Doses to be Evaluated .................................................................................................59 
6.5.3.1.2 
Changes in Dose to be Administered ..........................................................................59 
6.5.3.2 
Route of Administration ................................................................................................60 
6.5.3.3 
Diluent and Delivery .....................................................................................................60 
6.5.3.4 
Volume of Infusion .......................................................................................................60 
6.5.3.5 
Duration of Infusion ......................................................................................................60 
6.5.3.6 
Schedule ........................................................................................................................61 
6.5.4 
Premedication ..................................................................................................................61 
6.6 
Cycle 1 ...............................................................................................................................61 
6.6.1 
Rules for Dose-Escalation and Cohort Expansion ..........................................................62 
6.6.2 
Rules for Duration of Exposure Prior to Start of Next Patient and Next Cohort ............63 
6.6.3 
Rules for Establishing the MTD and/or RP2D ................................................................64 
6.6.4 
Rules for Stopping the Study ...........................................................................................64 
6.7 
Continued Treatment After Cycle 1 ...................................................................................64 
6.7.1 
Retreatment Guidelines ...................................................................................................65 
6.7.2 
Doses and Regimens ........................................................................................................65 
6.7.3 
Evaluation Schedules .......................................................................................................66 
6.7.4 
Duration of Treatment .....................................................................................................66 
6.7.5 
Continued Treatment after Radiologic Disease Progression ...........................................66 
6.7.6 
Retreatment Following an Objective Response ..............................................................66 
6.8 
Adverse Events and Dose-Limiting Toxicities ..................................................................67 
6.8.1 
Adverse Event Grading ...................................................................................................67 
6.8.2 
Management of Dose-Limiting Toxicities and Other Toxicities ....................................67 
6.8.3 
Definition of Dose-Limiting Toxicity .............................................................................67 
6.9 
Definition of Maximum Tolerated Dose............................................................................69 
6.10 
Review of Safety Data During Study.................................................................................69 


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6.11 
Duration of Study Follow-Up ............................................................................................70 
6.12 
Concurrent Treatments and Supportive Care .....................................................................71 
7 
STUDY ASSESSMENTS .....................................................................................................73 
7.1 
Consent and Medical History.............................................................................................73 
7.1.1 
Signing of Informed Consent/Assessment of Eligibility .................................................73 
7.1.2 
Demography ....................................................................................................................74 
7.1.3 
Past Medical History .......................................................................................................74 
7.1.4 
History of the Primary Malignancy .................................................................................74 
7.2 
Safety Assessments (1) ......................................................................................................74 
7.2.1 
Medication and Procedure Surveys .................................................................................74 
7.2.2 
Adverse Event Reporting ................................................................................................74 
7.2.3 
Dose-Limiting Toxicity Assessment ...............................................................................75 
7.2.4 
Performance Status Evaluation ........................................................................................75 
7.2.5 
Vital Signs .......................................................................................................................76 
7.2.6 
Physical Examination ......................................................................................................76 
7.2.7 
Laboratory Assessments and Pregnancy Test .................................................................77 
7.2.7.1 
Hematology Panel .........................................................................................................77 
7.2.7.2 
Biochemistry Panel .......................................................................................................78 
7.2.7.3 
Coagulation Panel .........................................................................................................78 
7.2.7.4 
Thyroid Function Tests .................................................................................................79 
7.2.7.5 
Urinalysis ......................................................................................................................79 
7.2.7.6 
Pregnancy Testing .........................................................................................................80 
7.2.8 
Electrocardiogram ...........................................................................................................80 
7.3 
Safety Assessments (2) ......................................................................................................81 
7.3.1 
Multi-Gated Acquisition Scan or Echocardiogram .........................................................81 
7.3.2 
Ophthalmology Examination ...........................................................................................81 
7.3.3 
Pulmonary Function Tests ...............................................................................................81 
7.4 
Disease Assessments ..........................................................................................................82 
7.4.1 
Tumor Marker Measurement ...........................................................................................82 
7.4.2 
Diagnostic Imaging for Assessment of Disease (and Pulmonary Status) .......................82 
7.4.3 
Response Assessment ......................................................................................................83 
7.5 
Immunogenicity Assessment .............................................................................................83 
7.5.1 
Peripheral Blood for Immunogenicity Assessment (Specialty Lab) ...............................84 
7.6 
Pharmacokinetic Assessments ...........................................................................................84 
7.6.1 
Peripheral Blood for Pharmacokinetic Assessment (Specialty Lab) ...............................84 
7.7 
Pharmacodynamic and Other Biomarker Assessments (Specialty Lab) ............................85 
7.7.1 
Pharmacodynamic Assessments ......................................................................................85 
7.7.2 
Biomarker Assessments ...................................................................................................85 
7.7.2.1 
Blood Samples for Biomarker Assessments .................................................................86 
7.7.2.2 
Tumor Sample for Biomarker Assessment (Biopsies Optional) ...................................86 
8 
MANAGEMENT OF TOXICITY .........................................................................................87 
8.1 
Grading and Recording of Toxicity ...................................................................................87 
8.2 
Evaluation and Treatment of Toxicity ...............................................................................87 
8.3 
Determination of DLT versus Non-DLT ...........................................................................87 
8.4 
Premedication ....................................................................................................................88 
8.4.1 
Infusion-Related Reactions .............................................................................................88 


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8.4.2 
Premedication for IRRs (Prior to the First Dose) ............................................................88 
8.4.3 
Premedication for IRRs (Following an IRR) ...................................................................89 
8.4.4 
Premedication for other Study Drug-Related Toxicities .................................................89 
8.5 
Dose Modification Options ................................................................................................90 
8.5.1 
Prolongation of Infusion Duration ...................................................................................90 
8.5.1.1 
Instructions for Infusion Prolongation for IRRs ...........................................................90 
8.5.1.2 
Treatment Following Infusion Prolongation .................................................................90 
8.5.2 
Dose Reduction ...............................................................................................................90 
8.5.3 
Dose Delay ......................................................................................................................91 
8.5.4 
Schedule Alterations ........................................................................................................91 
9 
DISCONTINUING PATIENTS FROM STUDY TREATMENT ........................................92 
9.1 
Criteria for Treatment Discontinuation ..............................................................................92 
9.2 
Replacements .....................................................................................................................93 
10 ADVERSE EVENTS .............................................................................................................94 
10.1 
Definitions of Adverse Events ...........................................................................................94 
10.1.1 
Adverse Event .................................................................................................................94 
10.1.2 
Events Not to be Considered as Adverse Events .............................................................94 
10.1.3 
Adverse Events of Medical Interest ................................................................................94 
10.1.4 
Serious Adverse Events ...................................................................................................95 
10.1.5 
Events That Do Not Meet the Definition of Serious Adverse Events .............................95 
10.2 
Adverse Event Recording and Reporting ..........................................................................96 
10.2.1 
Information to be Provided for each AE .........................................................................96 
10.2.2 
Required Follow-up for AEs ...........................................................................................97 
10.3 
Serious Adverse Event Recording and Reporting .............................................................97 
10.3.1 
Timeframes for Reporting to the Sponsor .......................................................................97 
10.3.2 
Safety Reporting to Health Authorities, Institutional Review Boards/Ethics Committees, 
and Investigators ............................................................................................................................98 
10.4 
Pregnancy ...........................................................................................................................98 
11 PRECAUTIONS WHEN DOSING WITH STUDY DRUG ...............................................100 
11.1 
Precautions Regarding Procreation ..................................................................................100 
11.2 
Additional Precautions .....................................................................................................100 
12 SAFETY SURVEILLANCE DURING STUDY ................................................................102 
12.1 
Safety Review ..................................................................................................................102 
12.2 
Other Safety Surveillance Activities ................................................................................102 
13 REGULATORY AND ETHICAL CONSIDERATIONS ...................................................104 
13.1 
Conditions of Testing .......................................................................................................104 
13.2 
Institutional Review .........................................................................................................104 
13.3 
Informed Consent.............................................................................................................104 
13.4 
Conditions for Modifying or Terminating the Study .......................................................105 
13.4.1 
Modification of the Study Protocol ...............................................................................105 
13.4.2 
Modification of the Informed Consent Form ................................................................106 
13.4.3 
Conditions for Termination of the Study or a Study Site ..............................................106 
13.5 
Trial Registration .............................................................................................................106 
13.6 
Insurance and Liability ....................................................................................................107 
14 INVESTIGATOR RESPONSIBILITIES ............................................................................108 
14.1 
Medical Supervision ........................................................................................................108 


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14.2 
Confidentiality .................................................................................................................108 
14.3 
Use of Information ...........................................................................................................108 
14.4 
Publications ......................................................................................................................109 
14.5 
Patient Screening Log ......................................................................................................109 
14.6 
Drug Dispensing Inventory ..............................................................................................109 
14.7 
Handling and Disposal of Study Drug .............................................................................110 
14.8 
Recording of Data ............................................................................................................110 
14.9 
Source Document Requirements ......................................................................................110 
14.10 Laboratory Reports ..........................................................................................................111 
14.11 Record Retention .............................................................................................................111 
14.12 Monitoring of the Study ...................................................................................................111 
14.13 Patient Confidentiality .....................................................................................................112 
14.14 Financing and Insurance ..................................................................................................113 
15 HANDLING AND PROCESSING OF DATA ...................................................................114 
15.1 
Data Handling ..................................................................................................................114 
15.2 
Data Review During this Study .......................................................................................114 
15.3 
Data Processing ................................................................................................................114 
15.4 
Clinical Trial Report ........................................................................................................114 
15.5 
Compliance with the General Data Protection Regulation ..............................................114 
16 STATISTICAL ANALYSIS ...............................................................................................116 
16.1 
Statistical Considerations .................................................................................................116 
16.2 
Sample Size Considerations .............................................................................................116 
16.3 
Analysis Populations ........................................................................................................116 
16.4 
Trial Endpoints.................................................................................................................116 
16.4.1 
Primary Endpoints .........................................................................................................116 
16.4.2 
Secondary Endpoints .....................................................................................................117 
16.5 
Statistical Analysis ...........................................................................................................117 
16.5.1 
General Specifications ...................................................................................................117 
16.5.2 
Patient Disposition, Baseline and Treatment Characteristics ........................................117 
16.5.3 
Study Treatment ............................................................................................................118 
16.5.4 
Maximum Tolerated Dose .............................................................................................118 
16.5.5 
Adverse Events ..............................................................................................................118 
16.5.6 
Laboratory Determinations ............................................................................................119 
16.5.7 
Vital Signs, Body Weight, Physical Exam Findings .....................................................119 
16.5.8 
ECG Findings ................................................................................................................119 
16.5.9 
Other Safety Data ..........................................................................................................119 
16.5.10 Antineoplastic Activity ..................................................................................................119 
16.5.11 Pharmacokinetic Analysis .............................................................................................120 
16.6 
Additional Endpoints and Analyses .................................................................................121 
16.6.1 
Pharmacodynamic and other Biomarker Analyses ........................................................121 
16.7 
Modeling of Pharmacokinetic and Pharmacodynamic/Biomarker Data .........................121 
16.8 
Deviations from the Statistical Plan .................................................................................121 
16.9 
Interim Analysis ...............................................................................................................122 
17 REFERENCES ....................................................................................................................123 
18 APPENDICES .....................................................................................................................125 
Appendix 1 Performance Status Evaluation..............................................................................125 


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Appendix 2 New York Heart Association Functional Criteria .................................................126 
Appendix 3 Clinical Adverse Events: Grading Scale ...............................................................127 
Appendix 4 Clinical Adverse Events: Determining Relationship to Study Drug .....................128 
Appendix 5 Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ............................129 
Appendix 6 Immunotherapeutics RECIST (iRECIST) .............................................................134 
Appendix 7 Response Evaluation Criteria in Lymphoma (RECIL 2017) ................................141 
Appendix 8 Adverse Events Observed with Antibodies to PD-1 and PD-L1 ...........................142 
Appendix 9 Grading and Management of Infusion-Related Reactions ....................................147 
Appendix 10 Management of Immune-Mediated Toxicities ....................................................150 
Appendix 11 Maximum Total Blood Collection Volumes .......................................................151 
Appendix 12 Schedule of Assessments .....................................................................................152 
19 SUMMARY OF CHANGES ...............................................................................................156 
19.1 
Protocol Amendment 1 dated 04-Apr-2018 .....................................................................156 
19.2 
Protocol Amendment 2 dated 02-Aug-2018 ....................................................................166 
19.3 
Protocol Amendment 3 dated 18-Mar-2019 ....................................................................169 
19.4 
Protocol Amendment 4 dated 02-May-2019....................................................................170 
 
List of Figures 
 
Figure 1:  Dose-Escalation Schema ...............................................................................................42 
 
List of Tables 
 
Table 1:  Overall Trial Plan ...........................................................................................................44 
Table 2:  Schedule of Safety Blood and Urine Sampling ..............................................................77 
Table 3:  ADA and PK Sampling Timepoints ...............................................................................84 
Table 4:  Recommended Premedication Regimen .........................................................................89 
Table 5:  PK Endpoint, Definitions, and Derivations ..................................................................121 
Table 6:  Protocol Amendment 1 .................................................................................................157 
Table 7:  Protocol Amendment 2 .................................................................................................166 
Table 8:  Protocol Amendment 3 .................................................................................................169 
Table 9:  Protocol Amendment 4 .................................................................................................170 
 
 


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LIST OF ABBREVIATIONS AND EXPANDED TERMS  
Abbreviation 
Expanded Term 
1M FUP 
1-Month Follow-up 
Ab 
Antibody 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase  
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate Aminotransferase  
AUC 
Area Under the Concentration-Time Curve 
AUCτ 
Area Under the Concentration-Time Curve in a dosing interval 
AUCinf 
Area Under the Concentration-Time Curve from start of infusion to infinity 
AUCnorm, τ 
Dose-Normalized Area Under the Concentration-Time Curve in a dosing interval 
β-hCG 
Beta-Human Chorionic Gonadotropin 
BM 
Bone Marrow 
BNP 
 
 
Brain Natriuretic Peptide 
BP 
Blood Pressure 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
Bx 
Biopsy 
C 
Centigrade, Celsius 
C#/D# 
Cycle #/Day # 
Ca 
Calcium 
CBC 
Complete Blood Count 
CDC 
Complement-Dependent Cytotoxicity 
CEACAM1 
Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 
CEOI 
Concentration at the End of Infusion 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CIOMS 
Council for International Organizations of Medical Sciences 


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Abbreviation 
Expanded Term 
CK 
Creatine Kinase 
Cl 
Chloride 
CL 
Clearance 
Cmax 
Maximum Concentration 
CPD 
Confirmed Progressive Disease 
Ctrough 
Trough Concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CS 
Clinically Significant 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTCAE v5.0 
Common Terminology Criteria for Adverse Events (Version 5.0) 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Protein 4 
CV 
Curriculum Vitae 
D, d 
Day 
dL 
Deciliter 
DLCO 
Diffusing Capacity of Carbon Monoxide 
DLT 
Dose-Limiting Toxicity 
DMP 
Data Management Plan 
DNA 
Deoxyribonucleic Acid 
DRF 
Dose-Range-Finding 
DSUR 
Development Safety Update Report  
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EOC# 
End of Cycle # 
EOI 
End of Infusion 
EOS 
End of Study 


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Abbreviation 
Expanded Term 
EOT 
End of Treatment 
F 
Fahrenheit 
FAS 
Full Analysis Set 
FDG 
Fluorodeoxyglucose 
FEV1 
Forced Expiratory Volume in 1 Second 
FFPE 
Formalin-Fixed, Paraffin-Embedded 
FRC 
Functional Residual Capacity 
FSH 
Follicle-Stimulating Hormone 
fT3 
Free Triiodothyronine 
fT4 
Free Thyroxine 
FUP 
Follow-up 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
H, h 
 
Hour 
HAVCR2 
Hepatitis A Virus Cellular Receptor 2 
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HMGB1 
High Mobility Group Box 1 
HPF 
High Power Field 
HR 
Heart Rate 
HRT 
Hormone Replacement Therapy 
HSCT 
Hematopoietic Stem Cell Transplantation 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
Ig 
Immunoglobulin 


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Abbreviation 
Expanded Term 
IHC 
Immunohistochemistry 
IL-2 
Interleukin-2 
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board   
iRECIST 
Immunotherapeutics Response Evaluation Criteria in Solid Tumors 
IRR 
Infusion-Related Reaction 
IU 
International Units 
IV 
Intravenous 
K 
Potassium 
KD 
Dissociation Constant 
KLH 
Keyhole Limpet Hemocyanin 
kg 
Kilogram 
LSECtin 
Liver Sinusoidal Endothelial Cell Lectin 
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction 
M, m 
Month, Molar, Meter 
mAb 
Monoclonal Antibody 
MABEL 
Minimal Anticipated Biological Effect Level 
MAD 
Maximum Administered Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Magnesium 
mg 
Milligram 
MHC 
Major Histocompatibility Complex 
MI 
Myocardial Infarction 
min 
Minute 
mL 
Milliliter 
MLR 
Mixed Lymphocyte Reaction 
mm 
Millimeter 
MRI 
Magnetic Resonance Imaging 
MRSD 
Maximum Recommended Starting Dose 


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Abbreviation 
Expanded Term 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
MUGA 
Multi-Gated Acquisition  
Na 
Sodium 
NaCl 
Sodium Chloride 
NCS 
Not Clinically Significant 
NE 
Not Evaluable 
NK 
Natural Killer (cell) 
NL 
New Lesion 
NLNT 
New Lesion-Non-Target 
NLT 
New Lesion-Target 
NOAEL 
No Observed Adverse Effect Level 
NT 
Non-Target 
NYHA 
New York Heart Association 
OR 
Objective Response 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease, Disease Progression 
PDF 
Portable Document Format 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Death-Ligand 1 
PE 
Pulmonary Embolism 
PET 
Positron Emission Tomography 
PFT 
Pulmonary Function Test 
PK 
Pharmacokinetic 
PO 
Per Os (orally, by mouth) 
PR 
Partial Response 
PR Interval 
ECG interval between beginning of the P-wave to beginning of the QRS complex 
PS 
Performance Status 
PSA 
Prostate Specific Antigen 
PSPD 
Pseudoprogression 
PT 
Prothrombin Time 
PtdS 
Phosphatidylserine 
PTT 
Partial Thromboplastin Time 


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Abbreviation 
Expanded Term 
Q2M 
Every 2 Months 
Q2W 
QT Interval 
Every 2 Weeks 
ECG interval between onset of QRS complex to end of the T-wave 
QTc Interval 
Heart Rate-corrected QT interval 
RBC 
Red Blood Cell 
RECIL 2017 
Response Evaluation Criteria in Lymphoma (2017) 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors (Version 1.1) 
RNA 
Ribonucleic Acid 
RNA-seq 
Ribonucleic Acid Sequencing 
RSI 
Reference Safety Information 
RP2D 
Recommended Phase 2 Dose 
RV 
Residual Volume 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SAS 
Statistical Analysis System 
SD 
Stable Disease 
SEB 
Staphylococcal Enterotoxin B 
SOC 
System Organ Class 
SOI 
Start of Infusion 
SOM 
Sum of Measurements 
SOP 
Standard Operating Procedure 
SSA 
Somatostatin Analog 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Target 
T1/2  
Terminal Elimination Half-life 
TBD 
To Be Determined 
TCR 
T-cell Receptor 
TDAR 
T-cell Dependent Antibody Response  
TEAE 
Treatment Emergent Adverse Event 
TIM-3 
T-cell Immunoglobulin and Mucin-Domain Containing-3 
TK 
Toxicokinetic 
TLC 
Total Lung Capacity 


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Abbreviation 
Expanded Term 
Tmax 
Time to Maximum Concentration 
TP 
Timepoint 
TRAE 
Treatment Related Adverse Event 
TSH 
Thyroid Stimulating Hormone 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
µg 
Microgram 
µM 
Micromolar 
UPD 
Unconfirmed Progressive Disease 
U.S. 
United States 
U/S 
Ultrasound 
UV 
Ultraviolet 
V, v, Vol 
Volume 
Vd 
Volume of Distribution 
VS 
Vital Signs 
W, w 
Week 
w/v 
Weight to Volume 
WBC 
White Blood Cell 
WES 
Whole-exome Sequencing 
WHO 
World Health Organization 
WOCBP 
Woman of Childbearing Potential 


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1 SYNOPSIS 
CLINICAL TRIAL PROTOCOL 
Trial Title 
A Phase 1, Open-Label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary 
Antineoplastic Activity of Sym023 (Anti-TIM-3) in Patients with Advanced Solid Tumor 
Malignancies or Lymphomas 
Trial ID 
Sym023-01 
Trial Phase 
Phase 1 
INVESTIGATIONAL MEDICINAL PRODUCT 
Investigational 
Medicinal Product 
The Investigational Medicinal Product (IMP) is Sym023 (also referred to as study drug).   
Sym023 is a recombinant T-cell immunoglobulin and mucin-domain containing-3 (anti-TIM-3) 
human monoclonal antibody (mAb)  
Supplies 
Labeled supplies of study drug will be provided by the Sponsor.  Each single-use glass vial 
contains Sym023: 
•
As a liquid formulation for intravenous (IV) infusion
•
With a nominal fill volume of 8.0 milliliter (mL)
•
At a concentration of 20 mg/mL for a total vial content of 160 milligrams (mg) 
Formulation Excipients
Provided herein 
Storage 
Refrigerate (2ºC to 8ºC); store in an access-controlled, secure location; protect from direct sunlight 
Combination Agent 
None 
TRIAL OBJECTIVES 
Sym023 Dose-
Escalation 
Primary 
Evaluation of the safety, tolerability, and dose-limiting toxicities (DLTs) to establish the maximum 
tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of sequential escalating doses of 
Sym023 when administered once every 2 weeks (Q2W) by 30-minute IV infusion to patient 
cohorts with locally advanced/unresectable or metastatic solid tumor malignancies or lymphomas 
that are refractory to available therapy or for which no standard therapy is available   
Note:   Q2W dosing; 4 weeks equals 1 dosing cycle.  Goal is identification of the MTD or determination of a 
RP2D based on clinical data, including safety, pharmacokinetic (PK), and pharmacodynamic outcomes.  
The MTD, if identified, and the RP2D may not be the same as the RP2D may be lower.  If an MTD is 
not identified, a maximum administered dose (MAD) will be determined and will not exceed 20 mg/kg. 
Secondary 
•
Evaluation of the immunogenicity of Sym023
•
Characterization of the PK profile of Sym023
•
Evaluation of the preliminary antineoplastic effects of Sym023, including:
o
Evidence of objective response (OR) or stable disease (SD)*
o
Duration of OR or SD*
o
Time to progression (TTP) of disease*
*As assessed by Response Evaluation Criteria in Solid Tumors (Version 1.1) (RECIST v1.1),
Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST), and Response Evaluation
Criteria in Lymphoma (2017) (RECIL 2017)
Exploratory 
•
Evaluation of potential pharmacodynamic markers, e.g., receptor occupancy in peripheral
blood mononuclear cells (PBMCs) (peripheral blood to be collected)
•
Evaluation of potential biomarkers including but not limited to assessment of:
o
In peripheral blood: circulating tumor deoxyribonucleic acid (ctDNA), ribonucleic acid
(RNA), relevant proteins/cytokines, and cellular biomarkers
o
In tumor tissue: DNA, RNA, protein, and cellular biomarkers (biopsies optional)
Note:   Assay methodology and biomarker assessments to be determined (TBD). Potential analyses may
include but are not limited to: ctDNA sequencing; RNA sequencing (RNA-seq)/whole-exome 
sequencing (WES); measurement of relevant proteins/cytokines in the blood; cytometric analysis 
of cells in blood; and immunohistochemistry (IHC) of tumor material when collected (tumor 
sampling is optional)  


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TRIAL DESIGN 
Design Summary 
This is a Phase 1, multicenter, open-label, dose-escalation study designed to evaluate safety, 
tolerability, and DLTs to establish the MTD or MAD, and the RP2D of sequential escalating doses 
of Sym023 (study drug) when administered Q2W (4 weeks equals 1 cycle) by 30-minute IV 
infusion, to patients with advanced, refractory solid tumor malignancies or lymphomas. 
Approximately 20-48 male and female patients will be entered. Initially a modified, accelerated-
titration, dose-escalation design will be used, with entry of single patient cohorts for up to 2 dose 
levels, based on tolerability. Thereafter, dose-escalation will follow a standard 3+3 design, with a 
target toxicity level of 33.3% or less as determined by DLTs.  It is planned that 7 dose levels up to 
a maximum dose of 20 mg/kg will be evaluated. The number of patients treated, the number of 
cohorts evaluated, and the MTD/MAD will depend upon the observed tolerability of Sym023 
during Cycle 1. 
In the absence of documented progressive disease (PD) or unacceptable toxicity, patients may 
continue to receive additional 4-week cycles of study drug at the same dose, infusion duration, and 
schedule established for the patient. 
PATIENT SELECTION 
Recruitment Period 
Enrollment Dates 
•
Anticipated date of enrollment of first patient: Q2 2018
•
Anticipated date of enrollment of last patient: Q3 2019
End of Trial (i.e., data cut-off for primary analysis) 
Will be reached 1 month (30 +7 days) after all patient have discontinued trial treatment or 6 months 
after the last patient has started trial treatment, whichever occurs earlier.   
Investigational Sites 
This is a multicenter trial. It is anticipated that approximately 2-4 centers in North America may 
participate based on accrual. 
Number of Patients 
Considerations for estimating the number of patients are as follows: 
Sym023 Dose-Escalation   
Approximately 20-48 patients in escalating dose cohorts: 
•
Minimum of 1 patient per cohort for up to 2 dose cohorts
•
Minimum of 3 patients per dose cohort thereafter
•
Assume approximately 7 cohorts to establish the MTD, and/or RP2D
•
Expansion of any cohort to 6 patients in the event of a Cycle 1 DLT in any of the initial 1 to 3
patients
•
Minimum of 6 patients to be treated at the MTD and/or RP2D; expansion of this cohort (or any
other) up to 12 patients may be considered to further evaluate tolerability
In addition, there is potential for entry of additional patients to:  
•
Ensure sufficient evaluable patients by adding an additional patient to a cohort
•
Expand a lower dose cohort(s) if an initially identified MTD and/or RP2D is subsequently
determined to be not tolerated either with single or repeated cycles of therapy
•
Add and evaluate a previously unplanned intermediate dose level if indicated (inclusion of a
dose higher than those listed would require a protocol amendment)
Note:  This action would be taken in the event of an unacceptably high frequency of toxicities observed in
patients treated at one dose level considered to be in marked contrast to the tolerability noted at the 
preceding dose level, or if after review of study data, a more gradual dose-escalation appears 
warranted.
Eligibility 
Patients to be Included (patients must meet all the following criteria) 
1.
Male or female patients, ≥ 18 years
2.
Patients with a documented (histologically- or cytologically-proven) solid tumor malignancy
that is locally advanced or metastatic; patients with documented lymphomas
3.
Patients with a malignancy (solid tumor or lymphoma) that is currently not amenable to
surgical intervention due to either medical contraindications or non-resectability of the tumor
4.
Patients refractory to or intolerant of existing therapy(ies) known to provide clinical benefit.
Note:  Patients may have received and failed prior therapy with a programmed cell death protein 1/
programmed death-ligand 1 (PD-1/PD-L1) inhibitor and be considered eligible for this trial.
5.
Patients with measurable or non-measurable disease according to RECIST v1.1 or standard
criteria for lymphoma (RECIL 2017).


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6.
Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0
or 1, and anticipated life expectancy of ≥ 3 months
7.
Patients, both male and female, who are either not of childbearing potential or who agree to
use a highly effective method of contraception during the study beginning within 2 weeks
prior to the first dose and continuing until 6 months after the last dose of study drug.
8.
Patients with the ability to understand and give written informed consent for participation in
this trial, including all evaluations and procedures as specified by this protocol.
Patients to be Excluded (patients must not meet any of the following criteria) 
1.
Women who are pregnant or lactating, or intending to become pregnant before, during, or
within 6 months after the last dose of study drug. Women of childbearing potential (WOCBP)
and fertile men with WOCBP partner(s), not using and not willing to use a highly effective
method of contraception.
2.
Patients with central nervous system (CNS) malignancies; patients with known, untreated
CNS or leptomeningeal metastases, or spinal cord compression, patients with any of the above
not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS
involvement for which treatment is required.
Note:   Patients with treated CNS metastases will be eligible if they are asymptomatic, do not require
corticosteroids, and have confirmation of at least stable brain disease status as assessed by 2 
imaging studies performed ≥ 4 weeks apart with the most recent performed within 4 weeks prior to 
first trial drug administration.  Prophylactic anticonvulsant medications are allowed. 
3.
Patients with hematologic malignancies other than lymphomas
4.
Patients with any of the following hematologic abnormalities at baseline*:
•
Hemoglobin < 9 g/dL
•
Absolute neutrophil count (ANC) < 1,000 per mm3
•
Platelet count < 75,000 per mm3
*Throughout this protocol “baseline” is defined as the last available observation prior to the first 
administration of study drug on Cycle 1/Day 1 (C1/D1). 
5.
Patients with any of the following serum chemistry abnormalities at baseline: 
•
Total bilirubin > 1.5 × the upper limit of normal (ULN) for the institution
•
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the ULN for
the institution (> 5× ULN if due to hepatic involvement by tumor)
•
Serum creatinine > 1.5 × ULN for the institution
6.
Patients with any of the following coagulation parameter abnormalities at baseline (unless on
a stable dose of anticoagulant therapy for a prior thrombotic event, as determined by the
Investigator):
•
Prothrombin time (PT) (or international normalized ratio [INR]) > 1.5 × ULN for the
institution (> 3× ULN for the institution if anticoagulated)
•
Partial thromboplastin time (PTT) (or activated partial thromboplastin time [aPTT]) > 1.5
× ULN for the institution (> 3× ULN for the institution if anticoagulated)
7.
Patients with:
•
Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism
(PE) within 4 weeks prior to first administration of study drug unless adequately treated
and considered by the Investigator to be stable
•
Active uncontrolled bleeding or a known bleeding diathesis
8.
Patients with a clinically significant (CS) cardiovascular disease or condition, including:
•
Need for antiarrhythmic medical therapy for a ventricular arrhythmia or other
uncontrolled arrhythmia (patients with controlled atrial fibrillation (heart rate [HR] < 90)
for > 30 days prior to study entry are eligible)
•
Severe conduction disturbance (e.g., 3rd degree heart block)
•
HR-corrected QT interval (QTc interval) ≥ 480 milliseconds (msec)
•
Uncontrolled hypertension (per the Investigator’s discretion)
•
History of myocarditis
•
Left ventricular ejection fraction (LVEF)* known to be below the lower limit of normal
(LLN) for the center, or < 50% by multi-gated acquisition (MUGA) scan or
echocardiogram (ECHO) if no LLN is defined by the site
•
Congestive heart failure (CHF) currently requiring therapy
•
Class III or IV cardiovascular disease according to the New York Heart Association
(NYHA) Functional Classification
•
History of acute coronary syndromes (including myocardial infarction [MI] and unstable
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drug administration 
9.
Patients with a significant ocular disease or condition, including history of an autoimmune or
inflammatory disorder, e.g., episcleritis, uveitis, iritis
Note:    Patients with a history of dry eye for reasons other than an autoimmune disease or condition may 
be included if adequately treated. Patients with non-significant, non-inflammatory disorders (e.g., 
cataracts, glaucoma) will be allowed.   
10. Patients with a significant pulmonary disease or condition, including:
•
History of interstitial lung disease (ILD), pulmonary fibrosis
•
History of pulmonary inflammatory disease, interstitial or other pneumonitis*, acute
respiratory distress syndrome (ARDS)
*Patients with prior evidence of Grade 1 pneumonitis will be eligible provided they were 
asymptomatic and did not require treatment and provided pneumonitis has resolved prior to entry to
this trial. 
11. Patients with a current or recent (within 6 months) significant gastrointestinal (GI) disease or
condition, including:
•
History of inflammatory bowel disease
•
Diarrhea ≥ Grade 2 within 2 weeks prior to first administration of study drug 
12. Patients with an active, known or suspected autoimmune disease, or a documented history of
autoimmune disease or syndrome, requiring systemic steroids or other immunosuppressive
medications
Note:    Exceptions permitted include: type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders such as vitiligo, psoriasis or alopecia not requiring systemic treatment, 
conditions not expected to recur in the absence of an external trigger. 
13. Patients with a history of organ transplantation (e.g., stem cell or solid organ transplant)
14. Patients with a known or suspected hypersensitivity to any of the excipients of formulated
study drug
15. Patients with a history of significant toxicities associated with previous administration of
immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy
16. Patients with unresolved > Grade 1 toxicity associated with any prior antineoplastic therapy
except for persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin,
lymphopenia, hypomagnesemia, and/or end-organ failure being adequately managed by
hormone replacement therapy
17. Patients with inadequate recovery from any prior surgical procedure, or patients having
undergone any major surgical procedure within 4 weeks prior to first administration of study
drug
18. Patients who are known or suspected drug or alcohol abusers where compliance with protocol
requirements may be a concern
19. Patients with a known history of human immunodeficiency virus (HIV) or known active
infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
20. Patients with any other serious/active/uncontrolled infection, any infection requiring
parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to first administration
of study drug
21. Patients with any other serious, life-threatening, or unstable pre-existing medical condition
(aside from the underlying malignancy) including significant organ system dysfunction or
failure, or CS laboratory abnormality(ies), which, in the opinion of the Investigator, would
either compromise the patient’s safety or interfere with obtaining informed consent, compliance
with study procedures, or evaluation of the safety of study drug
22. Patients with a psychiatric disorder or altered mental status that would preclude understanding
of the informed consent process and/or completion of the necessary study-related evaluations
23. Patients with known or foreseeable inability, in the opinion of the investigator, to comply with
the protocol requirements
Drugs and Other Treatments to be Excluded (patients must not have received any of the 
following) 
1.
Other inhibitors of TIM-3 (e.g., mAbs)
2.
Any antineoplastic agent for the primary malignancy (standard or investigational) without
delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest, prior to first
administration of study drug and during study, except for:
•
Nitrosoureas and mitomycin C within 6 weeks prior to first administration of study drug
and during study
Note:  Patients may have received and failed prior therapy with a PD-1/PD-L1 and be considered eligible 
for this trial. 


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3.
Any other investigational treatments within 4 weeks prior to and during study. This includes
participation in any medical device or other therapeutic intervention clinical trials.
4.
Radiotherapy:
•
For target lesions within 4 weeks prior to first administration of study drug unless PD has
been documented in the lesion following treatment, and during study.
•
For non-target lesions within 1 week prior to first administration of study drug,
Note:   Palliative (limited-field) radiotherapy for management of pain associated with bone 
metastases present at baseline is permitted during study. Patients with suspected new bone 
lesions requiring pain management should be treated and evaluated for potential PD 
5.
Use of live vaccines against infectious diseases (e.g., varicella) 4 weeks prior to first
administration of study drug and during study
6.
Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent)
within 2 weeks prior to first administration of study drug and during study.  The following
therapies are allowed:
•
Hormonal therapy for appetite stimulation
•
Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations
•
Hormone replacement therapy at standard doses for end-organ failure
•
Stable hormonal therapy for prostate carcinoma
•
Stable hormonal therapy for ovarian suppression, hormonal contraceptive therapy, or
post-menopausal hormone replacement therapy (HRT)
•
Neuroendocrine tumor patients: stable hormonal therapy with a somatostatin analog
(SSA)
•
Steroid therapy for contrast reaction prophylaxis
•
Intra-articular steroid injections
•
Low-dose maintenance steroid therapy for other conditions (e.g., asthma exacerbation,
stable steroid therapy [excluding tapering dose of steroids] for brain
edema/metastases/radiation)
•
Higher dose steroid therapy for treatment of an acute intercurrent illness (e.g., immune-
related AEs or other adverse conditions) in patients with SD or an ongoing response.  In
such situations, study drug treatment should be interrupted for the duration of
immunosuppressive therapy.
7.
Prophylactic use of hematopoietic growth factors within 1 week prior to first administration of
study drug and during Cycle 1 of study; thereafter-prophylactic use of growth factors is
allowed as clinically indicated. Use of growth factors as treatment is permitted at any time
after initiation of study drug as clinically indicated.  Transfusions are permitted as needed.
Questions regarding patient eligibility must be addressed and resolved by the Investigator in 
consultation with the Sponsor prior to enrollment. 
EXPERIMENTAL PLAN 
Design Elements 
•
Open-label, uncontrolled, non-randomized
•
Escalating doses of study drug in sequential patient cohorts
•
Enrollment staggered between first and second patient in each new higher 3-patient dose
cohort to allow for initial safety observations
Study Schedule 
Screening Period 
•
Written informed consent
•
Safety screening, disease assessment, and eligibility confirmation
Treatment Period
•
C1/D1 initial dose of study drug
•
Continued dosing Q2W
•
28-day cycles until confirmed PD, unacceptable toxicity, or another discontinuation criterion is
met
•
End of Treatment (EOT) visit within approximately 10 days following treatment
discontinuation, or before initiation of a new treatment, whichever occurs first.
•
1-Month Follow-up (1M FUP) visit 30 days (+7 days) following last dose
Follow-Up Period
•
Response follow-up (FUP) every 2 months (Q2M) following discontinuation for reasons other
than confirmed PD until the end of trial
Observation 
Requirements 
Patients will be treated and followed on an outpatient basis. 
•
Patients will be observed for a minimum of 2 hours following completion of the first


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administration of study drug on C1/D1 and a minimum of 1 hour following completion of 
subsequent infusions of study drug (C1/D15, onward).   
•
At the end of each infusion the IV line must remain in place during the observation period to
allow for administration of IV drugs, if necessary.
Infusions will take place under the close supervision of a physician or other study personnel 
experienced in administration of IV agents, and in an environment where full resuscitation facilities 
are immediately available. 
INVESTIGATIONAL MEDICINAL PRODUCT ADMINISTRATION 
Doses to be 
Administered 
Doses to be Evaluated 
Dose cohorts will be numbered and entered sequentially.  The number of cohorts evaluated will be 
based upon toxicities experienced by patients during Cycle 1.   
Sym023 will be administered at up to 7 planned dose levels; anticipated dose levels include: 
•
Dose Cohort 1:  0.03 mg/kg
•
Dose Cohort 2:  0.1 mg/kg
•
Dose Cohort 3:  0.3 mg/kg
•
Dose Cohort 4:  1.0 mg/kg
•
Dose Cohort 5:  3.0 mg/kg
•
Dose Cohort 6:  10.0 mg/kg
•
Dose Cohort 7:  20.0 mg/kg
Changes in Dose to be Administered
Once assigned to a dose cohort, patients will continue to be treated with study drug at that same 
dose level throughout the duration of their time on study. There will be no intra-patient dose-
escalation.  
Dose adjustments should be made in the event of noted weight change (± 10%; less at the site’s discretion or if 
required by institution procedures) at visits that require weight measurement. Adjustments may be made more 
frequently at the site's discretion.   
Route of 
Administration 
IV infusions via indwelling venous access catheter, utilizing a controlled infusion device 
Infusion Materials 
Infusion set containing a 0.22 micron in-line filter. 
Diluent and Delivery 
Commercially available sterile 0.9% sodium chloride (NaCl) for IV infusion   
Once diluted for IV administration, study drug should be administered within 8 hours. 
Infusion Volume 
•
50 mL for doses < 1 mg/kg
•
100 mL for doses ≥ 1 mg/kg to ≤ 3 mg/kg
•
100 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with body weight ≤ 80 kg
•
250 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with body weight > 80 kg
•
250 mL for doses > 10 mg/kg for patients with body weight ≤ 100 kg
•
500 mL for doses > 10 mg/kg for patients with body weight > 100 kg
Infusion Duration 
•
Approximately 30 minutes (+10 minutes) for infusion volumes ≤ 250 mL
•
Approximately 60 minutes (+10 minutes) for infusion volumes of 500 mL
Start and stop times of each infusion, and any interruptions in infusion will be recorded.
Schedule 
Q2W (± 2 days) on Day 1 and Day 15 of each cycle (4 weeks [28 days] equals 1 dosing cycle)  
End of Cycle 1 (EOC1) assessments are to be performed on C1/D28 (±2 days).  Subsequent cycles 
may be administered Q2W (± 2 days), unless further delay is required to allow for amelioration of 
toxicities (or in the event of scheduling difficulties associated with weekends, holidays, etc.).  
Premedication 
Premedication for Infusion-Related Reactions 
Since the mechanism of action of the study drug is to stimulate the immune system premedication 
with agents such as glucocorticoids which are immunosuppressive is to be avoided. As a result, no 
premedication is required to be administered prior to patients receiving the first dose of study drug. 
In patients with a history of infusion-related reactions (IRRs) to mAbs or similar products, it is 
recommended that premedication be administered. In such cases, patients should be premedicated 
with a regimen that includes acetaminophen as well as an H1 (e.g., diphenhydramine/hydroxyzine) 
and possibly an H2-antagonist (e.g., ranitidine/famotidine).  
In the event of an IRR during study: 
•
For Grade 1 or Grade 2 reactions, premedication prior to subsequent infusions should be
considered. Thereafter, if a patient is without recurrence of an IRR, the Investigator may


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choose to withdraw premedication to determine whether such continued therapy is necessary 
for that patient. 
•
For Grade 3 reactions, not applicable as this is considered a DLT; therefore, no further
treatment with study drug is allowed.
Premedication for Other Toxicities 
In the event of other study-drug related toxicities (e.g., nausea, vomiting, diarrhea, etc.), patients 
may be premedicated with standard therapies to reduce the potential for such reactions in the 
future. Based on ongoing review of patient safety data, the Sponsor may implement mandatory 
premedication for all patients should a pattern begin to emerge of mild-to-moderate study drug-
related reactions that are amenable to prophylaxis with standard agents.  
DOSE-ESCALATION DECISION POINTS 
Dose-Escalation 
Cycle 1 
A minimum of 1 cycle of study drug will be administered, if tolerated. Determinations regarding 
dose-escalation and MTD will be based on tolerability during these initial 4 weeks (Cycle 1) of 
treatment, and the occurrence of DLTs thought to be related (i.e., possibly-related, probably-
related, or related) to study drug.   
•
Patients completing Cycle 1, and receiving their full planned doses of study drug in the
absence of a DLT, will be considered to have tolerated the dose level they were assigned to
receive.
•
Patients will be replaced if they have received < 2 full doses of study drug plus follow-up
through EOC1 (C1/D28 ± 2 days) for any reason other than a DLT to ensure MTD
determination rules can be followed with an adequate number of evaluable patients in any
dose cohort.
Dose Escalation and Cohort Expansion Decision Rules 
Initially a modified, accelerated-titration, dose-escalation design will be used with entry of single 
patient cohorts for up to 2 dose levels, based on tolerability. Thereafter, a standard 3+3 dose-
escalation design will be used, with a target toxicity level of 33.3% or less as determined by DLTs.  
The decision rules for dose-escalation are as follows: 
1.
A minimum of 1 patient will be entered into dose Cohort 1 and 2 ONLY
•
If during the initial 2 weeks of Cycle 1 no ≥ Grade 2 toxicity considered possibly-,
probably-, or related to study drug is encountered in the patient, dose-escalation may
continue to the next level when the patient has been followed for safety until C1/D15
•
If at any time during Cycle 1, a patient experiences a ≥ Grade 2 toxicity considered
possibly-, probably-, or related to study drug, the cohort will be expanded to 3 patients
•
If during Cycle 1 a patient experiences a DLT considered possibly-, probably-, or related
to study drug, the cohort will be expanded to 6 patients
2.
Beginning with Cohort 3, or earlier if required by observed toxicity, a minimum of 3 patients
will be entered to each cohort.
•
If during Cycle 1 no DLTs are encountered in any of the first 3 patients, dose-escalation
may continue to the next level when all patients have completed Cycle 1
•
If during Cycle 1, any 1 patient experiences a DLT considered possibly-, probably-, or
related to study drug, the cohort will be expanded to 6 patients.  If no DLTs are
encountered in the additional 3 patients, dose-escalation may continue to the next level
when all patients have completed and tolerated Cycle 1.
•
If during Cycle 1, > 1 patient experiences a DLT, dose-escalation will STOP.  This will
indicate that the MTD has been exceeded.
3.
If it is determined that a dose level is not tolerated:
•
The previous lower dose cohort will be expanded to 6 patients (if this has not already been
accomplished) as a total of 6 patients must be treated before establishing a dose as the
MTD.
•
There is also the potential to evaluate and expand a previously unplanned intermediate dose
level between 2 established dose levels to 6 patients to more fully characterize tolerability.
4.
The MTD will be the highest dose level of study drug at which no more than 1 of 6 evaluable
patients has had a DLT.
5.
Once the MTD (or maximum dose to be studied) is achieved and/or the RP2D is identified, that
cohort may be expanded up to 12 patients to more fully evaluate safety and tolerability at that
dose level, at the Sponsor’s discretion. Should the DLT rate equal or exceed 33.3% in an
expanded cohort, it will be determined that the dose is not tolerated.  If this occurs, the


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previous lower dose cohort or an intermediate dose level may be expanded as above.  
Therefore: 
• There is potential for expansion of lower dose cohort(s) if an initially identified MTD 
and/or RP2D is subsequently determined to be not tolerated (either with single or repeat 
cycles of therapy), and 
• There is potential to evaluate and expand a previously unplanned intermediate dose level(s) 
between 2 established dose levels to more fully characterize tolerability 
The RP2D may be equal to or lower than the MTD or the MAD. The RP2D will be selected based 
on safety data, as well as available PK, pharmacodynamic/biomarker results, and other data, as 
applicable. 
Duration of Exposure Prior to Start of Next Patient and Start of Next Cohort 
Single patient cohorts:  Dose-escalation and accrual to the next cohort will occur only after the 
patient has completed and tolerated the first dose of Cycle 1, including follow-up until C1/D15 to 
allow for review of clinical and laboratory assessments, and consultation with the Study Safety 
Team.  The DLT evaluation period for single patient cohorts will continue through to the 
EOC1. 
The following rules apply to single patient cohorts: 
• 
Should a patient experience an AE of concern in the latter half of Cycle 1 that would, per 
protocol, result in cohort expansion, protocol rules as outlined herein will be followed. 
• 
Additional patients entered to an expanded single patient cohort will follow rules as 
outlined below for 3+3 patient cohorts. 
• 
If a patient has been entered to receive the next higher dose level, that patient will be 
allowed to continue provided adequate tolerability is being demonstrated; however, 
further enrollment to the higher dose level cohort will be halted. 
3+3 patient cohorts:  Enrollment will be staggered by 2 weeks between the first and second patient 
in each new higher 3+3 dose level cohort tested.  The first patient within a cohort must complete 
and tolerate the first dose of Cycle 1, including follow-up until C1/D15 to allow for review of 
clinical and laboratory assessments. Thereafter patients within a cohort may be added concurrently. 
All cohorts:  Dose-escalation and accrual to the next cohort will occur only after the minimum 
number of patients required for tolerability assessment in the current cohort have completed until 
C1/D15 in a single patient cohort, or completed Cycle 1 in a 3+3 patient cohort,, and only after 
acceptable tolerance has been demonstrated in at least 1 of 1, 3 of 3 or 5 of 6 patients treated in the 
current cohort (depending on cohort size), and after consultation with the Study Safety Team.  
For all patients, EOC1 assessments are to be performed on C1/D28 (± 2 days). 
Establishment of the MTD and/or RP2D 
The MTD will be the highest dose level of study drug at which no more than 1 of 6 evaluable 
patients has had a DLT. 
The MAD, MTD, or a dose lower than the MAD or MTD, will be identified as the RP2D, provided 
a minimum of 6 evaluable patients have been treated at that dose, and provided acceptable 
tolerance has been demonstrated in at least 5 of 6 patients treated. 
The RP2D will be based on the MTD evaluation as well as other toxicities observed in the study, 
including observations in later cycles of administration of study drug, as well as on PK, 
pharmacodynamic/biomarkers, and/or other data. 
Rules for Stopping the Study 
The study will be stopped if the MTD is exceeded at the lowest dose level. 
CONTINUED TREATMENT 
Continued Treatment 
after Cycle 1  
 
 
Upon completion of Cycle 1, in the absence of unacceptable toxicity or documented disease 
progression, patients may continue to receive additional cycles of study drug unless further delay is 
required to allow for amelioration of ongoing AEs.   
Administration will be at the same dose level and infusion duration established for the patient, and 
on the same Q2W schedule provided retreatment guidelines are met.  If a delay is required, 
additional cycles should be initiated within approximately 2 weeks of the completion of the 
previous cycle, if feasible. 
Retreatment Guidelines:  To start any new cycle, a patient must meet the following criteria: 
• 
ANC ≥ 1,000 per mm3 


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•
Platelets ≥ 75,000 per mm3
•
Ongoing study drug-related AEs should NOT meet the criteria for DLT
•
Ongoing study drug-related AEs should have either ameliorated to ≤ Grade 1 severity, returned
to baseline status, or resolved, with the exceptions of:
o
Grade 2 alopecia,
o
Grade 2 clinical events that are being adequately controlled with best supportive care
(e.g., fatigue, nausea, vomiting, diarrhea), and
o
Grade 2 asymptomatic laboratory abnormalities that are considered clinically
insignificant and clinically uncomplicated, and/or that are resolving spontaneously or
with conventional medical interventions
•
Dosing must be delayed in patients with evidence of Grade 2 immune-mediated toxicities,
including:
o
Pneumonitis, myocarditis, adrenal insufficiency, encephalitis, nephritis/renal dysfunction
(serum creatinine elevation), episcleritis/uveitis/iritis
o
Colitis, hypophysitis, hyperglycemia, inflammatory arthritis, myositis, rash 
o
Hepatitis (transaminitis, total bilirubin elevation)
Retreatment cycles may continue up to 12 months at which time plans for continued therapy will 
be discussed by the Medical Monitor(s) and Investigator. Patients who stop therapy with an 
ongoing OR or prolonged SD may be retreated in the event of relapse, if the trial is still open.   
Continued Treatment 
after Radiologic 
Disease Progression 
Immunotherapeutic agents may produce antitumor effects that can manifest as response after initial 
evidence of PD, a phenomenon referred to as “pseudoprogression” (PSPD). 
Patients will be permitted to continue treatment beyond initial RECIST v1.1 (or RECIL 2017) 
defined PD while waiting for confirmation of PD, provided they are clinically stable as defined by 
the following criteria (per iRECIST): 
•
Investigator-assessed clinical benefit and absence of rapid disease progression
•
Tolerating study drug
•
Stable PS
•
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring
urgent alternative medical intervention.
Retreatment 
Following an 
Objective Response 
Treatment with study drug may be restarted in a patient who previously achieved a documented OR 
or prolonged SD (> 16 weeks) in this study, stopped treatment, and subsequently progresses. Such 
action may be taken at the Investigator’s discretion, following discussion with the Medical 
Monitor(s), provided retreatment criteria are met, no anti-cancer treatment was administered since 
the last dose of study drug, and the trial is still open.  
This option for retreatment does not apply to patients who previously experienced a DLT that 
required permanent discontinuation from study drug (see DLT and Treatment Discontinuation 
Criteria).  
ADVERSE EVENTS AND DOSE-LIMITING TOXICITIES 
Adverse Event 
Grading 
For reported adverse events (AEs), the Common Terminology Criteria for Adverse Events (Version 
5.0) (CTCAE v5.0), will be used to grade the severity of the AE. 
Management of Dose-
Limiting Toxicities 
and Other Toxicities 
Management of Dose-Limiting Toxicities 
AEs that meet the protocol definition of DLT will require discontinuation from study treatment, 
without exception.   
Management of Other Toxicities 
AEs that do not meet the protocol definition of DLT, but nevertheless warrant dose modification 
may be managed by delay of study drug to allow for amelioration of the toxicity.  


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Dose-Limiting 
Toxicities Definition 
Any of the following toxicities occurring during Cycle 1, if judged to be related to study drug (i.e., 
possibly-related, probably-related, or related), will be considered a DLT for the purposes of 
tolerability assessment during this trial. 
1.
≥ Grade 3 evidence of any of the following immune-mediated toxicities:
•
Pneumonitis
•
Myocarditis
•
Adrenal insufficiency
•
Encephalitis
•
Nephritis, renal dysfunction (serum creatinine elevation)
•
Episcleritis, uveitis, or iritis
2.
≥ Grade 3 evidence of any of the following immune-mediated toxicities:
•
Colitis
•
Hypophysitis, hyperglycemia
•
Inflammatory arthritis
•
Myositis
•
Rash
3.
≥ Grade 2:
•
Uveitis, eye pain or blurred vision that does not resolve with topical therapy within 2
weeks
•
AEs that are prolonged excessively based upon the medical judgment of the investigator,
and/or lead to permanent discontinuation of the investigational agent due to poor
tolerance
•
Immune-mediated toxicity that requires use of glucocorticoids at a dose of ≥ 1 mg/kg/day
of prednisone equivalents for treatment of the toxicity
4.
Any confirmed reduction in visual acuity, regardless of grade or duration
5.
Hepatic-related findings consistent with Hy’s Law criteria:
•
AST and/or ALT elevation > 3 × ULN (or > 3 × baseline if elevated at study entry due to
hepatic involvement by tumor), with
•
total bilirubin ≥ 2 × ULN without initial findings of cholestasis (i.e., serum alkaline
phosphatase [ALP] < 2 × ULN), and
•
No explanation for the above findings such as viral hepatic injury, preexisting or acute
liver disease, or another drug or condition capable of causing the observed liver injury
6.
Any other ≥ Grade 3 or 4 non-hematologic toxicity regardless of duration with the exceptions
of:
•
Grade 3 fatigue
•
Grade 3 nausea, vomiting, or diarrhea lasting ≤ 2 days with best supportive care
•
Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 days that are not clinically
complicated, and resolve spontaneously or respond to conventional medical interventions
•
Other Grade 3 asymptomatic laboratory abnormalities that are clinically non-significant
in the investigator’s opinion, and that resolve spontaneously or with conventional medical
interventions
7.
Any Grade 4 non-hematologic laboratory toxicity regardless of duration
8.
Neutropenia that is:
•
Grade 3 meeting the CTCAE v5.0 criteria for febrile neutropenia (ANC < 1000 per mm3
and a single temperature > 38.3º C [101º F] or sustained temperature ≥ 38º C [100.4º F]
for > 1h)
•
Grade 4
9.
Thrombocytopenia that is:
•
Grade 3 with CS hemorrhage or requirement for transfusion
•
Grade 4 (platelets < 25,000 per mm3)
10. Anemia that is Grade 4 and not explained by underlying disease
11. Any other Grade 4 hematologic toxicity (other than those specifically excluded) lasting > 5
days
12. Any death where a relationship to study drug cannot be ruled out
13. Inability to complete Cycle 1 at the assigned dose (i.e., receipt of < 2 full planned doses of
study drug plus 2 weeks of follow-up) due to any toxicity
14. Treatment delays > 2 weeks from the scheduled next dose during Cycle 1 due to any toxicity
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the Study Safety Team. 
The above criteria will be used to make individual patient determinations regarding dose delays 
or discontinuation throughout the course of the trial, however, only those DLTs occurring 
during Cycle 1 will be used to make decisions regarding cohort dose-escalation and 
tolerability. 
Events occurring after Cycle 1 will also be evaluated by the Study Safety Team and taken into 
consideration when deciding upon further dose levels to be assessed as well as establishment of the 
RP2D. 
TOXICITY SAFETY MANAGEMENT AND SAFETY MONITORING 
Infusion-Related 
Reaction Management 
In addition to premedication as management for IRRs, the following infusion prolongation 
instructions are provided: 
•
For Grade 1 reactions, the infusion may be slowed to 50% of the prior rate such that the
remaining dose to be delivered is administered in 2× the amount of time as was initially
scheduled.
•
For Grade 2 reactions, the infusion should be interrupted for a minimum of 30 minutes, and at
least until there is either amelioration to ≤ Grade 1 severity or return to baseline status.
Supportive care should be provided. The infusion should then be restarted and slowed to 50%
of the prior rate, as described. Subsequent infusions should be administered at the prolonged
rate.
•
For Grade 3 reactions, the infusion will be STOPPED and supportive care will be provided.
The occurrence will be considered a DLT and the patient will be discontinued from treatment.
•
For Grade 4 reactions, the infusion will be STOPPED and supportive care will be provided.
The occurrence will be considered a DLT and the patient will be discontinued from treatment.
In all cases the Investigator should use best clinical judgment in managing such reactions. For 
Grade 1 and Grade 2 IRRs, rechallenge with a shorter duration of infusion (no less than the 
duration designated by the patient’s dose assignment and weight) may be attempted at the 
Investigator’s discretion, after a minimum of 2 doses with no evidence of infusion-related toxicity 
at the prolonged rate.  
Dose Delays 
Toxicities may be managed by delay in dosing, provided they do not meet the criteria for study 
discontinuation. 
For toxicities that are to be managed by dose delay, dosing may be restarted at the same dose, once 
study retreatment criteria have been met.   
Safety Monitoring 
Clinical and laboratory safety data will be reviewed on an ongoing basis throughout the study by 
the Investigators and Sponsor’s Medical Representative(s) so that decisions regarding the 
advisability of continuing accrual to a dose cohort, and/or escalating the dose and allowing accrual 
to a higher dose cohort may be made. In addition, patients will be carefully evaluated for evidence 
of potential cumulative and/or delayed toxicities throughout the duration of their time on study.   
To do so, Serious Adverse Events (SAEs), immune-related AEs of significance, AEs resulting in 
permanent discontinuation from study (regardless of seriousness or relationship to study drug), 
DLTs, IRRs, and dose delays will be promptly reported to the Sponsor (or designee). 
A Study Safety Team will be established and will be comprised of the Investigators(s) and the 
Sponsor’s Medical Representative(s).  Biweekly Study Safety Team teleconferences will be held to 
discuss ongoing patient status and any emerging safety concerns; the frequency of teleconferences 
may fluctuate based on accrual and study activity, as indicated. 
STUDY ASSESSMENTS 
Screening 
(within 14 days prior to 1st 
dose unless otherwise 
stipulated) 
•
Informed consent
•
Eligibility assessment
•
Demography
•
Past medical history
•
History of the primary malignancy (including data on the extent, duration, and best response
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Safety Assessments 
Patients to be monitored throughout the treatment and follow-up period for occurrence of AEs 
(acute, delayed, and/or cumulative), as well as for changes in clinical status, vital signs (VS), and 
laboratory data.   
Safety Assessments (1) (within 14 days prior to 1st dose unless otherwise stipulated) 
• 
Concomitant Medication/Procedure surveys 
• 
AE reporting (collection of data from signing of informed consent to 30 days after final dose, 
with long-term follow-up to surveil for [up to 6 months]and follow [up to 2 years] immune-
mediated toxicities) 
• 
DLT assessment (Cycle 1) 
• 
PS evaluation (ECOG) 
• 
VS assessment (including temperature, pulse, respiratory rate, blood pressure [BP], and 
oxygen saturation by pulse oximetry at rest and exertion) 
• 
Physical examination (with weight, and pulmonary/cardiac assessment at each visit) 
• 
Hematology panel 
• 
Biochemistry panel (to include creatine kinase [CK] for cardiac assessment) 
• 
Coagulation panel  
• 
Thyroid function studies (to include measurement of thyroid stimulating hormone [TSH], free 
triiodothyronine [fT3] and free thyroxine [fT4]) 
• 
Urinalysis (by multi-panel chemical test strip analysis; include microscopic examination of 
sediment if clinically indicated) 
• 
Pregnancy testing (if applicable) (serum test within 14 days, urine test repeated within 2 
working days prior to 1st dose) 
• 
Electrocardiogram (ECG), 12-lead 
Safety Assessments (2) (results from assessments previously performed as standard of care within 
28 days [+2 days] prior to 1st dose may be utilized, provided no antineoplastic therapy has been 
delivered between assessment and 1st dose; otherwise within 14 days prior to 1st dose) 
• 
Ophthalmology examination  
• 
MUGA scan or ECHO (To be performed ONLY in patients with a history of CHF) 
• 
Pulmonary function tests (PFTs) (to include spirometry and assessment of diffusing capacity 
of carbon monoxide [DLCO]) 
Disease Assessments 
 
Disease Status (within 28 days [+2 days] prior to 1st dose) 
• 
Tumor marker measurement (as indicated by tumor type) 
• 
Diagnostic imaging for assessment of disease (computed tomography [CT]/magnetic 
resonance imaging [MRI]) (The same method and technique should be used throughout the 
study.) For safety, imaging of the chest required at each evaluation to assess pulmonary status 
• 
Response assessment (per RECIST v1.1, RECIL 2017, and iRECIST). Data on evidence of 
and duration of any OR (CR or PR) or SD, as well as disease progression to be collected. 
Other Assessments  
(Specialty Lab) 
  
Immunogenicity 
Serum sampling to assess the potential for anti-drug antibody (ADA) formation 
Pharmacokinetics 
Serum sampling to assess the PK profile of the study drug  
Pharmacodynamic and other Biomarker Studies 
Peripheral blood sampling (pre- and post-dosing) 
• 
Pharmacodynamic evaluation (e.g., receptor occupancy) 
• 
Evaluation of DNA, RNA, proteins/cytokines, and cellular biomarkers 
Tumor tissue sampling (pre- and post-dosing) (biopsies optional) 
• 
Evaluation of DNA, RNA, protein, and cellular biomarkers 
DISCONTINUATION AND FOLLOW-UP 
Key Treatment 
Discontinuation 
Criteria 
Patients are to be discontinued from treatment in the event of any of the following: 
1. Adverse Events, including: 
• 
Any AE or SAE that meets the study DLT criteria at any time during the study  
• 
Another AE or SAE considered by the Investigator to require treatment discontinuation 
2. Progressive Disease: Confirmed radiologically  
3. Clinical Progression: Treatment failure not meeting the criteria for PD, but considered by the 
Investigator to require treatment discontinuation   
4. Physician Decision, including:  
• 
Use of or requirement for a non-permitted concomitant medication 


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• 
Requirement for a significant surgical procedure  
• 
Intercurrent illness that would prevent completion of study-related evaluations 
• 
Any other reason in the opinion of the Investigator that would justify treatment 
discontinuation   
5. Withdrawal by Patient: Withdrawal of consent and election to discontinue treatment  
Replacements 
Should a patient discontinue treatment with study drug for reasons other than the occurrence of a 
DLT prior to completing Cycle 1, a replacement patient will be obtained using the original 
eligibility criteria.   
Follow-up 
All follow-up visits and assessments, as described, should be conducted to the extent possible. 
• 
End of Treatment (EOT) evaluations to be conducted within approximately 10 days following 
treatment discontinuation, or before initiation of a new treatment, whichever occurs first    
• 
1-Month Follow-up (1M FUP) evaluations to be conducted approximately 30 days (+7 days) 
following the last dose of study drug.   
• 
Long-Term FUP for Safety: If an observed toxicity (non-immune-mediated) thought to be 
related to study drug has not resolved by the 1M FUP evaluation, an additional FUP AE 
assessment will be conducted approximately 2 months (may be repeated at 4 months if needed) 
following the last dose of study drug, if feasible, to confirm that the event has either resolved, 
returned to baseline status, or been adequately explained and assessed by the Investigator as 
chronic and/or stable, and that no long-term deleterious effects have become evident   
Since late-occurring immune-mediated toxicities have been reported to occur several weeks to 
months after treatment with other immune checkpoint inhibitors, long-term surveillance for 
such toxicities will be conducted in this study. Patients will be followed at approximately 2-
month intervals following the last dose of study drug for up to 6 months to assess for the onset 
of any post-therapy immune-mediated event thought to be related to study drug.  
Any patient who develops an immune-mediated toxicity during study, or during the 6-month 
post-therapy FUP period, will be followed at approximately 2-month intervals following the 
last dose of study drug for up to 2 years to assess the course of the condition and evaluate 
potential reversibility of the finding. 
• 
Long-Term FUP for Response: In the event of an ongoing OR or SD at the EOT, response 
assessments based on imaging studies will continue to be performed every 2 months following 
the last dose of study drug, until confirmed PD or another therapeutic intervention is initiated, 
until the end of trial, so that data may be collected on the duration of SD or OR, as well as 
disease progression 
ANALYSIS PLAN 
Endpoints 
Primary Endpoint  
DLTs to establish MTD and/or recommended RP2D  
 
Secondary Endpoints  
• 
Safety profile 
• 
Incidence and characterization of immunogenicity (ADA) 
• 
PK profile 
• 
Preliminary antineoplastic activity, to include occurrence/duration of OR or SD, and TTP 
Pharmacokinetic 
Parameters 
Evaluations to delineate dose-response and PK parameter-response relationships will be 
undertaken.  Based on the concentrations determined, the following PK parameters for the study 
drug will be calculated for each subject: area under the concentration-time curve (AUC) from start 
of first infusion (SOI) to 336 hours (AUCτ), from SOI to infinity (AUCinf), terminal elimination 
half-life (T1/2), clearance (CL), volume of distribution (Vd), maximum concentration (Cmax), 
concentration at end of infusion (CEOI), trough concentration (Ctrough), and time to reach Cmax (Tmax) 
Exploratory 
Pharmacodynamic 
and Biomarker 
Parameters 
A summary of the changes in potential pharmacodynamic and other biomarker(s) will be presented.   
Statistical Methods 
and Sample Size 
Calculation 
The primary endpoint of Sym023 dose-escalation is the occurrence of DLTs during Cycle 1 for 
each dosing regimen. The number of enrolled patients will depend on the extent of observed DLTs 
independently in each cohort. Based on the dose-escalation design, it is planned to enroll 
approximately (20-48) patients during this part of the trial. 


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All DLT events will be listed by dose cohort and patient. A summary table of DLTs across dose 
cohorts by System Organ Class (SOC) and preferred term will be presented, if applicable. The 
summaries will include number of DLTs and number and percentages of patients experiencing a 
DLT. 
Safety evaluation will be based on reported AEs and safety laboratory test results, immunogenicity, 
and other safety data. Unless otherwise specified, all summaries will be descriptive. 
Interim Analysis 
Safety evaluation will be performed prior to each dose-escalation. No other interim analyses are 
planned. 
TRIAL REPORTING 
Final Clinical Trial 
Report 
Final integrated clinical/statistical trial report to be prepared at the end of trial 
 


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2 SCIENTIFIC BACKGROUND AND RATIONALE 
2.1 
Background 
2.1.1 
Tumor Malignancies 
Cancers are malignant tumors formed by an abnormal growth of cells and tissue leading to organ 
failure. They fall into two categories: solid and hematological cancers. Solid tumors are formed 
by an abnormal growth of body tissue cells other than blood, bone marrow (BM), or lymphatic 
cells. A solid tumor consists of an abnormal mass of cells, which may stem from different tissue 
types such as lung, breast, colon, prostate, stomach, and liver, and which initially grows in the 
organ of its cellular origin. In advanced stages of the disease, solid tumors may spread to other 
organs through metastatic tumor growth.   
Cancer is the second-leading cause of death and disability in the world, only surpassed by heart 
disease. In 2012, 14.1 million people were diagnosed with cancer worldwide. An estimated 8.2 
million people died from the disease. The World Health Organization (WHO) projected that by 
2035, these figures could increase to 24 million new cases and 14.6 million cancer deaths 
worldwide. Lung, breast, colorectal, prostate, and stomach cancer are the most common 
malignancies (1). 
2.1.2 
Overview of the Target: TIM-3 
TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), also known as HAVCR2 
(hepatitis A virus cellular receptor 2) or CD366, is an immune checkpoint receptor expressed by 
a range of different immune cells, including T-cells, dendritic cells, macrophages, and natural 
killer (NK) cells. On naïve T-cells, TIM-3 expression is low, but becomes upregulated upon T-
cell activation.  In contrast to T-cells, dendritic cells, NK cells and monocytes have high basal 
TIM-3 expression.TIM-3 has been associated with several, mostly promiscuous, ligands, 
including galectin-9, phosphatidylserine (PtdS), carcinoembryonic antigen related cell adhesion 
molecule 1 (CEACAM1) and high mobility group box 1 (HMGB1) protein. The exact roles of 
these ligands are currently not well understood and most likely are context dependent (2-4).  
The role of TIM-3 in regulating immune cell function is complex and appears context-
dependent; both activating and inhibiting functions have been described (3, 4). TIM-3 
engagement on myeloid cells, such as dendritic cells and macrophages, has been reported to 
increase their state of activation. TIM-3 on T-cells, on the other hand, has been described to 
correlate with an “exhausted” phenotype. Most of the functional data related to TIM-3 and its 
role in tumor immunology come from studies in mice using various antibodies (5, 6).  
Antibody-mediated engagement of TIM-3 has been shown to induce increased proliferation and 
cytokine production by T-cells activated in vitro, as well as tumor growth inhibition in tumor 
xenograft models, especially in combination with Programmed Cell Death Protein 1 (PD-1) 
blockade (5, 6). In most of these studies, due to poor antibody validation, it is not clear whether 
the effects of the TIM-3 antibodies are mediated by inhibition of ligand binding, by antibody 
mediated target engagement, or both. Furthermore, due to the expression of TIM-3 in both 
myeloid cells and lymphocytes, the exact cellular mechanisms underlying the in vivo antitumor 
activity of anti-TIM-3 antibodies are still not understood.  


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Three anti-TIM-3 antibodies, MGB453 (Novartis), TSR-022 (Tesaro) and LY3321367 (Lilly) are 
in early clinical development for use as cancer immunotherapy in solid and hematologic 
malignancies. All three antibodies are to be tested alone (i.e., as monotherapy) and in 
combination with anti-PD-1 antibodies. Additional TIM-3 antibodies and small-molecule 
inhibitors are in pre-clinical development. TSR-022, a humanized IgG4 monoclonal anti-TIM-3 
antibody that enhances T-cell activation, is the only antibody drug candidate for which any 
clinical results have been published to date (7). The results indicate that TSR-022 monotherapy 
is well tolerated across multiple dose levels and that adverse events (AEs) are manageable and 
consistent with the safety profiles of other checkpoint inhibitors. Clinical activity in the form of 
disease stabilization and one case of partial response has been observed in patients with various 
cancer types, including rectal, thyroid, neuroendocrine, head and neck cancer, and soft-tissue 
sarcoma (7, 8). TSR-022 is currently being evaluated in the clinic in combination with an anti-
PD-1 antibody. 
2.1.3 
Overview of the Product: Sym023 
The investigational medicinal product (IMP) tested in this trial is Sym023. Sym023 is a 
recombinant, fully human, IgG2 antibody that binds human TIM-3 with nanomolar affinity and 
cynomolgus TIM-3 with 100-fold reduced affinity. Sym023 does not cross-react with mouse or 
rat TIM-3. Sym023 blocks PtdS binding to TIM-3 and induces cytokine secretion and activation 
of immune cells in vitro. 
2.2 
Summary of Nonclinical Studies  
2.2.1 
Nonclinical Pharmacology Studies 
The pharmacologic characterization of Sym023 includes in vitro functional evaluation in various 
relevant cell-based assays and in vivo testing in mouse models of human cancer. Sym023 
stimulates T-cell and dendritic cell activation and cytokine production in vitro. 
Sym023 enhances cytokine production and T-cell proliferation in one-way and two-way mixed 
lymphocyte reaction (MLR) assays and shows comparable activity in the 2-way MLR assay with 
human and cynomolgus cells. Sym023 has a direct effect on dendritic cells leading to increased 
expression of activation markers and secretion of cytokines. The functional activity of Sym023 is 
dependent on interaction with Fcγ receptors; however, Sym023 does not induce secondary 
effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-
dependent cytotoxicity (CDC) in vitro. 
The ability of Sym023 to stimulate immune cells in vitro translates into tumor growth 
suppression in vivo. Sym023 induced activation of immune cells and reduced tumor growth in 
humanized mouse models engrafted with human cell-line derived or patient-derived tumor 
xenografts. In a human xenograft tumor model in mice reconstituted with human peripheral 
blood mononuclear cells (PBMCs), the combination of Sym023 and an anti-PD-1 antibody 
enhanced the tumor growth inhibition compared to the limited effect of single antibody 
treatment. These in vivo studies demonstrate that administration of Sym023 induces a tumor-
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2.2.2 
Nonclinical Toxicology Studies 
The relevance of the cynomolgus monkey as the only species for prediction of potential human 
toxicity of Sym023 was demonstrated by amino acid sequence homology, target binding affinity 
and avidity, and functional activity. 
The non-clinical development program in the cynomolgus monkey consisted of two non-Good 
Laboratory Practice (GLP) studies as well as a GLP-compliant 4-week study. No adverse 
findings were observed in the 4-week dose-range-finding (DRF) study in cynomolgus monkeys, 
where Sym023 was administered at 10 and 40 mg/kg/week by four weekly intravenous (IV) 
injections. In the non-GLP pharmacokinetic (PK) study, single IV infusions of Sym023 at 1 or 
10 mg/kg were well tolerated by cynomolgus monkeys. No test article related effects on in-life 
parameters were noted.  
In a subsequent pivotal 4-week GLP-compliant toxicology study, Sym023 was administered 
once weekly IV at 0 (control), 10, or 100 mg/kg to the cynomolgus monkey for 4 weeks (a total 
of five doses). An assessment of delayed onset toxicity and/or reversibility of toxicity was made 
during a 12-week recovery period for the animals administered 10 mg/kg. The purpose of this 
study was to support a safe starting dose in first-in-human studies. Standard toxicology 
evaluations as well as specific immunotoxicology endpoints were included in this pivotal study. 
There were no decedents during the study. Weekly IV infusion of 10 or 100 mg/kg/week 
Sym023 was generally well tolerated, with no adverse findings noted.  
All animals were anti-drug antibody (ADA)-negative on Day 1 and Day 29, and the animals 
were adequately exposed to Sym023 throughout the study.  
No immunotoxicity was observed in this study. The results indicated that repeated IV 
administration of Sym023 did not result in any adverse test article-related changes to immune 
function as determined by cytokine levels in blood, ex vivo stimulation with staphylococcal 
enterotoxin B (SEB), immunophenotyping of blood and spleen, T-cell dependent antibody 
response (TDAR) to keyhole limpet hemocyanin (KLH), or ex vivo recall stimulation with KLH. 
No test article-related effects on body weight, food consumption, clinical observations, dosing 
observations, dose site observations, ophthalmic observations, blood pressures, functional 
observation battery, electrocardiogram (ECG), respiration, or rectal temperatures were recorded 
during the dosing phase. Likewise, there were no changes considered related to administration of 
Sym023 for hematology, coagulation, clinical chemistry, thyroid stimulating hormone (TSH), 
urinalysis, organ weights, and macroscopic or microscopic pathology. Based on the data from 
this study, the no-observed-adverse-effect level (NOAEL) for Sym023 is ≥100 mg/kg/week. 
In vitro safety pharmacology was addressed by assessing cytokine release, complement 
activation, as well as platelet counts, and white blood cell counts in human whole blood from 6 
healthy donors, and by assessing mast cell degranulation in human mast cells cultured from 
peripheral blood CD133+ stem cells. Sym023 responses in the human whole blood assay were 
overall comparable to vehicle for cytokine levels (IFN-γ, IL-2, IL-6, and TNF-α), complement 
activation, platelet count, and white blood cell count. Sym023 did not affect the immediate 
degranulatory response of mast cells in the human mast cell assay. Therefore, the likelihood of 
acute cytokine release syndrome or mast cell degranulation associated with administration of 
Sym023 to humans is considered to be low.  


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The half-life in cynomolgus monkeys was approximately 7 days and the half-life of Sym023 in 
humans is anticipated to be approximately 12 days. The planned dosing, every 2 weeks, is 
predicted to ensure sustained exposure to Sym023 during repeated dosing with little or no 
accumulation. No PK or pharmacodynamic properties have been identified which precludes 
administering Sym023 to humans. 
2.3 
Clinical Experience 
2.3.1 
Clinical Experience with Agents Related to Sym023 
2.3.1.1 
Clinical Evidence of Activity in Malignant Diseases 
As noted, anti-PD-1 and anti-programmed death-ligand 1 (PD-L1) monoclonal antibodies 
(mAbs) have been approved (accelerated and full approvals) for the treatment of various human 
cancers. These include: (a) solid tumors (non-small cell lung carcinoma, renal cell carcinoma, 
malignant melanoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, 
Merkel cell carcinoma; (b) hematological malignancies (classical Hodgkin Lymphoma); as well 
as (c) a number of tumors in adults or children characterized by high microsatellite instability 
without other available therapies (9-13). Additional agents targeting PD-1 are in development.  
These agents continue to be studied alone and in combination with other modalities including 
other agents with immune system targets. For example, the combination of anti-PD-1 mAbs and 
an antibody targeting Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) (ipilimumab) 
has been approved in patients with melanoma. These agents are also being studied with standard 
therapeutics such as chemotherapy, radiotherapy, and various targeted agents, all in efforts to 
both improve the initial efficacy of immune checkpoint blockers and/or to circumvent the 
refractoriness that emerges during or after treatment with these agents.  
Anti-PD-L1 mAbs have also been approved and are being developed alone and in combination 
with other agents. 
2.3.1.2 
Safety and Tolerability of anti-TIM-3 mAbs 
Data are available from a single Phase 1 study of TSR-022, a human monoclonal IgG4 antibody 
to TIM-3. As of October 2017, 38 pts had been treated with TSR-022 monotherapy: 3 pts at 0.03 
mg/kg, 3 pts at 0.1 mg/kg, 3 pts at 0.3 mg/kg, 9 pts at 1 mg/kg, 8 pts at 3 mg/kg, and 12 pts at 10 
mg/kg (7). TSR‐022 monotherapy was well tolerated across multiple dose levels. AEs that 
occurred in >15% of patients were fatigue (8 pts, 26%); abdominal pain (7 pts, 23%); nausea (6 
pts, 19%); elevated alanine aminotransferase (ALT); elevated aspartate aminotransferase (AST); 
back pain, constipation, and vomiting was each reported in 5 pts (16%). One dose-limiting 
toxicity (DLT) event occurred with TSR-022 monotherapy (immune-related Grade 3 lipase 
elevation), which did not require treatment modification. No treatment-related serious adverse 
events (SAEs) were observed. These data were updated in a presentation at the SITC meeting in 
November 2017. There were no Grade 4 or 5 AEs reported and additional AEs included: 
decreased neutrophil and lymphocyte counts; chills; dyspnea; decreased appetite; pain and 
peripheral sensory neuropathy. TSR-022 exposure and peripheral receptor occupancy increased 
in a dose proportional manner from 0.3 to 10 mg/kg (7, 8). 
The authors concluded that the AEs seen in patients receiving TSR-022 monotherapy were 
manageable and consistent with the safety profiles of other checkpoint inhibitors (7). 


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Although the mechanism of action is distinct, inhibitors of TIM-3 have many similarities to 
blockers of other immune checkpoint pathways. Preclinical data have documented that inhibition 
of the PD-1/PD-L1 pathway results in immune stimulation that may lead to antitumor effects, 
autoimmunity, effects on immune responses to viral infections, and alloimmunity following 
hematopoietic stem cell transplantation (HSCT). Because of these similarities, data on the 
potential AEs seen after treatment with antibodies to PD-1 and PD-L1 are being included in this 
clinical trial protocol (CTP) since there are limited available data on toxicities associated with 
administration of antibodies to TIM-3 alone (7).  
AEs associated with immune checkpoint blockers targeting PD-1 or PD-L1 have been well 
described in publications of clinical trials of these agents, in prescribing information from 
approved products (8-12), as well as in literature reviews (14-17). Unlike AEs observed after 
standard cancer therapy, many of the toxicities of these agents are only observed after several 
weeks to months and may not be clearly dose-related. The wide variety of potential AEs as well 
as their variable times of onset have complicated development, although the safety profiles of 
these agents have become clearer over time as additional agents targeting these pathways have 
been evaluated.   
The warnings and precautions variably associated with checkpoint inhibitors, specifically those 
directed to PD-1/PD-L1, have included  risk of developing: immune-mediated pneumonitis, 
immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, 
immune-mediated nephritis and renal dysfunction, immune-mediated skin adverse reactions, and 
immune-mediated encephalitis/meningoencephalitis, immune-mediated myasthenic syndrome, 
myasthenia gravis, or Guillain-Barre, immune-mediated ocular inflammatory toxicity, and 
immune-mediated pancreatitis. Increased infection risk, embryo-fetal toxicity, as well as 
increased complications associated with allogeneic HSCT have also been noted. Other immune-
mediated and non-immune-mediated AEs have been reported in the archival literature and/or 
prescribing information for PD-1/PD-L1 pathway inhibitors and are listed in Appendix 8 (8-12). 
2.3.1.3 
Patient Selection for Treatment with Sym023 
Preliminary studies have been undertaken to evaluate biomarkers that allow for selection of 
patients who may have an increased likelihood of responding to anti-TIM-3 mAbs, but there are 
no definitive data available at this time.   
2.3.1.4 
Potential Pharmacodynamic Biomarkers 
Limited information is available on potential pharmacodynamic biomarkers measuring responses 
to therapy with anti-TIM-3 mAbs. Assessment of antitumor effect in this study will be performed 
using standard response criteria as well as a modification of the Response Evaluation Criteria in 
Solid Tumors (Version 1.1) (RECIST v1.1) referred to as Immunotherapeutics Response 
Evaluation Criteria in Solid Tumors (iRECIST) (18, 19). 
2.3.2 
Clinical Experience with Sym023 
The study described in this clinical trial protocol is ongoing.  Sym023 is also being studied in a 
Phase 1 study in combination with Sym021 (anti-PD-1 monoclonal antibody; ClinicalTrials.gov 
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2.4 
Trial Rationale  
Data from the literature as well as nonclinical pharmacology, toxicology, PK and the in vitro 
safety study in human whole blood indicate that Sym023 can be safely evaluated in human 
cancer patients at an appropriate starting dose. Data on both Sym023 as well as other anti-TIM-3 
mAbs have been considered in developing this clinical trial. Sym023 is being evaluated as a 
single agent in preparation for subsequent studies in combination with other mAbs designed to 
improve antitumor responses by further interactions with other immune system targets. 
Combinations of immune checkpoint inhibitors and other agents that either increase immune 
function directly or interrupt immune suppressive pathways are under active development with 
an aim of improving the efficacy of currently available therapies. 
2.5 
Dose Rationale 
The starting dose and dose-escalation steps are based on a combination of the toxicity studies in 
cynomolgus monkeys (using the NOAEL as one criterion), in vitro safety pharmacology, 
observations in in vitro cell studies, and the Minimal Anticipated Biological Effect Level 
(MABEL) for Sym023 based on pre-clinical in vitro and in vivo pharmacology data.  
Based on a combined evaluation of the data, a cautious approach was used and a starting dose of 
0.03 mg/kg every 2 weeks (Q2W) equal to the MABEL was selected. The evaluation takes into 
account the uncertainties for predicting the effects of Sym023 in humans while recognizing the 
lack of toxicity in cynomolgus monkeys at exposure levels well above the predicted serum 
concentration for the first dose in humans. All relevant in vitro and in vivo PK and 
pharmacodynamic data were considered for Sym023. In the pivotal toxicity study in cynomolgus 
monkeys, Sym023 was dosed at 10 and 100 mg/kg/week for 4 weeks. The 100 mg/kg weekly 
dose for 4 weeks (5 dosing occasions) in this study was determined to be the NOAEL. The 
Maximum Recommended Starting Dose (MRSD) was determined to be 0.1 mg/kg Q2W after 
applying a standard safety factor (10) and adjusting for differences in affinity of Sym023 to 
human and cynomolgus TIM-3 (100).  
A starting dose of 0.03 mg/kg Q2W using the MABEL approach was selected based on 
evaluation of all available data for predicting the Sym023 effects in humans: 
• The potentially unique mechanism of action of Sym023 compared to other anti-TIM-3 
antibodies in early clinical development, yet the absence of safety signals and lack of 
cytokine release detected in the in vitro safety pharmacology studies using human whole 
blood. 
• The lack of toxicity in cynomolgus monkeys at exposure levels well above the predicted 
serum concentration for the first dose in humans, even when corrected for differences in 
affinity for Sym023 against human TIM-3 (KD 3.3 µg/mL) and cynomolgus TIM-3 
(dissociation constant [KD] 330 µg/mL). 
• The NOAEL of 100 mg/kg in the toxicity studies and a resulting affinity-corrected 
MRSD of 0.1 mg/kg Q2W, which is 3-fold higher than the proposed starting dose using 
the MABEL. 
• The MABEL of 0.03 mg/kg Q2W represents an average Sym023 serum concentration, 
which could elicit 20% of the maximal response in the in vitro 1-way MLR 


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pharmacology assay using dendritic cells and T-cells derived from two donors. Thus, as 
the MABEL is based on a low level of effect in an in vitro assay with isolated blood cells, 
it represents a cautiously selected benchmark for potential initial pharmacological activity 
and aims to mitigate the risk of potential acute effects. 
The starting dose (0.03 mg/kg, Q2W) and the subsequent dose level (0.1 mg/kg, Q2W) is 
intended to be administered to a limited number of patients to investigate the potential acute AEs 
while exposing as few patients as possible to potentially sub-therapeutic dose levels. The 
therapeutic effect is predicted to occur at higher dose levels; thus 10-20 mg/kg Q2W may be 
needed to ensure full saturation in vivo. The subsequent dose levels (from 0.1 mg/kg, Q2W) are 
to be administered to more patients per cohort as described in the study protocol. Dose levels are 
planned with 3-fold increase at all dose-escalations, except for the last one from 10 to 20 mg/kg. 
The 3-fold increase was based on a combined evaluation of the steepness of concentration-
response and non-clinical studies. The concentration-response curve based on the 1-way MLR 
assay did not indicate a steep concentration-response, which would have called for smaller 
escalation increases. The maximum proposed dose of 20 mg/kg is predicted to ensure full 
saturation of the target and full effect as assessed by the 1-way MLR assay (>95%) in humans. 
The maximum dose also takes in to account that the local concentration in tissue is typically less 
than 10% of the serum concentration for antibodies (20).  
In conclusion, the proposed starting dose is 0.03 mg/kg administered Q2W. The maximum dose 
to be administrated in this trial is not to exceed 20 mg/kg administered Q2W. 
2.6 
Overall Benefits/Risk 
No clinical information is available for patients treated with Sym023; therefore, the benefits and 
the safety profile of Sym023 have not been fully established. However, responses have been 
reported in a single Phase 1 trial of the anti-TIM-3 mAb TSR-022 in patients with rectal, thyroid, 
neuroendocrine, head and neck cancer, and soft-tissue sarcoma (7, 8).  Results from preclinical 
studies indicate that Sym023 has antitumor activity in different cancer models. Sym023 has also 
been shown to be efficacious in preclinical models at dose levels that are well tolerated in 
cynomolgus monkeys. 
During this trial, there will be an ongoing assessment of the risks with periodic evaluation of 
safety data. The trial will be discontinued in the event of any new finding indicating a risk that 
would render continuation of the trial unjustifiable. A Study Safety Team will review clinical 
and laboratory safety data on an ongoing basis and make decisions regarding the advisability of 
continuing accrual and/or dose-escalation. 
To mitigate potential risks, the trial is designed to detect DLTs, if any, and to define a maximum 
tolerate dose (MTD) in accordance with the dose-escalation scheme planned for the trial.  
Enrollment will be staggered by 2 weeks between the first and second patient in each new dose 
level tested to evaluate safety before allowing concurrent enrollment of further patients at the 
given dose level. If the dose administered in a cohort is well tolerated, dose-escalation may 
proceed, and enrollment of subsequent cohorts may occur to establish a recommended Phase 2 
dose (RP2D). The options to slow infusions, interrupt dosing, and discontinue administration of 
study drug in the event of specific AEs are outlined in this CTP (Section 8.5).   


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Information on AEs observed with an agent targeting the TIM-3 pathway is included (Section 
2.3.1.2, Section 11.2). Information on AEs observed with agents targeting the PD-1/PD-L1 
pathways is also included (Section 11.2, Appendix 8), along with recommendations for the 
management of infusion-related reactions (IRRs) (Appendix 9) and immune-mediated toxicities 
(Appendix 10). 
Patients participating in Sym023 studies will be closely monitored for anticipated adverse 
reactions as well any unanticipated safety findings. Because the risks associated with immune 
checkpoint inhibitors can occur several weeks to months after treatment, patients will be 
monitored for up to 6 months following the last dose to assess for the onset of any post-therapy 
immune-mediated event thought to be related to study drug. Any patient who develops an 
immune-mediated toxicity during study, or during the 6-month post-therapy follow-up period, 
will be followed for up to 2 years after the end of treatment to assess the course of the condition 
and evaluate potential reversibility of the finding. 
FOR ADDITIONAL INFORMATION, PLEASE REFER TO THE INVESTIGATOR’S 
BROCHURE (IB) 


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3 TRIAL OBJECTIVES AND DESIGN SUMMARY 
3.1 
Objectives: Sym023 (anti-TIM-3) Dose-Escalation 
3.1.1 
Primary Objective  
Evaluation of the safety, tolerability, and DLTs to establish the MTD and/or RP2D of sequential 
escalating doses of Sym023 (anti-TIM-3) when administered Q2W by 30-minute IV infusion to 
patient cohorts with locally advanced/unresectable or metastatic solid tumor malignancies or 
lymphomas that are refractory to available therapy or for which no standard therapy is available  
Note:  Q2W dosing; 4 weeks equals 1 dosing cycle.  Goal is the identification of the MTD or determination of a 
RP2D dose based on clinical data, including safety, PK, and pharmacodynamic (e.g., receptor occupancy in 
peripheral blood) outcomes. The MTD, if identified, and the RP2D dose may not be the same as the RP2D 
may be lower. If an MTD is not identified a maximum administered dose (MAD) will be determined and will 
not exceed 20 mg/kg.    
3.1.2 
Secondary Objectives  
• Evaluation of the immunogenicity of Sym023  
• Characterization of the PK profile of Sym023 
• Evaluation of the preliminary antineoplastic effects of Sym023, including:  
o Evidence of objective response (OR) or stable disease (SD)*   
o Duration of OR or SD*  
o Time to progression (TTP) of disease*  
* As assessed by RECIST v1.1 (Appendix 5), iRECIST (Appendix 6), and Response Evaluation Criteria 
in Lymphoma (RECIL 2017; Appendix 7) 
3.1.3 
Exploratory Objectives  
• Evaluation of potential pharmacodynamic markers, e.g., receptor occupancy in peripheral 
blood mononuclear cells (PBMCs) (peripheral blood to be collected) 
• Evaluation of potential biomarkers, including but not limited to assessment of:  
o In peripheral blood: circulating tumor deoxyribonucleic acid (ctDNA), 
ribonucleic acid (RNA), relevant proteins/cytokines, and cellular biomarkers  
o In tumor tissue: DNA, RNA, protein, and cellular biomarkers (biopsies optional) 
Note:  Assay methodology and biomarker assessments to be determined (TBD).  Potential analyses may 
include but are not limited to: ctDNA sequencing; RNA sequencing (RNA-seq)/whole-exome 
sequencing (WES); measurement of relevant proteins/cytokines in the blood; cytometric analysis of 
cells in blood; and immunohistochemistry (IHC) of tumor material when collected (tumor sampling 
is optional).  
3.2 
Trial Design Summary  
Patient Population and Objectives 


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Approximately 20-48 male and female patients with documented either solid tumor malignancies 
that are locally advanced/unresectable or metastatic, or lymphomas, and with disease that is 
either refractory to standard therapy or for whom no standard therapy is available, will be entered 
into this Phase 1, multicenter, open-label, dose-escalation, cohort study. The trial is designed to 
evaluate the safety, tolerability, and DLTs to establish the MAD or MTD and the RP2D of 
sequential escalating doses of Sym023 (study drug), an anti-TIM-3 mAb.    
Secondary objectives include evaluation of immunogenicity, characterization of the PK profile, 
and preliminary assessment of the antineoplastic effects of Sym023 in this patient population. 
Exploratory evaluation of the utility of potential pharmacodynamic and other biomarkers of 
Sym023 will also be undertaken in pre- and post-dosing peripheral blood samples and tumor 
tissue (tumor biopsies optional). Patients will be treated and followed on an outpatient basis 
throughout the trial, unless hospitalization is required for other reasons, or to ensure patient 
safety.   
Dosing Schedule and Treatment Duration 
• No premedication is required prior to receiving the first dose of study drug, except in 
patients with a history of IRRs to mAbs or similar products; in these patients, it is 
recommended that premedication be administered. Thereafter, premedication of 
individuals is at the Investigator’s discretion. Mandatory premedication will be 
implemented for all patients should a pattern begin to emerge of mild-to-moderate study 
drug-related reactions that are amenable to prophylaxis with standard agents.   
• On Day 1 of study, patients will receive study drug administered by 30-minute (+10 min) 
or by 60-minute (+ 10 min) IV infusion (depending on dose and body weight) in a fixed 
50 mL, 100 mL, 250 mL, or 500 mL volume depending on dose and body weight. 
Sym023 will be administered Q2W with administration on Day 1 and Day 15, with each 
dose followed by a 2-week recovery period. This 4-week (28 day) period will be 
considered Cycle 1.  Determinations regarding cohort escalation, DLTs, and MTD will be 
based on the toxicities observed during this initial cycle. Patients must receive their full 
planned doses of study drug, plus complete the designated 2-week follow-up period, to be 
considered evaluable for tolerability, unless dose delay or discontinuation was the result 
of a DLT.  End of Cycle 1 (EOC1) assessments are to be performed no sooner than Cycle 
1/Day 28 (C1/D28) (± 2 days).      
• In all patients entered, a minimum of at least Cycle 1 of study drug will be completed, if 
tolerated, after which in the absence of confirmed progressive disease (PD) or 
unacceptable toxicity a patient may continue to receive additional 4-week cycles of study 
drug at the same dose and infusion duration established for the patient, and on the same 
Q2W schedule, at the Investigator’s discretion and provided specified retreatment criteria 
have been met. Retreatment cycles may continue for up to 12 months at which time plans 
for continued therapy will be discussed by the Medical Monitor(s) and Investigator. 
Patients who stop therapy with an ongoing OR or prolonged SD may be retreated in the 
event of relapse, if the trial is still open. Confirmed PD as defined by response criteria 
(RECIST v1.1, iRECIST, RECIL 2017) at any point in the study will necessitate 
withdrawal of the patient from further participation so that alternative management of 
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Doses to be Evaluated 
At study entry, patients will be sequentially assigned to fill escalating dose cohorts of Sym023 
beginning at the dose of 0.03 mg/kg, with potential doses 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3.0 
mg/kg, 10 mg/kg, and 20.0 mg/kg to follow. These doses will be evaluated until the MTD is 
identified, a MAD is reached, or until a RP2D is determined based on clinical data, including 
safety, PK, and pharmacodynamic (e.g., receptor occupancy in peripheral blood) outcomes. The 
MAD, MTD if identified, and the RP2D may not be the same, as the RP2D may be lower.    
Initially, a modified, accelerated-titration, dose-escalation design will be used with entry of 
single patient cohorts for up to 2 dose levels, based on tolerability. Thereafter, a standard 3+3 
dose-escalation design will be used with a target toxicity level of 33.3% or less as determined by 
DLTs. The number of cohorts evaluated and the MAD will depend upon the observed tolerability 
of Sym023 during Cycle 1 of patient treatment; however, the maximum dose to be administered 
in this trial is not to exceed 20 mg/kg. Dose-escalation is shown in Figure 1.   
The Investigator(s) and Sponsor’s Medical Representative(s) as members of a Study Safety 
Team will review clinical and laboratory safety data on an ongoing basis throughout the study 
and make decisions regarding the advisability of continuing accrual to a dose cohort, and/or 
escalating the dose and allowing accrual to a higher dose cohort. Patients will also be monitored 
for evidence of cumulative or delayed toxicities, including the occurrence of delayed immune-
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Figure 1:  Dose-Escalation Schema 
 
Abbreviations (in alphabetical order): AE, adverse event; DLT, dose-limiting toxicity; kg, kilogram; MAD, maximum administered dose; MTD, 
maximum tolerated dose; mg, milligram; N, number; Q2W, dosing every 2 weeks; RP2D, recommended phase 2 dose; SAE, serious adverse 
event.  
Note: 20-48 patients anticipated for dose-escalation. Minimum of 6 patients to be treated at the MAD, MTD and/or RP2D dose; expansion of this 
cohort (or any other) up to 12 patients may be considered to further evaluate tolerability; therefore approximately 20-48 patients to be entered.  
Filling of Cohorts 
In single patient cohorts, dose-escalation and accrual to the next cohort will occur only after the 
patient has completed and tolerated the first dose of Cycle 1, including follow-up until C1/D15 to 
allow for review of clinical and laboratory assessments, and consultation with the Study Safety 
Team.  The DLT evaluation period for single patient cohorts will continue through to the 
EOC1.  Should a patient experience an AE of concern in the latter half of Cycle 1 that would, 
per protocol, result in cohort expansion, protocol rules as outlined herein will be followed. 
Additional patients entered to an expanded single patient cohort will follow rules as outlined 
below for 3+3 patient cohorts. If in the meantime a patient has been entered to receive the next 
higher dose level, that patient will be allowed to continue provided adequate tolerability is being 
demonstrated; however, further enrollment to the higher dose level cohort will be halted. 
In 3+3 patient cohorts, the first patient within a cohort must complete and tolerate the first dose 
of Cycle 1, including follow-up until C1/D15 before entry of the next patient to a cohort (i.e., 2-
week stagger); thereafter patients within a cohort may be added concurrently. Dose-escalation 
and accrual to the next cohort will occur after the minimum number of patients required for 
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cohort, or completed Cycle 1 in a 3+3 patient cohort, and only after acceptable tolerance has 
been demonstrated in at least 1 of 1, 3 of 3, or 5 of 6 patients treated in the current cohort 
(depending on cohort size), and review of the data with the Study Safety Team.   
Should the DLT rate equal or exceed 33.3% in any cohort, the previous lower dose cohort will be 
expanded to 6 patients (if not already accomplished).  Thus, there is potential for expansion of a 
lower dose if an initially identified MTD and/or RP2D is found to exceed tolerability, as well as 
potential to evaluate and expand a previously unplanned intermediate dose between 2 established 
dose levels, if indicated, to more fully characterize safety and tolerability. Once the MTD (or 
maximum dose to be studied) is achieved and/or the RP2D is identified, that cohort may be 
expanded up to 12 patients to more fully evaluate safety and tolerability at that dose level, at the 
Sponsor’s discretion. Should the DLT rate equal or exceed 33.3% in an expanded cohort, it will 
be determined that the dose is not tolerated and exceeds the MTD. If this occurs, the previous 
lower dose cohort or an intermediate dose level may be expanded as above. There will be no 
intrapatient dose-escalation in this trial.  
Study Assessments 
For safety, patients will be monitored throughout the treatment and 1-month follow-up (1M 
FUP) period for evidence of AEs, including changes in clinical status, laboratory data, 
electrocardiogram (ECG) findings, and either multi-gated acquisition (MUGA) scans or 
echocardiograms (ECHO) in patients with a history of congestive heart failure (CHF). Patients 
will be evaluated for evidence of immune-mediated toxicities. Patients will also be evaluated for 
evidence of antibody formation to study drug. Patients experiencing a DLT regarded as possibly-
, probably-, or related to study drug at any point during treatment will be discontinued from 
study treatment, without exception. Patients may not be retreated following the occurrence of a 
DLT. Only DLTs occurring during Cycle 1 will be used to make determinations regarding dose-
escalation and tolerability.   
 
The overall trial plan is introduced in Table 1. 
 
 
 
 


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Table 1:  Overall Trial Plan 
Screening Period 
Screening 
• 
Written informed consent 
• 
Disease assessment and eligibility confirmation (within 28 days [+2 days] prior to 1st dose) 
• 
Safety screening and eligibility confirmation (within 14 days prior to 1st dose unless otherwise 
stipulated) 
• 
Allocated dose of study drug dependent upon cohort assignment; to be confirmed on Screening and 
Allocation Form 
Treatment Period 
Treatment  
• 
C1/D1 initial dose of study drug  
• 
Continued dosing once Q2W  
• 
28-day cycles until confirmed PD, unacceptable toxicity, or other discontinuation criterion is met 
for up to 12 months at which time plans for continued therapy to be discussed by the Medical 
Monitor(s) and Investigator.  Patients who stop therapy with an ongoing OR or prolonged SD may 
be retreated in the event of relapse, if the trial is still open. 
• 
EOT visit within approximately 7-10 days following treatment discontinuation, or before initiation 
of a new treatment, whichever occurs first 
• 
1M FUP visit 30 days (+7 days) following last dose*   
*Completion of the 1M FUP visit will be considered the end of the treatment period   
Follow-up Period 
Post-Treatment 
Follow-up  
• 
Safety FUP if an observed non-immune-mediated toxicity thought to be related to study drug has 
not resolved by the 1M FUP evaluation (2 and 4 months following last study drug dose) 
• 
Safety FUP surveillance to assess for delayed onset immune-mediated toxicity (Q2M for up to 6 
months following last study drug dose) 
• 
Safety FUP for ongoing at the 1M FUP, and for delayed onset, immune-mediated toxicity (Q2M 
for up to 2 years following last study drug dose)  
• 
Response FUP following discontinuation for reasons other than confirmed PD until the end of trial 
(Q2M until PD or initiation of another therapy) 
*Completion of all indicated follow-up will be considered the EOS 
Abbreviations (in alphabetical order): 1M FUP, 1-month follow-up; C1/D1, Cycle1/Day1; EOS, end of study; EOT, end of treatment; FUP, 
follow-up; PD, progressive disease; Q2M, every 2 months; Q2W, every 2 weeks 
 


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4 PATIENT NUMBER AND SELECTION CRITERIA 
4.1 
Number of Patients 
4.1.1 
Investigational Sites 
This is a multicenter trial. It is anticipated that approximately 2-4 investigational sites in North 
America may participate based on accrual. 
4.1.2 
Number of Patients  
Considerations for estimating the number of patients to be entered are as follows: 
• Approximately 20-48 patients in escalating dose cohorts 
o Minimum of 1 patient per cohort for up to 2 dose cohorts 
o Minimum of 3 patients per dose cohort thereafter 
o Assume approximately 7 dose cohorts to be evaluated to establish the MTD 
and/or RP2D dose 
o Expansion of any cohort to 6 patients in the event of a Cycle 1 DLT in any of the 
initial 1 to 3 patients  
o Minimum of 6 patients to be treated at the MTD and/or RP2D dose; expansion of 
this cohort (or any other) up to 12 patients may be considered to further evaluate 
tolerability  
In addition, there is potential for entry of additional patients to: 
• Ensure sufficient evaluable patients by adding an additional patient to a cohort (e.g., 
increase a 1-patient cohort to 2 patients, a 3-patient cohort to 4 patients, or a 6-patient 
cohort to 7 patients)   
Note:   Should this action be taken, cohort tolerability assessment and subsequent dose-escalation will 
occur when the minimum number of patients required to evaluate tolerability have completed 
Cycle 1. However, if any additional patient experiences an event that would, per protocol, result in 
either cohort expansion or the halting of dose-escalation, protocol rules as outlined herein will be 
followed (Section 6.6.1). 
• Expand a lower dose cohort(s) if an initially identified MTD and/or RP2D is 
subsequently determined to be not tolerated either with single or repeated cycles of 
therapy  
• Add and evaluate a previously unplanned intermediate dose level(s) to further 
characterize safety and tolerability, if indicated (inclusion of a dose higher than those 
listed would require a protocol amendment) 
Note: 
This action would be taken in the event of an unacceptably high frequency of toxicities observed 
in patients treated at one dose considered to be in marked contrast to the tolerability noted at the 
preceding dose level, or if after review of study data, a more gradual dose-escalation appears 
warranted. 
Expanded accrual in any cohort will take place at the Sponsor’s discretion, after discussion with 
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4.2 
Criteria for Inclusion 
Patients must meet all the following criteria to be eligible for participation in the trial: 
1. Male or female patients, ≥ 18 years of age at the time of obtaining informed consent 
2. Patients with a documented (histologically- or cytologically-proven) solid tumor 
malignancy that is locally advanced or metastatic; patients with documented lymphomas   
3. Patients with a malignancy (solid tumor or lymphoma) that is currently not amenable to 
surgical intervention due to either medical contraindications or non-resectability of the 
tumor  
4. Patients refractory to or intolerant of existing therapy(ies) known to provide clinical 
benefit.   
Note:  Patients may have received and failed prior therapy with a PD-1/PD-L1 inhibitor and be considered 
eligible for this trial.  
5. Patients with measurable or non-measurable disease according to RECIST v1.1 or RECIL 
2017 (Appendix 5 and Appendix 7, respectively)   
6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
of 0 or 1 (or equivalent Karnofsky PS; Appendix 1), and anticipated life expectancy of ≥ 
3 months 
7. Patients, both male and female, who are either not of childbearing potential or who agree 
to use a highly effective method of contraception during the study beginning within 2 
weeks prior to the first dose and continuing until 6 months after the last dose of study 
drug.   
Note: 
Women are considered of childbearing potential unless they have undergone hysterectomy and/or 
bilateral tubal ligation or oophorectomy, or have been postmenopausal for at least one year. 
Postmenopausal status in non-surgerized females under 55 years of age should be confirmed with 
a serum follicle-stimulating hormone (FSH) level within laboratory reference range for 
postmenopausal women.  
A highly effective method of contraception is defined as non-hormonal contraception equivalent to 
a double-barrier method (includes a single-barrier method in combination with a spermicide) or 
intrauterine device (Section 11.1).  
Women of childbearing potential (WOCBP) must have a negative pregnancy test, serum at 
screening, serum or urine thereafter; negative test must be confirmed within ≤ 2 working days 
prior to administration of the first dose of study drug.   
8. Patients with the ability to understand and give written informed consent for participation 
in this trial, including all evaluations and procedures as specified by this protocol 
Note: 
Informed consent must be obtained prior to patient screening, and before any evaluations or 
procedures specifically related to this study are performed. 
4.3 
Criteria for Exclusion 
Patients meeting any of the following criteria are ineligible for participation in the trial.  


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4.3.1 
Patients to be Excluded  
1. Women who are pregnant or lactating or intending to become pregnant before, during, or 
within 6 months after the last dose of study drug. WOCBP, and fertile men with 
WOCBP-partner(s) not using and not willing to use a highly effective method of 
contraception.  
Note:  
WOCBP includes any female who has experienced menarche and who has not undergone surgical 
sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or is not 
postmenopausal.  Post-menopause is defined as: 1) amenorrhea for > 12 months with no other 
cause, or 2) irregular menstrual periods, on hormone replacement therapy (HRT), with a 
documented FSH level > 35 mIU/mL.  
WOCBP and fertile men will be informed as to the potential risk of procreation while participating 
in this trial. A pregnancy test will be performed, and the results reviewed, on each premenopausal 
WOCBP prior to first study drug administration. A negative pregnancy test performed within < 2 
working days prior to first study drug administration must be documented in the patient’s case 
report form (CRF) (Section 11.1). 
2. Patients with central nervous system (CNS) malignancies; patients with known, untreated 
CNS or leptomeningeal metastases, or spinal cord compression, patients with any of the 
above not controlled by prior surgery or radiotherapy, or patients with symptoms 
suggesting CNS involvement for which treatment is required  
Note: 
Patients with treated CNS metastases will be eligible if they are asymptomatic, do not require 
corticosteroids, and have confirmation of at least stable brain disease status as assessed by 2 
imaging studies performed ≥ 4 weeks apart with the most recent performed within 4 weeks prior to 
first trial drug administration. Prophylactic anticonvulsant medications are allowed.   
Patients with newly identified CNS disease during study treatment will be considered to have 
disease progression and will be discontinued from study to allow for appropriate management. 
3. Patients with hematologic malignancies other than lymphomas   
4. Patients with any of the following hematologic abnormalities at baseline*:   
• Hemoglobin < 9.0 g/dL 
• Absolute neutrophil count (ANC) < 1,000 per mm3 
• Platelet count < 75,000 per mm3 
Note: 
Patients may have received a blood/blood product transfusion prior to study, if clinically 
warranted.   
*Throughout this protocol “baseline” is defined as the last available observation prior to the first 
administration of study drug on C1/D1. 
5. Patients with any of the following serum chemistry abnormalities at baseline: 
• Total bilirubin > 1.5 × the upper limit of normal (ULN) for the institution*  
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the 
ULN for the institution (> 5 × ULN if due to hepatic involvement by tumor)  
• Serum creatinine > 1.5 × ULN for the institution  


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*Patients with evidence of Gilbert’s Syndrome as the etiology of elevated total bilirubin will be eligible, 
provided all other eligibility criteria are met. 
6. Patients with any of the following coagulation parameter abnormalities at baseline 
(unless on a stable dose of anticoagulant therapy for a prior thrombotic event, as 
determined by the Investigator): 
• Prothrombin time (PT) (or international normalized ratio [INR]) > 1.5 × ULN for 
the institution (> 3× ULN for the institution if anticoagulated)  
• Partial thromboplastin time (PTT) (or activated partial thromboplastin time 
[aPTT]) > 1.5 × ULN for the institution (> 3× ULN for the institution if 
anticoagulated)  
7. Patients with: 
• Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary 
embolism (PE), within 4 weeks prior to first study drug administration, unless 
adequately treated and considered by the Investigator to be stable 
• Active uncontrolled bleeding or a known bleeding diathesis  
8. Patients with a clinically significant (CS) cardiovascular disease or condition, including: 
• Need for antiarrhythmic medical therapy for a ventricular arrhythmia or other 
uncontrolled arrhythmia (patients with controlled atrial fibrillation (heart rate 
[HR] < 90) for > 30 days prior to study entry are eligible) 
• Severe conduction disturbance (e.g., 3rd degree heart block) 
• HR-corrected QT interval (QTc interval) ≥ 480 milliseconds (msec)  
• Uncontrolled hypertension (per the Investigator’s discretion) 
• History of myocarditis  
• Left ventricular ejection fraction (LVEF)* known to be below the lower limit of 
normal (LLN) for the center, or < 50% by MUGA scan or ECHO if no LLN is 
defined by the site 
• CHF currently requiring therapy 
• Class III or IV cardiovascular disease according to the New York Heart 
Association (NYHA) Functional Classification (Appendix 2) 
• History of acute coronary syndromes (including myocardial infarction [MI] and 
unstable angina), coronary angioplasty, stenting, or bypass within 6 months prior to 
first study drug administration 
*Assessment of LVEF will not be performed routinely in all patients.  Patients with a history of CHF 
will have either a MUGA scan or ECHO at Screening. If LLN is not defined for a given institution, 
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9. Patients with a significant ocular disease or condition, including history of an 
autoimmune or inflammatory disorder, e.g., episcleritis, uveitis, iritis  
Note:   Patients with a history of dry eye for reasons other than an autoimmune disease or condition may be 
included if adequately treated. Patients with non-significant, non-inflammatory disorders (e.g., 
cataracts, glaucoma) will be allowed.   
10. Patients with a significant pulmonary disease or condition, including: 
• History of interstitial lung disease (ILD), pulmonary fibrosis 
• History of pulmonary inflammatory disease, interstitial or other pneumonitis*, 
acute respiratory distress syndrome (ARDS) 
*Patients with prior evidence of Grade 1 pneumonitis will be eligible provided they were 
asymptomatic and did not require treatment and provided pneumonitis has resolved prior to entry 
to this trial. 
11. Patients with a current or recent (within 6 months) significant gastrointestinal (GI) 
disease or condition, including: 
• History of inflammatory bowel disease 
• Diarrhea ≥ Grade 2 within 2 weeks prior to first study drug administration 
Note:  
Patients with recent Grade 2 diarrhea secondary to administration of oral contrast are allowed, 
provided symptoms have resolved prior to first study drug administration 
12. Patients with an active, known or suspected autoimmune disease, or a documented 
history of autoimmune disease or syndrome, requiring systemic steroids or other 
immunosuppressive medications  
Note:     Exceptions permitted include: type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders such as vitiligo, psoriasis or alopecia not requiring systemic treatment, 
conditions not expected to recur in the absence of an external trigger. 
13. Patients with a history of organ transplantation (e.g., stem cell or solid organ transplant) 
14. Patients with a known or suspected hypersensitivity to any of the excipients of 
formulated study drug 
15. Patients with a history of significant toxicities associated with previous administration of 
immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy    
16. Patients with unresolved > Grade 1 toxicity* associated with any prior antineoplastic 
therapy except for persistent Grade 2 alopecia, peripheral neuropathy, decreased 
hemoglobin, lymphopenia, hypomagnesemia, and/or end-organ failure being adequately 
managed by hormone replacement therapy 
*Toxicity assessments based on Common Terminology Criteria for Adverse Events (Version 5.0) (CTCAE 
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17. Patients with inadequate recovery from any prior surgical procedure, or patients having 
undergone any major surgical procedure within 4 weeks prior to first study drug 
administration  
Note:  
Patients having undergone recent placement of a central venous access device will be considered 
eligible for enrollment.  
18. Patients who are known or suspected drug or alcohol abusers where compliance with 
protocol requirements may be a concern   
19. Patients with a known history of human immunodeficiency virus (HIV) or known active 
infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)   
20. Patients with any other serious/active/uncontrolled infection, any infection requiring 
parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to first study 
drug administration  
21. Patients with any other serious, life-threatening, or unstable pre-existing medical 
condition (aside from the underlying malignancy), including significant organ system 
dysfunction, or CS laboratory abnormality(ies), which, in the opinion of the Investigator, 
would either compromise the patient’s safety or interfere with obtaining informed 
consent, compliance with study procedures, or evaluation of the safety of the study drug  
22. Patients with a psychiatric disorder or altered mental status that would preclude 
understanding of the informed consent process and/or completion of the necessary study-
related evaluations   
23. Patients with the inability or with foreseeable incapacity, in the opinion of the 
Investigator, to comply with the protocol requirements 
4.3.2 
Drugs and Other Treatments to be Excluded  
1. Other inhibitors of TIM-3 (e.g., mAbs) 
2. Any antineoplastic agent for the primary malignancy (standard or investigational) without 
delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest, prior to first 
administration of study drug and during study, except for:  
• Nitrosoureas and mitomycin C within 6 weeks prior to first study drug 
administration and during study 
Note:  Patients may have received and failed prior therapy with a PD-1/PD-L1 inhibitor and may still be 
considered eligible for this trial. 
3. Any other investigational treatments within 4 weeks prior to and during study. This 
includes participation in any medical device or other therapeutic intervention clinical 
trials.    
4. Radiotherapy:  
• For target lesions within 4 weeks prior to first administration of study drug unless 
disease progression has been documented in the lesion following treatment, and 
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• For non-target lesions within 1 week prior to first administration of study drug  
Note:  Palliative (limited-field) radiotherapy for management of pain associated with bone 
metastases present at baseline is permitted during study.  Patients with suspected new bone 
lesions requiring pain management should be treated and evaluated for potential disease 
progression. 
5. Use of live vaccines against infectious diseases (e.g., varicella) 4 weeks prior to first 
study drug administration and during study  
6. Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent) 
within 2 weeks prior to first study drug administration and during study. The following 
therapies are allowed: 
• Hormonal therapy for appetite stimulation (e.g., Megace) 
• Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
• Hormone replacement therapy at standard doses for end-organ failure 
• Stable hormonal therapy for prostate carcinoma* 
• Stable hormonal therapy for ovarian suppression, hormonal contraceptive therapy, 
or post-menopausal HRT* 
• Neuroendocrine tumor patients: stable hormonal therapy with a somatostatin 
analog (SSA)** 
• Steroid therapy for contrast reaction prophylaxis 
• Intra-articular steroid injections 
• Low-dose maintenance steroid therapy for other conditions (e.g., asthma 
exacerbation, stable steroid therapy [excluding tapering dose of steroids] for brain 
edema/metastases/radiation) 
• Higher dose steroid therapy for treatment of an acute intercurrent illness (e.g., 
immune-related AEs or other adverse conditions) in patients with stable disease or 
an ongoing response.  In such situations, study drug treatment should be 
interrupted for the duration of immunosuppressive therapy. 
*Prior or concomitant therapies are permitted; however, patients must have been on a stable dose for 
at least 6 months prior to study start, and if continuing must remain on the stable dose while receiving 
study treatment (i.e., such treatment will not be considered as systemic hormonal therapy for the 
purpose of study eligibility). 
** Patients with metastatic low-grade neuroendocrine tumors (carcinoid tumors) are permitted to 
remain on concomitant SSA therapy; however, patients must have been on a stable dose for at least 2 
months (8 weeks) prior to study start and progressed on that dose, and if continuing, must remain on 
the stable dose while receiving study treatment (i.e., such treatment will not be considered as systemic 
hormonal therapy for the purpose of study eligibility). 
7. Prophylactic use of hematopoietic growth factors within 1 week prior to first study drug 
administration and during Cycle 1 of study; thereafter prophylactic use of growth factors 
is allowed as clinically indicated   
Note: 
Interventional/therapeutic use of growth factors is allowed at any time during study, including 
during Cycle 1, if deemed necessary by the Investigator.  Growth factor use must be consistent 
with product package insert instructions. Transfusions are permitted as needed. 
 


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Questions regarding patient eligibility must be addressed and resolved by the Investigator in 
consultation with the Sponsor's Medical Monitor(s) prior to enrollment. 




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5.4 
Labeling of IMP 
Vials of study drug will be open-label; label text will be in accordance with applicable local 
regulatory requirements. Each vial will be uniquely numbered for allocation, dispensing, and 
traceability purposes.    
5.5 
Packaging of IMP 
Study drug will be packed in cartons containing multiple vials. The vial number range in each 
carton will be detailed on the carton label.   
5.6 
Administration of IMP 
Study drug will be administered by IV infusion via an indwelling catheter. An appropriate dose, 
based on the patient’s cohort assignment, diluted to the total volume specified with 0.9% sodium 
chloride (NaCl) for IV infusion will be administered initially over:  
• Approximately 30 minutes (+10 minutes) for infusion volumes ≤ 250 mL 
• Approximately 60 minutes (+10 minutes) for infusion volumes of 500 mL  
Dosing will be once every 2 weeks (Q2W; 4 weeks [28 days] equals 1 dosing cycle).   
5.7 
Dose Calculation 
The Investigator (or designee) will be responsible for calculating the amount of study drug and 
the appropriate dose to dispense to the patient as determined by the patient’s dose cohort 
assignment.   
The dose level will be multiplied by the patient's weight in kilograms to arrive at the total dose to 
be delivered. In situations where this calculation results in a value with an unwieldy number of 
decimal places, it is permissible to round the value to the nearest "tenth". As a convention, values 
> 5 should be "rounded" to the next higher number.  
Dose adjustments should be made in the event of noted weight change (± 10%; less at the site’s 
discretion or if required by institution procedures) at visits that require weight measurement. 
Adjustments may be made more frequently at the site's discretion. 
5.8 
Dose Preparation  
The designated dose of study drug must be prepared by the study pharmacist (or designee) and 
should be administered by the study staff as soon as possible following preparation, within 8 
hours, and considering:  
• The total volume of study drug to be delivered will be withdrawn from the study drug 
vial(s) and added to a prefilled IV bag containing 0.9% NaCl for IV infusion (prior to 
adding the study drug and an appropriate volume of NaCl solution is removed, such that 
the final volume to be infused equals:   
o 50 mL for doses < 1 mg/kg  
o 100 mL for doses ≥ 1 mg/kg to ≤ 3 mg/kg  
o 100 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with body weight ≤ 80 
kg 


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o 250 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with body weight > 80 
kg 
o 250 mL for doses > 10 mg/kg for patients with body weight ≤ 100 kg 
o 500 mL for doses > 10 mg/kg for patients with body weight > 100 kg  
Note:  In a case where the amount of IMP is ≥ 40% of the total infusion volume, a larger IV solution 
bag should be used.   
• The IV bag containing the diluted study drug solution to be administered should be gently 
inverted to ensure that the material is well mixed.   
• Infusion sets must contain a 0.22 micron in-line filter.   
5.9 
Accountability  
The Investigator acknowledges that study drug supplies are investigational and, as such, must be 
used strictly in accordance with the protocol and only under the supervision of the Principal 
Investigator. No study drug will be sent to the site until all required regulatory documents, 
including Institutional Review Board (IRB) or Ethics Committee (EC) approval, are received by 
the Sponsor or its designee. 
The Investigator and site staff are responsible for maintaining an accurate inventory and 
accounting of study drug. Receipt, use, and destruction of study drug will be recorded on the 
dispensing log in use.   
5.10 
Disposition of Used IMP  
Once study drug is prepared for delivery and administered, the health care professional will 
maintain an inventory of all open/used vials of study drug. Such residual supplies may be 
destroyed in an appropriate manner according to institutional policy.   
Note: 
No other use of study drug intended for use in this trial is authorized by the Sponsor. The Investigator 
(or designee) will be responsible for the appropriate handling and disposition of residual study drug in 
partially used vials.   
 
5.11 
Unused IMP  
Unused study materials MUST be returned to the Sponsor (or designee) upon expiry or at the 
conclusion of the site’s participation in the trial, unless otherwise authorized in writing. 
5.12 
Destruction of IMP 
No unused IMP may be destroyed or discarded at the site without the written authorization of the 
Sponsor (or designee). The destruction of study drug materials must be carefully documented per 
instructions outlined in the IMP Manual. Disposition records must be available for review by a 
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6 EXPERIMENTAL PLAN 
6.1 
Design Elements 
• Open-label, uncontrolled, non-randomized 
• Escalating doses of study drug in sequential patient cohorts 
• Enrollment staggered between first and second patient in each new higher 3-patient dose 
cohort to allow for initial safety observations 
6.2 
Projected Recruitment Period and Duration of this Trial 
It is anticipated that enrollment to this study will be completed in approximately 12 months.  
• Anticipated date of enrollment of first patient: Q2 2018 
• Anticipated date of enrollment of last patient: Q3 2019 
• End of Trial (i.e., data cut-off for primary analysis):  Will be reached 1 month (30 + 7 
days) after all patients have discontinued trial treatment, or 6 months after the last patient 
has started trial treatment, whichever occurs earlier, at which point the trial objectives 
will be considered to have been met.     
• Patients still in treatment will be given the opportunity to continue receiving study drug.  
In such an event, while the Sponsor still needs to collect certain safety-related data to 
meet its regulatory obligations (AEs, SAEs, study drug dosing, reason for 
discontinuation, etc.), the Sponsor may elect to reduce non-safety-related protocol-
stipulated assessments, and/or transition patients to an extension/rollover protocol 
6.3 
Cohort Management 
For the purposes of this study, "enrollment" is defined as patient registration to participate in 
this trial; at that time, the patient's study identification code and dose cohort will be assigned. 
6.3.1 
Patient Screening and Dose Cohort Assignment 
Once a patient has given written informed consent, screening assessments will be conducted, and 
if the patient is identified as meeting the study eligibility criteria, the Investigator (or designee) 
will contact the Sponsor’s representative to authorize enrollment of the patient into the trial. 
Patients will be enrolled into the study in the order of confirmation of their eligibility, and 
assigned to a cohort on a “first-come-first-served” basis.   
6.3.1.1 
Screening of Potential Patients 
All screening activities must be performed within 14 days prior to the first day of dosing 
(C1/D1), unless otherwise specified.   
The Sponsor (or designee) will be made aware of potential patients for enrollment to track such 
study-related activities.   
Patients who sign informed consent and are ultimately deemed to be screen failures will be 
followed for the occurrence of SAEs/AEs during the screening process until such time that it is 
determined that they will not be participating in this trial. 


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6.3.1.2 
Submission of Patient Enrollment Documentation 
Once eligibility has been confirmed in accordance with the protocol-stipulated inclusion and 
exclusion criteria, patient enrollment information must be submitted to the Sponsor (or designee) 
via a Patient Screening and Allocation Form signed by the Principal Investigator (or designee). 
This information will serve to confirm patient eligibility and initiate the enrollment process. The 
following information must be provided by the site:   
• Patient gender  
• Date of birth (or age), as allowed by local regulatory requirements 
• Date written informed consent was obtained 
• Underlying diagnosis 
• Confirmation of compliance with all inclusion/exclusion criteria. 
The following information may be requested of the site: 
• Patient weight (for dose calculation) 
• Date of screening 
• Stage of disease and current PS 
• Sites of metastases (if applicable) 
• Brief description of the prior therapy for the primary diagnosis, including dates of 
initiation and discontinuation as well as best response 
• Planned date of first dosing 
The Sponsor (or designee) will review the information provided and by signing the form will 
authorize eligible patients for start of treatment. A copy of the fully executed Patient Screening 
and Allocation Form will be returned to the trial site for archiving. This form will document the 
allocated dose of study drug, and will serve to assign patients to a dose cohort at the time of 
enrollment.   
6.3.1.3 
Patient Identification Code Assignment 
Each patient who completes the study screening assessments and is enrolled for study 
participation will be assigned a unique identification code by the Sponsor (or designee). 
Identification codes will be assigned in chronological order, and will be concatenated to indicate 
relevant study information, including at minimum: the participating trial site and the patient’s 
order of enrollment to the trial. 
6.3.1.4 
Screen Failures 
A patient found not eligible for the trial after giving informed consent will be considered a screen 
failure.  A list of patients failing screening and the reason for ineligibility will be maintained by 
the site on a Patient Screening Log or other similar document.   


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Re-screening of a patient is allowed using the specified criteria and timing, if felt to be justified 
by the Investigator. 
6.3.2 
Cohort Closure 
The Sponsor (or designee) will be in communication with the sites when the target total 
enrollment for a cohort has been attained. Once recruitment to a cohort is completed, accrual to 
the cohort will be closed, and sites will be so notified in writing. Cohorts will remain closed to 
further accrual, unless a decision is later made by the Sponsor (or designee) to further expand 
that cohort, based on protocol-defined criteria. 
6.4 
Requirements for Patient Observation 
Patients will be treated on an outpatient basis, and will be evaluated and discharged from the 
clinic on days of scheduled study visits*, unless hospitalization is required for other reasons or to 
ensure patient safety.   
Study drug must be administered under close supervision of a physician, or other study personnel 
experienced in administration of IV agents, and in an environment where full resuscitation 
facilities are immediately available. IV infusions will be carefully monitored to assess safety and 
tolerability by qualified site medical personnel. Such personnel must be available to evaluate and 
treat any AEs, as well as to evaluate whether continued participation of the patient in the study is 
warranted or advisable. 
• Patients will be carefully observed for a minimum of 2 hours following completion of the 
first administration of study drug (C1/D1) for evidence of any treatment-related AE(s), 
and a minimum of 1 hour following completion of subsequent infusions (C1/D15 and 
onward).   
• At the end of each infusion, the IV line must remain in place during the observation 
period to allow for administration of IV drugs, if necessary.   
Patients will be followed on an outpatient basis during the interval between each scheduled study 
visit.   
*Clinical and laboratory assessments will occur at the frequencies indicated (Section 7).  In the event of an AE, 
assessment frequencies may be increased, as clinically indicated.  
6.5 
Drug Treatment Regimen  
6.5.1 
Study Start Day  
All patients will receive the initial dose of study drug on Day 1 of Cycle 1 (C1/D1).   
On the day of the first scheduled study drug infusion, and prior to the start of infusion (SOI), the 
Investigator must assess whether any changes have occurred in the clinical state of the patient 
since Screening which would exclude the patient from the trial. 
6.5.2 
Patient Availability  
The site should calculate study assessment days as well as sample collection dates and times in 
advance of scheduling a patient’s first day of study drug administration in order to plan 


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accordingly to avoid assessment or collection requirements during non-routine clinic times such 
as weekends, holidays, etc.   
Given the schedule of study drug administration outlined herein, and the PK sampling schedule 
(Section 7.6), patients must be available: 
• Cycle 1: Days 1, 2, 3 (± 1 day); Days 8, 15, and 22 (each ± 2 days); therefore, 
consideration should be given to scheduling Day 1 on a Monday, Tuesday, or 
Wednesday*   
• Cycles thereafter: Day 1 and Day 15 (± 2 days) 
• Patients must also be available at the end of cycles to determine whether continuation to 
the next cycle is feasible based on tolerability, and at the end of even-numbered cycles to 
evaluate disease status. 
*unless the study site has weekend hours of operation 
6.5.3 
Therapy with Study Drug 
Based on their cohort assignment, patients will receive the assigned dose of study drug by the 
route and schedule as described below: 
6.5.3.1 
Doses to be Administered 
6.5.3.1.1 Doses to be Evaluated  
Dose cohorts will be numbered sequentially (i.e., Cohort 1, Cohort 2, etc.). The number of 
cohorts evaluated will depend upon toxicities experienced during Cycle 1.   
Anticipated dose levels include: 
• Dose Level 1:  0.03 mg/kg 
• Dose Level 2:  0.1 mg/kg 
• Dose Level 3:  0.3 mg/kg 
• Dose Level 4:  1.0 mg/kg 
• Dose Level 5: 3.0 mg/kg  
• Dose Level 6: 10 mg/kg 
• Dose Level 7: 20 mg/kg 
6.5.3.1.2 Changes in Dose to be Administered  
Once assigned to a dose cohort, patients will continue to be treated with study drug at that same 
dose level throughout the duration of their time on study.  There will be no intrapatient dose-
escalation.  
Dose adjustments should be made in the event of noted weight change (± 10%; less at the site’s 
discretion or if required by institution procedures) at visits that require weight measurement. 
Adjustments may be made more frequently at the site's discretion.    


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6.5.3.2 
Route of Administration 
Study drug will be administered by the IV route, via indwelling venous access catheter, utilizing 
a controlled infusion device. Infusion sets must contain a 0.22 micron in-line filter. 
The catheter may be placed into a peripheral vein (if accessible); administration via central 
venous catheter or port (if in place) is allowed. 
In those instances when study drug administration is associated with PK sampling, and 
administration is via peripheral IV catheter, infusions will be delivered into the arm contralateral 
to that from which blood samples for PK analysis are being obtained. 
6.5.3.3 
Diluent and Delivery  
Commercially available sterile 0.9% NaCl for IV infusion is to be used as the diluent.  Once 
diluted for IV administration, study drug should be administered within 8 hours. 
6.5.3.4 
Volume of Infusion 
Infusions will be delivered in a final volume of:  
• 50 mL for doses < 1 mg/kg 
• 100 mL for doses ≥ 1 mg/kg to ≤ 3 mg/kg 
• 100 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with body weight ≤ 80 kg 
• 250 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with body weight > 80 kg 
• 250 mL for doses > 10 mg/kg for patients with body weight ≤ 100 kg 
• 500 mL for doses > 10 mg/kg for patients with body weight > 100 kg 
Note:  In a case where the amount of IMP is ≥ 40% of the total infusion volume, a larger IV solution bag should 
be used. 
6.5.3.5 
Duration of Infusion 
Study drug will be administered over: 
• Approximately 30 minutes (+10 minutes) for infusion volumes ≤ 250 mL 
• Approximately 60 minutes (+10 minutes) for infusion volumes of 500 mL 
Administration should be at a constant rate using a programmable volumetric infusion pump to 
ensure accuracy of delivery (as well as integrity of PK sampling). Start and stop times of each 
infusion, and any interruptions in infusion will be recorded on the appropriate page of the 
patient’s CRF. 
Note: 
In the event of a Grade 2 IRR, see Section 8.5.1, Appendix 9 for further instructions. 
Study drug will be administered over a longer period for all patients entered to the trial in the 
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• In the event of a Grade 2 IRR in ≥ two thirds of the patients entered to a cohort, the 
duration of infusion for subsequent patients entered to the trial will be extended by 30 
minutes (or longer, if indicated). 
• In the event of a Grade 3 or greater IRR in any patient within a cohort, the duration of 
infusion for subsequent patients entered to the trial will be extended by 30 minutes (or 
longer, if indicated). Such a case will also be considered to have met the protocol criteria 
for a DLT, thus requiring expansion of the cohort. 
These same criteria will be applied in the event IRRs occur on the extended infusion schedule.  
In such a case, the duration of infusion for subsequent patients entered to the trial will be further 
extended by 30 minutes (or longer, if indicated).  
6.5.3.6 
Schedule  
Study drug is to be administered once Q2W on Day 1 and Day 15 of each cycle (4 weeks [28 
days] equals 1 dosing cycle).   
 
EOC1 assessments are to be performed on C1/D28 (± 2 days). Subsequent cycles may be 
administered Q2W (± 2 days), unless further delay is required to allow for amelioration of 
toxicities (or in the event of scheduling difficulties associated with weekends, holidays, etc.).   
6.5.4 
Premedication  
Since the mechanism of action of the study drug is to stimulate the immune system, 
premedication with agents such as glucocorticoids which are immunosuppressive is to be 
avoided. As a result, no premedication is required to be administered prior to patients receiving 
the first dose of study drug.  
In patients with a history of IRRs to mAbs or similar products, it is recommended that 
premedication be administered. In such cases, patients should be premedicated with a regimen 
that includes acetaminophen as well as an H1 (e.g., diphenhydramine/hydroxyzine) and possibly 
an H2-antagonist (e.g., ranitidine/famotidine).   
Should a patient experience an IRR while on study, guidelines for instituting premedication prior 
to subsequent infusions are provided (Section 8.4.3). Guidelines for the grading and 
management of IRRs of all severities are also provided (Appendix 9). 
6.6 
Cycle 1 
A minimum of 1 cycle of study drug will be administered, if tolerated.  Any delays in dosing and 
the reasons for such delays must be documented. If an AE is the cause for dosing delay, it must 
be detailed on the Adverse Events page of the CRF.   
Determinations regarding cohort escalation and MTD will be based on the toxicities observed 
during this 4-week period (Cycle 1) of treatment, and the occurrence of DLTs* thought to be 
related (i.e., possibly-related, probably-related, or related) to study drug. 


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• Patients completing Cycle 1, and receiving their full planned doses of study drug in the 
absence of a DLT, will be considered to have tolerated the dose level they were assigned 
to receive.   
• Patients will be replaced if they have received < 2 full doses of study drug plus follow-up 
through EOC1 (C1/D28 ± 2 days) for any reason other than a DLT, to ensure MTD 
determination rules can be followed with an adequate number of evaluable patients in any 
dose cohort.   
• All treated patients will be considered in the assessment of safety and tolerability. 
*See Section 6.8.3 and Section 6.9 
6.6.1 
Rules for Dose-Escalation and Cohort Expansion  
Initially, a modified, accelerated-titration, dose-escalation design will be used with entry of 
single patient cohorts for up to 2 dose levels, based on tolerability. 
Thereafter, a standard 3+3 dose-escalation design will be used, with a target toxicity level of 
33.3% or less as determined by DLTs.   
Dose cohorts will be filled sequentially. Up to 6 patients may be treated at each dose level until 
the MTD and/or RP2D is determined. The decision rules for dose-escalation and cohort 
expansion are as follows:  
1. A minimum of 1 patient will be entered into dose Cohorts 1 and 2 ONLY. 
• If during the initial 2 weeks of Cycle 1 no > Grade 2 toxicity considered possibly-
, probably-, or related to study drug is encountered in the patient, dose-escalation 
may continue to the next level when the patient has been followed for safety until 
C1/D15 
• If at any time during Cycle 1, a patient experiences a > Grade 2 toxicity 
considered possibly-, probably-, or related to study drug, the cohort will be 
expanded to 3 patients 
• If during Cycle 1, a patient experiences a DLT considered possibly-, probably-, or 
related to study drug, the cohort will be expanded to 6 patients 
2. Beginning with Cohort 3, or earlier if required by observed toxicity, a minimum of 3 
patients will be entered to each cohort.  
• If during Cycle 1 no DLTs are encountered in any of the first 3 patients, dose-
escalation may continue to the next level when all patients have completed Cycle 
1. 
• If during Cycle 1, any 1 patient experiences a DLT considered possibly-, 
probably-, or related to study drug, the cohort will be expanded to 6 patients. If no 
DLTs are encountered in the additional 3 patients, dose-escalation may continue 
to the next level when all patients have completed and tolerated Cycle 1. 


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• If during Cycle 1, >1 patient experiences a DLT, dose-escalation will STOP.  This 
will indicate that the MTD has been exceeded. 
3. If it is determined that a dose level is not tolerated: 
• The previous lower dose cohort will be expanded to 6 patients (if this has not 
already been accomplished) as a total of 6 patients must be treated before 
establishing a dose as the MTD. 
• There is also the potential to evaluate and expand a previously unplanned 
intermediate dose level between 2 established dose levels to 6 patients to more 
fully characterize tolerability. 
4. The MTD will be the highest dose level of study drug at which no more than 1 of 6 
evaluable patients has had a DLT. 
5. Once the MTD (or maximum dose to be studied) is achieved and/or the RP2D is 
identified, that cohort may be expanded up to 12 patients to more fully evaluate safety 
and tolerability at that dose level at the Sponsor’s discretion. Should the DLT rate equal 
or exceed 33.3% in an expanded cohort, it will be determined that the dose is not 
tolerated. If this occurs, the previous lower dose cohort or an intermediate dose level may 
be expanded as above.  Therefore: 
• There is potential for expansion of a lower dose cohort(s) if an initially identified 
MTD and/or RP2D is subsequently determined not to be tolerated (either with 
single or repeat cycles of therapy), and 
• There is potential to evaluate and expand a previously unplanned intermediate 
dose level(s) between 2 established dose levels to more fully characterize 
tolerability. 
Note: 
Such action would be taken by the Sponsor (or designee) in the event of an unacceptably 
high frequency of toxicities observed in patients treated at one dose level considered to be 
in marked contrast to the tolerability noted in the immediately preceding dose cohort, or if 
after review of study data, a more gradual dose-escalation appears warranted. 
The RP2D may be equal to or lower than the MTD or the MAD. The RP2D will be selected based 
on safety data, as well as available PK, pharmacodynamic/biomarker, and other data, as applicable. 
6.6.2 
Rules for Duration of Exposure Prior to Start of Next Patient and Next Cohort  
Single patient cohorts: Dose-escalation and accrual to the next cohort will occur only after the 
patient has completed and tolerated the first dose of Cycle 1 including follow-up until C1/D15 to 
allow for review of clinical and laboratory assessments, and consultation with the Study Safety 
Team.  The DLT evaluation period for single patient cohorts will continue through to the 
EOC1.  
The following rules apply to single patient cohorts throughout the Cycle 1 DLT evaluation 
period (Cohort 1 and 2 only, receiving treatment at the lowest doses of 0.03 and 0.1 mg/kg, 
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• Should a patient experience an AE of concern in the latter half of Cycle 1 that would, 
per protocol, result in cohort expansion, protocol rules as outlined herein will be 
followed (Section 6.6.1).  For example, in the event of a ≥ Grade 2 toxicity, the 
cohort (and all cohorts thereafter) will be expanded to 3 patients; in the event of a 
DLT the cohort will be expanded to 6 patients.   
• Additional patients entered to an expanded single patient cohort will follow rules as 
outlined below for 3+3 patient cohorts.  Enrollment will be staggered by at minimum 
2 weeks between the first and second patient, Thereafter, patients within a cohort may 
be added concurrently. 
• If in the meantime, if a patient has been entered to receive the next higher dose level, 
that patient will be allowed to continue provided adequate tolerability is being 
demonstrated; however, further enrollment to the higher dose level cohort will be 
halted until the lower dose level cohort has been fully expanded and evaluated. 
3+3 patient cohorts:  Enrollment will be staggered by 2 weeks between the first and second 
patient in each new higher 3+3 dose level cohort. The first patient within a cohort must complete 
and tolerate the first dose of Cycle 1 including follow-up until C1/D15 to allow for review of 
clinical and laboratory assessments. Thereafter, patients within a cohort may be added 
concurrently. 
All cohorts:  Dose-escalation and accrual to the next cohort will occur only after the minimum 
number of patients required for tolerability assessment in the current cohort have completed until 
C1/D15 in a single patient cohort, or completed Cycle 1 in a 3+3 patient cohort, and only after 
acceptable tolerance has been demonstrated in at least 1 of 1, 3 of 3, or 5 of 6 patients treated in 
the current cohort (depending on cohort size), and after consultation with the Study Safety Team. 
For all patients, EOC1 assessments are to be performed no sooner than C1/D28 (± 2 days). 
6.6.3 
Rules for Establishing the MTD and/or RP2D 
The MTD will be the highest dose level of study drug at which no more than 1 of 6 evaluable 
patients has had a DLT.   
The MAD, MTD, or a dose lower than the MAD or MTD, will be identified as the RP2D, 
provided a minimum of 6 patients have been treated at that dose, and provided acceptable 
tolerance has been demonstrated in at least 5 of 6 patients treated. The RP2D choice will be 
based on the MTD evaluation as well as other toxicities observed in the study, including 
observations in later cycles of administration of study drug, as well as on PK, 
pharmacodynamics/biomarkers, and/or other data. 
6.6.4 
 Rules for Stopping the Study 
The study will be stopped if the MTD is exceeded at the lowest dose level. 
6.7 
Continued Treatment After Cycle 1 
Upon completion of Cycle 1, in the absence of unacceptable toxicity or documented PD, patients 
may continue to receive additional cycles of study drug, unless further delay is required to allow 
for amelioration of ongoing AEs.   


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Administration of subsequent dosing cycles is allowable at the discretion of the Investigator, 
provided the patient meets the retreatment criteria listed below. Additional cycles should be 
initiated as soon as possible, but not longer than 2 weeks after the completion of the previous 
cycle, if feasible. 
6.7.1 
Retreatment Guidelines 
Clinical judgment will be used when determining whether it is advisable to continue a patient on 
to the next cycle(s) of dosing. To start any new cycle, a patient must meet the following criteria: 
• ANC ≥ 1,000 per mm3 
• Platelets ≥ 75,000 per mm3 
• Any ongoing study drug-related AE should NOT meet the criteria for DLT 
• Any ongoing study drug-related AE should have either ameliorated to ≤ Grade 1 severity, 
returned to baseline status, or resolved, with the exceptions of: 
o Grade 2 alopecia,  
o Grade 2 clinical events that are being adequately controlled with best supportive 
care (e.g., fatigue, nausea, vomiting, diarrhea), and  
o Grade 2 asymptomatic laboratory abnormalities that are considered clinically 
insignificant, clinically uncomplicated, and/or that are resolving spontaneously or 
with conventional medical interventions. 
• Dosing must be delayed in patients with evidence of Grade 2 immune-mediated 
toxicities, including (Appendix 10):  
o Pneumonitis, myocarditis, adrenal insufficiency, encephalitis, nephritis/renal 
dysfunction (serum creatinine elevation), episcleritis/uveitis/iritis 
o Colitis, hypophysitis, hyperglycemia, inflammatory arthritis, myositis, rash 
o Hepatitis (transaminitis, total bilirubin elevation) 
Note:  Patients may receive standard doses of replacement hormonal therapy for adrenal insufficiency, 
hypothyroidism, or other endocrine end-organ failure, and may resume study drug once considered by 
the Investigator to be stable on such therapy provided a DLT criterion has not been met. 
Should above criteria not be met, dosing must be delayed until further evaluation is completed 
and it is determined that the patient is eligible for continued treatment.  
6.7.2 
Doses and Regimens 
For a given patient, subsequent cycles of therapy with study drug will be administered at the 
same dose level* and infusion duration established for the patient, and on the same Q2W 
schedule. 
* Unless a dose adjustment is necessary due to ± 10% fluctuation in patient weight (less at the site’s discretion or if 
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6.7.3 
Evaluation Schedules 
The same evaluations required during Cycle 1 of the study will be conducted during subsequent 
cycles, at the frequencies indicated (Section 7). 
6.7.4 
Duration of Treatment 
Additional cycles of study drug may continue to be administered if tolerated and in the absence 
of documented PD, at the Investigator’s discretion, provided retreatment criteria have been met 
(Section 6.7.1).   
Such extended therapy will continue for a period of up to 12 months after achieving the “best 
response,” at which time the Medical Monitor(s) and Investigator will discuss the advisability of 
continued therapy based upon the patient’s ongoing response status and the degree of 
demonstrated tolerability. Patients who stop therapy with an ongoing OR or prolonged SD may 
be retreated in the event of relapse, if the trial is still open (Section 6.7.6). 
6.7.5 
Continued Treatment after Radiologic Disease Progression 
Immunotherapeutic agents may produce antitumor effects that can manifest as response after 
initial evidence of PD, a phenomenon referred to as “pseudoprogression” (PSPD). 
Patients will be permitted to continue treatment beyond initial RECIST v1.1 (or RECIL 2017) 
defined PD while waiting for confirmation of PD, provided they are clinically stable as defined 
by the following criteria (per iRECIST): 
• Investigator-assessed clinical benefit and absence of rapid disease progression 
• Tolerating study drug 
• Stable PS 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
6.7.6 
Retreatment Following an Objective Response 
Treatment with study drug may be restarted in a patient who previously achieved a documented 
OR or prolonged SD (> 16 weeks) on this study, stopped treatment, and subsequently progresses. 
Such action may be taken at the Investigator’s discretion, following discussion with the Medical 
Monitor(s), provided retreatment criteria are met, no anti-cancer treatment was administered 
since the last dose of study drug, and the trial is still open.   
This option for retreatment does not apply to patients who previously experienced a DLT that 
required permanent discontinuation from study drug (Section 6.8.3, Section 9.1). 
Retreatment with study drug may be initiated at the same dose and infusion duration established 
for that patient during their previous course of treatment, and on the same schedule.  
The same evaluations required during previous treatment will be conducted during subsequent 
cycles, at the frequencies indicated. 
Retreatment cycles of study drug may continue to be administered if tolerated and in the absence 
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6.8 
Adverse Events and Dose-Limiting Toxicities 
6.8.1 
Adverse Event Grading 
For reported AEs, the CTCAE v5.0* will be used to grade the severity or the AE. 
*See < https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm > 
6.8.2 
Management of Dose-Limiting Toxicities and Other Toxicities 
If a significant toxicity thought to be related to study drug is experienced at any point during the 
patient’s participation in the study, the Investigator will determine:   
• Whether that toxicity is dose-limiting (Section 6.8.3), thus requiring discontinuation from 
study treatment, without exception.   
• Whether the toxicity does not meet the protocol definition of DLT, but nevertheless 
warrants dose modification, in which case the Investigator may elect to temporarily delay 
dosing with study drug to allow for amelioration of the toxicity.   
For additional information on toxicity management and dose modification, see Section 8. 
6.8.3 
Definition of Dose-Limiting Toxicity 
Any of the following toxicities occurring during Cycle 1, if judged to be related to study drug 
(i.e., possibly-related, probably-related, or related), will be considered a DLT for the purposes of 
tolerability assessment during this trial.  
1. ≥ Grade 3 evidence of any of the following immune-mediated toxicities: 
• Pneumonitis 
• Myocarditis 
• Adrenal insufficiency 
• Encephalitis 
• Nephritis, renal dysfunction (serum creatinine elevation) 
• Episcleritis, uveitis, or iritis 
2. ≥ Grade 3 evidence of any of the following immune-mediated toxicities: 
• Colitis 
• Hypophysitis, hyperglycemia 
• Inflammatory arthritis 
• Myositis 
• Rash  
3. ≥ Grade 2: 
• Uveitis, eye pain or blurred vision that does not resolve with topical therapy 
within 2 weeks 
• AEs that are prolonged excessively based upon the medical judgment of the 
investigator, and/or lead to permanent discontinuation of the study drug due to 
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• Immune-mediated toxicity that requires use of glucocorticoids at a dose of ≥ 1 
mg/kg/day of prednisone equivalents for treatment of the toxicity 
4. Any confirmed reduction in visual acuity, regardless of grade or duration 
Note:   Noted changes in visual acuity must be reevaluated by an ophthalmologist and confirmed within 48 
hours (if feasible, based on weekends or holidays) of the initial observation; study drug will be held 
pending evaluation by the ophthalmologist.   
Changes in visual acuity assessment, if associated with either an immune-related AE, including but 
not limited to iritis, episcleritis, uveitis, or any other condition that may be considered to be related 
to therapy with study drug will be considered to be a DLT.   
Patients in whom a minor fluctuation in visual acuity is due to another known or recently diagnosed 
underlying condition may continue to be treated once visual acuity fluctuation returns to baseline 
status, but must be reevaluated by an ophthalmologist prior to each cycle and upon the occurrence 
of any subsequent ophthalmologic sign or symptom, including but not limited to recurrent changes 
in visual acuity measurement, in order to reassess for DLT status.  
5. Hepatic-related findings consistent with Hy’s Law criteria: 
• AST and/or ALT elevation > 3 × ULN (or > 3 × baseline if elevated at study entry 
due to hepatic involvement by tumor), with  
• Total bilirubin ≥ 2 × ULN without initial findings of cholestasis (i.e., serum 
alkaline phosphatase [ALP] < 2 × ULN), and 
• No explanation for the above findings such as viral hepatic injury, preexisting or 
acute liver disease, or another drug or condition capable of causing the observed 
liver injury 
6. Any other ≥ Grade 3 non-hematologic toxicity regardless of duration, with the exceptions 
of:  
• Grade 3 fatigue 
• Grade 3 nausea, vomiting, or diarrhea lasting ≤ 2 days with best supportive care  
• Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 days that are not 
clinically complicated, and resolve spontaneously or respond to conventional 
medical interventions  
• Other Grade 3 asymptomatic laboratory abnormalities that are clinically non-
significant in the investigator’s opinion, and that resolve spontaneously or with 
conventional medical interventions 
7. Any Grade 4 non-hematologic laboratory toxicity regardless of duration 
8. Neutropenia that is: 


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• Grade 3 meeting the CTCAE v5.0 criteria for febrile neutropenia (ANC < 1000 
per mm3 and a single temperature > 38.3ºC [101ºF] or sustained temperature > 
38ºC [100.4ºF] for > 1 hour) 
• Grade 4  
9. Thrombocytopenia that is:  
• Grade 3 with CS hemorrhage or requirement for transfusion 
• Grade 4 (platelets < 25,000 per mm3)  
10. Anemia that is Grade 4 and not explained by underlying disease 
11. Any other Grade 4 hematologic toxicity (other than those specifically excluded) lasting > 
5 days 
12. Any death where a relationship to study drug cannot be ruled out 
13. Inability to complete Cycle 1 at the assigned dose (i.e., receipt of < 2 full planned doses 
of study drug plus 2 weeks of follow-up) due to any toxicity 
14. Treatment delays > 2 weeks from the scheduled next dose during Cycle 1 due to any 
toxicity 
Other toxicities may be considered a DLT as determined by the Investigator in conjunction 
with the Study Safety Team. 
The above criteria will be used to make individual patient determinations regarding dose delays 
or discontinuation throughout the course of the trial; however, only those DLTs occurring 
during Cycle 1 will be used to make decisions regarding cohort dose-escalation and 
tolerability.  
Events occurring after Cycle 1 will also be evaluated by the Study Safety Team and taken into 
consideration when deciding upon further doses to be assessed as well as to establish the RP2D. 
6.9 
Definition of Maximum Tolerated Dose 
MTD will be defined as the dose below that which produces, during Cycle 1 of treatment, any of 
the indicated DLTs either in > 1 patient in a 3 to 6 patient cohort, or in ≥ 33.3% of patients in the 
event of an expanded 7 to 12 patient cohort.  
The MTD will not be established until all patients in the cohort under evaluation have either 
completed Cycle 1 or discontinued further participation in the trial due to the occurrence of a 
DLT.   
Previously established tolerability of a dose level will be reevaluated if DLTs thought to be 
possibly-, probably-, or related to study drug are observed in later cycles or in the event of 
expansion of a cohort to > 6 patients. 
6.10 
Review of Safety Data During Study 
Clinical and laboratory safety data will be reviewed on an ongoing basis throughout the study by 
the Investigators and Sponsor’s Representative(s) so that decisions regarding the advisability of 


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continuing accrual to a dose cohort, and/or escalating the dose and allowing accrual to a higher 
dose cohort may be made. In addition, patients will be carefully evaluated for evidence of 
potential cumulative and/or delayed toxicities throughout the duration of their time on study.   
To do so, SAEs, immune-related AEs of significance, AEs resulting in permanent 
discontinuation from study (regardless of seriousness or relationship to study drug), DLTs, IRRs, 
and dosing delays will be promptly reported to the Sponsor (or designee). 
A Study Safety Team will be established and will be comprised of the Investigator(s) and the 
Sponsor’s Medical Representative(s). Biweekly Study Safety Team Teleconferences will be held 
to discuss ongoing patient status and any emerging safety concerns; frequency of teleconferences 
may fluctuate based on accrual and study activity, as indicated (Section 12.1).  
6.11 
Duration of Study Follow-Up 
Upon discontinuation of a patient from further treatment with study drug, every effort will be 
made to conduct follow-up assessments as detailed below.   
For patients continuing to another therapy, the expectation is that Investigators will show due 
diligence in obtaining adequate follow-up for this study, as indicated. In the event of ongoing 
toxicities, Investigators will do their best to continue patient follow-up, based on both patient 
availability and Investigator ability to determine the etiology of noted toxicities within the 
context of initiation of any new therapy (i.e., whether the finding is due to study drug or due to 
the other therapy).   
• End of Treatment (EOT) evaluations will be conducted within approximately 10 days 
following treatment discontinuation, or before initiation of a new treatment, whichever 
occurs first.   
• 1-Month Follow-up (1M FUP) evaluations will be conducted approximately 30 days (+7 
days) following the last dose of study drug.  
Note: 
The 1M FUP evaluation should be conducted ≥ 30 days following the last dose of study drug as all 
patients are to be followed for a minimum of 30 days after study drug discontinuation to monitor 
for the occurrence of suspected AEs that are both serious and unexpected.      
• Long-Term Follow-up (FUP) for Safety:  If an observed toxicity (non-immune-mediated) 
thought to be related to study drug has not resolved by the 1M FUP evaluation, an 
additional FUP AE assessment will be conducted approximately 2 months (may be 
repeated at 4 months if needed) following the last dose of study drug, if feasible, to 
confirm that the event has either resolved, returned to baseline status, or been adequately 
explained and assessed by the Investigator as chronic and/or stable, and that no long-term 
deleterious effects have become evident*      
Since late-occurring immune-mediated toxicities have been reported to occur several 
weeks to months after treatment with other immune checkpoint inhibitors, long-term 
surveillance for such toxicities will be conducted in this study. Patients will be followed 
at approximately 2-month intervals following the last dose of study drug for up to 6 
months to assess for the onset of any post-therapy immune-mediated event thought to be 
related to study drug.* 


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Any patient who develops an immune-mediated toxicity during study, or during the 6-
month post-therapy FUP period, will be followed at approximately 2-month intervals 
following the last dose of study drug for up to 2 years to assess the course of the 
condition and evaluate potential reversibility of the finding.* 
*Investigator discretion may be used with respect to the method of contact for this AE assessment; clinical 
events may be followed in writing or by telephone; an in-person visit will not be required. 
• Long-Term FUP for Response: In the event of an ongoing OR or SD at the EOT, 
response assessment-based imaging studies (as indicated by disease type) will continue to 
be performed every 2 months following the last dose of study drug, until confirmed PD or 
another therapeutic intervention is initiated, so that data may be collected on the duration 
of SD or OR, as well as disease progression*   
*To continue at the intervals specified until disease progression or another therapeutic intervention is 
initiated, or until the end of trial; documentation may be submitted in writing or by e-mail, an in-person 
visit will not be required. 
6.12 
Concurrent Treatments and Supportive Care 
Therapy for other ongoing medical conditions, as well as palliative and supportive care for the 
underlying malignancy will be provided prior to and during this trial, as clinically indicated, and 
in accordance with the standard practices of the institution, except as stipulated by study 
eligibility criteria (Section 4.3.2). 
Other therapies allowed during the conduct of this trial include: 
1. Prophylaxis for IRRs and Study Drug-Related Toxicities: Patients with a history of IRRs 
to mAbs or similar products, and patients who experience IRRs while on study, should 
receive premedication with standard therapies as defined herein prior to each dose of 
study drug to reduce the risk of such events. Patients experiencing other study drug-
related reactions may be premedicated with standard therapies to reduce the potential for 
such reactions in the future (Section 8.4). 
 
2. Treatment of Study Drug-Related AEs or Concurrent Diseases: Clinical judgment should 
be used in the treatment of any treatment-related AEs or concurrent diseases that occurs 
during the study and follow-up period.   
 
3. Blood Products and Growth Factors: Prophylactic hematopoietic growth factors should 
not be administered during Cycle 1 of study; thereafter prophylactic use of growth factors 
is allowed as clinically indicated. Interventional/therapeutic use of growth factors is 
allowed during study, including Cycle 1, if deemed necessary by the Investigator.  
Growth factor use must be consistent with product package insert instructions. 
 
4. Radiotherapy: Radiotherapy for pain control against non-target lesions, provided it does 
not influence BM function.  Such treatment should be discussed with the Sponsor’s 
Medical Monitor(s). 


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5. Bisphosphonates and denosumab: Bisphosphonates and denosumab for bone metastases 
and other skeletal conditions are allowed, provided the patient is on a stable dose for at 
least 2 months prior to study start and remains on the stable dose while receiving study 
treatment. 
 
6. Immunosuppressive or systemic hormonal therapy not exceeding 10 mg daily prednisone 
equivalent, as well as: 
• Hormonal therapy for appetite stimulation (e.g., Megace) 
• Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations 
• Hormone replacement therapy at standard doses for end-organ failure 
• Stable hormonal therapy for prostate carcinoma* 
• Stable hormonal therapy for ovarian suppression, hormonal contraceptive therapy, 
or post-menopausal HRT* 
• Steroid therapy for contrast reaction prophylaxis 
• Intra-articular steroid injections 
• Low-dose maintenance steroid therapy for other conditions (e.g., asthma 
exacerbation, stable steroid therapy [excluding tapering dose of steroids] for brain 
edema/metastases/radiation) 
• Higher dose steroid therapy for treatment of an acute intercurrent illness (e.g., 
immune-related AEs or other adverse conditions) in patients with SD or an 
ongoing response. In such situations study drug treatment should be interrupted 
for the duration of immunosuppressive therapy. 
*Concomitant therapies are permitted; however, patients must have been on a stable dose for at least 6 
months prior to study start, and if continuing must remain on the stable dose while receiving study 
treatment (i.e., such treatment will not be considered as systemic hormonal therapy for the purpose of study 
eligibility). 
Information on all concomitant therapies administered, as well as other interventions or 
procedures occurring during the trial period, must be recorded on the appropriate page of the 
patient’s CRF. 


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7 STUDY ASSESSMENTS   
All patients will be assessed by scheduled clinical, laboratory, and other diagnostic assessments 
throughout the study. All efforts should be made to perform assessments as close as possible to 
the scheduled timepoints. The projection of visit days within each cycle should be made from 
Day 1 of the respective cycle. Visit windows are provided below. Study assessments are to be 
performed as follows: 
• Screening evaluations are to be performed within 14 days prior to first study drug dose, 
unless otherwise specified (for exceptions see Section 7.2.7.6, Section 7.3, Section 7.4).   
• The day of first administration of study drug will be considered Day 1 of study.   
• C1/D3 evaluations may be conducted +1 day. 
• On-study evaluations (including laboratory assessments) are to be performed on or about 
the indicated study day (i.e., ± 2 working days) (a slightly longer allowance for routine 
assessments is permissible in the event of scheduling difficulties associated with 
weekends, holidays, etc.).   
• End of Cycle assessments may be conducted at any time during the week prior to Day 1 
of the next cycle, including on Day 1 of the next cycle, prior to dosing. 
• EOT* evaluations are to be performed within approximately 10 days following treatment 
discontinuation, or before initiation of a new treatment, whichever occurs first.   
• 1M FUP* evaluations are to be performed approximately 30 days (+7 days) following the 
last dose of study drug (i.e., as all patients are to be followed for a minimum of 30 days 
after study drug discontinuation to monitor for the occurrence of AEs). 
Note:  
When a patient discontinues treatment with study drug, for any reason, every effort will be made 
to collect routine EOT evaluations as well as subsequent 1M FUP evaluations, per protocol, until 
all protocol-specified assessments have been conducted.   
If during the study, significant changes from baseline are noted, additional monitoring or on-
study assessments may be undertaken by the Investigator, or requested by the Sponsor (or 
designee), to determine both the relevance of the finding(s) and the duration of the event(s).  
Refer to Appendix 11 and Appendix 12 for the maximum total blood collection volumes and 
the schedule of assessments, respectively. 
7.1 
Consent and Medical History 
7.1.1 
Signing of Informed Consent/Assessment of Eligibility 
• Screening 
Note:  
All patients must sign an IRB/EC-approved informed consent form (ICF) prior to enrollment and prior 
to submitting to any protocol-related procedure, unless such testing was performed previously as part 
of the routine clinical management of the patient. Disease evaluations (e.g., computed tomography 
[CT] scan, magnetic resonance imaging [MRI]) performed as part of standard of care and obtained 
prior to patient consent for this trial may be allowed as screening evaluations if conducted within 28 


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days (+2) prior to the first study drug dose. A copy of the fully executed ICF will be given to the 
patient.   
7.1.2 
Demography  
(To include date of birth, sex, race, and ethnicity) 
• Screening 
7.1.3 
Past Medical History  
(To include prior and ongoing medical illnesses and conditions, prior surgical procedures 
[not related to the primary diagnosis]) 
• Screening 
• C1/D1 (prior to dosing)*  
* Need not be assessed prior to Cycle 1 if ≤ 7 days since screening 
7.1.4 
History of the Primary Malignancy  
(To include details of the primary malignancy, including:  diagnosis and histological/ 
cytological classification; date of initial diagnosis; date metastatic disease is identified; 
stage of disease at entry; current sites of metastases; prior surgical procedures for the 
malignancy and dates; prior antineoplastic therapy; prior radiation therapy; dates of 
treatments, numbers of cycles, and best response to each therapy; and date of most recent 
disease progression) 
• Screening 
7.2 
Safety Assessments (1) 
(To be performed within 14 days prior to first dose of study drug unless otherwise specified) 
7.2.1 
Medication and Procedure Surveys  
(To include all medications taken other than study drug and all procedures performed during 
trial. For medications: Include name, indication for use, route of administration, start and 
stop dates or if ongoing at 1M FUP Visit. For procedures: Include date and reason for 
procedure. Corresponding illness or condition must appear on the Medical History or 
Adverse Event pages of the CRF, as appropriate) 
• Prior Medication/Procedure Surveys 
o Screening (to assess eligibility) 
o For 14 days prior to first study drug dose  
• Concomitant Medication/Procedure Surveys  
o Throughout the study 
o For 30 days following last study drug dose 
7.2.2 
Adverse Event Reporting  
• Starting from signing of informed consent*  


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• Throughout the study 
• For 30 days following last study drug dose  
• Long-Term FUP for Safety 
o For AEs (non-immune-mediated) ongoing at the 1M FUP 
 For 2 to 4 months following last study drug dose, if events related to study drug 
persist**#   
o For immune-mediated toxicity surveillance following 1M FUP 
 For up to 6 months (at 2-month intervals) following the last study drug dose, to 
assess for delayed onset of immune-related toxicity***# 
o For immune-mediated toxicity ongoing at the 1M FUP, and for delayed onset 
immune-mediated toxicity noted in the initial 6-month FUP period 
 For up to 2 years (at 2-month intervals) following the last study drug dose***#   
• As clinically indicated 
*To detail any symptoms that may be present prior to first study drug dose.  Patients who sign informed 
consent and are subsequently deemed to be screen failures will be followed for the occurrence of SAEs/AEs 
until it is determined that they will not be participating in the trial. 
**To confirm that events have resolved, returned to baseline status, or been adequately explained.   
*** Patients will be followed to assess for the onset of any post-therapy immune-mediated event thought to be 
related to study drug. Any patient who develops an immune-mediated toxicity during study, or during the 6-
month post-therapy FUP period, will be followed to assess the course of the disease and evaluate potential 
reversibility of the finding.     
#Investigator discretion may be used with respect to the method of contact for this AE assessment; clinical 
events may be followed in writing or by telephone; an in-person visit will not be required. 
7.2.3 
Dose-Limiting Toxicity Assessment 
(To include details about AEs meeting DLT criteria; Section 6.8.3) 
• Starting from first dose of study drug (C1/D1) 
• Through EOC1 (C1/D28 ± 2 days) 
7.2.4 
Performance Status Evaluation 
(To be assessed by ECOG score; Appendix 1) 
• Screening 
• Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
• Each cycle thereafter 
o Day 1 (prior to dosing) 
• EOT  
• 1M FUP 
• As clinically indicated 
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7.2.5 
Vital Signs  
(Vital signs [VS] to include temperature, pulse, respiratory rate, blood pressure [BP], and 
oxygen saturation by pulse oximetry) 
• Screening 
• Cycle 1 
o Day 1 
 Prior to SOI 
 End of infusion (EOI) (± 10 min)  
 2, 4 hours after EOI (± 30 min) 
 8 hours* after EOI (± 90 min)  
o Day 2 (24 hours after EOI) (± 6 hours) 
o Day 3 (48 hours after EOI) (- 12 to + 24 hours) 
o Day 15 
 Prior to SOI 
 EOI (± 10 min)  
• Each cycle thereafter 
o Day 1 (prior to dosing) 
• EOT  
• 1M FUP 
• As clinically indicated 
*Comprehensive assessment of VS is critical to the conduct of this study. In situations where an assessment at 8 
hours after EOI is logistically difficult due to clinic staff availability, the observation period may be shortened, 
and an "end of day" assessment may be obtained at the latest practical time.  Such an option (if to be routinely 
employed) is available only after discussion with and approval by the Sponsor. 
Note:  C1/D1 through C1/D3 window allowances align with PK timepoints windows 
7.2.6 
Physical Examination  
(Complete at screening including height, weight, general appearance, skin, head, eyes, ears, 
nose, throat, neck/thyroid, chest [includes pulmonary assessment, breasts], cardiovascular 
[includes heart, peripheral pulses] abdomen, musculoskeletal system, lymph nodes, 
neurologic and mental status; directed thereafter, must include weight** and pulmonary and 
cardiac assessments*** at each physical exam) 
• Screening 
• Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
• Each cycle thereafter 
o Day 1 (prior to dosing) 
• EOT  
• 1M FUP 
• As clinically indicated 


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* Need not be assessed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
** Dose adjustments may be made in the event of noted weight change (± 10% [less at the site’s discretion or if 
required by institution procedures]).   
*** Pulmonary and cardiac findings will be evaluated in detail at each visit by the Principal Investigator (or 
physician designee); evaluation to include review of pulmonary symptoms including but not limited to: cough, 
sputum production, hemoptysis, wheezing, dyspnea, dyspnea on exertion, chest pain, and/or chest pain 
associated with respirations, as well as review of cardiac symptoms including but not limited to chest pain, 
orthopnea, nocturia, edema, and palpitations  
7.2.7 
Laboratory Assessments and Pregnancy Test 
All routine laboratory analyses will be performed at a laboratory facility local to the trial site.  
Sponsor (or designee) must be provided with trial site laboratory normal ranges for all 
required parameters prior to screening of the first patient at the site. Likewise, any change in 
laboratory normal ranges during the trial should be forwarded to the Sponsor (or designee) 
promptly during the trial. 
Blood samples will be taken at the scheduled visits and analyzed for the following 
parameters as clinically indicated (Table 2, Appendix 12). Results must be available and 
assessed prior to dosing of study drug, when sampling is scheduled on days of dosing. 
Table 2:  Schedule of Safety Blood and Urine Sampling 
Sample Analysis 
Screening 
Cycle 1 
Cycles 
Thereafter 
EOT 
1M 
FUP 
D1 
D3 
D8 
D15 
D22 
D1 
D15 
 
 
Hematology Panel 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
Biochemistry Panel 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
X 
X1 
 
X 
 
X 
 
X 
X 
Thyroid Function Tests 
X 
X1 
 
 
 
X 
 
X 
X 
Urinalysis 
X 
X1 
 
X 
 
X 
 
X 
X 
Pregnancy Test 
X 
X 
 
 
 
 
 
X 
 
Abbreviations (in alphabetical order): D, day; EOT, end of treatment; 1M FUP, 1-month follow-up 
1) 
Does not need to be performed prior to C1/D1, if performed during screening ≤7 days from C1/D1 
7.2.7.1 
Hematology Panel  
(To include complete blood count [CBC] with hemoglobin, hematocrit, differential, ANC, 
and platelet count) 
• Screening 
• Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
o Day 3 (+1 day) 
o Day 8 
o Day 15 (prior to dosing) 
o Day 22 
• Each cycle thereafter 


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o Day 1 (prior to dosing) 
o Day 15 (prior to dosing) 
• EOT  
• 1M FUP 
• As clinically indicated**   
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
**In the event of hematologic toxicity, the evaluation frequency should be increased to include additional 
evaluations between the scheduled assessments, as clinically indicated. 
7.2.7.2 
Biochemistry Panel  
(Fasting not required; to include sodium [Na], potassium [K], chloride [Cl], bicarbonate 
or carbon dioxide, blood urea nitrogen [BUN], creatinine, glucose, bilirubin [total and 
direct], AST, ALT, ALP, calcium [Ca], magnesium [Mg], phosphorus, albumin, total 
protein, uric acid, amylase, lipase, and creatine kinase [CK]***)  
• Screening 
• Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
o Day 3 (+ 1 day) 
o Day 8 
o Day 15 (prior to dosing) 
o Day 22 
• Each cycle thereafter 
o Day 1 (prior to dosing) 
o Day 15 (prior to dosing) 
• EOT  
• 1M FUP 
• As clinically indicated**   
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
**In the event of significant serum chemistry abnormalities, the evaluation frequency should be increased 
to include additional evaluations between the scheduled assessments, as clinically indicated.  CS 
electrolyte abnormalities should be corrected prior to dosing. 
***In the event of CK abnormalities while on study, please perform isoenzyme analysis (to include at 
minimum CK-MB); in the event of ECG abnormalities while on study, please perform isoenzyme analysis 
(to include at minimum CK-MB), serial troponins, and measurement of brain natriuretic peptide (BNP) 
7.2.7.3 
Coagulation Panel 
(To include PTT [or aPTT], PT and/or INR) 
• Screening 
• Cycle 1 
o 
Day 1 (within ≤ 7 working days prior to dosing)* 


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o 
Day 15 (prior to dosing) 
• Each cycle thereafter 
o Day 1 (prior to dosing) 
• EOT  
• 1M FUP  
• As clinically indicated   
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
7.2.7.4 
Thyroid Function Tests 
(To include measurement of thyroid stimulating hormone [TSH], free triiodothyronine 
[fT3], and free thyroxine [fT4]) 
• Screening 
• Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
• Each cycle thereafter 
o Day 1 (prior to dosing) 
• EOT  
• 1M FUP  
• As clinically indicated   
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 
7.2.7.5 
Urinalysis   
(Multi-panel chemical test strips are acceptable and should include assessment of 
specific gravity, pH, protein, glucose, ketones, leukocytes, nitrite, bilirubin, urobilinogen, 
and blood. Microscopic examination of sediment, if clinically indicated, to include 
assessment of cells [white blood cells {WBC} per high power field {HPF} and red blood 
cells {RBC} per HPF] and casts) 
• Screening 
• Cycle 1 
o Day 1 (within ≤ 7 working days prior to dosing)* 
o Day 15 (prior to dosing) 
• Each cycle thereafter 
o Day 1 (prior to dosing) 
• EOT  
• 1M FUP  
• As clinically indicated   
*Need not be performed prior to the first dose of Cycle 1 if ≤ 7 days since screening 


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7.2.7.6 
Pregnancy Testing 
(Beta-human chorionic gonadotropin [β-hCG] in WOCBP; serum at screening, serum or 
urine thereafter; negative test must be confirmed within 2 working days prior to first dose 
of study drug) 
• Screening  
• Cycle 1 
o Day 1 (within ≤ 2 working days prior to dosing) 
• EOT 
• As clinically indicated 
7.2.8 
Electrocardiogram  
(To include standard 12-lead ECG with measurement of PR interval, QRS duration, QT 
interval, and QTc interval [msec], as well as HR [beats per minute {BPM}]) 
(To be evaluated locally; to be performed after patient has been supine or semi-recumbent 
for ≥ 10 minutes) (Repeat subsequent timepoints in triplicate separated by 5 minutes for 4 
cycles in patients with a Cycle 1 QTc interval that is either: a) >500 msec; b) increased by 
60 msec over baseline*; or c) decreased by 20 msec below baseline*) (If abnormalities 
suggest new evidence of myocardial ischemia, perform isoenzyme analysis [to include at 
minimum CK-MB], serial troponins, and measurement of BNP) 
• Screening  
• Cycle 1  
o Day 1 
 Prior to SOI 
 EOI (+ 15 min) 
• Cycle 2 
o Day 1 
 Prior to SOI 
 EOI (+ 15 min) 
• Subsequent 4 cycles, if QTc interval abnormalities are observed during Cycle 1 or 2  
o Day 1 
 Prior to SOI (in triplicate) 
 EOI (+ 15 min) (in triplicate) 
• EOT 
• As clinically indicated** 
*When evaluating QTc interval, baseline should be considered the ECG immediate preceding the start of study 
drug infusion on the day of assessment.   
**In the event of significant electrolyte abnormalities, the evaluation frequency should be increased to include 
additional evaluations between the scheduled assessments, as clinically indicated.   


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7.3 
Safety Assessments (2) 
(Results from assessments previously performed as standard of care within 28 days [+2 days] 
prior to first dose of study drug may be utilized, provided no antineoplastic therapy has been 
delivered between assessment and first dose of study drug; otherwise within 14 days of first 
dose) 
7.3.1 
Multi-Gated Acquisition Scan or Echocardiogram 
(For measurement of LVEF; to be performed ONLY in patients with a history of CHF; 
individual patients should be followed with the same testing procedure throughout the study)    
• Screening 
• EOT 
• As clinically indicated 
7.3.2 
Ophthalmology Examination 
(To include funduscopic and slit lamp evaluations for assessment of retinal and corneal 
integrity, visual acuity as assessed by standardized chart or other appropriate measurement 
tool, and any other noted ocular abnormality) 
• Screening 
• EOC1 (visual acuity only; by Snellen chart or similar measurement tool)* 
• EOC2 and every even-numbered cycle thereafter*, ** 
• EOT** 
• As clinically indicated 
*End of Cycle assessments may be conducted at any time during the week prior to Day 1 of the next cycle, 
including on Day 1 of the next cycle, prior to dosing.  Due to inherent variability of Snellen chart assessments 
(21), if changes in visual acuity are noted, a thorough ophthalmologic evaluation should be performed within 
48 hours (if feasible, based on weekends or holidays) of the initial observation in order to confirm the finding 
and determine if there is evidence of an immune-mediated AE, or other event that would preclude further 
treatment with study drug.  No patient with any documented decrease in visual acuity will receive further 
therapy with Sym023 unless the event is considered unrelated to study drug and unless cleared for retreatment 
by an ophthalmologist. 
**May be combined if patient discontinues treatment at the end of an even-numbered cycle 
7.3.3 
Pulmonary Function Tests 
(To include spirometry and diffusing capacity of carbon monoxide [DLCO] to assess for 
evidence of pulmonary fibrosis. Spirometry assessments to include at minimum: forced vital 
capacity [FVC], forced expiratory volume in 1 second [FEV1], functional residual capacity 
[FRC], residual volume [RV], and total lung capacity [TLC]) 
• Screening 
• EOT 
• As clinically indicated* 


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*To be repeated if evidence of interstitial pneumonitis, pulmonary fibrosis or other potential evidence of drug-
related pulmonary toxicity is documented on imaging studies or if pulmonary symptomatology indicates 
7.4 
Disease Assessments  
(Screening disease assessments to be performed within 28 days [+2 days] prior to first dose of 
study drug)  
Standard response criteria will be applied for disease assessments and response evaluations 
(RECIST v1.1, Appendix 5; iRECIST, Appendix 6; and RECIL 2017, Appendix 7).  
Assessments should be performed at the intervals specified and in the event of suspected PD.  
If PD and/or initiation of another therapeutic intervention is documented at any time, no further 
disease assessments will be required. Patients with confirmed PD will be discontinued from 
further treatment with study drug so that alternative management of their malignancy may be 
considered. 
Duration of OR to be measured from date initial response is observed to date PD is confirmed.  
To be assigned a status of partial response (PR) or complete response (CR), changes in disease 
status must be confirmed by repeat studies performed 4 weeks (+7 days) after the criteria for 
response are first met. In the case of SD, follow-up measurements must have met the SD criteria 
at least twice after study entry for a minimum duration in general not less than 16 weeks.   
In the event of an ongoing OR or SD at the EOT, data will continue to be collected on the 
duration of OR or SD, as well as on disease progression. 
7.4.1 
Tumor Marker Measurement  
(As indicated by tumor type) 
• Screening 
• EOC2 and every even-numbered cycle thereafter* 
• At least 4 weeks following documentation of an OR 
• EOT (if > 6 weeks since previous assessment) 
• 1M FUP (if PD was not confirmed before or at EOT) 
• Long-Term FUP for Response** (in the event of an ongoing OR or SD at EOT) 
o Every 2 months  
7.4.2 
Diagnostic Imaging for Assessment of Disease (and Pulmonary Status)  
The same method(s) of disease evaluation and the same technique should be used throughout 
the study.  
All patients: To include diagnostic imaging by CT or MRI of the chest with each evaluation 
(for disease evaluation where indicated, and to assess for evidence of pulmonary fibrosis) 
plus abdomen and pelvis, and other sites as indicated based on tumor type and clinical 
judgment to assess the status of the underlying malignancy. Use of contrast is preferred but 
is at the discretion of the Investigator, as medically indicated.  


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Lymphoma patients: In addition to above, patients will be followed as indicated and per 
Investigator discretion by: fluorodeoxyglucose-positron emission tomography (FDG-PET), 
X-ray, ultrasound (U/S), and/or BM aspiration/biopsy (Bx). 
For all imaging timepoints, the following will be recorded as per RECIST v1.1 (or other 
response criteria, as indicated): target lesions including size, location, and type (nodal/non-
nodal); sum of diameters of target lesions; any new lesions noted during trial, including size, 
location, and type (nodal/non-nodal). 
• Screening 
• EOC2 and every even-numbered cycle thereafter* 
• At least 4 weeks following documentation of an OR 
• EOT (if > 6 weeks since previous assessment) 
• 1M FUP (if PD was not confirmed before or at EOT) 
• Long-Term FUP for Response** (in the event of an ongoing OR or SD at EOT) 
o Every 2 months  
Imaging data (imaging studies and derived assessments) will be stored according to usual 
practice by the sites and will be available upon request for potential review by the Sponsor 
or an independent radiology reviewer.  
7.4.3 
Response Assessment 
(To be assessed by the Investigator or qualified designee as per RECIST v1.1 [or other 
response criteria, as indicated]; to be noted at each evaluation point as CR, PR, SD, PD, or 
Not Evaluable [NE]) 
• EOC2 and every even-numbered cycle thereafter* 
• At least 4 weeks following documentation of an OR 
• EOT (if > 6 weeks since previous assessment) 
• 1M FUP (if PD was not confirmed before or at EOT) 
• Long-Term FUP for Response** (in the event of an ongoing OR or SD at EOT) 
o Every 2 months  
*End of Cycle assessments may be conducted at any time during the week prior to Day 1 of the next cycle, including 
on Day 1 of the next cycle, prior to dosing. 
** To continue at the intervals specified until disease progression or another therapeutic intervention is initiated, or 
until the end of trial; documentation may be submitted in writing, an in-person visit will not be required. 
7.5 
Immunogenicity Assessment 
To assess formation of ADA. All samples must be taken prior to the study drug infusion of that 
visit. Analysis of ADA and residual serum levels of study drug will be performed at a central 
laboratory (Specialty Lab). A detailed laboratory manual specifying sample collection, 
handling, storage, and shipment will be provided to the trial sites; retention time for specimens 
will be specified therein. If a collected serum sample is inadequate or insufficient for ADA 
analysis, the analysis of ADA can be done using a PK serum sample from the same timepoint, if 
available. 


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7.5.1 
Peripheral Blood for Immunogenicity Assessment (Specialty Lab)  
(To assess the potential immunogenicity of study drug; serum to be isolated) 
ADA samples will be taken according to the schedule shown (Table 3; Appendix 12). 
Note: 
Whole blood (~ 5 mL) to be collected in serum acquisition tubes at each of the indicated timepoints.   
7.6 
Pharmacokinetic Assessments  
Every effort will be made to collect PK samples at the timepoints specified.  Sampling times may 
be adjusted according to early trial results to optimize evaluation. No additional samples will be 
collected without formal amendment to this protocol. Analysis will be performed at a central 
laboratory (Specialty Lab). A detailed laboratory manual specifying sample collection, 
handling, storage, and shipment will be provided to the trial sites; retention time for specimens 
will be specified therein.  If a collected serum sample is inadequate or insufficient for PK 
analysis, the analysis of PK can be done using an ADA serum sample from the same timepoint, 
if available. 
7.6.1 
Peripheral Blood for Pharmacokinetic Assessment (Specialty Lab)  
(To allow for assessment of parameters such as maximum concentration [Cmax], trough 
concentration [Tmax], area under the concentration-time curve [AUC], etc.; serum to be 
isolated) 
PK samples will be taken according to the schedule shown (Table 3; Appendix 12). 
Note: 
Whole blood (~ 5 mL) to be collected in serum acquisition tubes at each of the indicated timepoints.  
Table 3:  ADA and PK Sampling Timepoints 
Sample 
Sampling 
Time3 
Window 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
EOT 
1M 
FUP 
Long-
Term 
FUP 
if OR/ SD at 
EOT  
(or ongoing 
critical AE); 
following PD 
As 
Clinically 
Indicated 
D1
-
D3 
D8 
D15 
D22 
D 1 
D15 
D 1 
D15 
ADA 
Prior to 
SOI 
- 4h 
X 
 
X 
 
X 
 
Odd # 
cycles 
 
X 
X 
X2 
X 
PK 
Prior to 
SOI 
- 4h 
X 
 
X1 
 
X1 
X1 
X1 
X1 
 
 
 
 
EOI 
+ 10 min 
X 
 
X1 
 
X1 
X1 
X1 
X1 
 
 
 
 
EOI + 2h 
±30 min 
X 
 
 
 
 
 
 
 
 
 
 
 
EOI + 4h 
±30 min 
X 
 
 
 
 
 
 
 
 
 
 
 
EOI + 8h4 
±90 min 
X 
 
 
 
 
 
 
 
 
 
 
 
EOI + 
24h 
±6h 
X 
 
 
 
 
 
 
 
 
 
 
 
EOI + 
48h 
-12h to     
+ 24h 
X 
 
 
 
 
 
 
 
 
 
 
 
During 
Visit 
NA 
 
X 
 
X 
 
 
 
 
X 
X 
X2 
 
Abbreviations (in alphabetical order): 1M FUP, 1-month follow-up; ADA, anti-drug antibody; AE, adverse event; D, day; EOI, end of infusion; 
EOT, end of treatment; FUP, follow-up; h, hour; min, minutes; NA, not applicable; OR, objective response; PD, progressive disease; PK, 
pharmacokinetic; SOI, start of infusion 
1) 
If study drug administration is delayed to another day, only one PK sample should be taken during the visit 


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2) 
Collection of samples during Long-Term FUP to continue at 2-month intervals for 6 months (for patients who are available for blood 
collection)  
3) 
Actual collection times to be recorded in the patient’s CRF and/or sampling log 
4) 
Comprehensive collection of clinical samples is critical to the conduct of this study. In situations where collection of the EOI + 8h 
sample is logistically difficult due to clinic staff availability, the observation period may be shortened, and an "end of day" sample 
may be obtained at the latest practical time. Such an option (if to be routinely employed) is available only after discussion with and 
approval by the Sponsor. 
7.7 
Pharmacodynamic and Other Biomarker Assessments (Specialty Lab) 
To assess potential pharmacodynamic and other biomarkers; every effort will be made to collect 
samples as specified. Analyses will be performed at a central laboratory (Specialty Lab). A 
detailed laboratory manual specifying sample collection, handling, storage, and shipment will be 
provided to the trial sites; retention time for specimens will be specified therein.   
All analyses will be related to and used only in connection with the data collected in the present 
trial or other Sym023-related trials, and the identity of the patient will remain confidential. The 
analyses will not have any medical consequences for the patient or their relatives.  
7.7.1 
Pharmacodynamic Assessments 
(To include peripheral blood collection for evaluation of receptor occupancy) 
• Cycle 1 
o Day 1 (prior to dosing) 
o Day 1 (24 hours after dosing ± 6 hours, i.e., Day 2) 
o Day 15 (prior to dosing) 
• Cycle 2 
o Day 1 (prior to dosing) 
o Day 15 (after dosing + 0 to 7 days) (at the time of biopsy if performed)  
• EOC2* (combined with EOT if patient discontinues treatment prior to or at EOC2) 
• End of every 4th cycle thereafter* (i.e., EOC6, EOC10, etc.; may be combined with EOT 
if patient discontinues treatment) 
• EOT  
• 1M FUP 
Note: 
Whole blood (~ 10 mL) to be collected at each of the indicated timepoints; handling instructions will 
be provided.  
*End of Cycle assessments may be conducted at any time during the week prior to Day 1 of the next cycle, 
including on Day 1 of the next cycle, prior to dosing. 
7.7.2 
Biomarker Assessments  
The purpose of biomarker assessments is to develop an approach for the identification and 
validation of genes or proteins that may predict which patients are likely to respond to Sym023, 
and that may change with the possible development of acquired resistance. 
Analyses may include genes and/or proteins that are unknown or have not been included in the 
scientific hypotheses of this trial, but that, during the collection of data from this trial, may 
emerge as new candidate genes and markers related to Sym023 safety, efficacy, or mechanism of 
action.  


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All analyses will be related to and used in connection with the data collected in the present trial 
and the ongoing and future development of Sym023 as a single drug and in combination.  The 
identity of the patient will remain confidential. The analyses will not have any medical 
consequences for the patient or their relatives. 
Residuals from samples collected will be stored for up to 15 years after completion of the trial, 
where after all samples will be destroyed. 
7.7.2.1 
Blood Samples for Biomarker Assessments 
(To include peripheral blood collection for evaluation of potential biomarkers, including but 
not limited to ctDNA, RNA, relevant proteins/cytokines, and cellular biomarkers) 
• Screening (after confirmation of eligibility and study enrollment; may be collected C1/D1 
prior to dosing) 
• Cycle 2 
o Day 15 (after dosing + 0 to 7 days) (at the time of biopsy if performed) 
• EOT  
Note: 
Whole blood (~ 30 mL) to be collected at each of the indicated timepoints; handling instructions will 
be provided. For those timepoints where both a blood sample and a tumor biopsy are to be obtained, 
the blood sample is to be collected first.  
7.7.2.2 
Tumor Sample for Biomarker Assessment (Biopsies Optional) 
(To include tumor tissue collection for evaluation of potential biomarkers, including but not 
limited to DNA, RNA, protein, and cellular biomarkers) 
• Screening (after confirmation of eligibility and study enrollment; may be collected C1/D1 
prior to dosing) 
• Cycle 2  
o Day 15 (after dosing + 0 to 7 days) (with paired pharmacodynamic and biomarker 
peripheral blood) 
• EOT at the time of PD for patients with a previous OR or prolonged SD (> 16 weeks)  
Note: 
Tumor tissue for formalin-fixed paraffin-embedding (FFPE) to be collected at each of the indicated 
timepoints; handling instructions will be provided. For those timepoints where both a blood sample 
and a tumor biopsy are to be obtained, the blood sample is to be collected first. 
Tumor biopsies to include core samples of a locally recurrent or metastatic lesion; to be 
performed with minimal morbidity to the patient by a percutaneous core needle biopsy either 
with or without the aid of an imaging modality chosen at the discretion of the physician 
performing the biopsy.  
 
 


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8 MANAGEMENT OF TOXICITY 
Comprehensive assessments of any toxicity experienced by the patient will be performed 
throughout the course of this study.  Anticipated toxicities that may be experienced with study 
drug are detailed in this protocol (Section 2.4, Section 11), as well as in the IB.     
Grades of toxicity (CTCAE v5.0*), as well as clinical judgment, will be used to determine 
appropriate management of the patient experiencing any AE while participating in this study. 
*See < https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm > 
8.1 
Grading and Recording of Toxicity 
Any clinical AE, whether observed by the Investigator, or observed or experienced by the 
patient, will be reported.  Any CS change from baseline in a laboratory assessment will be 
recorded as an AE.  All clinical and laboratory AEs must be carefully evaluated for: 
• Severity (Grades 1-5; or mild, moderate, severe, life-threatening, fatal) (Appendix 3)* 
• Duration 
• Relationship to study drug (not-related, unlikely, possible, probable, related) (Appendix 
4)   
*In those cases where further definition of an event is provided by the CTCAE v5.0, please refer to those 
criteria for grading and severity information.  
This information will be documented on the appropriate page of the CRF. 
8.2 
Evaluation and Treatment of Toxicity 
The Principal Investigator, Sub-Investigator, or designated health professional must be available 
throughout the course of the study to evaluate and treat any AE(s), as well as to evaluate whether 
continued participation in the trial is warranted or advisable.  
If, at any point during the study, significant changes occur in either the patient’s clinical status or 
laboratory assessments, such changes will be followed until the abnormality either resolves, 
returns to baseline status, or is adequately explained. 
8.3 
Determination of DLT versus Non-DLT 
Patients will be evaluated throughout the course of the trial for evidence of acute as well as 
delayed and/or cumulative toxicities.   
If a significant toxicity thought to be related to study drug is experienced at any point during the 
patient’s participation in the study, the Investigator will determine whether that toxicity meets 
the protocol criteria for DLT (Section 6.8.3). 
If the protocol definition of DLT is met, the patient will be discontinued from study treatment, 
without exception.   
Alternatively, the Investigator may determine that the toxicity does not meet the protocol 
definition for DLT, but nevertheless warrants dose modification, because it is: 
• Not controlled by optimal supportive care, or 


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• Not tolerated due to symptomatology or interference with normal daily activities 
For toxicity that does not meet the protocol definition of DLT, the Investigator may, as described 
below, elect to prolong the infusion duration (for IRRs), or temporarily delay dosing with study 
drug, to allow for amelioration of the toxicity. 
8.4 
Premedication  
8.4.1 
Infusion-Related Reactions 
There is an inherent risk for IRRs with the administration of mAbs. An IRR is defined as an AE 
occurring during the study drug infusion and up to 24 hours after the EOI, which is assessed by 
the Investigator to be related to the infusion. Signs and symptoms of IRRs may include but are 
not limited to:   
• facial flushing and swelling 
• rash including urticaria  
• headache 
• fever  
• chills, rigors 
• diaphoresis 
• tachycardia  
• hypotension 
• nausea 
• dry mouth  
• chest/back/abdominal pain/discomfort 
• chest and throat tightness  
• shortness of breath 
• cough, wheeze, stridor  
• hypoxia 
• bronchospasm 
• laryngeal edema  
• angioedema  
• shock 
 
The risk of an IRR is highest for the first administration of a mAb and diminishes with 
subsequent infusions. If an IRR occurs, it should be classified according to the CTCAE v5.0. 
Guidelines for the grading and management of IRRs of all severities are provided (Appendix 9).  
8.4.2 
Premedication for IRRs (Prior to the First Dose) 
Since the mechanism of action of the study drug is to stimulate the immune system 
premedication with agents such as glucocorticoids which are immunosuppressive is to be 
avoided. As a result, no premedication is required to be administered prior to patients receiving 
the first dose of study drug. In patients with a history of IRRs to mAbs or similar products, it is 
recommended that premedication be administered. In such cases, patients should be 


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premedicated with a regimen that includes acetaminophen as well as an H1 (e.g., 
diphenhydramine/hydroxyzine) and an H2-antagonist (e.g., ranitidine/famotidine).   
8.4.3 
Premedication for IRRs (Following an IRR) 
For IRRs while on study, the following premedication instructions are provided: 
• For Grade 1 or Grade 2 reactions, premedication prior to subsequent infusions should be 
considered. Thereafter, if a patient is without recurrence of an IRR, the Investigator may 
choose to withdraw premedication to determine whether such continued therapy is 
necessary for that patient. Where practical, it is recommended that withdrawal of 
premedication be done in a gradual fashion (e.g., by reduction in dose, frequency, or 
number of agents administered, at the Investigator’s discretion). For those patients who 
experience recurrent signs/symptoms suggestive of an IRR, premedication should be re-
instituted for at minimum 2 additional doses before any future attempt to withdraw.  
• For Grade 3 reactions, not applicable as this is considered a DLT; therefore, no further 
treatment with study drug is allowed.  
• For Grade 4 reactions, not applicable as no further treatment with study drug is allowed. 
If premedication is to be administered, institutional standards may be followed; however, a 
recommended regimen includes administration of the following approximately 30 minutes prior 
to the start of infusion (Table 4).   
Table 4:  Recommended Premedication Regimen 
 
Medication 
 
Dose and Route 
 
Alternative 
Medication 
Dose and Route 
 
1 
acetaminophen 
1000 mg IV (or PO) 
 
 
2 
diphenhydramine 
50 mg, IV 
hydroxyzine 
25 mg, PO 
3 
ranitidine 
50 mg, IV 
famotidine 
20 mg, IV 
Abbreviations (in alphabetical order): IV, intravenous; mg, milligrams; PO, per os (orally, by mouth) 
Note: Doses may be adjusted based on standard institutional practice. In the event of a Grade 2 IRR, glucocorticoid therapy 
equivalent to a minimum of 25 mg IV hydrocortisone approximately 0.5 to 2 hours prior to the start of the next infusion 
may be considered. 
 
8.4.4 
Premedication for other Study Drug-Related Toxicities 
Following the first dose, should a patient experience symptoms suggestive of other mild-to-
moderate study drug-related reactions (e.g., nausea, vomiting, diarrhea, etc.), the patient may be 
premedicated with standard therapies to reduce the potential for such reactions in the future.   
Based on ongoing review of patient safety data, the Sponsor may implement mandatory 
premedication for all patients treated in this study should a pattern begin to emerge of other mild-
to-moderate study drug-related reactions that are amenable to prophylaxis with standard agents. 
Such action will occur following discussions between the Investigator(s) and the Sponsor's 
Medical Representative(s). 
Any medications administered for either prophylaxis or therapy of signs/symptoms considered to 
be related to study drug will be documented on the appropriate page of the CRF.   


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8.5 
Dose Modification Options 
8.5.1 
Prolongation of Infusion Duration 
All IRRs that result in infusion prolongation must be reported promptly to the Sponsor (or 
designee). 
8.5.1.1 
Instructions for Infusion Prolongation for IRRs 
For IRRs, the following infusion prolongation instructions are provided:   
• For Grade 1 reactions, the infusion may be slowed to 50% of the prior rate such that the 
remaining dose to be delivered is administered in 2× longer than the amount of time that 
was initially scheduled.     
• For Grade 2 reactions, the infusion should be interrupted for a minimum of 30 minutes, 
and at least until there is either amelioration to ≤ Grade 1 severity or return to baseline 
status. Supportive care should be provided. The infusion should then be restarted and 
slowed to 50% of the prior rate, as described. Subsequent infusions should be 
administered at the prolonged rate. 
• For Grade 3 reactions, the infusion will be STOPPED and supportive care will be 
provided. The occurrence will be considered a DLT and the patient will be discontinued 
from treatment. 
• For Grade 4 reactions, the infusion will be STOPPED and supportive care will be 
provided.  The occurrence will be considered a DLT and the patient will be discontinued 
from treatment. 
In all cases, the Investigator should use best clinical judgment in managing such reactions. All 
infusion interruptions and subsequent prolongations, including modified infusion times, as well 
as the toxicity that necessitated them, will be clearly documented on the appropriate page of the 
patient’s CRF. 
Note: 
Any assessments to be performed or samples to be collected (e.g., vital signs, PK) at the end of or 
following the EOI will still be performed or collected beginning at the delayed EOI timepoint. In situations 
where collection of late day samples, particularly the 8 hours after EOI sample, is logistically difficult due 
to clinic staff availability, an "end of day" sample may be obtained at the latest practical time on the day of 
the reaction. 
Guidelines for the grading and management of IRRs of all severities are provided (Appendix 9). 
8.5.1.2 
Treatment Following Infusion Prolongation 
To enhance patient safety following an infusion prolongation, subsequent infusions will be 
administered at the prolonged rate. For Grade 1 and Grade 2 IRRs, rechallenge with a shorter 
duration of infusion (no less than the duration designated by the patient’s dose assignment and 
weight) may be attempted at the Investigator's discretion, after a minimum of 2 doses with no 
evidence of infusion-related toxicity at the prolonged rate.  
8.5.2 
Dose Reduction  
There is no provision for dose reduction in this study. 


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8.5.3 
Dose Delay 
All delays of study drug must be reported promptly to the Sponsor (or designee).  
Toxicities may be managed by delay in dosing provided they do not meet the criteria for study 
discontinuation (Section 9.1).   
If indicated, the period between any 2 scheduled doses may be extended to allow for 
amelioration of the toxicity.  However, if any observed Grade 3 or Grade 4 toxicity thought to be 
possibly-, probably-, or related to study drug results in delay of dosing beyond 2 weeks of the 
next scheduled dose, the event will be considered a DLT.   
For toxicities that are to be managed by dose delay, dosing may be restarted at the same dose; 
however, administration of study drug may only be restarted upon amelioration to ≤ Grade 1, 
return to baseline status, or resolution of the observed toxicity.  
8.5.4 
Schedule Alterations 
Altered schedules of study drug (i.e., reduced number of treatment days, longer interval between 
treatment days) may be explored, only after discussion with the Sponsor (or designee), and only 
during subsequent cycles of treatment (Cycle 2 and beyond).   
Patients requiring such schedule alterations during Cycle 1 of the study will be considered to 
have met the criteria for DLT due to the inability to complete Cycle 1 of study drug treatment.    
Note: 
Any modification of study drug administration, and the reason for such action, must be clearly noted in the 
patient’s CRF. If such a modification impacts a PK sampling interval, the details of such action must also 
be documented on the appropriate page of the CRF (to aid in the interpretation of PK findings). 


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9 DISCONTINUING PATIENTS FROM STUDY TREATMENT 
Every reasonable effort will be made to keep patients in the study; however, if a patient is 
discontinued from study treatment, every effort will be made by the Investigator to complete and 
report the reasons for treatment discontinuation as thoroughly as possible. This includes EOT 
observations, as required by the protocol at the time of treatment discontinuation, or before 
initiation of a new treatment, whichever comes first, as well as 1M FUP evaluations to follow 
(Section 7). The reason for treatment discontinuation must be clearly documented on the 
appropriate page of the CRF. A CRF must be completed for any patient who receives any 
amount of study drug.  
9.1 
Criteria for Treatment Discontinuation 
Patients will be discontinued from further treatment with study drug in the event of any of the 
following:  
1. Adverse Events, including: 
• 
Any AE or SAE that meets the study DLT criteria at any time during the study   
• Another AE or SAE considered by the Investigator to require treatment 
discontinuation 
Note: 
AEs resulting in a patient’s permanent discontinuation from study treatment, regardless of 
seriousness or relationship to study drug, MUST be reported promptly to the Sponsor (or 
designee). 
2. Progressive Disease: Confirmed radiographically  
Note: 
An exception may be made in the case of suspected PSPD.  Patients will be permitted to continue 
treatment beyond initial RECIST v1.1 (or RECIL 2017) defined PD while waiting for confirmation of 
PD, provided they are clinically stable (per iRECIST).  
3. Clinical Progression: Treatment failure not meeting the criteria for PD, but considered by 
the Investigator to require treatment discontinuation 
4. Physician Decision, including:  
• Use of or requirement for a non-permitted concomitant medication 
• Requirement for a significant surgical procedure  
Note: 
Patients requiring a minor surgical procedure (e.g., port placement, skin abscess drainage) 
may continue at the Investigator’s discretion following discussion with the Sponsor's Medical 
Monitor(s). A brief interruption in therapy may be considered.  
• Intercurrent illness which would prevent completion of study-related evaluations 
• Any other reason in the opinion of the Investigator that would justify treatment 
discontinuation  
5. Withdrawal by Patient: Withdrawal of consent and election to discontinue treatment 
(patients may leave the study at any time for any reason if they wish to do so, without 
consequence) 


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6. Protocol Deviation: Significant deviation/violation from the protocol or eligibility criteria 
(discontinuation considered only following discussion with the Medical Monitor(s)) 
7. Noncompliance with study procedures 
8. Pregnancy 
9. Lost to Follow-up 
10. Death 
11. Study Terminated by the Sponsor 
12. Site Terminated by the Sponsor 
9.2 
Replacements 
Should a patient discontinue treatment with study drug for reasons other than the occurrence of a 
DLT prior to completing Cycle 1, a replacement patient will be obtained using the original 
eligibility criteria. Patients discontinued due to DLTs will not be replaced. 
Note:  
Patients must receive their full planned doses of study drug during Cycle 1 to be considered evaluable for 
tolerability, unless dose delay or discontinuation is the result of a DLT. Patients receiving < 2 full planned 
study drug doses plus 2 weeks of follow-up during Cycle 1 for reasons other than toxicity will be replaced. 


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10 ADVERSE EVENTS 
10.1 
Definitions of Adverse Events 
10.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient or a clinical investigation subject 
administered a pharmaceutical product and which 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), symptom, or disease temporally associated with the use of an IMP, 
whether or not considered related to the IMP. 
Causality for an AE will be assessed as related, possibly-related, probably-related, unlikely-
related, or not-related to IMP. Any AE, regardless of causality, that also meets the seriousness 
criteria, will be reported as an SAE. 
10.1.2 
Events Not to be Considered as Adverse Events 
A pre-existing condition (i.e., a disorder that is present before the AE recording period starts and 
is noted on the medical history/physical examination form) should not be recorded as an AE 
unless the condition worsens or episodes increase in frequency during the AE recording period. 
PD will not be captured as an AE as this will be recorded as part of the patient’s efficacy 
evaluation.  PD should be reported as an AE if the nature of the PD is different than expected 
(i.e., signs/symptoms are not typical of PD).   
Note:  PD may be reported as an AE in the case of patient death, with death being the outcome of the event. 
An abnormal laboratory value or an abnormal physiological test finding (e.g., ECG) need not be 
reported as an AE unless one of the following applies: 
• The Investigator considers the abnormality CS  
• The event meets the definition of an SAE 
• The event requires an intervention 
• The event results in an action taken with study drug (e.g., dose-delay and/or 
discontinuation) 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
recorded as AEs. A medical condition for which an unscheduled procedure was performed, 
should however be recorded if it meets the definition of an AE. For example, acute appendicitis 
should be recorded as the AE and not the appendectomy. 
Procedures to support the treatment regimens, such as insertion of central venous catheters, etc., 
should not be recorded as AEs, unless the procedures result in complications. 
10.1.3 
Adverse Events of Medical Interest 
Not applicable 


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10.1.4 
Serious Adverse Events  
An SAE is an AE that meets one or more of the following regulatory outcome criteria:      
• Results in death    
In the case of deaths, the event(s) leading to the death should be recorded and reported as 
SAE(s) with the outcome “Fatal”. The death itself will not be reported as an SAE, unless 
the cause of the death is unknown (e.g., in case of unexplained or sudden death)   
• Is life-threatening    
The term "life-threatening" refers to an event in which the patient is at immediate risk of 
death at the time of the event; it does not refer to an event which hypothetically might 
cause death if it was more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity   
A disability is defined as any substantial disruption of a person’s ability to conduct 
normal life functions.   
• Is a congenital anomaly/birth defect 
• Is medically important 
Medical and scientific judgment must be exercised in deciding whether an AE is believed 
to be “medically important”. Medically important events may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in this definition.  
10.1.5 
Events That Do Not Meet the Definition of Serious Adverse Events 
PD will not be captured as an SAE unless the nature of the PD is different than expected (i.e., 
signs/symptoms that are not typical of PD).   
Note:  PD may be reported as an SAE in the case of patient death, with death being the outcome of the event. 
Elective surgery or other scheduled hospitalization periods that were planned before the patient 
was included in this trial are not to be recorded as SAEs, unless an outcome of the 
surgery/hospitalization was considered serious.  
Hospitalization for observation or convenience prior to or following study drug infusions without 
an SAE occurring should not be recorded as an SAE, e.g., if a patient is hospitalized merely for 
observation, or if a patient begins or finalizes the infusion at a time of day requiring a 
convenience overnight stay in the hospital.  
Procedures to support the treatment regimen that require hospitalization should not be recorded 
as SAEs; however, in cases where a procedure results in complications requiring/prolonging 
hospitalization, this must be recorded and reported as an SAE. 
    


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10.2 
Adverse Event Recording and Reporting  
All AEs will be recorded from signing of informed consent for participation in the trial.  The 
recording period ends 30 days after receiving the final dose of study drug (at the time of the 1M 
FUP Visit), unless extended FUP is indicated, per the clinical trial protocol.   
Note:  Patients who sign informed consent and are subsequently deemed to be screen failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
10.2.1 
Information to be Provided for each AE 
The Investigator must record all directly observed AEs and all AEs spontaneously reported by 
the patient.  Information regarding the occurrence of AEs should be elicited through open-ended 
questioning of the patient, review of physical examination findings, and review of laboratory 
results or other safety information, e.g., ECGs.  
All AEs that occur in patients during the AE recording period must be recorded/entered to the 
AE section of the CRF, whether or not the event is assessed as related to study drug.  If the AE is 
serious, the SAE report forms must also be completed and submitted. The following information 
will be provided for each AE term reported: 
• Diagnosis 
A diagnosis should be recorded, if possible. If no diagnosis is available, signs and 
symptoms should be recorded instead. For fatal AEs, death is an outcome of the AE. The 
cause of death (rather than the term “death”) should be recorded.   
• Severity 
The Investigator will use the CTCAE version 5.0* to describe the severity of an AE.  If 
the severity of an AE is not specifically graded by the CTCAE guidance document, the 
Investigator should use the general definitions of Grades 1 to 5 as per the following, and 
use his/her best medical judgment to describe the severity of the AE (Appendix 3): 
o Grade 1: Mild 
o Grade 2: Moderate 
o Grade 3: Severe 
o Grade 4: Life-threatening or disabling 
o Grade 5: Death caused by the event 
Changes in severity of AEs will be recorded.  
Generally, an AE of CTCAE Grade 4 or 5 qualifies for SAE reporting to the Sponsor (or 
designee). However, a laboratory abnormality of Grade 4 does not need to be reported as 
an SAE, unless it meets one of the SAE criteria.  
*See < https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm > 
• Relationship to IMP/Causality 
The Investigator will attempt to assess causal relationship of the event to the study drug.  
Relatedness must be assessed and recorded within the initial report (CRF and SAE report 
form).   


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The causal relationship is an assessment of whether the event is related to the use of the 
IMP.  It is not an evaluation of whether the event could hypothetically occur in the 
investigational patient population. 
The causal relationship of an AE to the IMP will be rated using a 5-point causality scale 
(Appendix 4): 
o Not-related  
o Unlikely-related  
o Possibly-related  
o Probably-related  
o Related    
• Outcome 
The outcome of the AE must be assessed by the Investigator utilizing one of the 
following options: 
o Recovered/resolved  
o Recovered/resolved with sequelae  
o Recovering/resolving 
o Ongoing  
o Fatal  
o Unknown  
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial 
will be provided. 
10.2.2 
Required Follow-up for AEs 
Appropriate consultation and follow-up evaluations should be carried out until the event either 
resolves, returns to baseline status, or has been adequately explained and assessed by the 
Investigator as chronic and/or stable, and that no long-term deleterious effects have become 
evident.   
This follow-up may extend beyond the 1M FUP Visit, to up to 4 months after the end of 
treatment if indicated, if the event has not resolved or been adequately explained.   
Any patient who develops an immune-mediated event during study or after the end of treatment 
will be followed for up to 2 years to assess the course of the condition and evaluate potential 
reversibility of the finding. 
Note:  Patients who sign informed consent and are subsequently deemed to be screen failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
10.3 
Serious Adverse Event Recording and Reporting 
10.3.1 
Timeframes for Reporting to the Sponsor 
All SAEs occurring at any time from signing of informed consent for participation in the trial 
and until 30 days after receiving the final dose of study drug (at the time of the 1M FUP Visit) 
must be recorded on the SAE Report Form and recorded as an SAE in the CRF. 


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Note:  Patients who sign informed consent and are subsequently deemed to be screen failures will be followed for 
the occurrence of SAEs/AEs until it is determined that they will not be participating in the trial. 
In case of an SAE, the Investigator must, within 24 hours of awareness of the event, report the 
SAE to the Sponsor (or designee) by telefax or e-mail transmission. Fax number(s) and e-mail 
address(es) will be stated on the SAE Report Form and the SAE Report Form Completion 
Instructions. SAE follow-up information must also be reported to the Sponsor (or designee) 
within 24 hours of awareness. SAEs, still ongoing after the 1M FUP Visit, should be followed on 
a regular basis according to the Investigator’s clinical judgment, until the event resolves or until 
the Investigator assesses it as chronic or stable. The Sponsor (or designee) will pursue sufficient 
information and will return to the trial sites for such information as deemed required. 
If the Investigator becomes aware of an SAE that occurred after the 1M FUP Visit and finds it to 
be related to the IMP (possibly-, probably-, or related to the study drug) or trial conduct, it must 
be recorded and reported to the Sponsor (or designee) as an SAE.  
The Investigator should be aware of local reporting regulations to the IRB/EC. The Sponsor (or 
designee) will either supply the Investigator with the reports, which should be forwarded to the 
IRB/EC, or report directly to the IRB/EC depending on local regulations.    
10.3.2 
Safety Reporting to Health Authorities, Institutional Review Boards/Ethics 
Committees, and Investigators  
Reportability of an SAE as a “Suspected Unexpected Serious Adverse Reaction” (SUSAR) will 
be determined solely by the Sponsor, based on seriousness, causality, and expectedness criteria.   
In addition to SUSARs, the Sponsor or designee is responsible for reporting all relevant safety 
information regarding SUSARs, or other safety developments, to appropriate Health Authorities 
and central IRBs/ECs, as well as participating Investigators. Reporting of SUSARs to local 
IRBs/ECs will be handled either by the Sponsor or designee, or the Investigator depending on 
local regulations.  
The timeline for notification of SUSARs is within 7 calendar days for fatal/life-threatening 
events and within 15 calendar days for all other SUSARs.   
10.4 
Pregnancy 
If any trial patient becomes pregnant during the trial, the patient must be discontinued from study 
drug immediately and the pregnancy must be reported to the Sponsor or designee according to 
the same timelines as an SAE.  While pregnancy is not considered an AE, all pregnancies are 
tracked as SAEs within the safety database to follow-up on exposure to the fetus/infant. 
Pregnancies reported in female partners of male trial patients must also be included in the safety 
database; therefore, a female partner of a male patient on the trial who becomes pregnant will be 
approached for consent to have the pregnancy followed until term and reported upon to the 
Sponsor (or designee). 
All pregnancies must be followed up every third month and 1-month post-delivery to determine 
outcome and status of mother and child. Pregnancy complications and elective terminations for 
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medical reasons should be reported as follow-up, but not as a separate AE/SAE unless 
complications meet AE/SAE criteria. Spontaneous abortion must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention after 
the patient has completed the trial and considered by the Investigator as possibly-, probably-, or 
related to the study drug, must be promptly reported to the Sponsor (or designee). 
All pregnancy information including follow-up information must be reported on a designated 
pregnancy form provided by the Sponsor (or designee). 
 
 


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11 PRECAUTIONS WHEN DOSING WITH STUDY DRUG 
11.1 
Precautions Regarding Procreation 
Studies have not been performed to determine whether this study drug affects reproductive 
function in males or can cause fetal harm.  For this reason, men with partners of childbearing 
potential must use a highly effective method of contraception while receiving study drug. “A 
highly effective method of contraception” is defined as non-hormonal contraception 
equivalent to a double-barrier method (includes a single-barrier method in combination 
with a spermicide) or intrauterine device. 
There have been no studies in pregnant females; therefore, it is not known whether study drug 
can cause fetal harm when administered to a pregnant woman, or whether it can affect 
reproductive capacity. For this reason, WOCBP should only be administered study drug when 
highly effective contraceptive measures have been taken and when pregnancy tests are negative.   
WOCBP includes any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or is not 
postmenopausal. Post-menopause is defined as: 
• Amenorrhea for ≥ 12 months with no other cause 
• Irregular menstrual periods, on HRT, with documented FSH level > 35 mIU/mL 
Note:  
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, transdermal 
patches, or implanted or injectable products), or mechanical products such as an intrauterine device or 
barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence, or 
where their partner is sterile (e.g., vasectomy), should be considered of childbearing potential. 
 
Women and men of childbearing potential will be informed as to the unknown risk to procreation 
while participating in this trial and will be advised that they must use highly effective 
contraception within 2 weeks prior to the first dose and continuing until 6 months after final 
administration of study drug. A pregnancy test will be performed on each premenopausal female 
of childbearing potential within ≤ 2 working days prior to first study drug administration, and 
again at the end of the final treatment cycle.   
11.2 
Additional Precautions 
There are no known contraindications to the administration of study drug, however the following 
additional precautions are provided:   
• Lactating women and children:  Use in lactating women or in children has not been 
evaluated. These patients will be excluded from study entry.   
• Drug interactions: No formal drug interaction studies have been performed, therefore no 
specific guidance can be provided about use of concomitant medications.   
• Overdose: There is no experience with clinical overdose. If severe reactions occur in 
patients, study drug should be discontinued, and all appropriate supportive medical care 
should be instituted to ameliorate these potential AEs. 


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• Nonclinical toxicology studies: No adverse events have been observed at the highest dose 
level of Sym023 tested, which was weekly administration of 100 mg/kg. The highest 
dose to be administered in this trial is 20 mg/kg administered Q2W. 
• Studies of other mAbs: IRRs have been observed, therefore safety in patients with a 
history of IRRs to mAbs or similar products should be carefully evaluated prior to 
administration of study drug. It is recommended that premedication to prevent infusion 
reactions be administered to all patients with a history of such reactions, and facilities and 
personnel to treat such reactions, if they occur, should be available. In the event of an 
IRR, the infusion should be slowed/interrupted so that appropriate measures may be 
taken (Section 8.5.1, Appendix 9).  
• Studies of other anti-TIM-3 antibodies: For a listing of AEs observed with another TIM-3 
antibody, see Section 2.3.1.2. 
• Studies of other antibodies to immune checkpoints: For a listing of AEs observed with 
anti-PD-1/PDL1 antibodies, see Appendix 8. For information on grading and 
management of immune-mediated toxicities, see Appendix 10. 
 
 
 


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12 SAFETY SURVEILLANCE DURING STUDY 
12.1 
Safety Review 
The Investigator(s) and Sponsor's Medical Representatives will comprise a Study Safety Team. 
The team will review clinical and laboratory safety data on an ongoing basis throughout the 
study and make decisions regarding the advisability of continuing accrual to a dose cohort, 
and/or escalating the dose and allowing accrual to a higher dose cohort. To do so:   
• The following will be promptly reported to the Sponsor (or designee): 
o SAEs within 24 hours of Investigator awareness 
o Any immune-related AE of significance, even if not meeting the SAE or DLT 
definition 
o AEs resulting in permanent discontinuation from study, regardless of seriousness 
or relationship to study drug  
o DLTs 
o IRRs 
o Dose delays 
• AEs will be recorded in the CRF in a timely manner following a patient completing (or 
being discontinued from) each dosing cycle. Each event will be assessed as to grade and 
causality. 
• The Investigator will make critical laboratory safety data available in a timely manner.    
• Patients will be carefully evaluated for evidence of all AEs, including potential 
cumulative and/or delayed toxicities, throughout the duration of their time on study.  
• Biweekly Safety Team Teleconferences will be held between the Investigator(s) and the 
Sponsor’s Representative(s) to discuss ongoing patient status and any emerging safety 
concerns; frequency may fluctuate based on accrual and study activity, as indicated.  
Availability of these data also will enable the Sponsor (or designee) to act promptly in response 
to safety signals and ensure that governing Health Authorities, as well as Investigators who may 
be participating at other sites or in other clinical trials of the study drug, are informed of events 
occurring during the trial.  
12.2 
Other Safety Surveillance Activities 
At least one Medical Monitor will be assigned to review and evaluate relevant clinical/safety 
information concerning the clinical trial. The responsibilities of the Medical Monitor include, but 
are not limited to: 
• Consultation with Investigator(s) regarding evaluation of patients to be enrolled to the 
study, treatment delays, restarts, and/or discontinuations   
• Ongoing safety monitoring of all patients being treated in the study 
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• Performing surveillance on potential safety signals in conjunction with the Drug Safety 
physician 
• Evaluating abnormal laboratory values and other relevant safety data, e.g., ECGs 
• Providing medical support to the Sponsor in answering questions related to the study 
protocol 
• Updating the Safety Team on trial status  
A Drug Safety physician will be assigned to review, assess, and approve all SAE cases and 
associated reports. This physician will also perform the following: 
• Assess for safety signals and trends in conjunction with the Medical Monitor 
• Assist with questions regarding medical coding of SAEs 
• Discuss with the Sponsor’s Chief Medical Officer any cases which may present a concern 
regarding a signal or safety issue. 


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13 REGULATORY AND ETHICAL CONSIDERATIONS 
13.1 
Conditions of Testing 
In sponsoring this study, it is the intention of the Sponsor to obtain patient safety data for 
submission to governing Health Authorities. In agreeing to conduct this investigation, the 
investigative facility agrees to follow all requirements stipulated in this protocol as well as 
regulations described in the U.S. CFR and/or by governing Health Authorities concerning: 
• Responsibilities of Investigators (in the U.S. Title 21 CFR Part 312) 
• Informed Consent of Human Subjects (in the U.S. Title 21 CFR Part 50) 
• Institutional Review Boards (in the U.S. Title 21 CFR Part 56) 
In addition, the Investigator agrees to perform the study in accordance with the principles of the 
Declaration of Helsinki, and ICH E6(R2) GCP. 
13.2 
Institutional Review 
The Investigator will submit this protocol, any protocol modifications, and the patient ICF to be 
utilized in this study to the appropriate IRB/EC for review and approval. This committee must 
operate in accordance with ICH E6(R2) GCP, the U.S. Title 21 CFR Part 56, and/or governing 
Health Authorities, as appropriate.  A letter confirming approval of the protocol and the ICF 
must be forwarded to the Sponsor (or designee) prior to initiation of this study. The Investigator 
will not start the study, nor will study drug be shipped to the investigational site, before 
providing the Sponsor (or designee) with evidence of this approval.  
The Investigator is responsible for assuring continuing review and approval of the clinical study.  
The Investigator must also promptly report all changes in the research activity and all 
unanticipated problems involving risk to the patients or others to the IRB/EC. The Investigator 
will not make any changes in the protocol without IRB/EC approval, except where necessary to 
eliminate apparent immediate hazards to the patients. The Investigator will provide progress 
reports to the IRB/EC as required by the IRB/EC. If the study remains in progress for more than 
the IRB/EC-specified approval period, the Investigator must obtain renewal and re-approval 
from the IRB/EC where appropriate. Documentation of renewal must be submitted to the 
Sponsor (or designee). The Investigator will provide notice to the IRB/EC of completion of 
participation in the study.  
13.3 
Informed Consent 
The Investigator agrees to protect the rights, safety, and welfare of the patients entered into the 
study, including obtaining written informed consent prior to performing any study-related 
procedures, and informing each patient that the study drug is being used for investigational 
purposes.   
Prior to study start, the Sponsor will provide a sample ICF for modification, as appropriate, by 
each Investigator. The sample ICF must include all elements required by ICH E6(R2) GCP and 
must adhere to the IRB/EC requirements and ethical principles that have their origin in the 
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The Investigator's revision to the Sponsor's sample ICF, along with any other written study 
information to be provided to the patient, must be reviewed and approved by the IRB/EC. A 
copy of the IRB/EC-approved ICF to be utilized during the study must be submitted to the 
Sponsor (or designee) prior to study initiation. 
Prior to each patient's entry to the study, the Investigator or his/her staff will explain the nature 
of the study, its purpose and associated procedures, its expected duration, and the potential risks 
associated with participation. All questions about the trial will be answered to the satisfaction of 
the patient or the patient’s legal representative. The patient will be informed of the right to 
withdraw from the study at any time without consequence, and without having to provide a 
reason for this decision. Following the discussion, the patient will be asked if they are willing to 
personally sign and date the ICF. Only if the patient voluntarily agrees to sign the ICF and has 
done so, may he/she enter the study.   
It is the responsibility of the Investigator to obtain written informed consent from each patient, 
thereby attesting that consent was given freely in accordance with ICH E6(R2) GCP, the U.S. 
Title 21 CFR Part 50, or governing Health Authorities, as appropriate. An Investigator listed on 
the Form FDA 1572 will then co-sign the ICF. A copy of the signed and dated ICF will be 
provided to the patient. The original executed version must remain in the Investigator's file, per 
local requirements, and must be available for verification by a representative of the Sponsor (or 
designee). 
13.4 
Conditions for Modifying or Terminating the Study 
13.4.1 
Modification of the Study Protocol 
The study is to be conducted as described in this protocol. Departures from either the protocol 
eligibility criteria or the experimental plan, as outlined herein, will not be allowed. No protocol 
waivers will be granted.   
If modifications in the experimental design, dosages, assessments, patient selection, etc., of the 
protocol are indicated or required, such changes will only be instituted following consultation 
between the Sponsor (or designee) and Investigator and will be accomplished through formal 
amendment(s) to this protocol and approval by the appropriate regulatory authority (as indicated) 
and review committees, except where necessary to immediately eliminate apparent hazards to 
patients.   
A modification to the protocol will not be made without the express written approval of the 
Sponsor (or designee). Any amendment prepared by the Sponsor (or designee) will be 
implemented according to the Sponsor’s (or designee’s) standard operating procedures (SOPs) 
and will be reported to the appropriate regulatory authority, the appropriate IRB/EC, and made a 
formal component of the protocol document. 
Protocol changes to eliminate an apparent hazard to a trial patient may be implemented by the 
Investigator immediately. The Investigator must then, without delay, inform the local IRB/EC, 
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13.4.2 
Modification of the Informed Consent Form 
If modifications to the experimental design, dosages, assessments, patient selection, etc. of the 
protocol are indicated or required, and if such modifications substantially alter the study design 
or increase the potential risk to patients, the Sponsor (or designee) will prepare a revision to the 
existing sample ICF for modification, as appropriate, by each Investigator.  Any revision to the 
sample ICF prepared by the Sponsor (or designee) will be implemented according to the 
Sponsor’s (or designee’s) SOPs.  Such a revision will be reviewed and approved by the 
appropriate regulatory authority (as indicated) and IRB/EC.  
In addition, all current patients, as well as subsequent study candidates, will be informed of the 
study design modification or increase in potential risk, and written informed consent for the 
modification/risk will be obtained as outlined (Section 13.3). 
13.4.3 
Conditions for Termination of the Study or a Study Site 
The Sponsor reserves the right to terminate the study, or terminate a clinical trial site's 
participation in the study, at any time. Should the Sponsor, the Sponsor’s designee, and/or the 
Investigator(s) discover conditions that indicate the study or a study site should be discontinued, 
an appropriate procedure for termination will be instituted. Reasons for termination may include, 
but are not limited to, the following: 
• Termination of the Study 
o Safety concerns; incidence and/or severity of AEs in the study that indicate a 
potential health hazard or unexpected, serious, or unacceptable risk caused by the 
study treatment 
o Discovery of lack of efficacy 
o Unsatisfactory enrollment across the entirety of the trial 
o Drug supply or manufacturing issues 
o The Sponsor’s decision to modify or discontinue development of the study drug 
o A request to discontinue the study by a regulatory authority or Health Authority 
• Termination of a Study Site 
o Investigator non-compliance with the protocol, ICH E6(R2) GCP, or regulatory 
requirements 
o Unsatisfactory enrollment at the site with respect to quantity or quality 
o Incomplete data collection; inaccurate or knowingly false data submission 
If terminating the study, the Sponsor and Investigator(s) will ensure that adequate consideration 
is given to the protection of patients' interests. Further, the governing Health Authority and 
IRB/EC will be notified in writing and the reason for termination will be stated. 
13.5 
Trial Registration 
The trial will be registered in one or more public trial registries (e.g., ClinicalTrials.gov). The 
trial results will be posted in the same clinical trial registries as the initial registration in 


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accordance with the latest International Committee of Medical Journal Editors (ICMJE) 
recommendations (URL: www.icmje.org). 
13.6 
Insurance and Liability 
The Sponsor will obtain Human Clinical Trials Insurance for its legal liability in accordance with 
laws and regulations, and with limits customary or required by law in the territory in question. 


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14 INVESTIGATOR RESPONSIBILITIES 
14.1 
Medical Supervision 
An Investigator conducting a clinical study with an investigational agent is required to comply 
with regulations described in U.S. Title 21 CFR Parts 50, 56, and 312 and/or by governing 
Health Authorities, as well as ICH E6(R2) GCP. 
Medical supervision for the conduct of this protocol is the responsibility of the Principal 
Investigator. The Principal Investigator must name all Sub-Investigators and may delegate 
certain day-to-day activities to such Sub-Investigators, but retains overall responsibility for 
ensuring that the study is conducted properly and in accordance with the design and intent 
herein. A document outlining the specifics of the delegation will be maintained at the 
investigational site, in the study files, and will be updated as appropriate.   
The Principal Investigator is responsible for ensuring that drugs and devices are available for 
treating possible medical emergencies. The Principal Investigator is required to ensure 
compliance with respect to the study drug schedule, visit schedule, and procedures required by 
the protocol. The Principal Investigator is responsible for ensuring that the study is conducted 
according to sound medical practices. 
14.2 
Confidentiality 
All goods, materials, information (oral or written) and unpublished documentation provided to 
the Investigator (or any company acting on their behalf), inclusive of this protocol, the patient 
CRFs, and the IB, are the exclusive property of the Sponsor. Documents and information 
provided to the Investigator by the Sponsor may not be given or disclosed by the Investigator or 
by any person within his/her authority either in part or in totality to any unauthorized person 
without the prior written formal consent of the Sponsor. 
The submission of this protocol and other necessary documentation to the IRB/EC is expressly 
permitted; the IRB/EC members have the same obligation of confidentiality. 
The Investigator shall consider as confidential, and shall take all necessary measures to ensure 
that there is no breach of confidentiality, all information accumulated, acquired or deduced 
during the trial, other than that information to be disclosed to a third party mandated by 
applicable law. 
Note: 
Any language relating to these issues appearing in the clinical trial agreement will supersede that which is 
outlined in this section. 
14.3 
Use of Information 
All unpublished information relating to this trial and the study drug is considered confidential by 
the Sponsor and shall remain the sole property of the Sponsor. The Investigator must accept that 
the Sponsor may use information from this trial relating to the development of the study drug, 
and therefore, may disclose it as required to Investigators, government-licensing authorities, 
Health Authorities of other governments, investors, and commercial partners as indicated. 


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14.4 
Publications 
The Sponsor acknowledges the Investigators’ rights to publish the full results of the trial, 
regardless of the outcome, in accordance with the latest ICMJE recommendations. Publication of 
a summary of the results of the study is permissible according to the Sponsor and is not 
inconsistent with the preceding affirmation regarding confidentiality. Scientific dissemination of 
the results of this study is encouraged. Any formal publication of data collected from the study 
will be considered a joint publication by the Investigator and the appropriate personnel of the 
Sponsor or their designees. Authorship will be determined by agreement.   
The Sponsor retains the right to designate one of the authors or someone else involved to be 
named as the Coordinating Investigator. The Coordinating Investigator and the Sponsor will 
decide on the publication strategy. The Coordinating Investigator will have the right to publish 
and present the results and methods as first or last author of multicenter publications. Co-
authorship will be decided by the Sponsor and the Coordinating Investigator and will be limited 
to persons who have contributed substantially to the trial. The Sponsor will have representation 
in the list of authors. 
Publication is subject to the following conditions:   
• No publication before the completion of the trial at all participating trial sites without 
preceding written approval from the Sponsor 
• Publications shall not disclose any Sponsor confidential information and property (not 
including the trial results) 
• The Sponsor reserves the right to review results communications prior to public release 
and can embargo communications regarding trial results for a period that is less than or 
equal to 60 days. The Sponsor cannot require changes to the communication and cannot 
extend the embargo. 
Note:   Any language relating to these issues appearing in the Clinical Trial Agreement will supersede that which 
is outlined in this section. 
14.5 
Patient Screening Log 
A record listing all patients entered into the study, as well as those considered for entry into the 
study and subsequently excluded, must be maintained by the Investigator. Patients excluded from 
the study will have the reason for exclusion recorded on the Patient Screening Log (or similar 
document).  
14.6 
Drug Dispensing Inventory 
Study site personnel will maintain adequate records of the receipt, dispensing, and disposition of 
all study drug that the Sponsor ships to the site. Records will be maintained either on a form to 
be provided by the Sponsor or another similar document authorized for use by the Sponsor, and 
should include appropriate dates, quantities received, quantities dispensed, lot number (or kit 
number), disposition details, and the identification code of the patient who received the study 
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The Investigator agrees to administer study drug only to patients under his/her personal 
supervision.  The Investigator will not supply study drug to any person not authorized to receive 
it. 
14.7 
Handling and Disposal of Study Drug 
Study drug should be stored in a secure location, under the indicated conditions (Section 5.2). 
Information regarding the number of vials utilized for each patient, as well as the dose of study 
drug administered to the patient, will be recorded on the appropriate drug inventory form. 
Periodically throughout and at the conclusion of the study, vials of study drug will be inventoried 
by a representative of the Sponsor (or designee). At the completion of the study, all unused study 
materials MUST be returned to the Sponsor (or designee), unless otherwise authorized in 
writing.  
Information regarding the storage, handling, inventory, and disposition of study drug will be 
provided by the Sponsor (or designee).   
14.8 
Recording of Data 
Clinical trial data for this study will be captured in an electronic format. Electronic data capture 
(EDC) services will be provided by a vendor to be determined by the Sponsor. The Investigator 
agrees to provide all information requested in the CRF in an accurate manner according to 
instructions provided. CRFs are designed for computer processing and analysis. All data must be 
carefully entered to permit meaningful interpretation. Corrections to entered data will be 
identified and tracked by audit trails within the EDC system. Data must be entered into CRFs in 
a timely fashion. 
A CRF is required to be submitted for every patient who receives any amount of study drug.  
This includes submission of retrievable data on patients who withdraw before completion of the 
study. Prior to submission, CRFs must be reviewed for completeness and accuracy, and signed 
and dated where indicated, by either the Principal Investigator or a physician Sub-Investigator 
whose name is listed on the Form FDA 1572 for this study. 
All collected data will be entered into a validated database. 
14.9 
Source Document Requirements 
The Investigator will maintain adequate and accurate records for each patient treated with study 
drug. Source documents including but not limited to hospital, clinic or office charts, laboratory 
reports, radiology and pathology reports, pharmacy records, study worksheets, anonymized 
photographs aimed at documenting study-associated clinical findings, and signed ICFs, must 
completely reflect the nature and extent of the patient’s medical care, must be included in the 
Investigator’s files along with patient study records, and must be available for source document 
verification against entries in the CRF.    
Each trial site will permit authorized representatives of the Sponsor and relevant Health 
Authorities direct access to (and when required by applicable law, to copy) clinical records for 
the purposes of quality assurance reviews, audits, and evaluation of the trial safety and progress. 
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guidelines of ICH E6(R2) GCP. Data not requiring a separate written record, i.e., data which 
may be recorded directly in the CRF, will be determined before trial start. 
The ICF will include a statement by which patients allow the Sponsor (or designee), as well as 
authorized regulatory agencies, to have direct access to source data that support data in the CRF 
(e.g., patient medical files, appointment books, original laboratory records, etc.). The Sponsor (or 
designee), bound by confidentiality and privacy regulations, will not disclose patient identities or 
personal medical information. 
14.10 Laboratory Reports 
Prior to initiation of this study, the Investigator must supply the Sponsor (or designee) with the 
normal laboratory values for the laboratories to be utilized; specifically, the normal laboratory 
values for analytes required to be measured, per protocol, are to be supplied.   
Laboratory safety evaluations must be performed at the intervals specified.  If unexplained 
laboratory abnormalities occur, corroborative tests will be performed until the laboratory 
abnormality has resolved, returned to baseline status, and/or adequate explanation of the 
abnormality has been provided. 
Copies of any additional records pertinent to the study (e.g., laboratory data, radiological reports, 
patient chart summaries, autopsy reports) must be made available to the Sponsor (or designee) or 
governing Health Authorities, if requested, with due precaution taken to ensure patient 
confidentiality. 
14.11 Record Retention 
Regulatory authorities require that the Investigator retain copies of all files pertaining to the 
study according to local requirements. In addition, the Investigator is responsible for archiving 
all relevant source documents so that trial data may be compared against source data after 
completion of the trial, e.g., in case of inspection from authorities. Study records must be stored 
in a safe and secure location permitting timely retrieval, if necessary. The Investigator must 
obtain written permission from the Sponsor prior to disposing of any records. 
If the Investigator relocates, retires, or withdraws for any reason from the study, trial records 
may be transferred to an acceptable designee, such as another Investigator within the institution. 
The Sponsor (or designee), as well as the responsible IRB/EC, must be notified of the identity of 
the individual assuming responsibility for maintaining the study records and the location of their 
storage.   
14.12 Monitoring of the Study 
The Sponsor has responsibility to governing Health Authorities to take all reasonable steps to 
ensure the proper conduct of the study with respect to trial ethics, protocol adherence, and data 
integrity and validity. 
This study will be closely monitored by representatives of the Sponsor (and/or designee) 
throughout its duration. Monitoring will be in the form of periodic personal visits with the 
Investigator and his/her staff as well as any appropriate communications by telephone, telefax, 
mail, or e-mail transmission. The purpose of these contacts is to review study progress, 
Investigator and patient adherence to protocol requirements, and any emergent problems 


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associated with the conduct of the study. The following usually will be assessed during 
monitoring visits at the site: 
• Required regulatory documentation 
• Signed ICFs 
• Patient accrual and follow-up 
• Study drug inventory records 
• Investigator and patient compliance to the study protocol 
• Concomitant therapy usage 
• AE documentation  
• Data is accurate, complete, and verifiable when compared to source documents 
The Investigator and study staff are expected to cooperate with monitors during such visits and 
provide them with all relevant study documents. The Investigator must give the Sponsor (and/or 
designee) direct access to all relevant source documents to confirm consistency with the CRF 
entries. It is important that the Investigator and relevant personnel are available during 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
In addition, the study may be evaluated by Sponsor auditors (and/or designees) and government 
inspectors who must be allowed access to CRFs, source documents, and other study files. 
Sponsor reports will be kept confidential. The Investigator should promptly notify the Sponsor of 
any audits scheduled by any regulatory authorities, and promptly forward copies of audit reports. 
As applicable, in accordance with the Health Insurance Portability and Accountability Act 
(HIPAA) and associated privacy regulations, patient authorization to use personally identifiable 
health information may be required from each patient before research activities. This 
authorization document must clearly specify what parties will have access to a patient’s personal 
health information, for what purpose, and for how long. 
14.13 Patient Confidentiality 
Every effort will be made to maintain the anonymity and confidentiality of patients during this 
clinical study. Each participating site will maintain appropriate medical and research records for 
this trial, in compliance with ICH E6(R2) GCP, regulatory, and institutional requirements for the 
protection of confidentiality of patients.   
Coded patient identifiers will be utilized always (including in any publications) when referring to 
a patient. However, because of the experimental nature of this treatment, the Investigator agrees 
to allow representatives of the Sponsor (and/or designee), as well as authorized representatives of 
the governing Health Authority, to inspect the facilities used in this study and to inspect, for 
purposes of verification, the hospital or clinic records of all patients enrolled into this study. A 
statement to this effect should be included in the ICF. 


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14.14   
Financing and Insurance 
The study will be supported by the Sponsor. Specifics of the financing and insurance coverage 
will be addressed in the clinical study agreement between the Sponsor and the Investigator or 
Institution. 


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15 HANDLING AND PROCESSING OF DATA 
15.1 
Data Handling 
Study data collection, processing, transfer, and reporting, as well as handling of study personnel 
information, will be in compliance with ICH E6(R2) GCP and all applicable data protection 
regulations, including Regulation (EU) 2016/679 of the European Parliament and of the Council 
of 27 April 2016 on the protection of natural persons with regard to the processing of personal 
data and on the free movement of such data (General Data Protection Regulation). 
15.2 
Data Review During this Study 
Data obtained from the study will be reviewed in a timely manner throughout by the Sponsor (or 
designee) and Sponsor's Medical Representative(s) to assess safety and the progress of the 
project. 
15.3 
Data Processing 
A Data Management Plan (DMP) will be prepared for this trial. The Sponsor (or designee) will 
be responsible for data processing in accordance with applicable Data Management SOPs and 
the trial DMP.  
Once recorded within the electronic CRF, study data will pass through a set of pre-programmed 
data validation checks designed to identify inconsistencies and other data errors, and also will 
undergo an additional study-specific data review process, as stated above in Section 15.2.  Data 
issues will be queried via the EDC system and query resolutions will be documented.  
Entry and processing of data other than those directly recorded on electronic CRFs by trial sites 
(e.g., imports of laboratory results) will follow vendor(s) SOPs. Transfer of such data from 
vendor(s) to Sponsor (or designee) will be handled according to vendor(s) data transfer SOPs and 
the Sponsor data transfer requirements with full compliance to applicable regulations. 
Database Lock will occur upon reaching the pre-defined data cut-off for primary analysis and 
completion of Sponsor’s (or designee’s) quality control and quality assurance procedures. 
Portable Document Format (PDF) files of the electronic CRFs will be provided to the 
Investigator upon removal of access to the electronic CRFs. 
15.4 
Clinical Trial Report 
Following study completion, a final integrated clinical/statistical Clinical Trial Report (CTR) 
will be prepared.  
15.5 
Compliance with the General Data Protection Regulation 
The applicable data protection legislation requires that parties enter into a written contract if one 
party (data processor) processes personal data on behalf of the other party (data controller). This 
written contract must regulate the subject-matter and duration of the processing, the nature and 
purpose of the processing, the types of personal data and categories of data subjects, as well as 
the obligations and rights of the data controller. Accordingly, the parties must enter into a data 
processing agreement. To the extent the processing of personal data involves transfers of 
personal data to third countries (e.g., jurisdictions outside of the European Economic Area 
[EEA]), the parties will enter into the European Commission's standard contractual clauses 


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between the data controller, the data processor, and all sub-processors, if any. The European 
Commission's standard contractual clauses ensure an adequate level of protection in relation to 
transfers of personal data to third countries. 
 


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16 STATISTICAL ANALYSIS  
16.1 
Statistical Considerations 
A Statistical Analysis Plan (SAP) that includes a more technical and detailed description 
(including templates for Tables, Listings, and Figures) of the planned statistical summaries 
analyses will be prepared and finalized prior to database lock. 
Further data-driven and exploratory analyses may be defined and performed and presented in the 
CTR as appropriate.   
16.2 
Sample Size Considerations 
Approximately 20-48 male and female patients will be enrolled and treated, based on a modified 
accelerated titration Phase 1 design (more specifically, up to 2 single patient cohorts, followed by 
a standard 3+3 design), to allow determination of the MTD and/or RP2D. It is assumed that 
approximately 7 cohorts may be required during the dose-escalation. However, the protocol 
allows for enrollment of > 7 cohorts, should this be necessary to identify the MTD and/or RP2D. 
Expansion of the MTD/MAD cohort to treat up to 12 patients may be considered for further 
evaluation of tolerability.   
16.3 
Analysis Populations 
Two analysis sets will be defined in accordance with the consolidated guidelines, ICH E9 
Statistical Principles for Clinical Trials.  
The Full Analysis Set (FAS) will comprise all enrolled patients who have received at least a 
fraction of one dose of study drug. The FAS will be used for evaluation of all endpoints except 
evaluation of DLTs. The patients in the FAS will contribute to the analyses as allocated to 
treatment. For the evaluation of PK endpoints, patients, full profiles, or single measurements can 
be excluded from the analyses. The decision of excluding patients, full profiles, or part of 
profiles will be described in the CTR. 
The DLT Analysis Set will comprise all patients in the FAS enrolled in the dose-escalation, 
except patients who did not complete Cycle 1 for reasons other than drug toxicity. The DLT 
Analysis Set will be used for evaluation of DLTs.   
16.4 
Trial Endpoints 
16.4.1 
Primary Endpoints 
DLTs to establish MTD as defined in Section 6.9, and/or the RP2D as defined in Section 6.6.3, 
will be the primary study endpoint.  RP2D will be determined by: 
• Incidence, severity, and relationship of treatment emergent AEs measured from 
administration of the first dose of study drug or worsening after taking study drug, to the 
last dose of study drug plus 30 days  
• AEs leading to dose interruption, dose delays, dose reduction, and permanent treatment 
cessation 
• Changes in safety laboratory values from baseline to end of safety follow up 
 


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16.4.2 
Secondary Endpoints  
• Additional safety endpoints, including: 
o Exposure to study medication, including duration, dose reduction and/or delay 
o Changes in vital signs, body weight, and physical examination findings from 
baseline to end of trial participation 
o ECG Findings 
• Occurrence of ADA measured in serum at selected timepoints from baseline to end of 
trial participation 
• Antineoplastic Activity, measured by tumor response to study treatment and tumor 
shrinkage, time to progression (TTP) based on radiological evident as per RECIST v1.1 
and relevant lymphomas assessment criteria. 
• PK profile of study drug, derived based on the concentration-time curves after the first 
infusion 
16.5 
Statistical Analysis 
16.5.1 
General Specifications 
Statistical analyses will be carried out using Statistical Analysis System (SAS®) Version 9.4 or 
higher. 
All data summaries and statistical analyses will be performed based on the FAS population, 
unless otherwise specified. 
In general, continuous variables, including baseline characteristics, will be summarized using 
descriptive statistics by reporting the number of observations, mean, standard deviation, median, 
minimum, and maximum. Categorical/discrete variables will be summarized using frequency 
distributions showing the number and percentage of patients within a category.  Time-to-event 
data will be summarized using the Kaplan-Meier method, as appropriate. 
Unless indicated otherwise, summary statistics will be presented using observed data only. 
Missing data will not be imputed. If a baseline value is missing, no change from baseline will be 
calculated. Baseline is defined as the last available observation prior to the first administration of 
study drug on C1/D1. 
16.5.2 
Patient Disposition, Baseline and Treatment Characteristics 
Patient disposition, including withdrawals of patients from study drug and reason, will be 
summarized using frequency distributions.  
Patient demographics, baseline and disease characteristics such as age, sex, race, cancer type, 
prior anti-cancer therapies, and ECOG PS, will be presented using descriptive statistics or 
Frequency distributions, as appropriate. 


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16.5.3 
Study Treatment 
Exposure to study drug and the administration profile will be summarized descriptively for each 
cohort with respect to number of cycles taken, the cumulative dose, the dose intensity, the 
relative dose intensity, and dose modifications. 
16.5.4 
Maximum Tolerated Dose 
All DLT events will be listed by dose cohort and patient. A summary table of DLTs across dose 
cohorts by System Organ Class (SOC) and preferred term will be presented, if applicable. The 
summaries will include number of DLTs, and number and percentages of patients experiencing a 
DLT. 
A table will be presented showing the MTD, if identified, as well as a summary of the dose-
escalation. 
16.5.5 
Adverse Events 
AEs will be coded by SOC and preferred term using the most current version of MedDRA.   AEs 
including SAEs will be recorded starting at signing of informed consent* through 30 days 
following the last dose of study drug (1M FUP Visit), and will be tabulated by maximum 
severity according to the CTCAE v5.0.   
*Patients who sign informed consent and are subsequently deemed to be screen failures will be followed for the 
occurrence of SAEs/AEs until it is determined that they will not be participating in the trial 
AEs will be regarded as TEAEs if they occur after first treatment. Non-treatment emergent AEs 
(non-TEAEs) are defined as AEs collected before administration of the first dose. If non-TEAEs 
increase in frequency or severity after treatment, these will be considered TEAEs. TEAEs will be 
presented by SOC and preferred term unless stated otherwise. The frequencies of TEAEs will be 
presented including number and percentages of patients having experienced an event and the 
total number of events. 
The calculation of AE incidence will be based on the number of patients per AE category. For 
each patient who has multiple AEs classified to the same category, that patient will be tabulated 
under the highest toxicity grade for that AE category. Summary tables will be presented by: 
1. AEs, in total and sorted by frequency  
2. AEs by relationship 
3. AEs by grade and maximum grade 
4. SAEs, in total, and by relationship 
5. AEs leading to dose interruption, dose delays, dose reduction, and permanent treatment 
cessation 
6. AEs leading to trial drug delay  
7. Fatal AEs 
During dose-escalation, first-cycle DLTs, AEs leading to death or to discontinuation of study 
treatment, and SAEs will be evaluated with special attention. 


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16.5.6 
Laboratory Determinations 
Biochemistry, hematology, and coagulation parameters will be presented using box plots, if 
appropriate.  In addition, individual patient biochemistry, hematology, and coagulation 
parameters during the trial will be presented graphically using longitudinal plots. Urinalysis 
parameters will be summarized using descriptive statistics.   
Laboratory measurements will be graded according to CTCAE v5.0, when applicable. The 
frequencies of the highest CTCAE v5.0 grade observed will be displayed for each AE and for 
each starting dose level.   
Laboratory values outside normal range will be flagged and laboratory values will be listed 
including grading of abnormal values. Laboratory determinations categorized as in or out of 
normal range may be summarized in some cases using worst-case shift tables. CS or not 
clinically significant (NCS) criteria may be applied for out-of-range values. 
16.5.7 
Vital Signs, Body Weight, Physical Exam Findings 
Actual values and change-from-baseline values for VS, body weights, PS, as well as physical 
examination findings, will be summarized descriptively. Normal and abnormal findings in 
physical examination will be presented in shift tables by visit, if appropriate. 
16.5.8 
ECG Findings 
Descriptive statistics of ECG observations will be presented. The frequency and percentage of 
ECG results will be summarized for the following ECG measurements:  HR, PR interval, QRS 
duration, QT interval, and QTc interval. The QTc interval, indicating repolarization time, will be 
calculated. T-wave and ST-segment ECG abnormalities will be graded based on definitions in 
the Common Toxicity Criteria (CTC).   
Normal and abnormal findings will be presented in shift tables by visit. Additional details 
regarding the ECG analyses will be provided in the SAP. 
16.5.9 
Other Safety Data 
Concomitant medications and findings in ophthalmology examinations, PFTs, thyroid function 
tests, and ADA analyses will be summarized in text as recorded in the CRF, and as made 
available from an independent central assay laboratory, in the case of ADA data. 
16.5.10 Antineoplastic Activity  
All antineoplastic activity analyses will be descriptive and exploratory in nature. Disease status 
will be summarized by cycle and dose group, including changes from baseline. As a secondary 
objective, OR, duration of OR, SD, and TTP will be assessed and calculated, wherever possible, 
according to standard response criteria.    
Response Calculations 
In the event of an OR (CR or PR) the duration of the OR will be determined from the day the 
initial response is observed (using screening/baseline images for comparison) to the day that 
progression is observed. Number and percentages of patients with documented OR will be 
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Duration of SD (minimum duration of not less than 16 weeks) will also be assessed using the 
time from the first dose of study drug to the day that PD is confirmed based on radiological 
evidence or censored at the last on-study tumor assessment without PD. The number and 
percentages of patients with SD for more than 16 weeks will be presented. 
Best overall response will be summarized by cohort using frequency distribution. 
Waterfall plots will be presented for patients with measurable disease. 
TTP calculated as from the first dose of study drug to the day that PD is confirmed based on 
radiological evidence or censored at the last on-study tumor assessment without PD will be 
presented in a Kaplan-Meier plot, as appropriate.   
Other Antineoplastic Assessments 
Tumor markers will be listed and summarized, as appropriate. 
16.5.11 Pharmacokinetic Analysis 
PK analyses will be performed in dose-escalation cohorts on patients who receive any amount of 
their assigned dose of study drug and have an adequate number of concentration determinations 
to allow for PK calculation. 
The PK profile of study drug will be derived based on the concentration-time curves after the 
first infusion. Cmax, CEOI, Ctrough and Tmax will be derived from observed data while AUCinf, 
AUCτ, AUCnorm, τ, CL, Vd, and T½ will be estimated using non-compartmental methods and 
actual timepoints.  For repeated dosing, CEOI and Ctrough (equivalent to the concentration at EOI 
and SOI, respectively) will be assessed. 
Individual curves of serum concentration of total study drug versus time after the first infusion 
will be presented on log- and linear scale for all patients in the PK population. Furthermore, 
maximum and trough serum concentrations for the period from first dose to EOT will be 
presented on linear scale individual plots. In addition, mean concentration-time curves will be 
presented on linear scale using nominal timepoint by cohort and trial part. All PK endpoints will 
be listed and summarized by trial part and cohort (Table 5).  
 
 
 


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Table 5:  PK Endpoint, Definitions, and Derivations 
Symbol 
Definition and Derivation 
Ctrough 
Trough concentration (i.e., concentration of study drug measured pre-infusion) 
AUCinf 
Area under the concentration-time curve from start of infusion to infinity 
AUCτ 
Area under the concentration-time curve from start of infusion up to 336 hours.  
AUCnorm, τ 
 
Dose-normalized area under the concentration-time curve in a dosing interval, calculated as AUC τ divided by the 
dose infused 
Cmax 
Maximum concentration 
Tmax 
Time to maximum concentration 
CEOI 
Concentration at the end of infusion 
λz 
Terminal rate constant (negative of the slope of an ln-linear regression of the un-weighted data considering the 
terminal phase of the concentration-time curve ≥ limit of quantification). λz is not an endpoint, but is used for 
derivation of endpoints 
T½ 
Terminal elimination half-life, calculated as ln(2)/ λz 
CL 
Clearance after first dose, calculated as Dose/AUCinf for C1/D1, where AUCinf will be calculated as the sum of 
the area from time zero to time of last quantifiable concentration, tz, and the area from tz to infinity. The second 
area will be estimated using the observed concentration at tz and the terminal rate constant  
Vd 
Volume of distribution during the terminal phase after first dose (CLS/ λz) 
 
16.6 
Additional Endpoints and Analyses 
16.6.1 
Pharmacodynamic and other Biomarker Analyses 
Pharmacodynamic and other biomarker assessments, to include collection of peripheral blood, 
will be conducted in all patients. Tumor biopsies are optional and biomarker analysis of biopsied 
tumors may be performed on material collected.    
Exploratory analysis may be performed. Endpoints may include genes and/or proteins that are 
unknown or have not been included in the scientific hypotheses at the time of the trial, but that, 
during the collection of data from this trial, may evolve as new candidate genes and markers 
related to safety, efficacy, or mechanism of action of the study drug. 
Pharmacodynamic and other biomarker analyses will be performed according to standard 
methodologies and will examine relationships between the pharmacodynamic/biomarker 
assessments and clinical toxicities observed during the study.  
16.7 
Modeling of Pharmacokinetic and Pharmacodynamic/Biomarker Data 
PK samples will be analyzed on an on-going basis during the trial. All data collected in this trial 
may be used for modeling of PK, pharmacodynamic and other biomarker assessment to support 
the planning and dose setting within the current trial as well as for future trials. Preliminary data 
generated during the trial may be used for exploratory modelling. The final data (i.e., after 
Database Lock) will be used for the final model and potentially for cross-trial modelling. These 
modelling activities will be reported separately from the current trial. 
16.8 
Deviations from the Statistical Plan 
Any deviation(s) from the original analysis plan will be described in a protocol amendment 
and/or in the SAP and/or in the final CTR, as appropriate. 


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16.9 
Interim Analysis 
Safety evaluation will be performed prior to each dose-escalation. No other interim analyses are 
planned. 
All relevant safety, PK, and toxicity data will be reviewed on an ongoing basis throughout the 
trial.  Based on an overall evaluation of data collected, the RP2D will be chosen. 


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17 REFERENCES 
1. WHO World Cancer Report 2014. Edited by Bernard W. Stewart and Christopher P. Wild.  
2. Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of 
negative checkpoint regulators. Front Immunol. 2015; 6: 418. 
 
3. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory 
receptors with specialized functions in immune regulation. Immunity 2016; 44(5): 989-1004. 
 
4. Du W, Yang M, Turner A, et al. TIM-3 as a target for cancer immunotherapy and 
mechanisms of action. Int. J. Mol. Sci. 2017; 18(645): 1-12. 
 
5. Ngiow SF, von Scheidt B, Akiba H, et al. Anti-TIM3 antibody promotes T cell IFN-γ–
mediated antitumor immunity and suppresses established tumors. Cancer Res 2011; 71 (10): 
3540–3551. 
 
6. Sakuishi K, Apetoh L, Sullivan JM, et al. Targeting Tim-3 and PD-1 pathways to reverse T 
cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 2010; 207(10): 2187–2194. 
 
7. Weiss GJ, Luke JJ, Falchook G, et al. Abstract O13: A phase 1 study of TSR-022, an anti-
TIM-3 monoclonal antibody, in patients (pts) with advanced solid tumors. J Immunother. 
Cancer 2017, 5 (Suppl 2); 86: 7. 
 
8. Weiss GJ, Luke JJ, Falchook G, et al. A phase 1 study of TSR-022, an anti-TIM-3 
monoclonal antibody, in patients with advanced solid tumors. Presented at Society of 
Immunotherapy of Cancer Annual Meeting, November 8-12, 2017. 
 
9. Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017. 
 
10. Keytruda (pembrolizumab) [package inset]. Whitehouse Station, NJ: Merck & Co., Inc; 
2017. 
 
11. Tecentriq (atezolizumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2017. 
 
12. Bavencio (avelumab) [package insert]. Rockland, MA; EMD Serono, Inc.; 2017. 
 
13. Imfinzi (durvalumab) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 
2017. 
 
14. Postow M and Wolchok J. Toxicities associated with checkpoint inhibitor immunotherapy. 
UpToDate 2017; 13.57: 1-21. 
 
15. Adbel-Wahab N, Sha M, and Suarez-Almazor ME. Adverse events associated with immune 
checkpoint blockade in patients with cancer: a systematic review of case reports.  PLoS ONE 
2016; 11(7): e0160221. 
 


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16. Heinzerling L and Goldinger SM. A review of serious adverse effects under treatment with 
checkpoint inhibitors. Current Opinion-Oncol. 2017; 29: 1-9. 
 
17. Kumar V, Chaudhary N, Garg M, et al. Current diagnosis and management of immune 
related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Frontiers in 
Pharmacol. 2017; 8: 1-14. 
 
18. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol. 2017; 18: e143-e152. 
 
19. Litière S, Collette S, de Vries EGE, et al. RECIST-learning from the past to build the future. 
Nature Reviews-Clinical Oncol. 2017; 14: 187-192. 
 
20. Bumbaca D, Xiang H, Boswell CA, et al. Maximizing tumour exposure to anti-neuropilin-1 
antibody requires saturation of non-tumour tissue antigenic sinks in mice. Br J Pharmacol. 
2012; 166(1): 368-377. 
 
21. Kaiser PK. Prospective evaluation of visual acuity assessment: a comparison of Snellen 
versus ETDRS charts in clinical practice (an AOS thesis). Trans Am Ophthalmol Soc. 2009; 
107:311-324. 
 
 


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18 APPENDICES 
Appendix 1 
Performance Status Evaluation 
 
 
Measures of Performance Status 
 
 
Percent 
 
KARNOFSKY  
Performance Status Description1 
 
 
 
Level 
 
Eastern Cooperative Oncology Group 
(ECOG)  
Performance Status Description2 
 
 
100 
 
Normal; no complaints, no evidence of 
disease 
 
 
0 
 
 
 
Normal activity 
 
90 
 
Able to carry on normal activity; minor signs or 
symptoms of disease 
 
 
80 
 
Normal activity with effort; some signs or 
symptoms of disease 
 
 
1 
 
 
 
Symptoms but ambulatory 
 
70 
 
Cares for self; unable to carry on normal activity or 
do active work 
 
 
60 
 
Requires occasional assistance but is able to care 
for most needs 
 
 
2 
 
 
 
In bed < 50% of time 
 
50 
 
Requires considerable assistance and frequent 
medical care 
 
 
40 
 
Disabled; requires special care and assistance 
 
 
3 
 
 
 
In bed > 50 % of time 
 
30 
 
Severely disabled; hospitalization is indicated 
although death is not imminent 
 
 
20 
 
Very sick; hospitalization is necessary 
 
 
 
4 
 
 
 
100 % bedridden 
 
10 
 
Moribund; fatal processes progressing rapidly 
 
 
0 
 
Death 
 
 
 
5 
 
Death 
 
1Karnofsky DA, Abelman WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the palliative treatment of carcinoma.  Cancer. 
1948;1:634-656. 
2Oken M, Creech RH, Tormey DC, Horton J, Davis TE, McFadden E, Carbone PP. Toxicity and response criteria of the eastern cooperative 
oncology group.  Am J Clin Oncol. (CCT) 1982; 5:649-655. 
 
 


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Appendix 2 
New York Heart Association Functional Criteria 
 
 
New York Heart Association Functional Criteria 
 
 
Class I 
 
No limitation of physical activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
 
 
Class II 
 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
 
 
Class III 
 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
 
 
Class IV 
 
 
Unable to carry on any physical activity without discomfort.  Symptoms of cardiac insufficiency or 
anginal syndrome may be present even at rest.  If any physical activity is undertaken discomfort 
increases. 
 
 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great 
Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256 
 


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Appendix 3 
Clinical Adverse Events: Grading Scale 
 
Severity 
CTCAE* 
Grade 
Definition 
Mild 
1 
Awareness of symptom, but easily tolerated.  Event is usually transient requiring 
no special treatment; does not interfere with usual status or activities 
 
Moderate 
2 
Event may be ameliorated by simple therapeutic measures; may interfere with 
usual activities 
 
Severe 
3 
Event results in temporary disability or incapacity; inability to perform usual 
activities; requires intervention 
 
Life-threatening 
4 
Event requires immediate intervention; need for emergency treatment; patient is at 
risk of death at the time of the event 
 
Fatal 
5 
Event resulting in the subsequent death of the patient 
 
 
Note: 
In those cases where further definition of an event is provided by the Common Terminology Criteria for Adverse Events 
(CTCAE v5.0), please refer to that document for grading and severity information. 
*< https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm > 


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Appendix 4 
Clinical Adverse Events: Determining Relationship to Study Drug 
 
NOT-RELATED 
This category applies to those AEs which, after careful medical consideration, are clearly felt to be due to extraneous causes 
(disease, environment, etc.) that are not-related to the administration of study drug. 
UNLIKELY-RELATED (must have first 2) 
This category applies to those AEs which, after careful medical consideration, are felt unlikely to be related to the administration 
of the study drug.  The relationship of an AE to the study drug can be considered unlikely if: 
• 
It does not follow a reasonable temporal sequence from administration of the drug. 
• 
It could readily have been a result of the patient’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the patient. 
• 
It does not follow a known response pattern to the suspected drug. 
• 
It does not reappear or worsen when the drug is re-administered. 
 
POSSIBLY-RELATED (must have first 2) 
This category applies to those AEs which, after careful medical consideration, are felt unlikely to be related to the administration 
of the study drug, but the possibility cannot be ruled out with certainty.  The relationship of an AE to the study drug can be 
considered possible if: 
• 
It follows a reasonable temporal sequence from administration of the drug. 
• 
It could readily have been a result of the patient’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the patient. 
• 
It follows a known response pattern to the suspected drug. 
 
PROBABLY-RELATED (must have first 3) 
This category applies to those AEs which, after careful medical consideration, are felt with a high degree of certainty to be 
related to the administration of the study drug.  The relationship of an AE to the study drug can be considered probable if: 
• 
It follows a reasonable temporal sequence from administration of the drug.  
• 
It could not be reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
• 
It disappears or decreases upon cessation of drug or reduction in dose (if applicable).* 
• 
It follows a known response pattern to the suspected drug. 
 
RELATED (must have first 3) 
This category applies to those AEs, which, after careful medical consideration, are felt to be related to the administration of the 
study drug.  The relationship of an AE to the study drug can be considered related if: 
• 
It follows a reasonable temporal sequence from administration of the drug or drug levels have been established in body 
fluids or tissues. 
• 
It could not be reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
• 
It disappears or decreases upon cessation of drug or reduction on dose (if applicable) and appears upon rechallenge.* 
• 
It follows a known response pattern to the suspected drug. 
 
Adapted from:  Karch FE and Lasagna L. Adverse drug reactions: a critical review. JAMA. 1975 Dec 22; 234 (12):1236-1241.  
 
*There are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-relatedness clearly exists, e.g., 
1) tardive dyskinesia, 2) fixed drug eruptions. 
 
 


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Appendix 5 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
 
Summary of RECIST v1.1 Guidelines 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In addition to a baseline scan, 
confirmatory scans should also be obtained > 4 weeks following initial documentation of objective response (OR). 
 
Response and progression will be evaluated in this study using the new international criteria proposed by the revised 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in 
the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST v1.1 criteria. 
 
A. DEFINITIONS 
 
Evaluable for Toxicity:  All patients will be evaluable for toxicity from the time of their first treatment with study drug.   
Evaluable for Objective Response:  Only those patients who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.  These patients 
will have their response classified according to the definitions stated below.   
 
Note:        Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable. 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are evaluable but do not meet 
the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
B. DISEASE PARAMETERS 
 
Measurable Disease:  Measurable lesions are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥10 mm with CT scan, or as ≥10 mm with calipers by 
clinical exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note:  
Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable.   
If the investigator thinks it appropriate to include them, the conditions under which such lesions should be considered must be 
defined in the protocol. 
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 at 
follow-up, only the short axis will be measured and followed. 
Non-Measurable Disease:  All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI) are considered as non-measurable. 
 
Note:  
Cystic 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 non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
 
Target Lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline.  Target lesions should be 
selected based on 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 


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measured reproducibly should be selected.  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 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. 
 
Non-Target Lesions:  All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline.  Measurements of these lesions 
are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout 
follow-up. 
 
C. METHODS FOR EVALUATION OF MEASURABLE DISEASE 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
Note: 
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at 
baseline and during follow-up.  Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest X-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by 
aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline defines measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g., for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; however, there are many 
image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications 
of the scanning sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed 
on the same pulse sequence.  It is beyond the scope of the RECIST v1.1 guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal 
diagnostic CT quality for use with RECIST v1.1 measurements.  However, if the site can document that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST v1.1 measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces additional data 
which may bias an Investigator if it is not routinely or serially performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement.  
Ultrasound examinations cannot be reproduced in their entirety for independent review later, and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next.  
If new lesions are identified by ultrasound during the study, confirmation by CT or MRI is advised.  If there is concern about 
radiation exposure using CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is not advised.  However, 
such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. 
 


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Tumor Markers:  Tumor markers alone cannot be used to assess response.  If markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in complete clinical response.  Specific guidelines for both CA-125 
response (in recurrent ovarian cancer) and prostate specific antigen (PSA) response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses (PR) and complete responses 
(CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use 
of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease).  New 
lesions based on FDG-PET imaging can be identified according to the following algorithm:  
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion. 
b. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:   
• 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.   
• 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will 
be the date of the initial abnormal FDG-PET scan).   
• 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing based on the anatomic images, this is not PD. 
c. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring.  The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false positive CR due to limitations 
of FDG-PET and biopsy resolution/sensitivity. 
 
Note: 
A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image. 
D. RESPONSE CRITERIA 
 
1. 
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 < 10 mm. 
 
 Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 
 
 Progressive Disease (PD):  At least a 20% increase in the sum of the 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 progressions. 
 
 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. 
 
2.  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 (< 10 mm short axis). 


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Note:  
 If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
 
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):  Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions.  Unequivocal progression should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status should be confirmed later by the review panel (or Principal 
Investigator). 
 
3.  
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥ 4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
≥ 4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/Not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/Not evaluated 
No 
SD 
Documented at least once  
≥ 4 wks. from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST v1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
 
Note:   Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
 
Abbreviations (in alphabetical order):  CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/Non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*   Non-CR/non-PD is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials, so to assign this category when no lesions can be measured is not 
advised. 
 
Abbreviations (in alphabetical order):  CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease 
 
 
 


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E. DURATION OF RESPONSE 
 
Duration of Overall Response:  The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 
 
 
Duration of Stable Disease:  Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started, including the baseline 
measurements.  
 
F. PROGRESSION FREE SURVIVAL 
 
Progression Free Survival is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
Adapted from: Eisenhauer EA, Therasse P, Bogaerts J, et. al.  New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur. J. Cancer. 2009; 45:229-247. 
 
 
<http://www.eortc.be/recist/documents/RECISTGuidelines.pdf >  
 
 


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Appendix 6 
Immunotherapeutics RECIST (iRECIST)  
 
1. DEFINITIONS 
 
1.1 Evaluable for adverse events.  All patients will be evaluable for adverse event evaluation for the time of their 
first treatment.   
 
1.2 Evaluable for response.  All patients who have received at least one cycle of therapy and have their disease re-
evaluated will be considered evaluable for response (exceptions will be those who exhibit objective disease 
progression prior to the end of cycle 1 who will also be considered evaluable).  Patients on therapy for at least 
this period and who meet the other listed criteria will have their response classified according to the definitions 
set out below. 
 
Response and progression will be evaluated in this study using the revised international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (Version 1.1) (RECIST v1.1) committee as well as the modified 
iRECIST guidelines.  Investigators should note the different requirements for confirmatory scans as well as 
follow-up for the two criteria. 
 
See below for criteria for continuing treatment past RECIST v1.1 disease progression. 
 
2 
RECIST v1.1 RESPONSE AND EVALUATION ENDPOINTS 
 
2.1 Measurable Disease.  Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid organ 
metastases) are defined as those that can be accurately measured in at least one dimension (longest diameter to 
be recorded) as ≥ 20 mm with chest x-ray and as ≥ 10 mm with CT scan or clinical examination.  Bone lesions 
are considered measurable only if assessed by CT scan and have an identifiable soft tissue component that 
meets these requirements (soft tissue component ≥ 10 mm by CT scan).  Malignant lymph nodes must be ≥ 15 
mm in the short axis to be considered measurable; only the short axis will be measured and followed.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).  Previously irradiated 
lesions are not considered measurable unless progression has been documented in the lesion. 
 
2.2 Non-measurable Disease.  All other lesions (or sites of disease), including small lesions are considered non-
measurable disease.  Bone lesions without a measurable soft tissue component, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic 
involvement of lung or skin and abdominal masses followed by clinical examination are all non-measurable.  
Lesions in previously irradiated areas are non-measurable, unless progression has been demonstrated.   
 
2.3 Target Lesions.  When more than one measurable tumor lesion is present at baseline, all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline.  Target lesions should be selected 
based on their size (lesions with the longest diameter), be representative of all involved organs, and should be 
those that lend themselves to reproducible repeated measurements.  Note that pathological nodes must meet the 
criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum.  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.  At baseline, the sum of the target lesions (longest diameter of tumor lesions plus short 
axis of lymph nodes: overall maximum of 5) is to be recorded.   
 
After baseline, a value should be provided on the CRF for all identified target lesions for each assessment, even 
if very small.  If extremely small and faint lesions cannot be accurately measured but are deemed to be present, 


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a default value of 5 mm may be used.  If lesions are too small to measure and indeed are believed to be absent, a 
default value of 0 mm may be used.   
 
2.4 Non-target Lesions.  All non-measurable lesions (or sites of disease) plus any measurable lesions over and 
above those listed as target lesions are considered non-target lesions.  Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present” or “absent”. 
 
2.5 Response.  All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
 
Complete Response (CR):  disappearance of target and non-target lesions and normalization of tumor markers.  
Pathological lymph nodes must have short axis measures < 10 mm (Note:  continue to record the measurement 
even if < 10 mm and considered CR).  Residual lesions (other than nodes < 10 mm) thought to be non-
malignant should be further investigated by cytology specialized imaging or other techniques as appropriate for 
individual cases before CR can be accepted.  Confirmation of response is only required in non-randomized 
studies. 
 
Partial Response (PR):  at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and 
short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameter.  Non-target 
lesions must be non-PD.  Confirmation of response is only required in non-randomized studies.   
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum of diameters on study.   
 
Progressive Disease (PD): at least 20% increase in the sum of diameters of measured lesions taking as reference 
the smallest sum of diameters recorded on study (including baseline) AND an absolute increase of ≥ 5 mm.  
Appearance of new lesions will also constitute progressive disease (including lesions in previously unassessed 
areas).  In exceptional circumstances, unequivocal progression of non-target disease may be accepted as 
evidence of disease progression, where the overall tumor burden has increased by at least 73% in volume.  
Modest increases in the size of one or more non-target lesions are NOT considered unequivocal progression.  If 
the evidence of PD is equivocal (target or non-target), treatment may continue until the next assessment, but if 
confirmed, the earlier date must be used.   
 
 
 


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Integration of Target, Non-Target and New Lesions into Response Assessment 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this Category Also Requires 
Target lesions + non-target lesions 
CR 
CR 
No 
CR 
Normalization of tumor markers, tumor nodes < 10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
 
PR 
Non-PD/not all evaluated 
No 
PR 
 
SD 
Non-PD/not all evaluated 
No 
SD 
Documented at least once ≥ 4 weeks from baseline 
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Non-target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumor markers, tumor nodes < 10 mm 
No Target 
Non-CR/non-PD 
No 
Non-CR/non-PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes* 
PD 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic deterioration”.  This is a reason for stopping therapy, but is NOT objective PD.  
Every effort should be made to document the objective progression even after discontinuation of treatment.   
*Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may be continued pending further 
assessments. 
Abbreviations (in alphabetical order):  CR, complete response; NE, not evaluable; PD, progressive disease; SD, stable disease 
 
3 
iRECIST RESPONSE ASSESSMENT 
Overall response will also be assessed using iRECIST.  Immunotherapeutics may result in infiltration of 
immune cells leading to transient increase in the size in malignant lesions, or undetectable lesions becoming 
detectable for instance where an increase in tumor burden, or the appearance of new lesions, does not reflect 
true tumor progression.  
 
Key differences are described below.  All responses defined using iRECIST criteria are designated with a prefix 
“i”.  iRECIST time-point and best overall responses will be recorded separately.   
 
3.1 Confirming Progression 
Unlike RECIST v1.1, iRECIST requires the confirmation of progression and uses the terms iUPD (unconfirmed 
progression) and iCPD (confirmed progression).  Confirmatory scans should be performed at least 4 weeks, but 
no longer than 8 weeks, after iUPD. 
 
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is evidenced by one or 
more of the following: 
• Continued increase in tumor burden (from iUPD) where RECIST v1.1 definitions of progression had 
been met (from nadir) in target, non-target disease or new lesions.  
o 
Progression in target disease worsens with an increase of at least 5 mm in the absolute value 
of the sum 
o 
Continued unequivocal progression in non-target disease with an increase in tumor burden 


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o 
Increase in size of previously identified new lesion(s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions.  
• RECIST v1.1 criteria are met in lesion types (target or non-target or new lesions) where progression was 
not previously identified, including the appearance of additional new lesion.  
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned (iUPD if the 
criteria are still met, but no worsening, or iSD, iPR, or iCR if those criteria are met compared to baseline).  As 
can be seen in the table below, the prior documentation of iUPD does not preclude assigning iCR, iPR, or iSD 
in subsequent time-point assessments or as best overall response providing that iCPD is not documented at the 
next assessment after iUPD. 
 
3.2 New Lesions 
New lesions should be assessed and measured as they appear using RECIST v1.1 criteria (maximum of 5 
lesions, no more than 2 per site, at least 10 mm in long axis [or 15 mm in short axis for nodal lesions]), and 
recorded as New Lesion-Target (NLT) and New Lesion-Non-Target (NLNT) to allow clear differentiation from 
baseline target and non-target lesions.   
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD).  However, the 
measurements of target lesions should NOT be included in the sum of measures of original lesions identified at 
baseline.  Rather, these measurements will be collected on a separate table in the CRF.    
 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 weeks (but not 
more than 8 weeks) after iUPD confirms further progression from iUPD with either an increase of at least 5 mm 
in the absolute value of the sum of NLT or an increase (but not necessarily unequivocal increase) in the size of 
NLNT lesions or the appearance of additional new lesions.  
 
 
 


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iRECIST Timepoint Response 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Timepoint Response 
No 
Prior 
iUPD** 
Prior iUPD**, *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non-
iUPD 
No 
iSD 
iSD 
iUPD with no 
change or 
decrease from 
last TP 
iUPD with no 
change or 
decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously identified and increase in 
size (≥ 5 mm in SOM for NLT or any increase for NLNT) or number.  
If no change in NLs (size or number) from last TP, remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase in size 
of NT lesion (need not meet RECIST v1.1 criteria for unequivocal PD) 
iUPD 
Non-iCR/Non-
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
• Further increase in SOM of at least 5 mm, otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase in: 
• Previously identified T lesion iUPD SOM ≥ 5 mm and/or  
• NT lesion iUPD (prior assessment – need not be unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase in: 
• Previously identified T lesion iUPD ≥ 5 mm and/or  
• Previously identified NT lesion iUPD (need not be unequivocal) 
and/or 
• Size or number of NLs previously identified 
Non-iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
• Increase in size or number of NLs previously identified 
*Using RECIST v1.1 principles.  If no PSPD occurs, RECIST v1.1 and iRECIST categories for CR, PR, and SD would be the same 
**in any lesion category 
***previously identified in assessment immediately prior to this TP 
Abbreviations (in alphabetical order):  CPD, confirmed progressive disease; CR, complete response; NE, not evaluable; NL, new lesion; 
NLNT, new lesion-non-target; NLT, new lesion-target; NT, non-target; PD, progressive disease; PR, partial response; PSPD, 
pseudoprogression; SD, stable disease; SOM, sum of measurements; T, target; TP, timepoint; UPD, unconfirmed progressive disease 
 


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All patients will have their iRECIST best overall response (iBOR) from the start of study treatment until the end 
of treatment classified as outlined below. 
 
iRECIST Best Overall Response 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR, iPR, iUPD, NE 
iCR, iPR, iUPD, NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, NE 
iCR 
iCR, iPR, iSD, iUPD, NE 
iCR, iPR, iSD, iUPD, iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, NE, iCPD 
iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, NE 
iSD, iUPD, iCPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
• 
Table assumes a randomized study where confirmation of CR or PR is not required 
• 
NE=not evaluable that cycle 
• 
Designation “i” for BOR can be used to indicate prior iUPD to aid in data interpretation 
• 
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each TPR but is not shown in 
the table for ease of presentation. 
Abbreviations (in alphabetical order):  BOR, best overall response; CPD, confirmed progressive disease; CR, complete response; NE, not 
evaluable; NL, new lesion; PD, progressive disease; PR, partial response; PSPD, pseudoprogression; SD, stable disease; SOM, sum of 
measurements; TP, timepoint; TPR, timepoint response; UPD, unconfirmed progressive disease 
 
 
4 
RESPONSE AND STABLE DISEASE DURATION (RECIST v1.1 AND iRECIST) 
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively documented, 
taking as reference the smallest measurements recorded on study (including baseline). 
 
Stable disease duration will be measured from the time of start of treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (including baseline). 
 
5 
METHODS OF MEASUREMENT 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up.  Assessments should be identified on a calendar schedule and 
should not be affected by delays in therapy.  While on study, all lesions recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm.  
If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned.  For lesions which fragment/split, add together the longest diameters of the fragmented 
portions; for lesions which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
5.1 Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm as 
assessed using calipers (e.g., skin nodules).  For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended.  If feasible, imaging is preferred.   
 
5.2 Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions.  However, lesions ≥ 20 mm on 
chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. 
 
5.3 CT, MRI.  CT is the best currently available and reproducible method to measure lesions selected for response 
assessment.  This guideline has defined measurability of lesions on CT scan based on the assumption that CT 


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slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g., for 
body scans).  Other specialized imaging or other techniques may also be appropriate for individual cases.  For 
example, while PET scans are not considered adequate to measure lesions, PET-CT scans may be used 
providing that the measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast).    
 
5.4 Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  If new lesions are identified by ultrasound during the study, confirmation by CT is advised.  
 
5.5 Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is not advised.  
However, they can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response or surgical resection is an endpoint.   
 
5.6 Tumor Markers.  Tumor markers alone cannot be used to assess objective tumor response.  If markers are 
initially above the upper normal limit, however, they must normalize for a patient to be considered in complete 
response.   
 
5.7 Cytology, Histology.  These techniques can be used to differentiate between PR and CR in rare cases if required 
by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain).  When effusions are known to be a potential adverse effect of treatment (e.g., with 
certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of 
any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response 
or stable disease is advised to differentiate between response or stable disease and progressive disease.   
 
Adapted from: 
Seymour L, Bogaerts J, Perrrone A, et. al.  iRECIST: guidelines for response criteria for use in trials 
testing immunotherapeutics. Lancet. 2017; 18:143-152. (supplemental materials) 
 
    <http://www.eortc.org/recist/irecist/>  


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Appendix 7 
Response Evaluation Criteria in Lymphoma (RECIL 2017) 
 
Response Evaluation Criteria in Lymphoma 
International Working Group: Response Criteria Based on Assessment of Target 
Lesions 
Response 
% Change from Baseline 
FDG-PET 
Bone Marrow 
Involvement 
New 
Lesions 
CR 
Complete disappearance of all target lesions and 
all nodes with long axis < 10 mm 
 
≥ 30% decrease in the sum of longest diameter 
of target lesions (PR) with normalization of 
FDG-PET 
Normalization of FDG-
PET (Deauville score 1-3)* 
Not involved 
No 
PR 
≥ 30% decrease in the sum of longest diameters 
of target lesions but not a CR 
Positive  
(Deauville score 4-5)* 
Any 
No 
MRa 
≥ 10% decrease in the sum of longest diameters 
of target lesions but not a PR (< 30%) 
Any 
Any 
No 
SD 
< 10% decrease or ≤ increase in the sum of 
longest diameters of target lesions 
Any 
Any 
No 
PD 
20% increase in the sum of longest diameters of 
target lesions 
 
For small lymph nodes measuring < 15 mm post 
therapy, a minimum absolute increase of 5 mm 
and the long diameter should exceed 15 mm 
 
Appearance of a new lesion 
Any 
Any 
Yes or No 
a A provisional category 
 
*Deauville Scoring (for FDG avidity in Hodgkin’s or Non-Hodgkin’s Lymphoma) (as seen by FDG-PET) 
Score 1:  No uptake above the background 
Score 2:  Uptake ≤ mediastinum 
Score 3:  Uptake > mediastinum but ≤ liver 
Score 4:  Uptake moderately increase compared to the liver at any site 
Score 5:  Uptake markedly increased compared to the liver at any site 
Score X:  New areas of update unlikely to be related to lymphoma 
 
Abbreviations (in alphabetical order):   CR, complete response; FDG, fluorodeoxyglucose; mm, millimeter; MR, minor response; PD, progressive 
disease; PET, positron emission tomography; PR, partial response; SD, stable disease 
 
Adapted from: Younes A, Hilden P, Coiffier B, et. al.  International Working Group consensus response evaluation criteria in 
lymphoma (RECIL 2017). Annals Oncol. 2017 Apr 3. doi: 10.1093/annonc/mdx097. 
Barrrington SF, Qian W, Somer EJ, et al., Concordance between four European centres of PET reporting criteria 
designed for use in multicentre trials in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging. 2010. 37: 1824-1833. 
 
Fellows GA, Ardeshna KM, Barrington ST, et al. Guidelines for the first line management of classical Hodgkin 
lymphoma. British J Haemotology, 2014. 166: 34-49. 


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Appendix 8 
Adverse Events Observed with Antibodies to PD-1 and PD-L1 
 
Although the mechanism of action is distinct, inhibitors of TIM-3 have many similarities to 
blockers of immune checkpoint pathways. Because of these similarities, data on the potential 
AEs seen after treatment with antibodies to PD-1 and PD-L1 are being included in this CTP.  
Immune-mediated and non-immune-mediated AEs reported in the literature and/or prescribing 
information for PD-1 and PD-L1 pathway inhibitors are listed below, organized by System 
Organ Class.  These data have been collated from the prescribing information of approved 
products as well as applicable literature and are listed below. 
 
Adverse Events Observed with Antibodies to PD-1 and PD-L1 
Blood and lymphatic 
system disorders  
 
Anaemia 
Lymphopenia 
Haemolytic anaemia 
Neutropenia 
Thrombocytopenia 
Pure red cell aplasia 
Pancytopenia 
Eosinophilia 
Acquired haemophilia A 
Cryoglobulinemia 
Disseminated intravascular coagulopathy 
Cardiac disorders 
Myocarditis 
Ventricular arrhythmias 
Hypotension 
Cardiomyopathy 
Pericarditis 
Ear and labyrinth 
disorders 
Autoimmune inner ear disease (listed below under Immunologic Disorders) 
Endocrine disorders 
Autoimmune inflammation of pituitary, thyroid, adrenal glands 
Hypophysitis, hypopituitarism, panypopituitarism 
Autoimmune thyroid disease (thyroiditis, hypothyroidism, hyperthyroidism) 
Thyroid disorders 
Adrenal insufficiency (central or primary) 
Diabetes mellitus (type 1) 
Syndrome of inappropriate antidiuretic hormone secretion 
Eye disorders (Intraocular 
inflammation is rare ~1% in 
patients treated) 
Uveitis 
Iridocylitis 
Retinal detachment 
Decreased visual acuity 
Ocular inflammatory toxicity 
Iritis 
Episcleritis 
Conjunctivitis 
Orbital inflammation (symptoms include photophobia, dryness of the eye, pain, 
blurred vision) 
Gastrointestinal disorders 
Diarrheal colitis (common, presents ~ 6-8 weeks into treatment; Grade 3-4 in 1-2%) 
Diarrhea 
Colitis, enterocolitis, gastroenteritis 
Nausea 
Vomiting 
Abdominal pain (abdominal discomfort, upper and lower abdominal pain) 
Decreased appetite 
Intestinal perforation 
Intestinal obstruction 


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Adverse Events Observed with Antibodies to PD-1 and PD-L1 
Constipation 
Pancreatitis (increased amylase and lipase)  
Stomatitis 
Dysphagia 
Hypogeusia 
Ulcer haemorrhage 
General disorders and 
administration site 
conditions 
Fatigue-includes asthenia and fatigue, decreased activity, malaise 
Pyrexia 
IRR (Mild up to 25%, Severe < 2%; composite term includes chills, fever, back pain, 
flushing, dyspnea, hypotension) 
Oedema (includes periorbital, face oedema, generalized oedema, localized oedema, 
gravitational oedema, peripheral oedema, pulmonary oedema, and lymph 
oedema 
Weight loss (also listed under investigations) 
Cachexia secondary to dysphagia 
Hepatobiliary disorders 
Hepatitis 
Immune system disorders 
(See also endocrine and 
other classes) 
Pneumonitis 
Inflammatory myositis 
Myositis 
Myocarditis 
Colitis 
Hepatitis 
Autoimmune inflammation of pituitary, thyroid, adrenal glands 
Pancreatitis 
Myasthenia gravis and other autoimmune neurologic disorders  
Inflammatory arthritis 
Bullous pemphigoid 
Complications after allogeneic HSCT (veno-occlusive disease, graft versus host 
disease) 
Vasculitis 
Arthritis 
Psoriasis 
Histiocytic necrotizing lymphadenitis 
Systemic inflammatory response 
Polymyositis 
Pericarditis 
Dry eye (sicca syndrome) 
 
Defined systemic disease 
Sarcoidosis (cutaneous, pulmonary, muscle, neurological) 
Polymyalgia rheumatica-giant cell arteritis 
Celiac disease 
Lupus nephritis 
Dermatomyositis 
Autoimmune inflammatory myopathy 
Psoriasis 
Polymyositis 
Myasthenia gravis 
Sjogren’s syndrome 
Bullous skin diseases (pemphigoid, bullous pemphigus) 
Autoimmune endocrinopathies (pituitary, thyroid, adrenals) 
Autoimmune hepatitis 
Autoimmune pancreatitis 
Autoimmune haemolytic anaemia 
Pure red cell aplasia 
Cryoglobulinemia 
Acquired Haemophilia A 
Autoimmune hepatitis 


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Adverse Events Observed with Antibodies to PD-1 and PD-L1 
Systemic inflammatory response syndrome 
Autoimmune colitis 
Autoimmune pneumonitis 
Infections and infestations 
Upper respiratory tract infection (rhinitis, viral rhinitis, pharyngitis, nasopharyngitis) 
Respiratory tract infection 
Pneumonia/bronchopneumonia (bacterial, mycoplasma, Pneumocystis jiroveccii 
pneumonia) 
Nasal congestion 
Urinary tract infection (bacterial, fungal) 
Severe infections including sepsis, herpes encephalitis, mycobacterial infection 
leading to retroperitoneal haemorrhage 
Sepsis 
Investigations 
Increased ALT 
Increased AST 
Increased bilirubin 
Increased alkaline phosphate 
Increased GGT 
Increased creatinine 
Hyponatremia 
Hyperkalaemia 
Hypocalcemia 
Hypercalcemia 
Hypomagnesemia 
Hypermagnesemia 
Hypophosphatemia 
Decreased bicarbonate 
Increased amylase  
Increased lipase 
Increased thyroid stimulating hormone (TSH) 
Decreased weight 
Anaemia 
Lymphopenia 
Leukopenia 
Thrombocytopenia 
Increased triglycerides 
Increased cholesterol 
Hyperglycaemia 
Hypoalbuminemia 
Glomerular filtration rate decreased 
Musculoskeletal and 
connective tissue 
disorders 
Arthralgia 
Sjogren’s syndrome 
Spondyloarthropathy 
Myositis 
Myopathy 
Rhabdomyolysis 
Musculoskeletal pain (includes back pain, bone pain, musculoskeletal chest pain, 
musculoskeletal discomfort, myalgia, pain in jaw, pain in extremities, neck pain, 
and spinal pain) 
Inflammatory arthritis-polyarthritis 
Myalgia 
Sarcoidosis 
Dry eye (sicca syndrome) 
Nervous system disorders 
(neurologic syndromes in 
~1-3% of patients) 
Guillain-Barre syndrome 
Myasthenia gravis 
Non-infectious meningitis 
Transverse myelitis 


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Adverse Events Observed with Antibodies to PD-1 and PD-L1 
Peripheral neuropathy and sensory neuropathy (hyperesthesia, hypoesthesia, 
paraesthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory 
neuropathy, polyneuropathy); motor and sensory neuropathy 
Autoimmune encephalitis 
Encephalitis 
Dizziness 
Peroneal nerve palsy 
Neuritis 
Headache/migraine headache 
Partial seizures associated with focal inflammatory foci in brain 
Dizziness 
Dysgeusia  
Confusional state 
Meningitis/encephalitis 
Demyelination 
Encephalopathy 
Paralysis 
Polymyositis 
Insomnia  
Hypersomnia 
Recurrent seizures-bradykinesia (Parkinsonism) 
Polyradiculopathy 
Necrotizing myelopathy 
Symmetrical multifocal neuropathy 
Phrenic nerve palsy 
Meningoradiculoneuritis 
Posterior reversible encephalopathy syndrome (PRES) 
Aseptic Meningitis-Immune related meningitis 
Enteric neuropathy  
Autoimmune inner ear disease 
Multiple sclerosis 
Pregnancy, puerperium 
and perinatal conditions 
Embryo-foetal toxicity 
 
Psychiatric disorders 
Insomnia 
Renal and urinary 
disorders 
Nephritis and renal dysfunction 
Renal failure 
Acute kidney injury (rare ~ 1-2% of any grade; Grade 3-4 < 1%; Onset median 91 
days; range 21-245 days) 
Glomerular filtration rate decreased 
Hematuria 
 
Urinary obstruction 
Tubulointerstitial nephritis-acute granulomatous interstitial nephritis 
Acute tubular necrosis 
Immune complex glomerulonephritis  
Thrombotic microangiopathy  
Creatinine elevation 
Reproductive system and 
breast disorders 
Lymphocytic vasculitis of the uterus 
 
Respiratory, thoracic, and 
mediastinal disorders 
Pneumonitis (uncommon~3%, but potentially severe or life-threatening; median 
onset 2.8 months) 
Cough, productive cough 
Dyspnea, exertional dyspnea 
Pleural effusion 
Respiratory failure 
Respiratory distress 
Pneumonia 
Pulmonary embolism 
Pneumothorax 


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Adverse Events Observed with Antibodies to PD-1 and PD-L1 
Hypoxia 
Acute respiratory distress syndrome 
Radiation recall pneumonitis 
Skin and subcutaneous 
tissue disorders-
Dermatologic (Overall 30-
40%; average onset 3.6 
weeks 
Rash (includes maculopapular rash, erythematous rash, macular rash, popular rash, 
reticular rash, pustular rash, vesicular rash, acneiform rash, follicular rash, 
pruritic rash, drug eruption, generalized rash, seborrheic keratosis, lichenoid 
keratosis, genital rash) 
Palmar plantar erythrodysesthesia 
Erythema 
Vitiligo 
Pruritus 
Exfoliative dermatitis 
Erythema multiforme 
Pemphigoid 
Bullous dermatitis 
Erythema multiforme 
Toxic epidermal necrolysis 
Stevens-Johnson syndrome 
Alopecia 
Dermatitis 
Sweet syndrome (neutrophil infiltration of skin) 
Oral mucositis 
Xerostomia 
Vascular disorders 
Venous thromboembolism 
Hypertension/hypertensive crisis 
Angiopathy 
Adapted from:  Opdivo (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017. 
 Keytruda (pembrolizumab) [package inset]. Whitehouse Station, NJ: Merck & Co., Inc; 2017. 
 Tecentriq (atezolizumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2017. 
 Bavencio (avelumab) [package insert]. Rockland, MA; EMD Serono, Inc.; 2017. 
 Imfinzi (durvalumab) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 
 
 


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Appendix 9 
Grading and Management of Infusion-Related Reactions 
 
Grading of Infusion-Related Reactions 
The CTCAE v5.0* definition of IRRs (General Disorders and Administration Site Conditions) is shown below. 
Symptoms occurring during or following infusion of investigational therapy may also be defined according to AE 
categories such as allergic reaction, anaphylaxis, or cytokine release syndrome. In the setting of symptoms occurring 
during or following infusion of investigational therapy, investigators are encouraged to use the AE term “Infusion-
Related Reaction” and any additional terms (including those not listed here) that best describe the event. Those 
described should be graded as follows: 
 
Grading of Infusion-Related Reactions 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Infusion-
related 
reaction 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for clinical sequelae 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances. 
Allergic 
reaction 
Systemic 
intervention not 
indicated 
Oral intervention indicated 
Bronchospasm; 
hospitalization indicated for 
clinical sequelae; intravenous 
intervention indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
Anaphylaxis 
- 
- 
Symptomatic bronchospasm, 
with or without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances 
from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis 
and loss of consciousness and may lead to death. 
Cytokine 
release 
syndrome 
Fever with or 
without 
constitutional 
symptoms 
Hypotension responding 
to fluids; hypoxia 
responding to < 40% O2 
Hypotension managed with 
one pressor; hypoxia 
requiring ≥ 40% O2 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of 
cytokines. 
*See <https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm > 
 


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Guidelines for Management of Infusion-Related Reactions 
Consistent with usual medical practice, selected parenteral medications may be utilized for Grade > 2 
allergic/hypersensitivity reactions. The Sponsor should be contacted immediately if questions arise concerning the 
grade of the reaction. The following are recommended management guidelines for IRRs associated with study drug 
administration. In all cases the Investigator should use best clinical judgment in managing such reactions. 
Management of Infusion-Related Reactions 
Grade 1 
• Consider slowing the infusion to 50% of the prior rate 
• Monitor the patient for worsening condition 
• If the infusion is extended, administer subsequent infusions at the prolonged rate 
• Consider premedication or adjustment to premedications for subsequent infusions 
Grade 2 
 
• Interrupt the infusion for a minimum of 30 minutes 
• Administer additional pharmacologic therapy (e.g., diphenhydramine, acetaminophen) and appropriate 
supportive care (e.g., oxygen), as medically indicated  
• Resume the infusion at 50% of the prior rate once the infusion-related reaction has resolved or decreased to 
Grade 1 
• Monitor the patient for worsening condition 
• Administer subsequent infusions at the prolonged rate 
• Consider premedication or adjustment to premedications for subsequent infusions 
≥ Grade 3 
 
• Stop the infusion  
• Administer additional pharmacologic therapy (diphenhydramine, dexamethasone) and appropriate 
supportive care (e.g., oxygen), as medically indicated  
• Administer epinephrine or bronchodilators as medically indicated 
• Hospital admission for observation may be indicated 
• Do not resume infusion after a ≥ Grade 3 reaction 
• Patients who have a Grade 3 infusion-related reaction will be considered to have had a DLT and will be 
discontinued from treatment. 
• Patients who have a > Grade 3 infusion-related reaction will be considered to have had a DLT and will be 
discontinued from treatment 
 
In the Event of Infusion Prolongation 
Any assessments to be performed or samples to be collected (e.g., VS, PK) at the end of or following EOI will still 
be performed or collected beginning at the delayed EOI timepoint. In situations where collection of late day 
samples, particularly the 8 hours after EOI sample, is logistically difficult due to clinic staff availability, an "end of 
day" sample may be obtained at the latest practical time on the day of the reaction.  
 
For Grade 1 and Grade 2 reactions, rechallenge with a shorter duration of infusion (no less than the duration 
designated by the patient’s dose assignment and weight) may be attempted at the Investigator's discretion, after a 
minimum of 2 doses with no evidence of infusion-related toxicity at the prolonged rate.   
 
All infusion interruptions and subsequent prolongations, including modified infusion times, as well as the toxicity 
that necessitated them, will be clearly documented on the appropriate page of the patient’s CRF. 
 
Modification of Infusion Duration for the Trial 
The duration of infusion will be prolonged for all subsequent patients entered to the trial in the following situations: 
• 
In the event of a Grade 2 IRR in ≥ two thirds of the patients entered to a cohort, the duration of infusion for 
subsequent patients entered to the trial will be extended by 30 minutes (or longer, if indicated). 
• 
In the event of a Grade 3 or greater IRR in any patient within a cohort, the duration of infusion for 
subsequent patients entered to the trial will be extended by 30 minutes (or longer, if indicated). Such a case 
will also be considered to have met the protocol criteria for a DLT, thus requiring expansion of the cohort. 
 


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These same criteria will be applied in the event IRRs occur on the extended 1-hour infusion schedule. In such a case, 
the duration of infusion for subsequent patients entered to the trial will be further extended by 30 minutes (or longer, 
if indicated). See Section 6.5.3.5.  


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Appendix 10 Management of Immune-Mediated Toxicities  
 
Instructions for management of immune-mediated toxicities are provided below and are to be implemented as 
detailed EXCEPT where AEs meet the protocol-specified DLT criteria (Section 6.8.3). AEs that meet the protocol 
definition of DLT will require discontinuation from study treatment, without exception (Section 6.8.2); this 
instruction supersedes those provided below.    
Adverse Reaction 
Severity* 
Dose Modification 
Pneumonitis 
Grade 2 pneumonitis 
Withhold dose^ 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Myocarditis** 
Grade 2 myocarditis 
Withhold dose^ 
Grade 3 or 4 myocarditis 
Permanently discontinue 
Adrenal 
Insufficiency 
Grade 2 adrenal insufficiency 
Withhold dose^ 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Encephalitis 
New-onset moderate or severe neurologic signs or symptoms 
Withhold dose^ 
Immune-mediated encephalitis 
Permanently discontinue 
Nephritis and 
Renal Dysfunction 
Serum creatinine more than 1.5 and up to 6 × ULN 
Withhold dose^ 
Serum creatinine more than 6 times the ULN 
Permanently discontinue 
Episcleritis, 
Uveitis, or Iritis** 
Grade 2 episcleritis, uveitis, or iritis     
Withhold dose^ 
Grade 3 or 4 episcleritis, uveitis, or iritis 
Permanently discontinue 
Colitis/Diarrhea 
Grade 2 or 3 diarrhea or colitis 
Withhold dose^ 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold dose^ 
Grade 4 hypophysitis 
Permanently discontinue 
Type 1 Diabetes 
Mellitus 
Grade 2 or 3 hyperglycemia 
Withhold dose^ 
Grade 4 hyperglycemia 
Permanently discontinue 
Inflammatory 
arthritis 
Grade 2 arthritis 
Withhold dose^ 
Grade 3 arthritis 
Permanently discontinue 
Myositis** 
Grade 2 myositis 
Withhold dose^ 
Grade 3 myositis 
Permanently discontinue 
Rash 
Grade 2 or 3 rash 
Withhold dose^ 
Grade 4 rash 
Permanently discontinue 
Hepatitis 
AST or ALT > 3 - 5 × ULN or  
total bilirubin > 1.5 - 3 × ULN (Grade 2) 
Withhold dose^ 
AST or ALT > 5 × ULN or  
total bilirubin > 3 × ULN (≥ Grade 3) 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction: 
  
 First occurrence 
 Recurrence of same event 
Withhold dose^ 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Requirement for 10 mg per day or greater prednisone or 
equivalent for more than 12 weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions lasting ≥ 12 weeks  
Permanently discontinue 
Abbreviations (in alphabetical order):  ALT, alanine aminotransferase; AST, aspartate aminotransferase; mg, milligram; ULN, upper limit of 
normal 
* Toxicity graded per Common Terminology Criteria for Adverse Events (Version 5.0) (CTCAE v5.0) 
**Adapted from product package inserts to include these reactions; there are no recommended dose modifications for hypothyroidism or 
hyperthyroidism. 
^ May resume treatment when adverse reaction returns to Grade 0 or Grade 1 and glucocorticoid therapy for reaction is discontinued 


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Appendix 11 Maximum Total Blood Collection Volumes 
 
Maximum Total Blood Collection Volumes 
STUDY 
ASSESSMENTS 
Vol./ 
sample 
(mL) 
Screening 
Cycle 1 
Cycle 2 
EOT 
1M FUP 
TOTAL 
VOLUME 
# 
Vol.  
(mL) 
# 
Vol.   
(mL) 
# 
Vol.  
(mL) 
# 
Vol.  
(mL) 
# 
Vol.   
(mL) 
Hematology Panel  
5 
1 
5 
5 
25 
2 
10 
1 
5 
1 
5 
50 
Biochemistry Panel 
10 
1 
10 
5 
50 
2 
20 
1 
10 
1 
10 
100 
Coagulation Panel 
5 
1 
5 
2 
10 
1 
5 
1 
5 
1 
5 
30 
Thyroid Function 
Tests 
5 
1 
5 
1 
5 
1 
5 
1 
5 
1 
5 
25 
Pregnancy Test 
5 
1 
5 
1 
5 
 
 
1 
5 
 
 
15 
Tumor Markers 
5 
1 
5 
 
 
1 
5 
1 
5 
1 
5 
20 
ADA Testing 
5 
 
 
2 
10 
1 
5 
1 
5 
1* 
5 
25 
PK Studies 
5 
 
 
11 
55 
4 
20 
1 
5 
1* 
5 
85 
Pharmacodynamic 
Studies (Receptor 
Occupancy) 
10 
 
 
3 
30 
3 
30 
1 
10 
1 
10 
80 
Biomarker Studies 
30 
1 
30 
 
 
1 
30 
1 
30 
 
 
90 
Total Volume  
 
65 
 
190 
 
130 
 
85 
 
50 
520 
Abbreviations (in alphabetical order): #, number of samples; 1M FUP, 1-month follow-up; ADA, anti-drug antibody; EOT, end of treatment; mL, 
milliliter; PK, pharmacokinetic; Vol, volume 
 
*additional samples to be obtained at 2, 4, and 6 months after EOT if patient is available for blood collection  
 
 
Along with Screening, days with maximum blood volume requirements: 
• 
C1/D1: 
100 mL  
• 
Cx/D1: 
40 mL (+ 5 mL for odd number cycles) 
• 
EOT: 
85 mL 
• 
1M FUP:   50 mL 
 
Blood volumes for each additional cycle:   
 
• 
Additional odd number cycles:  ~70 mL 
• 
Additional even number cycles: ~ 70 mL 
If sites can perform hematology, serum chemistry, and coagulation studies with smaller volumes of blood per sample, they are encouraged to do 
so.  Required PK, ADA, and PD/biomarker volumes are fixed and should not be reduced.   
To estimate a patient’s total blood collection volume during study participation, maximum estimates are used. During a patient’s study 
participation, the maximum amounts of venous blood that will be collected are listed above.  Study duration is based on 8 weeks estimated 
average patient participation, i.e., an average of Cycle 1 (4 weeks) plus Cycle 2 (4 weeks).   
An indwelling venous access device is required for PK blood sample collections on Day 1 of Cycle 1.  When an indwelling catheter (or 
equivalent venous access) is utilized, a blood flush discard of up to 3 mL is to be done before drawing the first blood tube collected on the 
scheduled day/time for routine laboratory tests and PK samples. Blood flush discard volumes ARE NOT included in volume calculations in 
table above and should be considered when summarizing actual blood collection volumes. 


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Appendix 12 Schedule of Assessments 
 
STUDY ASSESSMENTS 
Screening 
CYCLE 1 
CYCLE 2 
SUBSEQUENT CYCLES 
EOT     
within 10d after 
treatment 
discontinuation 
1M FUP* 
30d (+7) 
after last 
dose 
Long-Term 
FUP*         
if OR/ SD at 
EOT, 
for new-onset 
or ongoing 
immune-
mediated AEs    
As 
Clinically 
Indicated 
D1 
D2 
D3 
(+1) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
(±2) 
D15 
(±2) 
End of 
Cycle 2 
(final 
week) 
D1 
(±2) 
D15 
(±2) 
End of 
Even 
Numbered 
Cycles 
(final week) 
CONSENT AND MEDICAL HISTORY 
Informed Consent1/ Eligibility 
Assessment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past Medical History2 
x 
xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of Primary Malignancy3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAFETY ASSESSMENTS (screening assessments within 14 days prior to first dose of study drug unless otherwise specified) 
Medication/Procedure Survey4 
from 14 days prior to 1st dose through 30 days after last dose 
 
 
AE Reporting5 
from signing of informed consent through 30 days after last dose; through 2 months (or 4 months to 2 years) FUP if related critical AEs persist 
Q2Md 
x 
DLT Assessment6  
 
C1/D1 through C1/D28 (+/- 2 days) 
 
 
 
 
 
 
 
 
x 
ECOG PS Evaluation 
x 
xa 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Vital Signs7  
x 
SOI; 
EOI; 
2h, 4h, 8h 
after EOI 
x 
x 
 
SOI, 
EOI 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Physical Exam (to include weight, 
pulmonary and cardiac 
assessments)8 
x 
xa 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Hematology Panel9 
x 
xa 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
 
x 
Biochemistry Panel10 
x 
xa 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
 
x 
Coagulation Panel11 
x 
xa 
 
 
 
x 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Thyroid Function Tests12 
x 
xa 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Urinalysis13 
x 
xa 
 
 
 
x 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Pregnancy Testing14 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
ECG (12-lead)15 
x 
SOI, 
EOI        
+15 min     
 
 
 
 
 
SOI, 
EOI   
+15 
min 
 
 
 
 
 
x 
 
 
x 
SAFETY ASSESSMENTS (results from assessments previously performed as standard of care within 28 days [+2d] prior to 1st dose may be utilized provided no antineoplastic therapy has been delivered between assessment and 1st dose; 
otherwise within 14 days of 1st dose) 
MUGA Scan or ECHO16 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Ophthalmology Exam17 
x 
 
 
 
 
 
 
EOC1 
visual 
acuity 
only 
 
xb 
 
 
xb 
x 
 
 
x 
Pulmonary Function Tests18 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
DISEASE ASSESSMENTS (screening assessments within 28 days [+2d] prior to first dose of study drug) 
Tumor Marker Measurement19 
x 
 
 
 
 
 
 
 
 
xb 
 
 
xb 
xc 
If no  
prior PD 
Q2Me 
 


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STUDY ASSESSMENTS 
Screening 
CYCLE 1 
CYCLE 2 
SUBSEQUENT CYCLES 
EOT     
within 10d after 
treatment 
discontinuation 
1M FUP* 
30d (+7) 
after last 
dose 
Long-Term 
FUP*         
if OR/ SD at 
EOT, 
for new-onset 
or ongoing 
immune-
mediated AEs    
As 
Clinically 
Indicated 
D1 
D2 
D3 
(+1) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
(±2) 
D15 
(±2) 
End of 
Cycle 2 
(final 
week) 
D1 
(±2) 
D15 
(±2) 
End of 
Even 
Numbered 
Cycles 
(final week) 
Imaging for Disease (and 
Pulmonary Status)20 
x 
 
 
 
 
 
 
 
 
xb 
 
 
xb 
xc 
If no  
prior PD 
Q2Me 
 
Lymphoma patients:  FDG-PET, X-
ray, U/S, BM aspiration/Bx  
As 
indicated 
 
 
 
 
 
 
 
 
As 
indicatedb 
 
 
As 
indicatedb 
As indicated 
As 
 indicated 
Q2Me 
 
Response Assessment (in event of 
OR or SD)21 
 
 
 
 
 
 
 
 
 
xb 
 
 
xb 
xc 
If no  
prior PD 
Q2Me 
 
ADDITIONAL ASSESSMENTS 
ADAAssessment22 
 
x 
 
 
 
x 
 
x 
 
 
Odd 
# Cs 
 
 
x 
x 
Q2M for 6 
monthsf 
x 
PK Assessment23 
 
SOI; EOI; 
2h, 4h, 8h 
after EOI 
24h 
after 
EOI 
-12h 
to 
+24h 
x 
SOI, 
EOI 
x 
SOI, 
EOI 
SOI, 
EOI 
 
SOI, 
EOI 
SOI, 
EOI 
 
x 
x 
Q2M for 6 
monthsf 
 
Peripheral Blood for 
Pharmacodynamic Studies (receptor 
occupancy)24 
 
x 
24h 
 
 
x 
 
x 
D15   
(+ 0-7) 
EOC2 or 
C3/D1b 
 
 
Q4C (C6, 
C10, etc.)b 
x 
x 
 
 
Peripheral Blood for Biomarker 
Studies25 
upon 
eligibility 
 
 
 
 
 
 
 
D15   
(+ 0-7) 
 
 
 
 
x 
 
 
 
Tumor Biopsy for Biomarker 
Studies (optional)26 
upon 
eligibility 
 
 
 
 
 
 
 
D15   
(+ 0-7) 
 
 
 
 
Upon PD if 
prior OR or 
SD > 16wks 
 
 
 
TRIAL TREATMENT 
Premedication Administration (if 
indicated) 
 
x 
 
 
 
x 
 
x 
x 
 
x 
x 
 
 
 
 
 
Study Drug Infusion (30 minutes) 
(+10 min) 
 
x 
 
 
 
x 
 
x 
x 
 
x 
x 
 
 
 
 
 
Post-Infusion Monitoring 
 
2h 
 
 
 
1h 
 
1h 
1h 
 
1h 
1h 
 
 
 
 
 
Abbreviations (in alphabetical order): 1M FUP, 1-month follow-up; ADA, anti-drug antibody; AE, adverse event; BM, bone marrow; Bx, biopsy; C, cycle: D/d, day; DLT, dose-limiting toxicity; h, hour; ECG, 
electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; EOC, end of cycle; EOI, end of infusion; EOT, end of treatment; FDG, fluorodeoxyglucose; FUP, follow-up; MUGA, 
multi-gated acquisition; OR, objective response; PET, positron emission tomography; PK, pharmacokinetic; PS, performance status; Q2M, every 2 months; Q4C, every 4 cycles; SD, stable disease; SOI, start of 
infusion; U/S, ultrasound 
 
a Need not be assessed prior to Cycle 1 if ≤ 7 days since screening 
b End of Cycle assessments may be conducted at any time during the week prior to Day 1 of the next cycle, including on Day 1 of the next cycle, prior to dosing  
c Conduct only if > 6 weeks since the previous assessment  
d To be conducted to assess for delayed onset of any post-therapy immune-mediated AE (up to 6 months following last dose), and in the event of an immune-mediated toxicity 
ongoing at the 1M FUP or noted during the 6-month post-therapy FUP period (up to 2 years). Clinical events may be followed in writing or by telephone; an in-person visit will 
not be required. 


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e To be conducted in the event of ongoing OR or SD at the end of treatment; continue until confirmed PD or another therapeutic intervention is initiated, or until the end of trial.  
Documentation may be submitted in writing or by e-mail; an in-person visit will not be required.   
f Samples to be obtained if patient is available for blood collection 
 
1. Informed Consent: To be signed prior to enrollment and prior to performing any protocol-related procedure, unless such testing was performed previously as part of the routine 
clinical management of the patient.   
2. Past Medical History: To include history of prior/ongoing diseases or conditions as well as prior surgical procedures not related to the underlying malignancy. 
3. History of Primary Malignancy: To include details of the primary malignancy, including:  diagnosis and histological/cytological classification; date of initial diagnosis; stage of 
disease at diagnosis and at entry; current sites of metastases; prior surgical procedures for the malignancy and dates; prior antineoplastic therapy, prior radiation therapy, as well as 
dates of treatments, numbers of cycles, and best response to each therapy; date of most recent disease progression.  
4. Medication/Procedure Survey:  To include period within 14 days prior to first study drug dose and throughout study for a period of 30 days following last study drug dose. 
5. AE Reporting: To detail symptoms that may be present prior to/at the time of first administration.  AEs to be assessed from signing of informed consent, throughout study, and for 
the 1-month period (30 days) following last study drug dose; AEs to continue to be assessed for 2 months (and if necessary 4 months) following last study drug dose if events 
associated with study drug persist (to confirm that events have resolved, returned to baseline status, or been adequately explained. Investigator discretion may be used with respect 
to the method of contact for this AE assessment; clinical events may be followed in writing or by telephone, an in-person visit will not be required). Any patient who develops an 
immune-related toxicity (e.g., pulmonary fibrosis, myocarditis, ocular toxicity, drug-induced hepatotoxicity, etc.) will be followed at approximately 2-month intervals for up to 2 
years to assess the course of the condition and evaluate potential reversibility of the finding. 
6. DLT Assessment: Beginning on C1/D1 and ending at EOC1 (C1/D28 ± 2 days).  To include evaluation for the occurrence of events meeting the trial DLT criteria.  Only DLTs 
occurring during Cycle 1 will be used to make decisions regarding dose-escalation and tolerability. Events occurring after Cycle 1 will also be evaluated and taken into 
consideration when deciding upon further doses to be assessed as well as establishment of the RP2D.  
7. Vital Signs:  To include temperature, pulse, respiratory rate, blood pressure, and pulse oximetry.  C1/D1 through C1/D3 window allowances align with PK timepoints windows 
8. Physical Examination: Complete at screening including height, weight, general appearance, skin, head, eyes, ears, nose, throat, neck/thyroid, chest [includes pulmonary assessment, 
breasts], cardiovascular [includes heart, peripheral pulses] abdomen, musculoskeletal system, lymph nodes, neurologic and mental status; directed thereafter, must include weight as 
well as pulmonary and cardiac assessments. Dose adjustments should be made in the event of noted weight change (± 10% [less at the site’s discretion or if required by institution 
procedures]).  Pulmonary findings will be evaluated in detail at each visit by the Investigator (or physician designee). Evaluation to include review of pulmonary symptoms 
including but not limited to: cough, sputum production, hemoptysis, wheezing, dyspnea, dyspnea on exertion, chest pain, and/or chest pain associated with respirations, as well as 
review of cardiac symptoms including but not limited to chest pain, orthopnea, nocturia, edema, and palpitations. 
9. Hematology Panel:  To include CBC with hemoglobin, hematocrit, differential, ANC, and platelet count. Evaluation frequency should be increased in the event of hematologic 
toxicity. 
10. Biochemistry Panel (fasting not required): To include Na, K, Cl, bicarbonate or carbon dioxide, BUN or equivalent, creatinine, glucose, bilirubin [total and direct], AST, ALT, ALP, 
Ca, Mg, phosphorous, albumin, total protein, uric acid, amylase, lipase, and CK (if abnormal, perform isoenzyme analysis to include at minimum CK-MB), serial troponins, and 
measurement of BNP. Evaluation frequency should be increased in the event of significant serum chemistry abnormalities. Clinically significant electrolyte abnormalities should be 
corrected prior to dosing. 
11. Coagulation Panel: To include PTT (or aPTT), PT and/or INR. 
12. Thyroid Function Tests: To include measurement of TSH, fT3, and fT4. 
13. Urinalysis: Multi-panel chemical test strips are acceptable and should include assessment of specific gravity, pH, protein, glucose, ketones, leukocytes, nitrite, bilirubin, 
urobilinogen, and blood. Microscopic examination of sediment, if clinically indicated, to include assessment of cells (WBC and RBC per HPF, and casts).   
14. Pregnancy Testing:  β-hCG in WOCBP; serum at Screening, serum or urine thereafter; negative test must be confirmed within 2 working days prior to first dose of study drug. 
15. ECG (12-Lead): To include measurement of PR interval, QRS duration, QT interval, and QTc interval (msec), as well as HR (BPM); to be performed after patient has been supine 


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or semi-recumbent for ≥ 10 minutes; repeat subsequent timepoints in triplicate separated by 5 minutes for 4 cycles (Day 1, SOI and EOI) in patients with a Cycle 1 or Cycle 2 QTc 
that is either:  a) > 500 msec; b), increased by 60 msec over baseline; or c) decreased by 20 msec below baseline. If abnormities suggest new evidence of myocardial ischemia, 
perform isoenzyme analysis (to include at minimum CK-MB), serial troponins, and measurement of BNP. 
16. MUGA Scan or ECHO: For measurement of LVEF; to be performed ONLY in patients with a history of CHF, individual patients should be followed with the same testing 
procedure throughout the study. 
17. Ophthalmology Examination: To include funduscopic and slit lamp evaluations for assessment of retinal and corneal integrity, visual acuity as assessed by standardized chart or 
other appropriate measurement tool (e.g., Snellen chart), and any other noted ocular abnormality. If changes in visual acuity are noted, a thorough ophthalmologic evaluation should 
be performed within 48 hours (if feasible, based on weekends or holidays) of the initial observation in order to confirm the finding and determine if there is evidence of an immune-
mediated AE, or other event that would preclude further treatment with study drug. 
18. Pulmonary Function Tests: To include spirometry and diffusing capacity of carbon monoxide [DLCO] to assess for evidence of pulmonary fibrosis.  Spirometry assessments to 
include at minimum:  FVC, FEV1, FRC, RV, and TLC.  To be repeated if evidence of interstitial pneumonitis, pulmonary fibrosis or other potential evidence of drug-related 
pulmonary toxicity is documented on imaging studies or if pulmonary symptomatology indicates. 
19. Tumor Marker Measurement: As indicated by tumor type. 
20. Imaging for Assessment of Disease (and Pulmonary Status): To include diagnostic imaging by CT or MRI of the chest with each evaluation (for disease evaluation where indicated, 
and to assess for evidence of pulmonary fibrosis) plus abdomen and pelvis, and other sites as indicated based on tumor type and clinical judgment to assess the status of the 
underlying malignancy. Use of contrast is preferred but is at the discretion of the Investigator, as medically indicated.  The same method(s) of disease evaluation and the same 
technique should be used throughout the study. For all imaging timepoints, the following will be recorded as per RECIST v1.1 (or other response criteria, as indicated): target 
lesions including size, location, and type (nodal/non-nodal); sum of diameters of target lesions; any new lesions noted during trial, including size, location, and type (nodal/non-
nodal). 
21. Response Assessment: To be assessed by the Investigator or qualified designee as per RECIST v1.1 (or other response criteria, as indicated). 
22. ADA (Specialty Lab): To assess immunogenicity; whole blood (~5 mL at each timepoint) will be collected for serum acquisition.  If sampling is on a dosing day, collect prior to 
infusion. If a collected serum sample is inadequate or insufficient for ADA analysis, the analysis of ADA can be done using a PK serum sample from the same timepoint, if available. 
A detailed laboratory manual specifying sample collection, handling, storage, and shipment will be provided to the trial sites.   
23. PK Sampling (Specialty Lab): See Section 7.6.1 for window allowances. Whole blood (~5 mL at each timepoint) will be collected for serum acquisition. If a collected serum sample 
is inadequate or insufficient for PK analysis, the analysis of PK can be done using an ADA serum sample from the same timepoint, if available.  A detailed laboratory manual 
specifying sample collection, handling, storage, and shipment will be provided to the trial sites.  PK sampling times may be adjusted according to early trial results to optimize 
evaluation.   
24. Peripheral Blood for Pharmacodynamic Studies (Receptor Occupancy) (Specialty Lab): Whole blood (~10 mL at each timepoint) will be collected for assessment of receptor 
occupancy.  C2D15 (+ 0 to 7 days) after dosing; to be collected on the day of tumor biopsy, if performed. End of Cycle sampling may be combined with EOT if patient discontinues 
treatment. A detailed laboratory manual specifying sample collection, handling, storage, and shipment will be provided to the trial sites.   
25. Peripheral Blood for Biomarker Studies (Specialty Lab): To be obtained only after eligibility has been confirmed.  (May be collected C1/D1 prior to dosing.)  Whole blood (~30 
mL at each timepoint) to be collected.  C2D15 (+ 0 to 7 days) after dosing; to be collected on the day of tumor biopsy, if performed. For those timepoints where both a blood sample 
and a tumor biopsy are to be obtained, the blood sample must be collected first. A detailed laboratory manual specifying sample collection, handling, storage, and shipment will be 
provided to the trial sites.  
26. Tumor Biopsy for Biomarker Studies (optional) (Specialty Lab): To be obtained only after eligibility has been confirmed.  (May be collected C1/D1 prior to dosing.)  Tissue for 
FFPE to be collected. C2D15 (+ 0 to 7 days) after dosing; to be collected with paired peripheral blood for biomarker studies. For those timepoints where both a blood sample and a 
tumor biopsy are to be obtained, the blood sample must be collected first.  EOT sample upon PD only in patients with a prior OR or prolonged SD (> 16 weeks). A detailed 
laboratory manual specifying sample collection, handling, storage, and shipment will be provided to the trial sites 
 


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19 SUMMARY OF CHANGES 
19.1 
Protocol Amendment 1 dated 04-Apr-2018 
• All DLTs will require discontinuation from study treatment, without exception. 
• Any treatment delay >2 weeks during Cycle 1 due to toxicity will be considered a DLT, regardless of severity of the event. 
• Failure to complete Cycle 1 due to any AE will be considered a DLT, regardless of severity of the event. 
• Clarified that immune-mediated toxicity that requires use of glucocorticoids at a dose of ≥ 1 mg/kg/day of prednisone 
equivalents for treatment of the toxicity will be considered a DLT. 
• Any reduction in visual acuity will be considered a DLT, regardless of grade or duration. 
• All Grade 4 non-hematologic laboratory changes will be considered a DLT, regardless of rapidity of resolution. 
• Any Grade 4 hematologic toxicity (other than those specifically covered which include neutropenia, thrombocytopenia, and 
anemia) lasting >5 days will be considered a DLT. 
• Patients with a history of organ transplantation (e.g., stem cell or solid organ transplant) have been added as an exclusion 
criterion. 
• Added a notation to the retreatment guidelines to indicate that patients may receive standard doses of replacement hormonal 
therapy for adrenal insufficiency, hypothyroidism, or other endocrine end-organ failure, and may resume study drug once 
considered by the Investigator to be stable on such therapy. This was added to be consistent with eligibility criteria. 
• Tables have been updated based on changes described, including correction to the recommended premedication dose of 
famotidine from 30mg to 20mg (Table 4). 
• Formatting adjustments, outline modifications, cross-reference links and link corrections, and other minor typographical 
corrections and slight wording changes are included. 
Refer to Table 6 for the changes in Protocol Amendment 1. 
 
 
 


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Table 6:  Protocol Amendment 1 
SECTION 
ORIGINAL TEXT 
NEW TEXT 
1 Synopsis: Patient 
Selection: Eligibility 
 
4.3.1 Patients to be 
Excluded 
Patients to be Excluded 
8. 
Patients with a clinically significant (CS) cardiovascular disease or 
condition, including:… 
• 
History of acute coronary syndromes (including myocardial 
infarction [MI] and unstable angina), coronary angioplasty, or stenting 
within 6 months prior to first study drug administration 
 
Not applicable (new exclusion criterion added, shifting list) 
Patients to be Excluded 
8. 
Patients with a clinically significant (CS) cardiovascular disease or 
condition, including:… 
• 
History of acute coronary syndromes (including myocardial 
infarction [MI] and unstable angina), coronary angioplasty, stenting, or 
bypass within 6 months prior to first study drug administration 
 
12. Patients with a history of organ transplantation (e.g. stem cell or 
solid organ transplant) 
1 Synopsis: IMP 
Administration: 
Doses to be 
Administered 
 
5.7 Dose Calculation 
 
6.5.3.1.2 Changes in 
Dose to be 
Administered 
Changes in Dose to be Administered 
Dose adjustments should be made in the event of noted weight change (± 
10%; less at the site’s discretion or if required by institution 
procedures) at visits that require weight measurement. Adjustments may 
be made in the event of lesser incremental changes in weight and more 
frequently at the site's discretion.   
Changes in Dose to be Administered 
Dose adjustments should be made in the event of noted weight change 
(± 10%; less at the site’s discretion or if required by institution 
procedures) at visits that require weight measurement. Adjustments may 
be made more frequently at the site's discretion.   
 
(Text was added to section 5.7) 
1 Synopsis: IMP 
Administration: 
Premedication 
Premedication for Infusion-Related Reactions 
In the event of an IRR during study: 
• 
For Grade 3 reactions, premedication prior to subsequent infusions 
is required. Patients experiencing a Grade 3 reaction after having 
received premedication will be discontinued from treatment. 
Premedication for Infusion-Related Reactions 
In the event of an IRR during study: 
• 
For Grade 3 reactions, not applicable as this is considered a DLT; 
therefore, no further treatment with study drug is allowed. 
1 Synopsis: 
Continued Treatment: 
Retreatment 
Following an 
Objective Response  
This option for retreatment does not apply to patients who previously 
experienced an immune-mediated toxicity that required permanent 
discontinuation from study drug (see Treatment Discontinuation 
Criteria). 
This option for retreatment does not apply to patients who previously 
experienced a DLT that required permanent discontinuation from study 
drug (see DLT and Treatment Discontinuation Criteria). 
1 Synopsis: AEs and 
DLTs: Management 
of DLTs and Other 
Toxicities 
Management of Dose-Limiting Toxicities 
AEs that meet the protocol definition of DLT will be managed by either 
discontinuing the patient from further participation in the study, or the 
patient may continue if there is evidence of response or other clinical 
benefit, but dosing must be delayed, and the patient may not be retreated 
until retreatment criteria are met.   
Management of Dose-Limiting Toxicities 
AEs that meet the protocol definition of DLT will require 
discontinuation from study treatment, without exception.   


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Patients experiencing certain immune-mediated toxicities may not be 
retreated and will be discontinued from further participation (see 
Treatment Discontinuation Criteria). 
1 Synopsis: AEs and 
DLTs: Dose-Limiting 
Toxicities Definition 
 
6.8.3 Definition of 
Dose-Limiting 
Toxicity 
Any of the following toxicities occurring during Cycle 1, if judged to be 
related to study drug (i.e. possibly-related, probably-related, or related), 
will be considered a DLT for the purposes of this trial.  
 
1. 
≥ Grade 3 evidence of any of the following immune-mediated 
toxicities (patient must be permanently discontinued)… 
2. 
≥ Grade 3 evidence of any of the following immune-mediated 
toxicities (if > Grade 3, patient must be permanently 
discontinued)… 
3. 
≥ Grade 2… 
Not applicable (new bullet point added) 
 
 
Not applicable (new toxicity added, shifting list) 
4. 
Hepatic-related findings consistent with Hy’s Law criteria… 
5. 
Any other ≥ Grade 3 or 4 non-hematologic toxicity regardless of 
duration with the exceptions of…  
• 
≥ Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 
days that are not clinically complicated, and resolve 
spontaneously or respond to conventional medical interventions 
Not applicable (new toxicity added, shifting list) 
 
6. 
Neutropenia that is…  
7. 
Thrombocytopenia that is… 
8. 
Anemia that is Grade 4 and not explained by underlying disease 
Not applicable (new toxicity added, shifting list) 
 
9. 
Any death where a relationship to study drug cannot be ruled out 
10. Inability to complete Cycle 1 at the assigned dose (i.e. receipt of < 
2 full planned doses of study drug plus 2 weeks of follow-up) due to ≥ 
Grade 3 toxicity 
Any of the following toxicities occurring during Cycle 1, if judged to be 
related to study drug (i.e. possibly-related, probably-related, or related), 
will be considered a DLT for the purposes of tolerability assessment 
during this trial. 
1. 
≥ Grade 3 evidence of any of the following immune-mediated 
toxicities… 
2. 
≥ Grade 3 evidence of any of the following immune-mediated 
toxicities… 
3. 
≥ Grade 2… 
• 
Immune-mediated toxicity that requires use of glucocorticoids 
at a dose of ≥ 1 mg/kg/day of prednisone equivalents for 
treatment of the toxicity 
4. 
Any reduction in visual acuity, regardless of grade or duration 
5. 
Hepatic-related findings consistent with Hy’s Law criteria… 
6. 
Any other ≥ Grade 3 or 4 non-hematologic toxicity regardless of 
duration with the exceptions of... 
• 
Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 
days that are not clinically complicated, and resolve 
spontaneously or respond to conventional medical interventions 
7. 
Any Grade 4 non-hematologic laboratory toxicity regardless of 
duration 
8. 
Neutropenia that is…  
9. 
Thrombocytopenia that is… 
10. Anemia that is Grade 4 and not explained by underlying disease 
11. Any other Grade 4 hematologic toxicity (other than those 
specifically excluded) lasting > 5 days 
12. Any death where a relationship to study drug cannot be ruled out 
13. Inability to complete Cycle 1 at the assigned dose (i.e. receipt of < 
2 full planned doses of study drug plus 2 weeks of follow-up) due to any 
toxicity 
14. Treatment delays > 2 weeks from the scheduled next dose during 
Cycle 1 due to any toxicity 


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11. Treatment delays > 2 weeks from the scheduled next dose during 
Cycle 1 due to ≥ Grade 3 toxicity 
1 Synopsis: Toxicity 
Safety Management 
and Safety 
Monitoring: IRR 
Management 
 
8.5.1.1 Instructions 
for Infusion 
Prolongation for 
IRRs 
• 
For Grade 3 reactions, the infusion will be STOPPED and 
supportive care will be provided.  The occurrence will be considered a 
DLT and the patient will be either discontinued from treatment, or must 
receive subsequent doses at a prolonged infusion rate (slowed to 50% of 
the prior rate, or longer). 
 
In all cases the Investigator should use best clinical judgment in 
managing such reactions. For Grade 1 and 2 IRRs, rechallenge with a 
shorter duration of infusion (no less than 30 minutes) may be attempted 
at the Investigator’s discretion, after a minimum of 2 doses with no 
evidence of infusion-related toxicity at the prolonged rate. For Grade 3 
IRRs, continue administration at the prolonged rate. 
• 
For Grade 3 reactions, the infusion will be STOPPED and 
supportive care will be provided.  The occurrence will be considered a 
DLT and the patient will be discontinued from treatment. 
 
 
 
In all cases the Investigator should use best clinical judgment in 
managing such reactions. For Grade 1 and 2 IRRs, rechallenge with a 
shorter duration of infusion (no less than 30 minutes) may be attempted 
at the Investigator’s discretion, after a minimum of 2 doses with no 
evidence of infusion-related toxicity at the prolonged rate. 
1 Synopsis: 
Discontinuation and 
Follow-Up: Key 
Treatment 
Discontinuation 
Criteria 
 
9.1 Criteria for 
Treatment 
Discontinuation 
1. 
Adverse Events, including: 
• 
≥ Grade 3 evidence of any of the following immune-mediated 
toxicities: 
o 
Pneumonitis 
o 
Myocarditis 
o 
Adrenal insufficiency 
o 
Encephalitis 
o 
Nephritis, renal dysfunction (serum creatinine elevation) 
o 
Episcleritis, uveitis, or iritis 
• 
> Grade 3 evidence of any of the following immune-mediated 
toxicities: 
o 
Colitis 
o 
Hypophysitis, hyperglycemia 
o 
Inflammatory arthritis 
o 
Myositis 
o 
Rash 
• 
Hepatotoxicity characterized by:  
o AST and/or ALT elevation > 3 × ULN (or > 3 × baseline 
if elevated at study entry due to hepatic involvement by 
tumor), with  
o total bilirubin ≥ 2 × ULN without initial findings of 
cholestasis (i.e. serum ALP < 2 × ULN), and  
1. 
Adverse Events, including: 
• 
Any AE or SAE that meets the study DLT criteria at any time 
during the study  
• 
Another AE or SAE considered by the Investigator to require 
treatment discontinuation 
 
(All other AEs listed in the original text were removed) 


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o No explanation for the above findings, such as viral 
hepatic injury, preexisting or acute liver disease, another 
drug or condition capable of causing the observed liver 
injury   
• 
> Grade 3 IRR; Grade 3 IRR in a patient who has received 
premedication 
• 
Any DLT considered by the Investigator to require treatment 
discontinuation 
• 
Another AE or SAE considered by the Investigator to require 
treatment discontinuation 
3.2 Trial Design 
Summary 
Study Assessments 
…Patients will be evaluated for evidence of immune-mediated 
toxicities, evidence of certain specified conditions will result in 
immediate discontinuation from treatment with study drug. Patients will 
also be evaluated for evidence of antibody formation to study drug. 
Patients experiencing a DLT regarded as possibly-, probably-, or related 
to study drug at any point during treatment will either be discontinued 
from treatment with study drug, or may continue if there is evidence of 
an OR, SD, or other clinical benefit, but may do so ONLY following 
discussion with the Sponsor’s Medical Monitor(s). Patients may not be 
retreated following the occurrence of a DLT until there is amelioration 
to ≤ Grade 1 severity, return to baseline status, or resolution of the 
toxicity. Only DLTs occurring during Cycle 1 will be used to make 
determinations regarding dose-escalation and tolerability. Exceptions to 
continuing on-study include evidence of certain immune-mediated 
toxicities, as detailed in Section 9.1; in such instances patients must be 
permanently discontinued from treatment with study drug.   
Study Assessments 
…Patients will be evaluated for evidence of immune-mediated 
toxicities. Patients will also be evaluated for evidence of antibody 
formation to study drug. Patients experiencing a DLT regarded as 
possibly-, probably-, or related to study drug at any point during 
treatment will be discontinued from study treatment, without exception. 
Patients may not be retreated following the occurrence of a DLT. Only 
DLTs occurring during Cycle 1 will be used to make determinations 
regarding dose-escalation and tolerability.   
6.5.3.5 Duration of 
Infusion 
Note: In the event of a Grade 2 IRR, the Investigator may prolong the infusion 
duration to extend longer than the initially assigned duration (for further 
instructions see Section 8.5.1, Appendix 9). 
 
Study drug will be administered over a longer period for all patients 
entered to the trial in the following situations: 
• 
In the event of a Grade 2 IRR in ≥ two thirds of the patients entered 
to a cohort, the duration of infusion for subsequent patients entered to 
the trial will be extended to 1 hour (or longer, if indicated). 
Note: In the event of a Grade 2 IRR, see Section 8.5.1, Appendix 9 for further 
instructions. 
 
 
Study drug will be administered over a longer period for all patients 
entered to the trial in the following situations: 
• 
In the event of a Grade 2 IRR in ≥ two thirds of the patients entered 
to a cohort, the duration of infusion for subsequent patients entered to 
the trial will be extended by 30 minutes (or longer, if indicated). 


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• 
In the event of a Grade 3 or greater IRR in any patient within a 
cohort, the duration of infusion for subsequent patients entered to the 
trial will be extended to 1 hour (or longer, if indicated). Such a case will 
also be considered to have met the protocol criteria for a DLT, thus 
requiring expansion of the cohort. 
These same criteria will be applied in the event IRRs occur on the 
extended 1-hour infusion schedule.  In such a case, the duration of 
infusion for subsequent patients entered to the trial will be extended to 
1.5 hours (or longer, if indicated). 
• 
In the event of a Grade 3 or greater IRR in any patient within a 
cohort, the duration of infusion for subsequent patients entered to the 
trial will be extended by 30 minutes (or longer, if indicated). Such a case 
will also be considered to have met the protocol criteria for a DLT, thus 
requiring expansion of the cohort. 
These same criteria will be applied in the event IRRs occur on the 
extended infusion schedule.  In such a case, the duration of infusion for 
subsequent patients entered to the trial will be further extended by 30 
minutes (or longer, if indicated). 
6.7.1 Retreatment 
Guidelines 
Not applicable (new text added) 
Note:  Patients may receive standard doses of replacement hormonal therapy for 
adrenal insufficiency, hypothyroidism, or other endocrine end-organ failure, and 
may resume study drug once considered by the Investigator to be stable on such 
therapy provided a DLT criterion has not been met. 
6.7.6 Retreatment 
Following an 
Objective Response 
This option for retreatment does not apply to patients who previously 
experienced an unacceptable toxicity that required permanent 
discontinuation of study drug (Section 9.1). 
This option for retreatment does not apply to patients who previously 
experienced a DLT that required permanent discontinuation from study 
drug (Section 6.8.3, Section 9.1). 
6.8.2 Management of 
Dose-Limiting 
Toxicities and Other 
Toxicities 
If a significant toxicity thought to be related to study drug is experienced 
at any point during the patient’s participation in the study, the 
Investigator will determine:   
• 
Whether that toxicity is dose-limiting (Section 6.8.3), thus 
requiring either discontinuation from study, or the patient may continue 
if there is evidence of response or other clinical benefit, but dosing must 
be delayed and the patient may not be retreated until retreatment criteria 
are met.   
Patients experiencing certain immune-mediated toxicities may not be 
retreated and will be discontinued from further participation (Section 
9.1) 
• 
Whether the toxicity does not meet the protocol definition of DLT, 
but nevertheless warrants dose modification, in which case the 
Investigator may elect to temporarily delay dosing with study drug to 
allow for amelioration of the toxicity.   
If a significant toxicity thought to be related to study drug is 
experienced at any point during the patient’s participation in the study, 
the Investigator will determine:   
• 
Whether that toxicity is dose-limiting (Section 6.8.3), thus 
requiring discontinuation from study treatment, without exception.   
• 
Whether the toxicity does not meet the protocol definition of DLT, 
but nevertheless warrants dose modification, in which case the 
Investigator may elect to temporarily delay dosing with study drug to 
allow for amelioration of the toxicity.   
7.1.3 Past Medical 
History 
• 
Screening 
• 
C1/D1 (prior to dosing) 
 
• 
Screening 
• 
C1/D1 (prior to dosing)*  
* Need not be assessed prior to Cycle 1 if ≤ 7 days since screening 


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7.2.8 
Electrocardiogram 
(To be evaluated locally; to be performed after patient has been supine 
for ≥ 10 minutes) 
(To be evaluated locally; to be performed after patient has been supine 
or semi-recumbent for ≥ 10 minutes) 
7.3.2 Ophthalmology 
Examination 
(To include funduscopic and slit lamp evaluations for assessment of 
retinal and corneal integrity, visual acuity, and any other noted ocular 
abnormality) 
• 
Screening 
• 
EOC2 and every even-numbered cycle thereafter*, ** 
• 
EOT** 
• 
As clinically indicated 
(To include funduscopic and slit lamp evaluations for assessment of 
retinal and corneal integrity, visual acuity as assessed by standardized 
chart or other appropriate measurement tool, and any other noted 
ocular abnormality) 
• 
Screening 
• 
EOC1 (visual acuity only; by Snellen chart or similar measurement 
tool)* 
• 
EOC2 and every even-numbered cycle thereafter*, ** 
• 
EOT** 
• 
As clinically indicated 
7.7.1 
Pharmacodynamic 
Assessments 
• 
Cycle 2 
o Day 1 
o Day 15 (after dosing + 7 days) (at the time of biopsy if 
performed) 
• 
Cycle 2 
o Day 1 (prior to dosing) 
o Day 15 (after dosing + 7 days) (at the time of biopsy if 
performed) 
8.3 Determination of 
DLT versus Non-
DLT 
If the protocol definition of DLT is met, the patient will be either 
discontinued from further treatment, or may continue if there is evidence 
of an OR, SD, or other clinical benefit, but may do so ONLY following 
discussion with the Sponsor’s Medical Monitor(s). Patients may not be 
retreated following the occurrence of a DLT until there is amelioration 
to ≤ Grade 1 severity, return to baseline status, or resolution of the 
toxicity.   
Exceptions to continuing on study include evidence of certain immune-
mediated toxicities as detailed in Section 9.1. In such instances patients 
must be permanently discontinued from treatment with study drug.   
If the protocol definition of DLT is met, the patient will be discontinued 
from study treatment, without exception.   
8.4.3 Premedication 
for IRRs (Following 
an IRR) 
• 
For Grade 3 reactions, premedication prior to subsequent infusions 
will be required (if the patient is to be retreated). Patients experiencing a 
Grade 3 reaction after having received premedication will be 
discontinued from treatment. 
• 
For Grade 3 reactions, not applicable as this is considered a DLT; 
therefore, no further treatment with study drug is allowed. 
8.5.1.2 Treatment 
Following Infusion 
Prolongation 
For Grade 3 IRRs, continue administration at the prolonged rate. 
Text removed 


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10.1.2 Events Not to 
be Considered as 
Adverse Events 
PD may be reported as an AE/SAE in the case of patient death, with 
death being the outcome of the event. 
Note: PD may be reported as an AE in the case of patient death, with death being 
the outcome of the event. 
10.1.5 Events That 
Do Not Meet the 
Definition of Serious 
Adverse Events 
PD may be reported as an SAE in the case of patient death, with death 
being the outcome of the event. 
Note: PD may be reported as an SAE in the case of patient death, with death 
being the outcome of the event. 
10.3.1 Timeframes 
for Reporting to the 
Sponsor 
In case of an SAE, the Investigator must, within 24 hours of awareness 
of the event, report the SAE to the Sponsor (or designee) by telefax or e-
mail transmission. Fax number(s) and e-mail address(es) will be stated 
on the SAE Report Form and the SAE Report Form Completion 
Instructions. 
 
Timelines for reporting of SAEs and SAE follow-up information are 
shown (Table 5). 
In case of an SAE, the Investigator must, within 24 hours of awareness 
of the event, report the SAE to the Sponsor (or designee) by telefax or e-
mail transmission. Fax number(s) and e-mail address(es) will be stated 
on the SAE Report Form and the SAE Report Form Completion 
Instructions.  SAE follow-up information must also be reported to the 
Sponsor (or designee) within 24 hours of awareness. 
 
Removed Table 5: Timelines for Submission of SAEs and SAE Follow-
up 
10.4 Pregnancy 
Elective terminations for non-medical reasons should not be reported as 
AEs. 
Elective terminations for non-medical reasons should be reported as 
follow-up, but not as a separate AE/SAE unless complications meet 
AE/SAE criteria. 
11.1 Precautions 
Regarding 
Procreation 
Studies have not been performed to determine whether this study drug 
affects reproductive function in males. For this reason, men with 
partners with childbearing potential must use a highly effective method 
of contraception while receiving study drug. 
Studies have not been performed to determine whether this study drug 
affects reproductive function in males or can cause fetal harm. For this 
reason, men with partners of childbearing potential must use a highly 
effective method of contraception while receiving study drug. 
13.4.2 Modification 
of the Informed 
Consent Form 
If modifications… the Investigator will prepare a revision to the existing 
ICF.  Such a revision will be reviewed and approved by the appropriate 
regulatory authority (as indicated) and IRB/EC, and documentation of 
this approval will be forwarded to the Sponsor (or designee) for 
submission to the appropriate regulatory body. 
If modifications… the Sponsor (or designee) will prepare a revision to 
the existing sample ICF for modification, as appropriate, by each 
Investigator.  Any revision to the sample ICF prepared by the Sponsor 
(or designee) will be implemented according to the Sponsor’s (or 
designee’s) SOPs. Such a revision will be reviewed and approved by the 
appropriate regulatory authority (as indicated) and IRB/EC. 
14.1 Medical 
Supervision 
An Investigator conducting a clinical study with an investigational agent 
is required to comply with regulations described in U.S. Title 21 CFR 
Part 312 and ICH E6(R2) GCP. 
An Investigator conducting a clinical study with an investigational agent 
is required to comply with regulations described in U.S. Title 21 CFR 
Parts 50, 56, and 312 and/or by governing Health Authorities, as well as 
ICH E6(R2) GCP. 
14.8 Recording of 
Data 
All data must be carefully entered to permit meaningful interpretation. 
Corrections to entered data will be tracked within the EDC system. Data 
must be entered into CRFs in a timely fashion. 
CRFs are designed for computer processing and analysis. All data must 
be carefully entered to permit meaningful interpretation. Corrections to 


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entered data will be identified and tracked by audit trails within the EDC 
system. Data must be entered into CRFs in a timely fashion. 
15.1 Data Handling 
Data will be handled according to good data management practices, all 
applicable data protection regulations, and will comply with ICH 
E6(R2) GCP. 
Study data collection, processing, transfer, and reporting as well as 
handling of study personnel information will be in compliance with ICH 
E6(R2) GCP and all applicable data protection regulations. 
15.3 Data Processing 
A Data Management Plan will be prepared for this trial. The Sponsor (or 
designee) will be responsible for data processing in accordance with 
applicable Data Management SOPs.  
 
Database Lock will occur once quality control procedures and quality 
assurance procedures (if applicable) have been completed upon reaching 
the data cut-off for primary analysis. 
 
Portable Document Format (PDF) files of the CRFs will be provided to 
the Investigator before access to the CRF system is revoked. 
A Data Management Plan (DMP) will be prepared for this trial. The 
Sponsor (or designee) will be responsible for data processing in 
accordance with applicable Data Management SOPs and the trial DMP.  
 
Database Lock will occur upon reaching the pre-defined data cut-off for 
primary analysis and completion of Sponsor’s (or designee’s) quality 
control and quality assurance procedures. 
 
Portable Document Format (PDF) files of the electronic CRFs will be 
provided to the Investigator upon removal of access to the electronic 
CRFs. 
Appendix 9: Grading 
and Management of 
Infusion-Related 
Reactions 
In the Event of Infusion Prolongation 
For Grade 3 reactions, subsequent infusions must be administered at the 
prolonged rate. 
 
Modification of Infusion Duration for the Trial 
• 
In the event of a Grade 2 IRR in ≥ two thirds of the patients entered 
to a cohort, the duration of infusion for subsequent patients entered to 
the trial will be extended to 1 hour (or longer, if indicated). 
• 
In the event of a Grade 3 or greater IRR in any patient within a 
cohort, the duration of infusion for subsequent patients entered to the 
trial will be extended to 1 hour (or longer, if indicated). Such a case will 
also be considered to have met the protocol criteria for a DLT, thus 
requiring expansion of the cohort. 
 
These same criteria will be applied in the event IRRs occur on the 
extended 1-hour infusion schedule. In such a case, the duration of 
infusion for subsequent patients entered to the trial will be extended to 
1.5 hours (or longer, if indicated). See Section 6.5.3.5. 
In the Event of Infusion Prolongation 
Text removed 
 
 
Modification of Infusion Duration for the Trial 
• 
In the event of a Grade 2 IRR in ≥ two thirds of the patients entered 
to a cohort, the duration of infusion for subsequent patients entered to 
the trial will be extended by 30 minutes (or longer, if indicated). 
• 
In the event of a Grade 3 or greater IRR in any patient within a 
cohort, the duration of infusion for subsequent patients entered to the 
trial will be extended by 30 minutes (or longer, if indicated). Such a case 
will also be considered to have met the protocol criteria for a DLT, thus 
requiring expansion of the cohort. 
 
These same criteria will be applied in the event IRRs occur on the 
extended 1-hour infusion schedule. In such a case, the duration of 
infusion for subsequent patients entered to the trial will be further 
extended by 30 minutes (or longer, if indicated). See Section 6.5.3.5. 


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Appendix 10: 
Management of 
Immune-Mediated 
Toxicities 
Not applicable (new text added) 
Instructions for management of immune-mediated toxicities are 
provided below and are to be implemented as detailed EXCEPT where 
AEs meet the protocol-specified DLT criteria (Section 6.8.3). AEs that 
meet the protocol definition of DLT will require discontinuation from 
study treatment, without exception (Section 6.8.2); this instruction 
supersedes those provided below.    
 
 
 


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19.2 
Protocol Amendment 2 dated 02-Aug-2018 
• Patient exclusion criterion 9 has been added to exclude patients with a significant ocular disease or condition. Patients with 
non-significant, non-inflammatory disorders (e.g., cataracts, glaucoma) will be allowed.   
• DLT criterion 4 has been modified to indicate that study drug-related changes in visual acuity will continue to be considered 
dose-limiting but changes must now be confirmed by subsequent ophthalmologic exam.  In addition, a footnote has been 
added providing further guidance. 
• The Study Safety Committee has been renamed to the Study Safety Team to better align with scope. 
• Vital Signs windows have been modified to correspond with PK sampling windows. 
• Instructions for ophthalmology reassessment in the event of changes in visual acuity are provided (i.e., within 48 hours, if 
feasible).  The notation also indicates that no patient with a documented decrease in visual acuity may be retreated unless the 
event is considered unrelated to study drug, and unless the patient is cleared for retreatment by an ophthalmologist. 
• Guidelines pertaining to the General Data Protection Regulation have been added. 
• Formatting adjustments, minor typographical corrections, outline modifications, and slight wording changes are included. 
• The synopsis and tables have been updated based on changes described, where applicable. 
Refer to Table 7 for the changes in Protocol Amendment 2. 
 
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4.3.1 Patients to be 
Excluded 
Not applicable (new text added) 
9. 
Patients with a significant ocular disease or condition, including 
history of an autoimmune or inflammatory disorder, e.g., episcleritis, 
uveitis, iritis  
Note:   Patients with a history of dry eye for reasons other than an autoimmune 
disease or condition may be included if adequately treated. Patients with 
non-significant, non-inflammatory disorders (e.g., cataracts, glaucoma) 
will be allowed.   
6.8.3 Definition of 
Dose-Limiting 
Toxicity 
 
4. 
Any reduction in visual acuity, regardless of grade or duration 
4. 
Any confirmed reduction in visual acuity, regardless of grade or 
duration 
Note:  Noted changes in visual acuity must be reevaluated by an ophthalmologist 
and confirmed within 48 hours (if feasible, based on weekends or holidays) 
of the initial observation; study drug will be held pending evaluation by the 
ophthalmologist.   
Changes in visual acuity assessment, if associated with either an immune-
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other condition that may be considered to be related to therapy with study 
drug will be considered to be a DLT.   
Patients in whom a minor fluctuation in visual acuity is due to another 
known or recently diagnosed underlying condition may continue to be 
treated once visual acuity fluctuation returns to baseline status, but must be 
reevaluated by an ophthalmologist prior to each cycle and upon the 
occurrence of any subsequent ophthalmologic sign or symptom, including 
but not limited to recurrent changes in visual acuity measurement, in order 
to reassess for DLT status. 
7.2.5 Vital Signs  
 
(Vital signs [VS] to include temperature, pulse, respiratory rate, blood 
pressure [BP], and oxygen saturation by pulse oximetry)* 
• 
Screening 
• 
Cycle 1 
o 
Day 1 
 
Prior to SOI 
 
End of infusion (EOI) (± 5 min)  
 
2, 4, 8 hours after EOI (± 15 min)  
o 
Day 2 
o 
Day 3 (+ 1 day) 
o 
Day 15 
 
Prior to SOI 
 
EOI (± 5 min)  
• 
Each cycle thereafter 
o 
Day 1 (prior to dosing) 
• 
EOT  
• 
1M FUP 
• 
As clinically indicated 
*Comprehensive assessment of VS is critical to the conduct of this study. In 
situations where an assessment at 8 hours after EOI is logistically difficult due to 
clinic staff availability, the observation period may be shortened, and an "end of 
day" assessment may be obtained at the latest practical time.  Such an option (if 
to be routinely employed) is available only after discussion with and approval by 
the Sponsor. 
(Vital signs [VS] to include temperature, pulse, respiratory rate, blood 
pressure [BP], and oxygen saturation by pulse oximetry)* 
• 
Screening 
• 
Cycle 1 
o 
Day 1 
 
Prior to SOI 
 
End of infusion (EOI) (± 10 min)  
 
2, 4 hours after EOI (± 30 min) 
 
8 hours after EOI (± 90 min  
o 
Day 2 (24 hours after EOI) (± 6 hours) 
o 
Day 3 (48 hours after EOI) (- 12 to + 24 hours) 
o 
Day 15 
 
Prior to SOI 
 
EOI (± 10 min)  
• 
Each cycle thereafter 
o 
Day 1 (prior to dosing) 
• 
EOT  
• 
1M FUP 
• 
As clinically indicated 
*Comprehensive assessment of VS is critical to the conduct of this study. In 
situations where an assessment at 8 hours after EOI is logistically difficult due to 
clinic staff availability, the observation period may be shortened, and an "end of 
day" assessment may be obtained at the latest practical time.  Such an option (if 
to be routinely employed) is available only after discussion with and approval by 
the Sponsor. 
Note:  C1/D1 through C1/D3 window allowances align with PK timepoints 
windows 


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7.3.2 Ophthalmology 
Examination 
 
*End of Cycle assessments may be conducted at any time during the week prior 
to Day 1 of the next cycle, including on Day 1 of the next cycle, prior to dosing.   
*End of Cycle assessments may be conducted at any time during the week prior 
to Day 1 of the next cycle, including on Day 1 of the next cycle, prior to dosing.  
Due to inherent variability of Snellen chart assessments, if changes in visual 
acuity are noted, a thorough ophthalmologic evaluation should be performed 
within 48 hours (if feasible, based on weekends or holidays) of the initial 
observation in order to confirm the finding and determine if there is evidence of 
an immune-mediated AE, or other event that would preclude further treatment 
with study drug.  No patient with any documented decrease in visual acuity will 
receive further therapy with Sym023 unless the event is considered unrelated to 
study drug and unless cleared for retreatment by an ophthalmologist. 
7.7.1 
Pharmacodynamic 
Assessments 
• 
Cycle 2 
o 
Day 1 (prior to dosing) 
o 
Day 15 (after dosing + 7 days) (at the time of biopsy if 
performed) 
• 
Cycle 2 
o 
Day 1 (prior to dosing) 
o 
Day 15 (after dosing + 0 to 7 days) (at the time of biopsy if 
performed) 
7.7.2.1 Blood 
Samples for 
Biomarker 
Assessments 
• 
Cycle 2 
o 
Day 15 (after dosing + 7 days) (at the time of biopsy if 
performed) 
• 
Cycle 2 
o 
Day 15 (after dosing + 0 to 7 days) (at the time of biopsy if 
performed) 
7.7.2.2 Tumor 
Sample for 
Biomarker 
Assessment (Biopsies 
Optional) 
• 
Cycle 2  
o 
Day 15 (after dosing + 7 days) (with paired pharmacodynamic 
and biomarker peripheral blood) 
• 
Cycle 2  
o 
Day 15 (after dosing + 0 to 7 days) (with paired 
pharmacodynamic and biomarker peripheral blood) 
15.1 Data Handling 
 
Study data collection, processing, transfer, and reporting as well as 
handling of study personnel information will be in compliance with ICH 
E6(R2) GCP and all applicable data protection regulations. 
Study data collection, processing, transfer, and reporting, as well as 
handling of study personnel information, will be in compliance with 
ICH E6(R2) GCP and all applicable data protection regulations, 
including Regulation (EU) 2016/679 of the European Parliament and of 
the Council of 27 April 2016 on the protection of natural persons with 
regard to the processing of personal data and on the free movement of 
such data (General Data Protection Regulation). 
15.5 Compliance 
with the General Data 
Protection Regulation 
 
Not applicable (new section and text added) 
The applicable data protection legislation requires that parties enter into 
a written contract if one party (data processor) processes personal data 
on behalf of the other party (data controller). This written contract must 
regulate the subject-matter and duration of the processing, the nature 
and purpose of the processing, the types of personal data and categories 
of data subjects, as well as the obligations and rights of the data 
controller. Accordingly, the parties must enter into a data processing 


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agreement. To the extent the processing of personal data involves 
transfers of personal data to third countries (e.g., jurisdictions outside of 
the European Economic Area [EEA]), the parties will enter into the 
European Commission's standard contractual clauses between the data 
controller, the data processor, and all sub-processors, if any. The 
European Commission's standard contractual clauses ensure an adequate 
level of protection in relation to transfers of personal data to third 
countries. 
 
19.3 
Protocol Amendment 3 dated 18-Mar-2019 
• In order to apply more current adverse event grade descriptions and term definitions, the version of the Common 
Terminology Criteria for Adverse Events (CTCAE) used for this study has been updated from Version 4.03 to Version 5.0. 
All references to the CTCAE version throughout this protocol have been updated accordingly.  
• Grading of infusion-related reactions specified in Appendix 9 have been updated to reflect the use of CTCAE Version 5.0.  
• Formatting adjustments, minor typographical corrections, and slight wording changes are included. 
• The synopsis and tables have been updated based on changes described, where applicable. 
Refer to Table 8 for the changes in Protocol Amendment 3. 
 
Table 8:  Protocol Amendment 3 
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ORIGINAL TEXT 
NEW TEXT 
2.3.2 Clinical 
Experience with 
Sym023 
No prior studies with Sym023 have been conducted. 
The study described in this clinical trial protocol is ongoing.  Sym023 is 
also being studied in a Phase 1 study in combination with Sym021 (anti-
PD-1 monoclonal antibody; ClinicalTrials.gov number NCT03311412). 
4.3.1 Patients to be 
Excluded 
6. 
Patients with any of the following coagulation parameter 
abnormalities at baseline (unless on a stable dose of anticoagulant 
therapy for a prior thrombotic event, as determined by the Investigator): 
• 
Prothrombin time (PT) (as assessed by international normalized 
ratio [INR]) > 1.5 × ULN for the institution (> 3× ULN for the 
institution if anticoagulated)… 
6. 
Patients with any of the following coagulation parameter 
abnormalities at baseline (unless on a stable dose of anticoagulant 
therapy for a prior thrombotic event, as determined by the Investigator): 
• 
Prothrombin time (PT) (or international normalized ratio [INR]) > 
1.5 × ULN for the institution (> 3× ULN for the institution if 
anticoagulated)… 


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6.8.3 Definition of 
Dose-Limiting 
Toxicity 
6. 
Any other ≥ Grade 3 non-hematologic toxicity regardless of 
duration, with the exceptions of:  
• 
Grade 3 fatigue 
• 
Grade 3 nausea, vomiting, or diarrhea lasting ≤ 2 days with best 
supportive care  
• 
Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 days 
that are not clinically complicated, and resolve spontaneously or respond 
to conventional medical interventions 
6. 
Any other ≥ Grade 3 non-hematologic toxicity regardless of 
duration, with the exceptions of:  
• 
Grade 3 fatigue 
• 
Grade 3 nausea, vomiting, or diarrhea lasting ≤ 2 days with best 
supportive care  
• 
Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 days 
that are not clinically complicated, and resolve spontaneously or respond 
to conventional medical interventions  
• 
Other Grade 3 asymptomatic laboratory abnormalities that are 
clinically non-significant in the investigator’s opinion, and that resolve 
spontaneously or with conventional medical interventions 
7.2.7.3 Coagulation 
Panel 
(To include PTT [or aPTT], PT, INR) 
(To include PTT [or aPTT], PT and/or INR) 
 
19.4 
Protocol Amendment 4 dated 02-May-2019 
• Final infusion volumes have been revised and made more granular to accommodate higher doses of drug product as well as 
patients who have a higher body weight. Additionally, where the amount of IMP is ≥ 40% of the total infusion volume, a 
larger IV solution bag should be used to prevent the infusion from becoming hypotonic.  
• Infusion duration for Sym023 infusion volumes of 500 mL has been specified as 1 hour. 
• Formatting adjustments, typographical corrections, and slight wording changes are included. 
• The synopsis has been updated based on changes described, where applicable. 
Refer to Table 9 for the changes in Protocol Amendment 4. 
 
Table 9:  Protocol Amendment 4 
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ORIGINAL TEXT 
NEW TEXT 
3.2 Trial Design 
Summary 
• 
On Day 1 of study, patients will receive study drug administered by 
30-minute (+10 min) IV infusion in a fixed 50 mL volume for doses < 1 
mg/kg, or in a fixed 100 mL volume for doses ≥ 1 mg/kg to ≤ 10 mg/kg, 
or in a fixed 250 mL volume for doses > 10 mg/kg. 
• 
On Day 1 of study, patients will receive study drug administered by 
30-minute (+10 min) or by 60-minute (+ 10 min) IV infusion 
(depending on dose and body weight) in a fixed 50 mL, 100 mL, 250 
mL, or 500 mL volume depending on dose and body weight. 
4.3.1 Patients to be 
Excluded 
16. Patients with unresolved > Grade 1 toxicity* associated with any 
prior antineoplastic therapy except for persistent Grade 2 alopecia, 
16. Patients with unresolved > Grade 1 toxicity* associated with any 
prior antineoplastic therapy except for persistent Grade 2 alopecia, 


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peripheral neuropathy, decreased hemoglobin, hypomagnesemia, and/or 
end-organ failure being adequately managed by hormone replacement 
therapy 
peripheral neuropathy, decreased hemoglobin, lymphopenia, 
hypomagnesemia, and/or end-organ failure being adequately managed 
by hormone replacement therapy 
5.6 Administration of 
IMP 
 
Study drug will be administered by IV infusion via an indwelling 
catheter. An appropriate dose, based on the patient’s cohort assignment, 
diluted to the total volume specified with 0.9% sodium chloride (NaCl) 
for IV infusion will be administered initially over 30 minutes (+10 
minutes), once every 2 weeks (Q2W; 4 weeks [28 days] equals 1 dosing 
cycle).   
Study drug will be administered by IV infusion via an indwelling 
catheter. An appropriate dose, based on the patient’s cohort assignment, 
diluted to the total volume specified with 0.9% sodium chloride (NaCl) 
for IV infusion will be administered initially over:  
• Approximately 30 minutes (+10 minutes) for infusion volumes 
≤ 250 mL 
• Approximately 60 minutes (+10 minutes) for infusion volumes 
of 500 mL  
Dosing will be once every 2 weeks (Q2W; 4 weeks [28 days] equals 1 
dosing cycle).   
5.8 Dose 
Preparation 
• 
The total volume of study drug to be delivered will be withdrawn 
from the study drug vial(s) and added to a prefilled IV bag containing 
0.9% NaCl for IV infusion (prior to adding the study drug and an 
appropriate volume of NaCl solution is removed, such that the final 
volume to be infused equals:   
o 
50 mL for doses < 1 mg/kg  
o 
100 mL for doses ≥ 1 mg/kg to ≤ 10 mg/kg  
o 
250 mL for doses > 10 mg/kg.     
• 
The total volume of study drug to be delivered will be withdrawn 
from the study drug vial(s) and added to a prefilled IV bag containing 
0.9% NaCl for IV infusion (prior to adding the study drug and an 
appropriate volume of NaCl solution is removed, such that the final 
volume to be infused equals:   
o 50 mL for doses < 1 mg/kg  
o 100 mL for doses ≥ 1 mg/kg to ≤ 3 mg/kg  
o 100 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with 
body weight ≤ 80 kg 
o 250 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with 
body weight > 80 kg 
o 250 mL for doses > 10 mg/kg for patients with body weight ≤ 
100 kg 
o 500 mL for doses > 10 mg/kg for patients with body weight > 
100 kg  
Note:  In a case where the amount of IMP is ≥ 40% of the total infusion 
volume, a larger IV solution bag should be used.   
6.5.3.4 Volume of 
Infusion 
 
Infusions will be delivered in a final volume of:  
• 
50 mL for doses < 1 mg/kg 
• 
100 mL for doses ≥ 1 mg/kg to ≤ 10 mg/kg 
• 
250 mL for doses > 10 mg/kg 
Infusions will be delivered in a final volume of:  
• 50 mL for doses < 1 mg/kg 
• 100 mL for doses ≥ 1 mg/kg to ≤ 3 mg/kg 
• 100 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with 
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• 250 mL for doses of > 3 mg/kg to ≤ 10 mg/kg for patients with 
body weight > 80 kg 
• 250 mL for doses > 10 mg/kg for patients with body weight ≤ 
100 kg 
• 500 mL for doses > 10 mg/kg for patients with body weight > 
100 kg 
Note:  In a case where the amount of IMP is ≥ 40% of the total infusion 
volume, a larger IV solution bag should be used. 
6.5.3.5 Duration of 
Infusion 
 
Study drug will be administered over 30 minutes (+10 minutes) 
Study drug will be administered over: 
• Approximately 30 minutes (+10 minutes) for infusion volumes 
≤ 250 mL 
• Approximately 60 minutes (+10 minutes) for infusion volumes 
of 500 mL 
6.7.1 Retreatment 
Guidelines 
• 
Any ongoing study drug-related AE should have either ameliorated 
to ≤ Grade 1 severity, returned to baseline status, or resolved, with the 
exceptions of:… 
o Asymptomatic laboratory abnormalities that are considered 
clinically insignificant, clinically uncomplicated, and/or that are 
resolving spontaneously or with conventional medical 
interventions. 
• 
Any ongoing study drug-related AE should have either ameliorated 
to ≤ Grade 1 severity, returned to baseline status, or resolved, with the 
exceptions of:… 
o Grade 2 asymptomatic laboratory abnormalities that are 
considered clinically insignificant, clinically uncomplicated, 
and/or that are resolving spontaneously or with conventional 
medical interventions. 
8.5.1.2 Treatment 
Following Infusion 
Prolongation 
 
To enhance patient safety following an infusion prolongation, 
subsequent infusions will be administered at the prolonged rate. For 
Grade 1 and 2 IRRs, rechallenge with a shorter duration of infusion (no 
less than 30 minutes) may be attempted at the Investigator's discretion, 
after a minimum of 2 doses with no evidence of infusion-related toxicity 
at the prolonged rate. 
To enhance patient safety following an infusion prolongation, 
subsequent infusions will be administered at the prolonged rate. For 
Grade 1 and Grade 2 IRRs, rechallenge with a shorter duration of 
infusion (no less than the duration designated by the patient’s dose 
assignment and weight) may be attempted at the Investigator's 
discretion, after a minimum of 2 doses with no evidence of infusion-
related toxicity at the prolonged rate. 
16.5.11 
Pharmacokinetic 
Analysis 
Individual curves of serum concentration of total study drug versus time 
after the first and fourth infusion will be presented on log- and linear 
scale for all patients in the PK population. 
Individual curves of serum concentration of total study drug versus time 
after the first infusion will be presented on log- and linear scale for all 
patients in the PK population. 
Appendix 9: Grading 
and Management of 
Infusion-Related 
Reactions 
For Grade 1 and 2 reactions, rechallenge with a shorter duration of 
infusion (no less than 30 minutes) may be attempted at the Investigator's 
discretion, after a minimum of 2 doses with no evidence of infusion-
related toxicity at the prolonged rate.   
For Grade 1 and Grade 2 reactions, rechallenge with a shorter duration 
of infusion (no less than the duration designated by the patient’s dose 
assignment and weight) may be attempted at the Investigator's 
discretion, after a minimum of 2 doses with no evidence of infusion-
related toxicity at the prolonged rate.   


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SAP_001.pdf: 
 
 
 
 
 
DOC.ST.101.04-01 Rev 00 
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CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Trial Sponsor: 
Protocol Number: 
Symphogen 
Sym023-01 
IND Number: 
137066 
EUDRACT Number: 
N/A 
Investigational Drug: 
Indication: 
Sym023 
Advanced Solid Tumors or Lymphomas 
Drug Number: 
N/A 
Dosage Form/Strength: Liquid (IV) – 0.03 mg/kg, 0.1 mg/kg, 0.3 
mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10.0 mg/kg, 
20 mg/kg 
 
 
Protocol Title:  
A Phase 1, Open-Label, Multicenter Trial Investigating the Safety, Tolerability, and 
Preliminary Antineoplastic Activity of Sym023 (Anti-TIM-3) in Patients with Advanced Solid 
Tumor Malignancies or Lymphomas 
 
 
 
First Sign-off Date: 
08May2019 
Final Sign-off Date: 
26Jun2020 
 








 
Statistical Analysis Plan 
Protocol No. Sym023-01 
Last Revision Date: 26Jun2020 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION .......................................................................................................................................... 10 
2 
STUDY OBJECTIVES................................................................................................................................... 10 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................. 10 
2.2 
SECONDARY OBJECTIVES .......................................................................................................................... 10 
2.3 
EXPLORATORY OBJECTIVES ...................................................................................................................... 11 
3 
STUDY DESIGN ............................................................................................................................................ 11 
3.1 
STUDY DESIGN .......................................................................................................................................... 11 
3.2 
RANDOMIZATION ...................................................................................................................................... 12 
3.3 
HYPOTHESIS TESTING ............................................................................................................................... 12 
3.4 
INTERIM ANALYSIS ................................................................................................................................... 12 
3.5 
SAMPLE SIZE ............................................................................................................................................. 12 
3.6 
STUDY PROCEDURES ................................................................................................................................. 12 
3.7 
SCHEDULE OF ASSESSMENTS..................................................................................................................... 14 
4 
DATA AND ANALYTICAL QUALITY ASSURANCE ............................................................................. 19 
5 
ANALYSIS SETS ........................................................................................................................................... 19 
5.1 
FULL ANALYSIS SET (FAS) ....................................................................................................................... 19 
5.2 
DLT ANALYSIS SET .................................................................................................................................. 19 
5.3 
PK ANALYSIS SET ..................................................................................................................................... 19 
5.4 
ADA ANALYSIS SET ................................................................................................................................. 19 
6 
SPECIFICATION OF ENDPOINTS AND VARIABLES .......................................................................... 19 
6.1 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 19 
6.2 
SAFETY ..................................................................................................................................................... 20 
6.2.1 
Safety Study Day and Visit Window Definitions ..................................................................... 21 
6.2.2 
Primary Endpoint and Analysis ................................................................................................ 22 
6.2.3 
Extent of Exposure to Study Medication .................................................................................. 23 
6.2.4 
Adverse Events ......................................................................................................................... 24 
6.2.5 
Deaths ....................................................................................................................................... 26 
6.2.6 
Laboratory Data ........................................................................................................................ 26 
6.2.7 
Vital Signs ................................................................................................................................ 27 
6.2.8 
Electrocardiogram (ECG) ......................................................................................................... 27 
6.2.9 
Physical Examination ............................................................................................................... 27 
6.2.10 
ECOG Performance Status ....................................................................................................... 27 
6.2.11 
Pregnancy Test ......................................................................................................................... 27 
6.2.12 
Concomitant Medications/Treatments ...................................................................................... 27 
6.2.13 
Other Safety Assessments ......................................................................................................... 28 
6.3 
EFFICACY .................................................................................................................................................. 28 
6.3.1 
Efficacy Study Day and Visit Window Definitions .................................................................. 28 
6.3.2 
Tumor Marker Measurement .................................................................................................... 29 
6.3.3 
Tumor and Response Evaluations ............................................................................................. 29 
6.3.4 
Time to Progression .................................................................................................................. 30 
6.3.5 
Duration of Objective Response ............................................................................................... 32 
6.4 
PHARMACOKINETIC PARAMETERS ............................................................................................................ 32 


 
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6.5 
IMMUNOGENICITY DATA ........................................................................................................................... 34 
6.6 
PHARMACODYNAMIC AND BIOMARKER ANALYSES .................................................................................. 34 
7 
STATISTICAL ANALYSIS .......................................................................................................................... 34 
7.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS .............................................................................. 34 
7.2 
PATIENT DISPOSITION ............................................................................................................................... 35 
7.3 
PROTOCOL DEVIATIONS ............................................................................................................................ 35 
7.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 35 
7.5 
SAFETY ANALYSES ................................................................................................................................... 35 
7.5.1 
DLT Analysis ........................................................................................................................... 35 
7.5.2 
Extent of Exposure to Study Medication .................................................................................. 36 
7.5.3 
Adverse Events ......................................................................................................................... 36 
7.5.4 
Laboratory Data ........................................................................................................................ 36 
7.5.5 
Vital Signs ................................................................................................................................ 37 
7.5.6 
Electrocardiogram (ECG) ......................................................................................................... 37 
7.5.7 
Physical Examination ............................................................................................................... 37 
7.5.8 
ECOG Performance Status ....................................................................................................... 37 
7.5.9 
Pregnancy Test ......................................................................................................................... 37 
7.5.10 
Concomitant Medications/Treatments ...................................................................................... 37 
7.5.11 
Other Safety Assessments ......................................................................................................... 37 
7.6 
EFFICACY ANALYSES ................................................................................................................................ 37 
7.6.1 
Tumor Marker Measurement .................................................................................................... 37 
7.6.2 
Disease Response...................................................................................................................... 38 
7.6.3 
Time to Progression .................................................................................................................. 38 
7.6.4 
Duration of Objective Response ............................................................................................... 38 
7.7 
PHARMACOKINETIC ANALYSES ................................................................................................................. 38 
7.8 
IMMUNOGENICITY ANALYSES ................................................................................................................... 39 
8 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE .............................................................. 39 
9 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ......................................................... 40 
10 
STATISTICAL SOFTWARE ........................................................................................................................ 40 
11 
REFERENCES ............................................................................................................................................... 40 
12 
APPENDIX 1 NCI-CTCAE V5.0 TOXICITY GRADING ......................................................................... 41 
12.1 PANEL: CHEMISTRY .................................................................................................................................. 41 
12.2 PANEL: HEMATOLOGY .............................................................................................................................. 42 
12.3 PANEL: COAGULATION .............................................................................................................................. 42 
13 
APPENDIX 2 PROGRAMMING CODES FOR STATISTICAL ANALYSIS ......................................... 44 


 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
C1D1 
Cycle 1 Day 1 
CHF 
Congestive Heart Failure 
CR 
Complete Response  
CRF 
Case Report Form 
ctDNA 
Circulating Tumor DNA 
DLT 
Dose-Limiting Toxicities 
DOR 
Duration of Objective Response 
DNA 
Deoxyribonucleic Acid 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOI 
End of Infusion 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
1M FUP 
1-Month Follow up 
IgG2 
Immunoglobulin G2 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
iRECIST 
Immunotherapeutics Response Evaluation Criteria in Solid Tumors 
IV 
Intravenous 


 
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GLOSSARY OF ABBREVIATIONS 
mAb 
Monoclonal Antibody 
MAD 
Maximum Administered Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major Histocompatibility Complex 
MTD 
Maximum Tolerated Dose 
MUGA 
Multi-Gated Acquisition 
NE 
Non-evaluable 
OR 
Objective Response 
ORR 
Overall Response Rate 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PFS 
Progression-free survival 
PR 
Partial Response 
PK 
Pharmacokinetics 
PtdS 
Phosphatidylserine 
Q2W 
Every 2 Weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RECIL 
Response Evaluation Criteria in Lymphoma 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SOI 
Start of Infusion 


 
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GLOSSARY OF ABBREVIATIONS 
TIM-3 
T-cell Immunoglobulin and Mucin-domain Containing-3 
TTP 
Time to Progression 
WES 
Whole Exome Sequencing 


 
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1 INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and analysis 
of data collected within the scope of Sym023-01 Version 5 dated 02May2019. As with any SAP, the 
proposed methods and approaches to the data analysis should be deemed as flexible. The analysis of the 
data should allow changes in the plan to the extent that deviations from the original plan would provide a 
more reliable and valid analysis of the data. As such, the statistical analysis to a certain degree is iterative 
since much of the planning is based on assumptions that require verification. The purpose of this plan is to 
provide general guidelines from which the analysis will proceed. Nevertheless, deviations from these 
guidelines must be substantiated by a sound statistical rationale. 
The SAP should be read in conjunction with the study protocol and the Case Report Forms (CRFs). This 
version of the SAP has been developed using the version of the protocol mentioned above and revision 2 of 
the annotated CRFs dated 29Aug2019. 
This is a Phase 1, multicenter, open-label, uncontrolled, non-randomized, dose-escalation study with one 
study drug. The trial is designed to evaluate safety, tolerability and dose-limiting-toxicities (DLTs) to 
establish the maximum tolerated dose (MTD) or maximum administered dose (MAD), and select the 
recommended Phase 2 dose (RP2D) of sequential escalating doses of Sym023 (anti-TIM-3 mAb) when 
administered every 2 weeks (Q2W) in 4-week cycles, to patients with locally advanced/unresectable or 
metastatic solid tumor malignancies or lymphomas that are refractory to available therapy or for which no 
standard therapy is available. 
TIM3 (T-cell immunoglobulin and mucin-domain containing-3) is an immune checkpoint receptor 
expressed by a range of different immune cells. The role of TIM-3 in regulating immune cell function is 
complex and appears context-dependent. Antibody-mediated engagement of TIM-3 has been shown to 
induce increased proliferation and cytokine production by T-cells in vitro, as well as tumor growth 
inhibition in tumor xenograft models, especially in combination with Programmed Cell Death Protein 1 
(PD-1). Multiple anti-TIM-3 antibodies are in early clinical development for use as cancer immunotherapy 
in solid and hematologic malignancies. Clinical activity in the form of disease stabilization across a variety 
of cancer types has been observed, as well as one partial response. 
Sym023 is a recombinant, fully human, IgG2 antibody that binds human TIM-3 with nanomolar affinity and 
cynomolgus TIM-3 with 100-fold reduced affinity. Sym023 does not cross-react with mouse or rat TIM-3. 
Sym023 blocks PtdS binding to TIM-3 and induces cytokine secretion and activation of immune cells in 
vitro. 
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is the evaluation of the safety, tolerability, and DLTs to establish the MTD and/or 
RP2D of sequential escalating doses of Sym023 (anti-TIM-3) when administered once Q2W by intravenous 
(IV) infusion to patient cohorts with locally advanced/unresectable or metastatic solid tumor malignancies 
or lymphomas that are refractory to available therapy or for which no standard therapy is available. 
2.2 
Secondary Objectives 
The secondary objectives are the following: 


 
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• 
Evaluation of the immunogenicity of Sym023 
• 
Characterization of the PK profile of Sym023 
• 
Evaluation of the preliminary antineoplastic effects of Sym023, including: 
o Evidence of objective response (OR) and stable disease (SD)* 
o Duration of OR and SD* 
o Time to progression (TTP) of disease* 
* As assessed by RECIST v1.1, iRECIST, and Response Criteria in Lymphoma (RECIL 2017) 
2.3 
Exploratory Objectives 
The exploratory objectives are the following: 
• 
Evaluation of potential pharmacodynamic markers, e.g. receptor occupancy in peripheral blood 
mononuclear cells (PBMCs) (peripheral blood to be collected) 
• 
Evaluation of potential biomarkers, including but not limited to assessment of: 
o In peripheral blood: circulating tumor DNA (ctDNA), ribonucleic acid (RNA), relevant 
proteins/cytokines and cellular biomarkers 
o In tumor tissue: DNA, RNA, protein, and cellular biomarkers (biopsies optional) 
Note: Assay methodology and biomarker assessments to be determined (TBD). Potential analyses may 
include but are not limited to: ctDNA sequencing; RNA sequencing (RNA-seq)/whole-exome 
sequencing (WES); measurement of relevant proteins/cytokines in the blood; cytometric analysis of 
cells in blood; and immunohistochemistry (IHC) of tumor material when collected (tumor sampling is 
optional). 
3 STUDY DESIGN 
3.1 
Study Design 
This is a Phase 1, multicenter, open-label, dose-escalation study designed to evaluate safety, tolerability, 
and DLTs to establish the MTD or MAD, and the RP2D of sequential escalating doses of Sym023 (study 
drug) when administered Q2W (4 weeks equals 1 cycle) by IV infusion, to patients with advanced, 
refractory solid tumor malignancies or lymphomas. 
Initially, a modified, accelerated-titration, dose-escalation design will be used with entry of single patient 
cohorts for up to two dose levels, based on tolerability. Thereafter, a standard 3+3 design will be used, with 
a target toxicity level of less than 33.3% as determined by DLTs. The number of patients treated, the 
number of cohorts evaluated, and the MTD/MAD will depend upon the observed tolerability of Sym023 
during Cycle 1; however, the maximum dose to be administered in the trial is not to exceed 20 mg/kg. 
In the absence of documented progressive disease (PD) or unacceptable toxicity, patients may continue to 
receive additional 4-week cycles of study drug at the same dose, infusion duration, and schedule established 
for the patient. 
Dose cohorts will be numbered and entered sequentially. Sym023 will be administered at up to 7 planned 
dose levels; anticipated dose levels include: 
• 
Dose Level 1: 0.03 mg/kg 


 
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• 
Dose Level 2: 0.1 mg/kg 
• 
Dose Level 3: 0.3 mg/kg 
• 
Dose Level 4: 1.0 mg/kg 
• 
Dose Level 5: 3.0 mg/kg 
• 
Dose Level 6: 10.0 mg/kg 
• 
Dose Level 7: 20.0 mg/kg 
Once assigned to a dose cohort, patients will continue to be treated with study drug at that same dose level 
throughout the duration of their time on study. There will be no intra-patient dose escalation. 
3.2 
Randomization 
Not applicable. This is an open-label, uncontrolled trial in which all patients will receive Sym023. 
3.3 
Hypothesis Testing 
No formal hypothesis testing is planned for this trial. Safety and antineoplastic activity analyses will be 
descriptive in nature. 
3.4 
Interim Analysis 
Safety evaluation will be performed prior to each dose-escalation. No other interim analyses are planned. 
3.5 
Sample Size 
Approximately 20-48 male and female patients will be enrolled and treated, based on a modified 
accelerated titration Phase 1 design (more specifically, up to 2 single patient cohorts, followed by a standard 
3+3 design), to allow determination of the MTD and/or RP2D. It is assumed that approximately 7 cohorts 
may be required during the dose escalation. However, the protocol allows for enrollment of > 7 cohorts, 
should this be necessary to identify the MTD and/or RP2D. Expansion of the MTD/MAD cohort to treat up 
to 12 patients may be considered for further evaluation of tolerability. 
3.6 
Study Procedures 
All patients will be assessed by scheduled clinical, laboratory, and other diagnostic assessments throughout 
the study. All efforts should be made to perform assessments as close as possible to the scheduled 
timepoints. The projection of visit days within each cycle should be made from Day 1 of the respective 
cycle. Visit windows are provided below. Study assessments are to be performed as follows: 
• 
Screening evaluations are to be performed within 14 days prior to first study drug dose, unless 
otherwise specified (for exceptions see protocol section 7.2, section 7.3, and section 7.4). 
• 
The day of first administration of study drug will be considered Day 1 of study. 
• 
C1/D3 evaluations may be conducted +1 day. 
• 
On-study evaluations (including laboratory assessments) are to be performed on or about the 
indicated study day (i.e. ± 2 working days) (a slightly longer allowance for routine assessments is 
permissible in the event of scheduling difficulties associated with weekends, holidays, etc.). 
• 
End of Cycle assessments may be conducted at any time during the week prior to Day 1 of the next 
cycle, including on Day 1 of the next cycle, prior to dosing. 


 
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• 
EOT evaluations are to be performed within approximately 10 days following the decision to 
discontinue treatment, or before initiation of a new treatment, whichever occurs first. 
• 
1M FUP evaluations are to be performed approximately 30 days (+7 days) following the last dose 
of study drug (i.e. as all patients are to be followed for a minimum of 30 days after study drug 
discontinuation to monitor for the occurrence of AEs). 
 


 
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3.7 
Schedule of Assessments 
STUDY ASSESSMENTS 
Screening 
CYCLE 1 
CYCLE 2 
SUBSEQUENT CYCLES 
EOT     
within 10d after 
treatment 
discontinuation 
1M FUP* 
30d (+7) 
after last 
dose 
Long-Term 
FUP*         
if OR/ SD at 
EOT, 
for new-onset 
or ongoing 
immune-
mediated AEs    
As 
Clinically 
Indicated 
D1 
D2 
D3 
(+1) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
(±2) 
D15 
(±2) 
End of 
Cycle 2 
(final 
week) 
D1 
(±2) 
D15 
(±2) 
End of 
Even 
Numbered 
Cycles 
(final week) 
CONSENT AND MEDICAL HISTORY 
Informed Consent1/ Eligibility 
Assessment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past Medical History2 
x 
xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of Primary Malignancy3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAFETY ASSESSMENTS (screening assessments within 14 days prior to first dose of study drug unless otherwise specified) 
Medication/Procedure Survey4 
from 14 days prior to 1st dose through 30 days after last dose 
 
 
AE Reporting5 
from signing of informed consent through 30 days after last dose; through 2 months (or 4 months to 2 years) FUP if related critical AEs persist 
Q2Md 
x 
DLT Assessment6  
 
C1/D1 through C1/D28 (+/- 2 days) 
 
 
 
 
 
 
 
 
x 
ECOG PS Evaluation 
x 
xa 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Vital Signs7  
x 
SOI; 
EOI; 
2h, 4h, 8h 
after EOI 
x 
x 
 
SOI, 
EOI 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Physical Exam (to include weight, 
pulmonary and cardiac 
assessments)8 
x 
xa 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Hematology Panel9 
x 
xa 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
 
x 
Biochemistry Panel10 
x 
xa 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
 
x 
Coagulation Panel11 
x 
xa 
 
 
 
x 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Thyroid Function Tests12 
x 
xa 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Urinalysis13 
x 
xa 
 
 
 
x 
 
x 
 
 
x 
 
 
x 
x 
 
x 
Pregnancy Testing14 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
ECG (12-lead)15 
x 
SOI, 
EOI        
+15 min    
 
 
 
 
 
SOI, 
EOI   
+15 
min 
 
 
 
 
 
x 
 
 
x 
SAFETY ASSESSMENTS (results from assessments previously performed as standard of care within 28 days [+2d] prior to 1st dose may be utilized provided no antineoplastic therapy has been delivered between assessment and 1st dose; 
otherwise within 14 days of 1st dose) 
MUGA Scan or ECHO16 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Ophthalmology Exam17 
x 
 
 
 
 
 
 
EOC1 
visual 
acuity 
only 
 
xb 
 
 
xb 
x 
 
 
x 
Pulmonary Function Tests18 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 


 
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STUDY ASSESSMENTS 
Screening 
CYCLE 1 
CYCLE 2 
SUBSEQUENT CYCLES 
EOT     
within 10d after 
treatment 
discontinuation 
1M FUP* 
30d (+7) 
after last 
dose 
Long-Term 
FUP*         
if OR/ SD at 
EOT, 
for new-onset 
or ongoing 
immune-
mediated AEs    
As 
Clinically 
Indicated 
D1 
D2 
D3 
(+1) 
D8 
(±2) 
D15 
(±2) 
D22 
(±2) 
D1 
(±2) 
D15 
(±2) 
End of 
Cycle 2 
(final 
week) 
D1 
(±2) 
D15 
(±2) 
End of 
Even 
Numbered 
Cycles 
(final week) 
DISEASE ASSESSMENTS (screening assessments within 28 days [+2d] prior to first dose of study drug) 
Tumor Marker Measurement19 
x 
 
 
 
 
 
 
 
 
xb 
 
 
xb 
xc 
If no  
prior PD 
Q2Md 
 
Imaging for Disease (and 
Pulmonary Status)20 
x 
 
 
 
 
 
 
 
 
xb 
 
 
xb 
xc 
If no  
prior PD 
Q2Md 
 
Lymphoma patients:  FDG-PET, X-
ray, U/S, BM aspiration/Bx  
As 
indicated 
 
 
 
 
 
 
 
 
As 
indicated
b 
 
 
As 
indicatedb 
As indicated 
As 
 indicated 
Q2Me 
 
Response Assessment (in event of 
OR or SD)21 
 
 
 
 
 
 
 
 
 
xb 
 
 
xb 
xc 
If no  
prior PD 
Q2Me 
 
ADDITIONAL ASSESSMENTS 
ADAAssessment22 
 
x 
 
 
 
x 
 
x 
 
 
Odd 
# Cs 
 
 
x 
x 
Q2M for 6 
monthsf 
x 
PK Assessment23 
 
SOI; EOI; 
2h, 4h, 8h 
after EOI 
24h 
after 
EOI 
-12h 
to 
+24h 
x 
SOI, 
EOI 
x 
SOI, 
EOI 
SOI, 
EOI 
 
SOI, 
EOI 
SOI, 
EOI 
 
x 
x 
Q2M for 6 
monthsf 
 
Peripheral Blood for 
Pharmacodynamic Studies (receptor 
occupancy)24 
 
x 
24h 
 
 
x 
 
x 
D15   
(+ 0-7) 
EOC2 or 
C3/D1b 
 
 
Q4C (C6, 
C10, etc.)b 
x 
x 
 
 
Peripheral Blood for Biomarker 
Studies25 
upon 
eligibility 
 
 
 
 
 
 
 
D15   
(+ 0-7) 
 
 
 
 
x 
 
 
 
Tumor Biopsy for Biomarker 
Studies (optional)26 
upon 
eligibility 
 
 
 
 
 
 
 
D15   
(+ 0-7) 
 
 
 
 
Upon PD if 
prior OR or 
SD > 16wks 
 
 
 
TRIAL TREATMENT 
Premedication Administration (if 
indicated) 
 
x 
 
 
 
x 
 
x 
x 
 
x 
x 
 
 
 
 
 
Study Drug Infusion (30 minutes) 
(+10 min) 
 
x 
 
 
 
x 
 
x 
x 
 
x 
x 
 
 
 
 
 
Post-Infusion Monitoring 
 
2h 
 
 
 
1h 
 
1h 
1h 
 
1h 
1h 
 
 
 
 
 
Abbreviations (in alphabetical order): 1M FUP, 1-month follow-up; ADA, anti-drug antibody; AE, adverse event; BM, bone marrow; Bx, biopsy; C, cycle: D/d, day; DLT, dose-limiting toxicity; h, hour; ECG, 
electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; EOC, end of cycle; EOI, end of infusion; EOT, end of treatment; FDG, fluorodeoxyglucose; FUP, follow-up; MUGA, 
multi-gated acquisition; OR, objective response; PET, positron emission tomography; PK, pharmacokinetic; PS, performance status; Q2M, every 2 months; Q4C, every 4 cycles; SD, stable disease; SOI, start of 
infusion; U/S, ultrasound 
 


 
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a Need not be assessed prior to Cycle 1 if ≤ 7 days since screening 
b End of Cycle assessments may be conducted at any time during the week prior to Day 1 of the next cycle, including on Day 1 of the next cycle, prior to dosing  
c Conduct only if > 6 weeks since the previous assessment  
d To be conducted to assess for delayed onset of any post-therapy immune-mediated AE (up to 6 months following last dose), and in the event of an immune-mediated toxicity 
ongoing at the 1M FUP or noted during the 6-month post-therapy FUP period (up to 2 years). Clinical events may be followed in writing or by telephone; an in-person visit will 
not be required. 
e To be conducted in the event of ongoing OR or SD at the end of treatment; continue until confirmed PD or another therapeutic intervention is initiated, or until the end of trial.  
Documentation may be submitted in writing or by e-mail; an in-person visit will not be required.   
f Samples to be obtained if patient is available for blood collection 
 
1. Informed Consent: To be signed prior to enrollment and prior to performing any protocol-related procedure, unless such testing was performed previously as part of the routine 
clinical management of the patient.   
2. Past Medical History: To include history of prior/ongoing diseases or conditions as well as prior surgical procedures not related to the underlying malignancy. 
3. History of Primary Malignancy: To include details of the primary malignancy, including:  diagnosis and histological/cytological classification; date of initial diagnosis; stage of 
disease at diagnosis and at entry; current sites of metastases; prior surgical procedures for the malignancy and dates; prior antineoplastic therapy, prior radiation therapy, as well as 
dates of treatments, numbers of cycles, and best response to each therapy; date of most recent disease progression.  
4. Medication/Procedure Survey:  To include period within 14 days prior to first study drug dose and throughout study for a period of 30 days following last study drug dose. 
5. AE Reporting: To detail symptoms that may be present prior to/at the time of first administration.  AEs to be assessed from signing of informed consent, throughout study, and for 
the 1-month period (30 days) following last study drug dose; AEs to continue to be assessed for 2 months (and if necessary 4 months) following last study drug dose if events 
associated with study drug persist (to confirm that events have resolved, returned to baseline status, or been adequately explained. Investigator discretion may be used with respect 
to the method of contact for this AE assessment; clinical events may be followed in writing or by telephone, an in-person visit will not be required). Any patient who develops an 
immune-related toxicity (e.g., pulmonary fibrosis, myocarditis, ocular toxicity, drug-induced hepatotoxicity, etc.) will be followed at approximately 2-month intervals for up to 2 
years to assess the course of the condition and evaluate potential reversibility of the finding. 
6. DLT Assessment: Beginning on C1/D1 and ending at EOC1 (C1/D28 ± 2 days).  To include evaluation for the occurrence of events meeting the trial DLT criteria.  Only DLTs 
occurring during Cycle 1 will be used to make decisions regarding dose-escalation and tolerability. Events occurring after Cycle 1 will also be evaluated and taken into 
consideration when deciding upon further doses to be assessed as well as establishment of the RP2D.  
7. Vital Signs:  To include temperature, pulse, respiratory rate, blood pressure, and pulse oximetry.  C1/D1 through C1/D3 window allowances align with PK timepoints windows 
8. Physical Examination: Complete at screening including height, weight, general appearance, skin, head, eyes, ears, nose, throat, neck/thyroid, chest [includes pulmonary 
assessment, breasts], cardiovascular [includes heart, peripheral pulses] abdomen, musculoskeletal system, lymph nodes, neurologic and mental status; directed thereafter, must 
include weight as well as pulmonary and cardiac assessments. Dose adjustments should be made in the event of noted weight change (± 10% [less at the site’s discretion or if 
required by institution procedures]).  Pulmonary findings will be evaluated in detail at each visit by the Investigator (or physician designee). Evaluation to include review of 
pulmonary symptoms including but not limited to: cough, sputum production, hemoptysis, wheezing, dyspnea, dyspnea on exertion, chest pain, and/or chest pain associated with 
respirations, as well as review of cardiac symptoms including but not limited to chest pain, orthopnea, nocturia, edema, and palpitations. 
9. Hematology Panel:  To include CBC with hemoglobin, hematocrit, differential, ANC, and platelet count. Evaluation frequency should be increased in the event of hematologic 
toxicity. 
10. Biochemistry Panel (fasting not required): To include Na, K, Cl, bicarbonate or carbon dioxide, BUN or equivalent, creatinine, glucose, bilirubin [total and direct], AST, ALT, 
ALP, Ca, Mg, phosphorous, albumin, total protein, uric acid, amylase, lipase, and CK (if abnormal, perform isoenzyme analysis to include at minimum CK-MB), serial troponins, 


 
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and measurement of BNP. Evaluation frequency should be increased in the event of significant serum chemistry abnormalities. Clinically significant electrolyte abnormalities 
should be corrected prior to dosing. 
11. Coagulation Panel: To include PTT (or aPTT), PT/INR. 
12. Thyroid Function Tests: To include measurement of TSH, fT3, and fT4. 
13. Urinalysis: Multi-panel chemical test strips are acceptable and should include assessment of specific gravity, pH, protein, glucose, ketones, leukocytes, nitrite, bilirubin, 
urobilinogen, and blood. Microscopic examination of sediment, if clinically indicated, to include assessment of cells (WBC and RBC per HPF, and casts).   
14. Pregnancy Testing:  β-hCG in WOCBP; serum at Screening, serum or urine thereafter; negative test must be confirmed within 2 working days prior to first dose of study drug. 
15. ECG (12-Lead): To include measurement of PR interval, QRS duration, QT interval, and QTc interval (msec), as well as HR (BPM); to be performed after patient has been supine 
or semi-recumbent for ≥ 10 minutes; repeat subsequent timepoints in triplicate separated by 5 minutes for 4 cycles (Day 1, SOI and EOI) in patients with a Cycle 1 or Cycle 2 QTc 
that is either:  a) > 500 msec; b), increased by 60 msec over baseline; or c) decreased by 20 msec below baseline. If abnormities suggest new evidence of myocardial ischemia, 
perform isoenzyme analysis (to include at minimum CK-MB), serial troponins, and measurement of BNP. 
16. MUGA Scan or ECHO: For measurement of LVEF; to be performed ONLY in patients with a history of CHF, individual patients should be followed with the same testing 
procedure throughout the study. 
17. Ophthalmology Examination: To include funduscopic and slit lamp evaluations for assessment of retinal and corneal integrity, visual acuity as assessed by standardized chart or 
other appropriate measurement tool (e.g., Snellen chart), and any other noted ocular abnormality. If changes in visual acuity are noted, a thorough ophthalmologic evaluation 
should be performed within 48 hours (if feasible, based on weekends or holidays) of the initial observation in order to confirm the finding and determine if there is evidence of an 
immune-mediated AE, or other event that would preclude further treatment with study drug. 
18. Pulmonary Function Tests: To include spirometry and diffusing capacity of carbon monoxide [DLCO] to assess for evidence of pulmonary fibrosis.  Spirometry assessments to 
include at minimum:  FVC, FEV1, FRC, RV, and TLC.  To be repeated if evidence of interstitial pneumonitis, pulmonary fibrosis or other potential evidence of drug-related 
pulmonary toxicity is documented on imaging studies or if pulmonary symptomatology indicates. 
19. Tumor Marker Measurement: As indicated by tumor type. 
20. Imaging for Assessment of Disease (and Pulmonary Status): To include diagnostic imaging by CT or MRI of the chest with each evaluation (for disease evaluation where 
indicated, and to assess for evidence of pulmonary fibrosis) plus abdomen and pelvis, and other sites as indicated based on tumor type and clinical judgment to assess the status of 
the underlying malignancy. Use of contrast is preferred but is at the discretion of the Investigator, as medically indicated.  The same method(s) of disease evaluation and the same 
technique should be used throughout the study. For all imaging timepoints, the following will be recorded as per RECIST v1.1 (or other response criteria, as indicated): target 
lesions including size, location, and type (nodal/non-nodal); sum of diameters of target lesions; any new lesions noted during trial, including size, location, and type (nodal/non-
nodal). 
21. Response Assessment: To be assessed by the Investigator or qualified designee as per RECIST v1.1 (or other response criteria, as indicated). 
22. ADA (Specialty Lab): To assess immunogenicity; whole blood (~5 mL at each timepoint) will be collected for serum acquisition.  If sampling is on a dosing day, collect prior to 
infusion. If a collected serum sample is inadequate or insufficient for ADA analysis, the analysis of ADA can be done using a PK serum sample from the same timepoint, if 
available. A detailed laboratory manual specifying sample collection, handling, storage, and shipment will be provided to the trial sites.   
23. PK Sampling (Specialty Lab): See protocol Section 7.6.1 for window allowances. Whole blood (~5 mL at each timepoint) will be collected for serum acquisition. If a collected 
serum sample is inadequate or insufficient for PK analysis, the analysis of PK can be done using an ADA serum sample from the same timepoint, if available.  A detailed 
laboratory manual specifying sample collection, handling, storage, and shipment will be provided to the trial sites.  PK sampling times may be adjusted according to early trial 
results to optimize evaluation.   
24. Peripheral Blood for Pharmacodynamic Studies (Receptor Occupancy) (Specialty Lab): Whole blood (~10 mL at each timepoint) will be collected for assessment of receptor 


 
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occupancy.  C2D15 (+ 0 to 7 days) after dosing; to be collected on the day of tumor biopsy, if performed. End of Cycle sampling may be combined with EOT if patient 
discontinues treatment. A detailed laboratory manual specifying sample collection, handling, storage, and shipment will be provided to the trial sites.   
25. Peripheral Blood for Biomarker Studies (Specialty Lab): To be obtained only after eligibility has been confirmed.  (May be collected C1/D1 prior to dosing.)  Whole blood (~30 
mL at each timepoint) to be collected.  C2D15 (+ 0 to 7 days) after dosing; to be collected on the day of tumor biopsy, if performed. For those timepoints where both a blood 
sample and a tumor biopsy are to be obtained, the blood sample must be collected first. A detailed laboratory manual specifying sample collection, handling, storage, and shipment 
will be provided to the trial sites.  
26. Tumor Biopsy for Biomarker Studies (optional) (Specialty Lab): To be obtained only after eligibility has been confirmed.  (May be collected C1/D1 prior to dosing.)  Tissue for 
FFPE to be collected. C2D15 (+ 0 to 7 days) after dosing; to be collected with paired peripheral blood for biomarker studies. For those timepoints where both a blood sample and a 
tumor biopsy are to be obtained, the blood sample must be collected first.  EOT sample upon PD only in patients with a prior OR or prolonged SD (> 16 weeks). A detailed 
laboratory manual specifying sample collection, handling, storage, and shipment will be provided to the trial sites 




 
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cases, the following imputation rules will be applied to estimate date of birth for the purpose of 
calculating age when only partial information is known: if day and month are missing, December 
31 will be assigned to the missing fields; if day is missing, the last day of the month will be 
assigned to the missing day. Imputed values will not be listed in data listings. 
• 
Baseline characteristics include ECOG performance status, height, weight and BMI. 
• 
Medical history includes diagnosis or symptoms entered on the Medical History form. Verbatim 
descriptions of diagnoses or symptoms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA version 21.0 or later). 
• 
Surgical history includes surgical procedures entered on the General Surgical History form. 
• 
Cancer history includes: 
o cancer type (solid tumor malignancy or lymphoma) 
o primary tumor site (for solid tumors) 
o histological type 
o tumor grade 
o presence of metastases (yes, no) 
o sites of metastatic disease (for metastatic solid tumors) 
o lymphoma type 
o stage at initial diagnosis 
o stage at enrollment 
o date of most recent disease progression 
o time since initial diagnosis in months, defined as: (date of first treatment – date of initial 
diagnosis + 1)/30.4375 
o time since diagnosis of metastatic disease in months, defined as (date of first treatment – 
date of metastatic diagnosis + 1)/30.4375 
• 
Prior cancer treatments include radiotherapies entered on the prior radiotherapy for cancer form, 
prior cancer surgeries entered on the prior surgical procedures for cancer treatment form and prior 
treatments (intent, regimen, drug, start and end dates, best response, reason for discontinuation) 
entered on the prior antineoplastic/systemic drug therapies for cancer treatment form: 
o prior radiotherapies will be categorized by intent (Curative, Palliative, Other) 
o prior surgeries will be categorized by type (Biopsy, Resection of primary lesion, Resection 
of metastatic lesion, Other) 
o number of antineoplastic/systemic drug therapies/regimens (1, 2, 3, 4 or more) will be 
calculated for each patient 
o number of antineoplastic/systemic drug therapies/regimens for advanced/metastatic disease 
(excluding neoadjuvant and adjuvant therapies) will be calculated for each patient 
o prior exposure to checkpoint inhibitors (yes/no) will be determined for each patient 
o prior exposure to anti-TIM-3 agent (yes/no) will be determined for each patient 
6.2 
Safety 
Safety parameters that will be measured in the study are: 
1. Adverse events 
2. Laboratory measurements 
3. Vital signs 
4. ECG 
5. Physical examination 


 
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6. ECOG performance status 
7. Pregnancy test 
8. Concomitant medications/treatments 
9. Ophthalmology exam 
10. Pulmonary function tests 
11. MUGA Scan or ECHO (to be performed only in patients with a history of congestive heart failure) 
Unless stated otherwise, safety endpoints will all be presented for the FAS by cohort and tumor type. Safety 
data will be presented descriptively; no formal statistical analyses will be performed. 
6.2.1 
Safety Study Day and Visit Window Definitions 
The study visit windows listed in Table 1 (based on visit dates) will be used to analyze laboratory, vital 
signs, ECG, physical examination, ECOG performance status, ophthalmology exam, and pulmonary 
function tests. 
Table 1 - Safety Study Visit Windows 
Visit 
Safety Parameters 
Target Day 
Window 
Baseline 
ECOG Performance 
Status, Vital Signs, 
Physical Examination, 
Hematology, 
Biochemistry, 
Coagulation, Thyroid 
Function Tests, 
Urinalysis, 
Ophthalmology 
Examination, 
Pulmonary Function 
Tests 
Day -14 to Day 1 
Day -14 to 1 
Cycle 1 Day 2 
Vital Signs 
Day 2 of Cycle 1 
No window will be used 
Cycle 1 Day 3 
Vital Signs, 
Hematology, 
Biochemistry 
Day 3 of Cycle 1 
Day 3 to 4 of Cycle 1 
Cycle 1 Day 8 
Hematology, 
Biochemistry 
Day 8 of Cycle 1 
Day 5 to 11 of Cycle 1 
Cycle 1 Day 15 
Vital Signs, 
Hematology, 
Biochemistry, 
Coagulation, 
Urinalysis 
Day 15 of Cycle 1 
Day 12 of Cycle 1 to Day 
of 2nd infusion of Cycle 1 
Cycle 1 Day 22 
Hematology, 
Biochemistry 
Day 22 of Cycle 1 
Day of 2nd infusion of 
Cycle 1 + 1 to Day -3 of 
Cycle 2 


 
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Visit 
Safety Parameters 
Target Day 
Window 
Cycle n Day 1 (Cycle 2 
and up) 
ECOG Performance 
Status, Vital Signs, 
Physical Examination, 
Hematology, 
Biochemistry, 
Coagulation, Thyroid 
Function Tests, 
Urinalysis, ECG 
Day 1 of Cycle n 
For Cycle 2: Day -2 of 
Cycle 2 to Day 1 of Cycle 2 
For Cycle 3 and later: Day 
of 2nd infusion of Cycle (n – 
1) (i.e. Day of previous 
dose) + 1 to Day 1 of Cycle 
n 
Cycle n Day 15 (Cycle 2 
and up) 
Hematology, 
Biochemistry 
Day 15 of Cycle n 
Day 2 of Cycle n to Day of 
2nd infusion of Cycle n 
End of Cycle n 
Ophthalmology 
Examination 
Day 28 of Cycle n 
Day of 2nd infusion of 
Cycle n + 1 to Day 1 of 
Cycle (n + 1), prior to 
dosing 
End of Treatment 
ECOG Performance 
Status, Vital Signs, 
Physical Examination, 
Hematology, 
Biochemistry, 
Coagulation, Thyroid 
Function Tests, 
Urinalysis, ECG, 
Ophthalmology 
Examination 
Within 7-10 days after 
date of treatment 
discontinuation, and 
before initiation of a 
new antineoplastic 
treatment 
Date of treatment 
discontinuation to date of 
treatment discontinuation + 
10 or date of new 
antineoplastic treatment, 
whichever occurs first 
One-Month Follow-up  
ECOG performance 
status, vital signs, 
physical examination, 
Hematology, 
Biochemistry, 
Coagulation, Thyroid 
Function Tests, 
Urinalysis 
30 days after last dose 
of study medication 
Last dose of study 
medication + 23 to last dose 
of study medication + 37 
(i.e. +/-7 days) 
Baseline is defined as the last available observation prior to the first administration of study drug on Cycle 1 
Day 1. 
6.2.2 
Primary Endpoint and Analysis 
The primary objective is to evaluate the safety and tolerability and to establish the maximum tolerated dose 
(MTD) and/or recommended Phase 2 dose (RP2D) of sequential escalating doses of Sym023. This will be 
assessed by the primary endpoint of occurrence of DLTs during Cycle 1. 
The MTD is defined as the highest dose with a maximum of 1 out of 6 patients experiencing a DLT. The 
MTD may or may not be determined within the dose levels tested. Based on an overall evaluation of the 
dose-escalation, the RP2D will be selected. The RP2D may be equal to or lower than the MTD. 


 
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6.2.3 
Extent of Exposure to Study Medication 
The number of treatment cycles received, the total dose received, the exposure to study treatment and the 
treatment duration will be derived using data from the study drug infusion form. The percentage volume 
infused (%) by cycle will be based on the data from the CRF. 
The number of treatment cycles initiated is the number of cycles with at least a fraction of one dose taken 
during a cycle. 
The total dose received (mg/kg) for Sym023 is the sum of dose received at each cycle. The dose received 
for each cycle is defined as the planned study drug dose (mg/kg) multiplied by percentage volume infused 
(%)/100. 
The exposure to study treatment (in days) is calculated as the date of last dose – date of first dose + 1. 
The treatment duration (in days) is calculated from the date of first dose to the date of last dose + 14. 
The relative dose intensity (RDI) is the ratio of the actual dose intensity to the planned dose intensity, 
more specifically: 
RDI = 100% × 
Actual Total Received (mg/kg) 
Planned Dose (mg/kg) × Number of 2-week intervals in Treatment Duration 
The relative dose intensity will be categorized as follows: 
• 
> 110% 
• 
> 100% - 110% 
• 
> 90% - 100% 
• 
> 80% - 90% 
• 
>70% - 80% 
• 
>60% - 70% 
• 
≤ 60% 
The mean number of days between infusions will be calculated as treatment duration (days) / number of 
infusions. 
A treatment delay is defined as a period of more than 16 days between two consecutive infusions. The 
number of days will be calculated for each delay as [date of infusion (i) – date of infusion (i – 1)] – 14 days, 
where i = 2, 3,…,j and j is the last infusion received. If the value is > 2 days, then the infusion will be 
considered to be delayed. The number of weeks delay will also be classified as follows (a patient may have 
more than one treatment delay throughout the course of the study): 
• 
< 1 week delay (more than 16 days and less than 21 days between 2 consecutive infusions) 
• 
≥ 1 week delay (21 days or more and less than 28 days between 2 consecutive infusions) 
• 
≥ 2 weeks delay (28 days or more between 2 consecutive infusions) 
The maximum number of days delay between 2 consecutive infusions will be calculated for each patient 
requiring a treatment delay, defined as the maximum treatment delay.  
The reasons for any treatment delay and maximum number of days delay between 2 consecutive infusions 
will be categorized as adverse event or other. 


 
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A dose modification is defined as any infusion that is not completed as planned, according to the eCRF, 
and identified as having been delayed, prolonged, temporarily interrupted or stopped prematurely. 
The number of dose modifications will be calculated and categorized (0, 1, 2, ≥ 3) for each type of 
modification (dose delays, prolonged infusions, infusion interruptions, infusions stopped prematurely). 
The reasons for dose modifications will be categorized (Adverse Event, Other) for each type of 
modification. 
6.2.4 
Adverse Events 
Adverse Events will be recorded from signing of informed consent for participation in the trial. The 
recording period ends 30 days after receiving the final dose of study drug (at the time of the one-month 
follow-up visit), unless extended follow-up is indicated, per the clinical trial protocol. 
Adverse events will be coded using version 21.0 or later of the Medical Dictionary for Regulatory Activities 
and the severity of the toxicities will be graded according to the NCI CTCAE. Analysis of adverse events 
will be carried out on the FAS.  
Only treatment emergent adverse events will be included in summary tabulations; all adverse events will be 
included in individual patient data listings. Treatment-emergent adverse events will be defined as adverse 
events with onset dates on or after the first dose of study medication or that occurred before the first dose of 
study medication and increased in severity after the first dose of study medication, up to the last dose of 
study drug plus 30 days. Treatment-related adverse events will be defined as adverse events with 
relationship to study drug of: possibly related, probably related, related, or not determined (missing 
relationship). Fatal adverse events will be defined as adverse events with toxicity grade 5. 
NCI CTCAE Version: 
Protocol version 1 through 3 were using the NCI CTCAE version 4.03. Beginning with protocol version 4.0 
(18Mar2019), the NCI CTCAE version used for adverse event reporting was updated from version 4.03 to 
version 5.0. Within each research site, the applicable criteria version will be inferred based upon the event 
start date and the protocol version 4.0 approval date (the presumed start date of use of CTCAE v5.0.). The 
effective dates for CTCAE v5.0 for each site are shown in Table 2. 
Table 2 - CTCAE v5.0 Effective Dates by Site 
Site ID 
CTCAE v5.0 Effective Date 
12401 
03May2019 
84001 
29Mar2019 
84002 
10Apr2019 
84003 
27Mar2019 
For adverse events reported with start date prior to the CTCAE v5.0 approval date, the original reported 
toxicity grade based on CTCAE v4.03 will be stored in a supplemental variable. The toxicity grade based 
on CTCAE v5.0 will be determined, with clinical input where necessary, for purposes of analysis and 
listing. The CTCAE v5.0 Clean, Tracked, and Mapping Document (7) will be used to determine which 
preferred terms has definition or grade updates from CTCAE v4.03 to CTCAE v5.0. Adverse events 


 
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reported with start date on or after the CTCAE v5.0 effective date will be listed and summarized based on 
the original reported toxicity grade. 
All adverse events summaries and listings will report toxicity grade based on CTCAE v5.0. 
Adverse Events Incidence Counting Rules: 
1. Adverse Events reported with identical verbatim terms and contiguous dates (i.e., end date of the 
first reported record is equal to or 1 day prior to the start date of the next reported record within the 
same reported term) will be considered to be the same event, and will therefore be grouped and 
categorized based upon the following conservative criteria (within identical verbatim term with 
contiguous dates): 
a. Worst (maximum) toxicity grade 
b. Worst seriousness 
c. Worst (most related) degree of relationship (possible causal relationships, in order from 
least related to most related are: not related, unlikely related, possibly related, probably 
related, and related) 
d. First start date 
e. Last end date 
f. Last outcome 
g. Any reported action taken of delay 
h. Any reported action taken of interruption 
i. 
Any reported action taken of discontinuation 
j. 
Any reported DLT during Cycle 1 
k. Any reported DLT after Cycle 1 
l. 
Any reported infusion related reaction 
2. When summarizing number of events, AEs will be counted after being grouped as described above 
3. When summarizing number of patients, patients will be summarized within system organ class or 
preferred term conservatively as applicable: 
a. Maximum grade 
b. Worst seriousness 
Missing Grade: 
Missing grades will not be imputed. AEs with missing grade will be reported as ‘No Grade’. 
Missing Relationship to Study Drug 
An AE with a missing relationship to study drug will be categorized as ‘Not determined’ and will be 
included in summaries of related AEs. Imputed values will not be listed in data listings. 
Adverse Events with Incomplete Dates 
Imputation of dates for adverse events with incomplete dates will be performed only for determination of 
treatment emergent categorization. Imputed dates will not be presented in data listings. The following 
algorithm should be used to estimate adverse event start dates for which only partial information is known: 
• 
Missing day and month 
- If the year is same as the year of first day on drug, then the day and month of the start date of 
drug will be assigned to the missing fields. 
- If the year is prior to the year of first day on drug, then December 31 will be assigned to the 
missing fields. 


 
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- If the year is after the year of first day on drug, then January 1 will be assigned to the missing 
fields. 
• 
Missing month only 
- Treat day as missing and replace both month and day according to the above procedure. 
• 
Missing day only 
- If the month and year are same as the year and month of first day on drug, then the start date of 
drug will be assigned to the missing day. 
- If the month and year are before the year and month of first day on drug, then the last day of the 
month will be assigned to the missing day. 
- If the month and year are after the year and month of first day on drug, then the first day of the 
month will be assigned to the missing day. 
If the AE stop date is complete and the imputed start date as above is after the stop date, the start date will 
be imputed using the stop date. 
Adverse events with partially missing stop dates will be imputed a stop date as follows: 
- year is missing - date left missing. 
- month is missing - impute 'December'. 
- day is missing - impute 'last day of that month'. 
6.2.5 
Deaths 
All deaths occurring within 30 days of the last dose of study medication are to be reported on the Death 
form. All deaths reported are to be categorized as within 30 days of last dose of study medication or 
beyond. 
6.2.6 
Laboratory Data 
Laboratory assessments include: 
• 
Hematology: red blood cell (RBC) count, hemoglobin, hematocrit, platelet count, white blood cell 
(WBC) count, neutrophils (ANC), lymphocytes (ALC), monocytes, eosinophils, basophils, 
neutrophils (%), lymphocytes (%), monocytes (%), eosinophils (%), basophils (%) 
• 
Biochemistry: sodium, potassium, chloride, bicarbonate (carbon dioxide), blood urea nitrogen 
(BUN), creatinine, glucose (non-fasting), total bilirubin, direct bilirubin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, calcium, 
magnesium, phosphorus, albumin, total protein, uric acid, amylase, lipase, creatine kinase 
(CK), creatine kinase-MB (CK-MB), brain natriuretic peptide (BNP), troponin (note: CK-MB, 
BNP and troponin are only performed in case of ECG abnormalities) 
• 
Coagulation: prothrombin time, international normalized ratio (INR) 
• 
Thyroid Function Test: thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free 
thyroxine (fT4) 
• 
Urinalysis: specific gravity, pH, protein, glucose, ketones, leukocyte, nitrite, bilirubin, urobilinogen, 
blood, whole blood cells (/HPF), red blood cells (/HPF), casts (/HPF) 
• 
Pregnancy Test 
All laboratory data will be stored in the database with the units in which they are originally reported. 
Laboratory data in summary tables and patient data listings will be presented in the International System of 
Units (SI units; Système International d’Unités). Laboratory data not reported in SI units will be converted 


 
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to SI units before further processing or data analysis, and results in both units will be displayed in data 
listings. The original lab test units will be converted to SI units according to published reference values (4, 
5). Laboratory tests will be graded using NCI-CTCAE v5.0 toxicity grading (see Appendix 1 NCI-CTCAE 
V5.0 Toxicity Grading). 
For laboratory results entered with inequality symbols (<, ≤, >, ≥), numeric values will be imputed by 
ignoring the inequality symbol(s) (e.g. “<1.71” will be imputed as 1.71 for numeric analyses). Imputed 
values will not be listed in data listings (i.e., results will be presented as entered, with inequality symbols). 
For each laboratory test, the worst (maximum) CTCAE grade during the course of the study and the grade 
at discontinuation will be identified for each patient. 
6.2.7 
Vital Signs 
Vital signs include systolic/diastolic blood pressure, heart rate, respiration rate, oxygen saturation and 
temperature. 
6.2.8 
Electrocardiogram (ECG) 
The electrocardiogram assessment includes heart rate (beats/min), PR interval (msec), QRS duration 
(msec), QT interval (msec) and QTc interval (msec). 
The maximum post-baseline QTc value (msec) will be determined for each patient and categorized (≤ 450, 
> 450 and ≤ 480, > 480 and ≤ 500, > 500). 
The maximum increase from baseline in QTc value (msec) will be determined for each patient and 
categorized (≤ 30, > 30 and ≤ 60, > 60). 
6.2.9 
Physical Examination 
A physical examination will be performed at baseline, Day 1 of each cycle, at the End of Treatment and 30-
day Follow-up visits and as clinically indicated; however, only the height (baseline only) and weight results 
will be entered in the database. The significant findings from the physical examination will be reported in 
the Medical History (prior to study drug administration) or the Adverse Event (after study drug 
administration) forms. 
The height will be summarized with the baseline characteristics. The weight will be summarized with the 
vital signs. 
6.2.10 
ECOG Performance Status 
An ECOG performance status assessment will be performed at baseline, Day 1 of each cycle, at the End of 
Treatment and 30-day Follow-up visits and as clinically indicated. 
6.2.11 
Pregnancy Test 
A pregnancy test will be performed at the screening and end of treatment visits and as clinically indicated 
for females with childbearing potential. 
6.2.12 
Concomitant Medications/Treatments 
Concomitant medications will be collected for all visits. 


 
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Verbatim descriptions of concomitant medications and therapies will be mapped to the World Health 
Organization (WHO) Drug Dictionary Enhanced (WHO-DDE) and Herbal Dictionary (WHO-HD) (version 
1Q2018 or later). 
Concomitant Medications Counting Rules: 
• 
For each patient with multiple medications in a particular category (i.e., preferred term or drug 
class), that patient will be tabulated under the first occurrence of any medication within that 
category. 
Partial medications dates will be imputed the same way as adverse events dates. 
6.2.13 
Other Safety Assessments 
6.2.13.1 Ophthalmology Exam 
An ophthalmology examination will be performed at the screening, end of cycle 1 (visual acuity only), end 
of treatment, at the end of even-numbered cycle visits and as clinically indicated. The ophthalmology 
examination includes visual acuity assessment, corneal integrity assessment, slit lamp evaluation and 
funduscopic evaluation. 
6.2.13.2 Multi-Gated Acquisition Scan or Echocardiogram 
A multi-gated acquisition (MUGA) scan or echocardiogram will be performed in patients with a history of 
CHF at the screening and end of treatment visits and as clinically indicated. The assessment includes left 
ventricular ejection fraction (LVEF) as well as an assessment of clinical significance. 
6.2.13.3 Pulmonary Function Tests 
Pulmonary function tests will be performed at the screening and end of treatment visits and as clinically 
indicated. The pulmonary function tests include forced vital capacity (FVC), forced expiratory volume in 1 
second (FEV1), functional residual capacity (FRC), residual volume (RV), total lung capacity (TLC) and 
diffusing capacity of carbon monoxide (DLCO). 
6.3 
Efficacy 
6.3.1 
Efficacy Study Day and Visit Window Definitions 
The study visit windows listed in Table 3 (based on visit dates) will be used to analyze the tumor marker 
results. 
Table 3 - Efficacy Study Visit Windows 
Visit 
Efficacy Parameters 
Target Day 
Window 
Baseline 
All 
Day -28 to Day 1 
Day -30 to 1 
End of Cycle n (even-
numbered cycles) 
All 
Day 28 of Cycle n 
Day of 2nd infusion of 
Cycle n + 1 to Day -1 of 
Cycle (n + 1) 


 
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Visit 
Efficacy Parameters 
Target Day 
Window 
End of Treatment 
All 
Within 7-10 days after 
date of treatment 
discontinuation, and 
before initiation of a 
new antineoplastic 
treatment 
Date of treatment 
discontinuation to date of 
treatment discontinuation + 
10 or date of new 
antineoplastic treatment, 
whichever comes first 
One-Month Follow-up 
All 
30 days after last dose 
of study medication 
Last dose of study 
medication + 23 to last dose 
of study medication + 37 
(i.e. +/-7 days) 
Long-Term Follow-up 
for Response 
All 
56 days after previous 
assessment 
For assessments more than 
37 days after last dose of 
study medication, use the 
visit as reported in SDTM 
Baseline is defined as the last available observation prior to the first administration of study drug on Cycle 1 
Day 1. 
6.3.2 
Tumor Marker Measurement 
Tumor marker measurements will be performed at the screening, end of treatment, at the end of even-
numbered cycles and as clinically indicated. The individual tumor markers assessed will be based on tumor 
type. 
6.3.3 
Tumor and Response Evaluations 
Best overall response (BOR) will be derived for each patient, based on evaluation of response at each 
tumor assessment visit per investigator assessment using RECIST v1.1, iRECIST or RECIL, and reported in 
the following categories: 
• 
CR or iCR 
o CR or iCR – Confirmed 
o CR or iCR – Unconfirmed 
• 
PR or iPR 
o PR or iPR – Confirmed 
o PR or iPR – Unconfirmed 
• 
SD 
o SD – > 16 weeks in duration 
o SD – ≤ 16 weeks in duration 
• 
PD 
• 
NE 
Duration of SD for patients with best overall response = SD is defined as the time from the day of first 
study treatment to the start of radiologic disease progression or death. If the patient does not have a 
radiological disease progression or death, the duration of SD is defined as the time from the day of first 


 
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study treatment to the date of the last SD assessment. This duration will be calculated in weeks as: (end date 
– date of first study treatment + 1)/7, rounded to the nearest integer, then categorized as >16 or ≤ 16. 
Overall Response Rate (ORR) is defined as the proportion of patients with objective evidence of complete 
response (CR for RECIST v1.1 and RECIL or iCR for iRECIST) or partial response (PR for RECIST v1.1 
and RECIL or iPR for iRECIST) prior to the first evidence of progressive disease (PD for RECIST v1.1 and 
RECIL or iCPD for iRECIST) 
For patients achieving a best overall response of stable disease (SD for RECIST v1.1 and RECIL or iSD for 
iRECIST), the duration of stable disease will be categorized as either > 16 weeks or ≤ 16 weeks. 
Clinical Benefit Rate (CBR) is defined as the proportion of patients with objective evidence of complete 
response (CR for RECIST v1.1 and RECIL or iCR for iRECIST) or partial response (PR for RECIST v1.1 
and RECIL or iPR for iRECIST) or minor response (MR for RECIL) or prolonged stable disease (SD > 16 
weeks for RECIST v1.1 and RECIL or iCR > 16 weeks for iRECIST) prior to the first evidence of 
progressive disease (PD for RECIST v1.1 and RECIL or iCPD for iRECIST). 
For further details regarding response criteria, refer to protocol Appendix 5 through 7. 
6.3.4 
Time to Progression 
Time to progression (TTP) is defined as the time (in months) from the day of first study treatment to the 
start of radiologic disease progression: (date of first radiologic PD – date of first treatment +1)/30.4375. 
Patients who do not have disease progression will be censored at the last known time that the patient was 
progression free (e.g. date of last evaluable tumor assessment) before receiving any new anti-cancer 
treatment. Patients without disease assessment post-baseline will be censored at the time of the first study 
treatment. 
Refer to Table 4 for censoring rules for time to progression. 
Table 4 - Censoring Rules for Time to Progression and Duration of Objective Response 
Situation 
End Date 
Censored 
1. Documented radiological PD 
before initiation of non-study 
anti-cancer treatment (for 
patients with missed tumor 
assessment, check #3) 
Date of the first tumor assessment that determined PD 
No 
2. Death during the study with 
no prior PD and no prior 
initiation of non-study anti-
cancer treatment (for patients 
with missed tumor 
assessment, check #3) 
Date of death 
Yes 


 
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Situation 
End Date 
Censored 
3. Radiologic PD after a missed 
(or not available/not 
evaluable) tumor assessment 
Date of last adequate tumor assessment prior to missed 
tumor assessment 
A response assessment is considered “missed” if more 
than 16 weeks (112 days) has elapsed since the last 
image-based response assessment. If a patient develops 
progressive disease or dies after this interval, the tumor 
response assessment will be excluded from the analysis 
and censored at the last evaluable assessment. However, 
if a response assigned as CR, PR, or SD is obtained after 
more than 16 weeks, then the tumor response assessment 
will not be excluded from the analysis as long as no 
other censoring events have occurred.  
Yes 
4. Non-study anti-cancer 
treatment initiated before 
radiologic PD 
Date of last adequate tumor assessment prior to initiation 
of non-study anti-cancer treatment 
Yes 
5. Treatment discontinuation 
for other than radiologic PD 
or death (and not followed by 
radiologic PD or death) with 
no post-baseline tumor 
assessments  
Date of first treatment 
Yes 
6. Treatment discontinuation 
for other than radiologic PD 
or death (and not followed by 
radiologic PD or death) with 
post-baseline tumor 
assessments 
Date of last adequate tumor assessment prior to initiation 
of non-study anti-cancer treatment 
Yes 
7. Patients still followed 
without radiologic PD as of 
cut-off date 
Date of last adequate tumor assessment prior to cut-off 
date 
Yes 
8. Only non-evaluable (NE) 
tumor assessments after CR, 
PR, or SD without radiologic 
PD 
Date of last adequate tumor assessment prior to NE 
tumor assessments 
Yes 
General Considerations: 
Radiologic PD for RECIST v1.1 and RECIL is defined as overall response of ‘PD’. For iRECIST, 
radiologic PD is defined as overall response of ‘iCPD’. Clinical progression will not be considered for this 
analysis. 
Note: Tumor response assessments will be considered “adequate” for analysis if they are assigned as CR, 
PR, SD, or PD and are not censored (e.g., obtained within 9 weeks since the last assessment and prior to 
initiation of non-study anti-cancer treatment: systemic anti-cancer therapy, radiotherapy or cancer surgery). 


 
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Tumor response assessments obtained after initiation of non-study anti-cancer treatment will not be 
included in the efficacy analyses, but will be flagged in the data listings. Tumor response assessments 
obtained the same day as initiation of non-study anti-cancer treatment will not be excluded. 
6.3.5 
Duration of Objective Response 
Duration of objective response (DOR) is derived for those patients with confirmed objective evidence of PR 
or CR. DOR (in months) is defined as the time from the first documentation of response (CR or PR) to the 
first documentation of objective tumor progression or death: (date of first radiologic PD or death – date of 
first CR or PR +1)/30.4375. 
Patients who do not have disease progression or death will be censored at the last known time that the 
patient was alive with evidence of PR or CR (e.g. date of last evaluable tumor assessment of CR or PR) 
before receiving any new anti-cancer treatment. Patients without disease assessment post-response will be 
censored at the time of the initial CR or PR. 
Refer to Table 4 for censoring rules for duration of objective response. 
Note: Tumor response assessments will be considered “adequate” for analysis if they are assigned as CR, 
PR, SD, or PD and are not censored (e.g., obtained within 9 weeks since the last assessment and prior to 
initiation of non-study anti-cancer treatment: systemic anti-cancer therapy, radiotherapy or cancer surgery). 
Tumor response assessments obtained after initiation of non-study anti-cancer treatment will not be 
included in the efficacy analyses, but will be flagged in the data listings. Tumor response assessments 
obtained the same day as initiation of non-study anti-cancer treatment will not be excluded. 
6.4 
Pharmacokinetic Parameters 
Serum concentrations of Sym023 will be expressed in µg/mL. All concentrations below the lower limit of 
quantification (LLOQ) or missing data will be labelled as such in the concentration data listings. 
Concentrations below the LLOQ will be treated as LLOQ/2 in summary statistics for concentration data. 
PK samples are planned to be taken according to Table 5. 
Table 5 - Planned PK Sampling Time Points 
Sample 
Sampling 
Time 
Window 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
EOT 
1M 
FUP 
Long-
Term 
FUP 
As 
Clinically 
Indicated 
D1-
D3 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
PK 
Prior to 
SOI 
- 4h 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
EOI 
+ 10 
min 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
EOI + 2h 
±30 min 
X 
 
 
 
 
 
 
 
 
 
 
 
EOI + 4h 
±30 min 
X 
 
 
 
 
 
 
 
 
 
 
 
EOI + 8h 
±90 min 
X 
 
 
 
 
 
 
 
 
 
 
 
EOI + 24h 
±6h 
X 
 
 
 
 
 
 
 
 
 
 
 
EOI + 48h 
-12h to     X 
 
 
 
 
 
 
 
 
 
 
 


 
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Sample 
Sampling 
Time 
Window 
Cycle 1 
Cycle 2 
Cycle 3 
onward 
EOT 
1M 
FUP 
Long-
Term 
FUP 
As 
Clinically 
Indicated 
D1-
D3 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
+ 24h 
During 
Visit 
NA 
 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
The PK profile for the first dosing occasion is defined as all samples from C1D1 ‘Prior to SOI’ up until 
C1D15 ‘Prior to SOI’. This profile will be used to calculate the following pharmacokinetic parameters for 
each patient (data allowing) by standard model-independent, non-compartmental analysis (NCA) according 
to Symphogen’s local procedures: AUCinf, AUCτ, AUCnorm, τ, Cmax, Tmax, CEOI, λz, T½, CL, Vd. Definitions 
are given in Table 6. 
Table 6 - Definition and Derivation of PK Parameters 
Symbol 
Definition and Derivation 
Ctrough 
Trough concentration (i.e. concentration of study drug measured pre-infusion) 
AUCinf 
Area under the concentration-time curve from start of infusion to infinity 
AUCτ 
Area under the concentration-time curve from start of infusion up to 336 hours.  
AUCnorm, τ 
 
Dose-normalized area under the concentration-time curve in a dosing interval, calculated as 
AUC τ divided by the dose infused 
Cmax 
Maximum concentration 
Tmax 
Time to maximum concentration 
CEOI 
Concentration at the end of infusion 
λz 
Terminal rate constant (negative of the slope of an ln-linear regression of the un-weighted 
data considering the terminal phase of the concentration-time curve ≥ limit of 
quantification). λz is not an endpoint, but is used for derivation of endpoints 
T½ 
Terminal elimination half-life, calculated as ln(2)/ λz 
CL 
Clearance after first dose, calculated as Dose/AUCinf for C1/D1, where AUCinf will be 
calculated as the sum of the area from time zero to time of last quantifiable concentration, 
tz, and the area from tz to infinity. The second area will be estimated using the observed 
concentration at tz and the terminal rate constant  
Vd 
Volume of distribution during the terminal phase after first dose (CLS/ λz) 
 
Furthermore, the CEOI and Ctrough concentrations will be derived for each infusion. EOT and 1MFUP are 
defined as Ctrough values. The PK parameters will be reported with 3 significant digits. 


 
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6.5 
Immunogenicity Data 
ADA samples are planned to be taken according to Table 7. ADA analysis is performed using a validated 
double antigen bridging method on the MesoScale discovery platform. Sample analysis is carried out in 
three tiered steps: i) screening, ii) confirmation and iii) quantification of the ADA titer in confirmed positive 
samples. 
Table 7 - ADA Sampling Time Points 
Sampling 
Time 
Window 
Cycle 1 
Cycle 2 
Cycle 3 onward 
EOT 
1M 
FUP 
Long-
Term 
FUP 
As 
Clinically 
Indicated 
D1-D3 
D8 
D15 
D22 
D 1 
D15 
D 1 
D15 
Prior to 
SOI 
-4h 
X 
 
X 
 
X 
 
Odd # 
cycles 
 
X 
X 
X1 
X 
Abbreviations (in alphabetical order): 1M FUP, one-month follow-up; ADA, anti-drug antibody; D, day; EOI, end of infusion; EOT, end 
of treatment; FUP, follow-up; h, hour; SOI, start of infusion; X, ADA sampling 
1) 
Collection of samples during Long-Term FUP to continue at 2-month intervals for 6 months (for patients who are available for 
blood collection) 
ADA results will be categorized as negative (=0) and positive (>0). ADA response will be defined as a 
shift from negative at baseline to positive post-baseline result. Onset of ADA response will be defined as 
the study day of the first shift from negative baseline ADA result to positive post-baseline ADA result. For 
patient with ADA response, the duration of ADA response will be defined as study day of last positive 
post-baseline ADA result – onset of ADA response + 1. 
6.6 
Pharmacodynamic and Biomarker Analyses 
The details of the pharmacodynamic and biomarker analyses are out of scope of this SAP and will be 
presented in a separate plan. 
7 STATISTICAL ANALYSIS 
7.1 
General Data Handling Rules and Definitions 
If any enrolled patient is found to not have valid documented informed consent, that patient’s data will be 
excluded from the report, except as necessary to document the error. 
All analyses will be conducted using SAS version 9.4 or later. 
Except where specified all continuous variables will be summarized with descriptive statistics (the number 
of non-missing values, mean, standard deviation, median, 25th and 75th percentiles, minimum and 
maximum) and all ordinal and categorical variables will be summarized with frequency counts and 
percentages, by treatment group. 
Missing data will be maintained as missing unless specified otherwise. For variables where missing data is 
imputed, the analysis dataset will contain one variable with the imputed value and the original variable with 
missing maintained as missing. 
Except where specified, all results will be summarized by cohort and tumor type (solid tumor malignancy or 
lymphoma). Total columns will be displayed in all summary tables except where specified. 


 
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Results by visit, including at end of treatment, will be determined based on derived analysis visit, as 
described in Section 6.2.1 and Section 6.3.1. If multiple scheduled or unscheduled assessments fall within 
the same visit window, the result with a non-missing value closest to the target date (and latest, if ties exist) 
will be used for the visit. Both collected (SDTM) and derived (ADaM) visits will be displayed in listings. 
Analysis (ADaM) datasets will contain all collected (SDTM) results, and will indicate individual records 
flagged for use in analyses. 
Worst measurements for applicable parameters will be determined using criteria defined for each parameter 
(maximum, minimum, etc.). Analysis (ADaM) datasets will contain all collected (SDTM) results, and will 
indicate individual records flagged for use in analyses. 
7.2 
Patient Disposition 
The number of patients in each analysis set and the reasons for exclusion will be summarized. In addition, 
patients’ status with regard to study treatment and follow-up will also be summarized, along with the 
reasons for study treatment discontinuation. The number of patients in each analysis set and reason for 
study discontinuation will also be summarized. 
7.3 
Protocol Deviations 
Protocol deviations will be summarized by category for all patients. 
7.4 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the FAS. Age, height, weight and BMI 
will be presented as continuous numeric variables. Age group (18-64, 65-74, 75-84, ≥ 85), sex, race, 
ethnicity will be presented categorically. ECOG performance status will be presented ordinally. 
Cancer diagnosis and history will be summarized for the FAS and will be presented categorically, except 
the following variables which will be listed only: histological type, tumor grade, stage at initial diagnosis, 
stage at enrollment, date of most recent disease progression, time since initial diagnosis and time since 
diagnosis of metastatic disease. 
Prior cancer treatments will be summarized for the FAS and will be presented categorically. 
Medical history and surgical history will be listed. All other data fields will also be presented in patient data 
listings. 
7.5 
Safety Analyses 
All safety data will be summarized by cohort and tumor type in tables and presented in patient data listings. 
The analysis set for all safety analyses will be the FAS. 
7.5.1 
DLT Analysis 
A summary table of all patients will be presented, indicating the number of patients included in the DLT 
analysis set for each treatment group as well as the DLT status at Cycle 1 (yes, no, NE) for each patient; a 
total column will not be presented. All DLT events will be listed by dose cohort and patient. A summary 
table of DLTs across dose cohorts by SOC and preferred term will be presented, if applicable.  


 
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7.5.2 
Extent of Exposure to Study Medication 
The number of cycles initiated, exposure to study treatment, treatment duration, mean number of days 
between infusions, total dose received and relative dose intensity will be summarized overall. Additionally, 
maximum number of days delay between two consecutive infusions and dose modifications (dose delays, 
prolonged infusions, infusion interruptions, infusions prematurely stopped), and their corresponding reasons 
will be summarized overall. 
7.5.3 
Adverse Events 
All treatment-emergent AEs will be summarized (incidence) by the system organ class, preferred term, 
toxicity/severity grade and causal relationship to study treatment. The total number of events will also be 
presented. 
The following adverse events summaries will be reported: 
• 
Overall summary of safety including AEs, treatment-related AEs, serious AEs, treatment-related 
serious AEs, fatal AEs, AEs of grade 3 and above, AEs leading to study drug delay, AEs leading to 
study drug interruptions/prolongation, AEs leading to study drug discontinuation, infusion-related 
reaction, and dose-limiting toxicities 
• 
DLTs by dose escalation cohort (as described in Section 7.5.1) 
• 
DLTs by System Organ Class and Preferred Term (as described in Section 7.5.1) 
• 
Adverse Events by System Organ Class, Preferred Term and NCI-CTCAE v5.0 Grade 
• 
Treatment-related Adverse Events by System Organ Class, Preferred Term and NCI-CTCAE v5.0 
Grade 
• 
Adverse Events by System Organ Class, Preferred Term and Relationship to Study Treatment 
• 
Adverse Events Causing Study Drug Delay by System Organ Class, Preferred Term and NCI-
CTCAE v5.0 Grade 
• 
Adverse Events Causing Study Drug Interruption/Prolongation by System Organ Class, Preferred 
Term and NCI-CTCAE v5.0 Grade 
• 
Adverse Events Causing Study Drug Discontinuation by System Organ Class, Preferred Term and 
NCI-CTCAE v5.0 
• 
Non-Serious Adverse Events with an Incidence Rate of at Least 5% by System Organ Class and 
Preferred Term 
• 
Serious Adverse Events by System Organ Class and Preferred Term 
• 
Serious Treatment-related Adverse Events by System Organ Class and Preferred Term 
• 
Fatal Adverse Events by System Organ Class and Preferred Term 
7.5.3.1 
Deaths 
Summaries of deaths (including cause of death) will be provided. All deaths reported will also be presented 
in a listing. 
7.5.4 
Laboratory Data 
Hematology, chemistry and coagulation tests will be graded using NCI CTCAE v5.0 toxicity grading (see 
Appendix 1 NCI-CTCAE V5.0 Toxicity Grading).For hematology tests that were converted from 
percentage to absolute, the percentage lower limit of normal (LLN) will be used to determine if the result is 
below normal range. If the value is below the normal range but is higher than the grade 2 value, toxicity 
grade 1 will be assigned. Local laboratory ranges will be used for grading. 


 
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Hematology, biochemistry and coagulation results will be summarized by study visit and at end of 
treatment (actual values and change from baseline) as well as by highest toxicity grade (using NCI CTCAE 
v5.0 toxicity grading). The worst (maximum) change from baseline in toxicity grade for selected laboratory 
parameters will be presented in shift tables: the patient’s baseline grade will be cross-tabulated by the 
patient’s maximum post-baseline grade during the treatment, including scheduled and unscheduled visits. 
Individual patient hematology, biochemistry and coagulation parameters during the trial will be presented 
graphically using longitudinal plots. 
The qualitative urinalysis results will be summarized and listed. 
7.5.5 
Vital Signs 
Vital signs and their changes from baseline will be summarized by visit and at end of treatment. 
7.5.6 
Electrocardiogram (ECG) 
Quantitative and qualitative results from the electrocardiogram will be summarized by scheduled visit and 
at end of treatment. QTc value and change from baseline will be summarized using the categories defined in 
ICH E14. 
7.5.7 
Physical Examination 
The physical examination results stored in the database (i.e., weight and height) will be summarized with 
vital signs data (weight) and baseline characteristics (height). 
7.5.8 
ECOG Performance Status 
ECOG performance status results and shifts from baseline will be summarized by visit and at end of 
treatment in shift tables. Shift tables presented by visit will include visits until there are less than 50% of the 
patients remaining. 
7.5.9 
Pregnancy Test 
The pregnancy test results will be listed. 
7.5.10 
Concomitant Medications/Treatments 
Concomitant medications will be summarized by treatment group, Anatomical-Therapeutic-Chemical 
classification (ATC) class and preferred drug name. 
7.5.11 
Other Safety Assessments 
The ophthalmology examination results and pulmonary function tests will be summarized by visit. The 
MUGA scan and echocardiogram results will be listed. 
7.6 
Efficacy Analyses 
Unless stated otherwise, all efficacy analyses will be based on the FAS. 
7.6.1 
Tumor Marker Measurement 
The tumor marker measurements will be listed. 


 
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7.6.2 
Disease Response 
Best response will be summarized separately for each response evaluation method: 
• 
RECIST v1.1: Best response will be summarized into four RECIST categories: complete response 
(CR), partial response (PR), stable disease (SD) and progressive disease (PD). The summary will 
also include a category for unevaluable patients if applicable. 
• 
iRECIST: Best response will be summarized into five iRECIST categories: complete response 
(iCR), partial response (iPR), stable disease (iSD), unconfirmed progressive disease (iUPD), 
confirmed progressive disease (iCPD). The summary will also include a category for unevaluable 
patients if applicable. 
• 
RECIL: Best response will be summarized into five RECIL categories: complete response (CR), 
partial response (PR), minor response (MR), stable disease (SD) and progressive disease (PD). The 
summary will also include a category for unevaluable patients if applicable. 
The overall response rate (ORR) and clinical benefit rate (CBR) estimates will be presented along with the 
associated Clopper-Pearson 95% CIs. 
A waterfall plot for best percent change from baseline of the sum of the target lesion measurements will 
also be presented, with primary disease site and study treatment dose indicated. If there are not many 
primary disease sites, waterfall plots may indicate the assigned dose by the color of the bar and the primary 
disease site may be shown using text annotations. 
7.6.3 
Time to Progression 
TTP will be summarized separately for each response evaluation method (RECIST v1.1, iRECIST, RECIL). 
Median durations will be estimated using the Kaplan-Meier method, along with the corresponding 95% CI. 
Confidence intervals for the median values will be based on the methods of Brookmeyer and Crowley. The 
25th and 75th percentiles will also be calculated. Kaplan-Meier estimates at 2, 4, 6, 8, 10 and 12 months and 
their confidence intervals (calculated with the log-log transformation methodology of Kalbfleisch and 
Prentice) will be tabulated. The TTP plot will be estimated using the Kaplan-Meier method. 
7.6.4 
Duration of Objective Response 
If there are a sufficient number of responses, DOR will be analyzed using the same methodology as Time to 
Progression. DOR will also be presented in swim plots. Swim plots may include bars indicating first and 
last treatment date (capped with an arrow if treatment is ongoing) and follow-up period (capped with an 
arrow if follow-up is ongoing). Dates of first response, first objective disease progression and death will 
also be indicated. 
7.7 
Pharmacokinetic Analyses 
Unless stated otherwise, all pharmacokinetic analyses will be based on the PK Analysis Set. All 
pharmacokinetic data will be presented in listings. PK concentration profiles will be summarized by 
assigned dose and over time in tabular and graphical formats. 
Descriptive statistics of pharmacokinetic parameters and concentrations will include mean, SD, minimum 
and maximum. The descriptive statistics will be rounded to one more digit than the individual values for the 
mean, and SD, and to the same number of digits for the minimum and maximum values. 


 
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The concentration data may also be used for exploratory population PK modelling which is outside the 
scope of this SAP as the results will be reported separately from the Sym023-01 CSR. 
The following descriptive summaries will be produced: 
• 
Summary of Sym023 concentrations by visit, nominal time point 
• 
Summary of PK Parameters for first dose of Sym023 
The following figures will be produced: 
• 
Individual concentration versus actual time for the first dose up to 336h – linear scale (overlaid for 
each cohort) 
• 
Individual concentration versus actual time for the first dose up to 336h – semi-log scale (overlaid 
for each cohort) 
• 
Individual concentration versus actual time for all PK sampling time points from first dose to 
1MFUP – semi-log scale (overlaid for each cohort) 
• 
Arithmetic Mean concentration versus nominal time for the first dose up to 336h – linear scale 
(overlaid for all cohorts) 
• 
Arithmetic Mean concentration versus nominal time for the first dose up to 336h – semi-log scale 
(overlaid for all cohorts) 
• 
Arithmetic Mean concentration versus nominal time for all PK sampling time points from first dose 
to 1MFUP – semi-log scale (overlaid for all cohorts) 
Data points collected after 336h but within window will be included in plots identified as ‘first dose up to 
336h’. This includes all samples collected from Cycle 1 Day 1 through Cycle 1 Day 8, as well as Cycle 1 
Day 15 (Prior to SOI sample only). 
7.8 
Immunogenicity Analyses 
Unless stated otherwise, all immunogenicity analyses will be based on the ADA Analysis Set. All ADA 
data will be presented in listings. Immunogenicity profiles will be summarized by assigned dose and over 
time in tabular format; graphical formats may also be presented if appropriate. 
Since study drug in the ADA sample interferes with the capacity of detecting ADA against the drug, the 
measured serum levels of Sym023 in the PK sample drawn at the same/corresponding time point will be 
presented along with ADA results. 
The following descriptive summaries will be produced: 
• 
Summary of ADA categorical results (negative/positive) by visit 
• 
Shift table of ADA categorical results from baseline to worst post-baseline result 
The following figure might be produced (providing there is sufficient data): 
• 
Sym023 concentration geometric mean over time by ADA status – semi-log scale 
8 ANALYSES PERFORMED BEFORE DATABASE CLOSURE 
Safety evaluation will be performed prior to each dose-escalation. No other interim analyses are planned. 


 
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9 CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
Any changes to methods planned in this statistical analysis plan will be documented in a revision to this 
statistical plan prior to database lock, or identified in the clinical study report. 
10 STATISTICAL SOFTWARE 
SAS Version 9.4 or later will be used for all statistical analyses. 
11 REFERENCES 
1. Brookmeyer and Crowley, A Confidence Interval for the Median Survival Time, Biometrics 38, 29-41, 
March 1982. 
2. Kaplan, E. L. Meier, P. (1958). Nonparametric estimation from incomplete observations. J. Amer. 
Statist. Assn. 53 (282): 457–481. JSTOR 2281868. 
3. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, FDA guidance, May 2007. 
4. Kratz, A, Lewandrowski, K.B. (1998). Normal Reference Laboratory Values. The New England Journal 
of Medicine, 339, 1063-1072. 
5. Kratz, A., Ferraro, M., Sluss, P.M., Lewandrowski, K.B. (2004). Normal Reference Laboratory Values. 
The New England Journal of Medicine, 351, 1548-1563. 
6. PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group. (2014). 
Analyses and Displays Associated to Non-Compartmental Pharmacokinetics – With a Focus on Clinical 
Trials [White paper]. Retrieved April 9, 2019 from: https://www.phuse.eu/documents/working-
groups/deliverables/analyses-displays-associated-to-non-compartmental-pharmacokinetics-version-10-
25-mar-14-pdf-11803.pdf 
7. National Cancer Institute Division of Cancer Treatment & Diagnosis. (2017). CTCAE v5.0 Clean, 
Tracked, and Mapping Document [Excel]. Retrieved June 26, 2019 from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5.0.xlsx 
8. Guideline, ICH Harmonised Tripartite. The Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs E14. 2005. 


 
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12 APPENDIX 1 NCI-CTCAE V5.0 TOXICITY GRADING 
12.1 Panel: Chemistry 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Albumin, serum- low 
(hypoalbuminemia)  
g/L 
[30, LLN) 
[20, 30) 
<20 
life-threatening 
consequences; 
urgent 
intervention 
indicated 
Alkaline phosphatase (ALK) 
increased 
U/L 
(ULN, 2.5*ULN] 
(2.5*ULN, 
5*ULN] 
(5*ULN, 
20*ULN] 
>20*ULN 
Alanine aminotransferase 
(ALT) increased 
U/L 
(ULN, 3.0*ULN] 
(3.0*ULN, 
5.0*ULN] 
(5*ULN, 
20*ULN]; 
>20*ULN 
Amylase increased 
U/L 
(ULN, 1.5*ULN] 
(1.5*ULN, 
2*ULN] 
(2*ULN, 5*ULN] 
> 5*ULN 
Aspartate aminotransferase 
(AST) increased 
U/L 
(ULN, 3.0*ULN] 
(3.0*ULN, 
5.0*ULN] 
(5*ULN, 
20*ULN]; 
>20*ULN 
Bilirubin increased 
umol/L 
(ULN, 1.5*ULN] 
(1.5*ULN, 
3*ULN] 
(3*ULN, 
10*ULN] 
>10*ULN 
Calcium high (hypercalcemia)  
mmol/L 
(ULN, 2.9] 
(2.9, 3.1] 
(3.1, 3.4]; 
hospitalization 
indicated 
>3.4; life-
threatening 
consequences 
Calcium low (hypocalcemia)  
mmol/L 
[2.0, LLN) 
[1.75, 2.0) 
[1.5, 1.75) ; 
hospitalization 
indicated 
[0, 1.5); life 
threatening 
consequences 
Creatine phosphokinase 
(CPK) increased 
U/L 
(ULN, 2.5*ULN] 
(2.5*ULN, 
5*ULN] 
(5*ULN, 
10*ULN] 
>10*ULN 
Creatinine increased 
umol/L 
 (ULN, 1.5*ULN] 
(1.5 – 3.0* 
baseline]; 
(1.5*ULN, 
3*ULN] 
>3.0*baseline; 
(3*ULN, 6*ULN] 
>6*ULN 
Glucose low (hypoglycemia) 
mmol/L 
[3.0, LLN) 
[2.2, 3.0) 
[1.7, 2.2) 
[0, 1.7); life 
threatening 
consequences; 
seizures 
Lipase increased 
U/L 
(ULN, 1.5*ULN] 
(1.5*ULN, 
2*ULN] 
(2*ULN, 5*ULN] 
> 5*ULN 


 
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Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Magnesium low 
(hypomagnesemia) 
mmol/L 
[0.5, LLN) 
[0.4, 0.5) 
[0.3, 0.4) 
<0.3 
Magnesium high 
(hypermagnesemia) 
mmol/L 
(ULN, 1.23] 
undefined 
(1.23, 3.3] 
> 3.3 
Potassium high 
(hyperkalemia)  
mmol/L 
(ULN, 5.5] 
(5.5, 6]; 
intervention 
initiated 
(6, 7]; 
hospitalization 
indicated 
>7; life-
threatening 
consequences 
Potassium low (hypokalemia)  
mmol/L 
[3, LLN) 
[3, LLN); 
symptomatic; 
intervention 
indicated 
[2.5, 3) ; 
hospitalization 
indicated 
[0, 2.5); life-
threatening 
consequences 
Sodium high (hypernatremia) 
mmol/L 
(ULN, 150] 
(150, 155] ; 
intervention 
initiated 
(155, 160]; 
hospitalization 
indicated 
>160; life-
threatening 
consequences 
Sodium low (hyponatremia) 
mmol/L 
[130, LLN) 
(125-129] and 
asymptomatic  
125-129 
symptomatic; 120-
124 regardless of 
symptoms 
[0, 120); life-
threatening 
consequences 
 
12.2 Panel: Hematology 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin increased 
g/dL 
 
Increase in >0 -2 
g/dL  
Increase in >2 -4 
g/dL  
Increase in >4 
g/dL  
undefined 
Hemoglobin decreased 
g/L 
[100, LLN) 
[80, 100) 
[0, 80); 
transfusion 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Platelet count decreased 
10^9/L 
[75, LLN) 
[50, 75) 
[25, 50) 
[0, 25) 
WBC increased 
10^9/L 
undefined 
undefined 
>100 
undefined 
WBC decreased 
10^9/L 
[3, LLN) 
[2, 3) 
[1, 2) 
[0, 1) 
Lymphocytes increased 
10^9/L 
undefined 
(4 ; 20] 
>20 
undefined 
Lymphocytes decreased 
10^9/L 
[0.8, LLN)  
[0.5, 0.8) 
[0.2, 0.5) 
[0, 0.2) 
Neutrophil count decreased 
10^9/L 
[1.5, LLN) 
[1, 1.5) 
[0.5, 1) 
[0, 0.5) 
 
12.3 Panel: Coagulation 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 


 
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Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
International normalized ratio 
of prothrombin time (INR) 
increased 
N/A 
>1.2 - 1.5; >1 - 1.5 
x baseline if on 
anticoagulation; 
monitoring only 
indicated 
>1.5 - 2.5; >1.5 - 
2.5 x baseline if 
on 
anticoagulation; 
dose adjustment 
indicated 
>2.5; >2.5 x 
baseline if on 
anticoagulation; 
bleeding 
- 
Activated partial 
thromboplastin time prolonged 
Seconds 
(ULN, 1.5xULN] 
(1.5xULN, 
2.5xULN] 
>2.5 x ULN 
- 
 
Reference: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 


 
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13 APPENDIX 2 PROGRAMMING CODES FOR STATISTICAL ANALYSIS 
Programming of the tables, listings and figures will be performed using SAS Version 9.4, running under 
UNIX environment. The following table presents the SAS codes for the analyses of efficacy endpoints. 
Endpoint 
Test 
SAS Code  
ORR 
Clopper-Pearson (exact) 95% 
confidence interval  
ods listing close; 
proc freq data = indata; 
 
ods output BinomialCLs=CI BinomialProp=prop; 
 
table objresp / binomial(level = 1 exact) out=freq1 
(keep=objresp count); 
run; 
ods listing; 
TTP, DOR 
Kaplan-Meier: median, 95% 
CI, 25th-75th percentile 
ods listing close; 
ods output Quartiles=Quartile; 
proc lifetest data=indata; 
 
time timevar*censvar(1); 
run; 
ods output close; 
ods listing;