A Phase 1, Multicenter, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAB001 in Subjects With Advanced Malignancies
Phase: PHASE1
Conditions: Advanced Malignancies
Sponsor: TopAlliance Biosciences



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Investigator Agreement 
 
A Phase 1, Multicenter, Open-label Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of TAB001 in Subjects with Advanced Malignancies 
I, the undersigned, have reviewed this protocol, and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Conference on Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP), any applicable laws and requirements, and any conditions required 
by a regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC).  
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt. 
 
Principal Investigator: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name (please type or print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Address 

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Drug Administration (FDA) if there are any changes in dose levels and dosing frequency. 
Any dose-escalation cohort that has not exceeded the MTD can be expanded up to a 
maximum of 10 subjects for further evaluation of safety, PK, pharmacodynamics, and clinical 
activity. 
The dose to be evaluated in Part B is 240 mg administered Q3W which was determined after 
review of safety, PK and pharmacodynamic data from subjects treated with toripalimab 
(JS001) in studies performed in China (see Section 1.4) as well as safety data from subjects 
treated in Part A of this study. 
All subjects will be evaluated regularly, and their clinical status classified according to 
RECIST v1.1 and irRECIST.  Subjects may continue to receive toripalimab Q2W (± 2 days) 
in Part A, or Q3W (± 2 days) in Part B, in the absence of confirmed progressive disease (a 
repeat scan will be conducted in 4 weeks ± 2 days in Part A and in 6 weeks ± 2 days in Part B 
to confirm disease progression), unacceptable toxicity, withdrawal of consent, intercurrent 
illness preventing further administration of study drug, or the investigator considers it in the 
best interest of the subject to discontinue study therapy.  If feasible, all subjects will be 
followed for PFS and OS (Part B only) until the end of the study, defined as the date of the 
last protocol-specified visit/assessment (including telephone contact), or the date the study is 
closed by the sponsor, whichever comes first.  AEs and SAEs will be followed from the start 
of the first dose of toripalimab through 90 days after the last dose of toripalimab unless a 
subject receives another experimental or anticancer therapy, at which time only related 
AE/SAEs will be collected through 90 days after the last dose of toripalimab. 
TARGET SUBJECT POPULATION 
Men and women, 18 years or older, with advanced malignancies that are evaluable by 
RECIST v1.1 and irRECIST criteria, that are refractory to standard therapy or for which no 
standard therapy exists may be enrolled.  Subjects must provide written informed consent, 
have adequate organ function, and agree to use effective contraception (if relevant).  Subjects 
with certain serious medical conditions would be excluded from participation in the trial. 
INCLUSION / EXCLUSION CRITERIA 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects.  If there is a question about the inclusion/exclusion criteria listed below, the 
principal investigator (PI) should contact the medical monitor or designee before enrolling 
the subject. 
Inclusion Criteria: 
Subjects must meet the following Inclusion criteria: 
1. Signed Informed Consent Form 
2. Age ≥ 18 years 
3.  Subject meets the following corresponding requirements for the part of the study they will 
enroll into: 
During Part A, subjects must have a histologically or cytologically documented, incurable 
or metastatic solid tumor that has progressed on (or they have been intolerant to) standard 
systemic therapy options for their tumor type in the metastatic setting or must have a 

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tumor type for which no such standard systemic option exists. 
During Part B, subjects must have a histologically or cytologically documented diagnosis 
of esophageal carcinoma, gastric carcinoma, cholangiocarcinoma, neuroendocrine tumors 
(NETs) (excluding lung derived NET), NPC, HCC, sarcomas, both chondrosarcoma and 
soft tissue sarcoma (excluding leiomyosarcoma and including angiosarcoma, 
undifferentiated pleomorphic sarcoma and alveolar soft part sarcoma), or with agreement 
of the Sponsor, other tumors (including NPC and HCC) that have been treated with at 
least one line of standard systemic therapy for their respective tumor type in the metastatic 
setting with progressive locally advanced or metastatic disease that is not amenable to 
definitive local therapy with curative intent. Patients with MSI-H/dMMR tumors are 
eligible to enroll. 
a) Subjects with nasopharyngeal cancer must have received (or been intolerant to) to 
a platinum-based combination as part of their prior therapy for advanced/metastatic 
disease.  
b) Subjects with soft tissue sarcoma and chondrosarcoma must have radiographic 
evidence of progression within the previous 6 months and must have received at 
least 1 line of systemic therapy. 
c) Subjects with esophageal cancer must have received (or been intolerant to) a 
platinum-based combination as part of their prior therapy for advanced/metastatic 
disease. 
d) Subjects with gastric cancer must have received (or been intolerant to) a 
fluoropyrimidine-platinum combination as part of their prior therapy for 
advanced/metastatic disease. 
e) Subjects with HCC must have received (or been intolerant to) sorafenib as part of 
their prior therapy for advanced metastatic disease. 
4.  Measurable disease per RECISTv1.1 and irRECIST   
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
 
6. Adequate organ and marrow function, as defined below: 
a) Hemoglobin ³ 8.0 g/dL within first 2 weeks prior to first dose of toripalimab 
b) Absolute neutrophil count (ANC) ³ 1.2 × 109/L (1,200/mm3) 
c) Platelet count ³ 75 × 109/L (75,000/mm3) 
d) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) except subjects with 
documented Gilbert’s syndrome who must have a baseline total bilirubin ≤ 3.0 
mg/dL 
e) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × 
ULN; for subjects with hepatic metastases, ALT and AST ≤ 5 × ULN 
f) Serum creatinine ≤ 1.5 × ULN OR calculated creatinine clearance (CrCl) or 
24-hour urine CrCl ≥ 40 mL/minute 
Cockcroft-Gault formula will be used to calculate CrCl.(Section 9.4); 24-hour 

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urine CrCl will be derived using the measured creatinine clearance formula 
(Section 9.5) 
g) International normalized ratio (INR) and activated partial thromboplastin time 
(aPTT) ≤ 1.5 ×ULN; applies only to subjects who do not receive therapeutic 
anticoagulation; subjects receiving therapeutic anticoagulation (such as low-
molecular weight heparin or warfarin) should be on a stable dose. 
7. Willingness to provide consent for biopsy samples (In Part A, fresh pre-treatment biopsies 
will be requested from subjects with safely accessible lesions.  For subjects who cannot 
provide a fresh pre-treatment biopsy, an archival specimen will be required.  In Part B, 
fresh pre-treatment biopsies will be required from subjects with safely accessible lesions.  
Archival specimens will be requested). 
8. Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use effective contraception from time of screening, and must agree to 
continue using such precautions for 90 days after the final dose of toripalimab; cessation 
of birth control after this point should be discussed with a responsible physician.  Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
birth control. 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as at least 12 months with no menses confirmed by follicle-
stimulating hormone [FSH] levels.  FSH testing will be conducted at the Screening visit to 
confirm post-menopausal status). 
Subjects must use effective contraception as described in Table 1-1. 
9. Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use effective contraception (see Table 1-1) from Day 1 and for 90 days 
after receipt of the final dose of toripalimab. 
Table 1-1: Highly Effective Methods of Contraception 
Barrier Methods 
Hormonal Methods 
• 
Male condom plus spermicide 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing intrauterine system 
(e.g., Mirena®) a 
• 
Implants 
• 
Hormone shot or injection 
• 
Combined pill 
• 
Minipill 
• 
Patch 
a This is also considered a hormonal method. 
 
Exclusion Criteria: 
Any of the following would exclude the subject from participation in the study: 
1. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study. 

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2. Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic therapy for 
cancer treatment.  Concurrent use of hormones for non-cancer-related conditions (e.g., 
insulin 
for 
diabetes 
and 
hormone 
replacement 
therapy) 
is 
acceptable. 
NOTE: Local treatment of isolated lesions for palliative intent is acceptable (e.g., by local 
surgery or radiotherapy). 
3. Receipt of any investigational anticancer therapy within 4 weeks prior to the first dose of 
toripalimab. 
4. Current or prior use of immunosuppressive medication within 2 weeks prior to the first dose 
of toripalimab, with the exception of intranasal and inhaled corticosteroids or systemic 
corticosteroids not to exceed 10 mg/day of prednisone or equivalent.  
5. In Part A: Prior exposure to immunotherapy such as but not limited to other anti-CTLA-4, 
anti-PD-1, or anti-PD-L1 antibodies excluding vaccines.  In Part B: Exclusion of prior 
immunotherapy exposure will be limited to anti-PD-1, anti-PD-L1, or anti-PD-L2. 
6. Prior allogeneic bone marrow transplantation or prior solid organ transplantation. 
7. Major surgery (as defined by the investigator) within 4 weeks prior to first dose of 
toripalimab or still recovering from prior surgery. 
8. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
baseline or to NCI-CTCAE v4.03 Grade 0 or 1, or to levels dictated in the inclusion / 
exclusion criteria with the exception of alopecia.  Subjects with irreversible toxicity that is 
not reasonably expected to be exacerbated by toripalimab may be included (e.g., hearing 
loss) after consultation with the medical monitor. 
9. Active or prior documented autoimmune disease within the past 2 years.  
NOTE: Subjects with vitiligo, Grave’s disease not requiring systemic treatment other than 
thyroid hormone replacement (within the past 2 years) , or psoriasis not requiring systemic 
treatment are not excluded. Subjects with a history of autoimmune hypothyroidism 
requiring only thyroid hormone replacement therapy will not be excluded. 
10. Known history of tuberculosis. 
11. Subjects who are known to be human immunodeficiency virus (HIV) positive.  
12. Subjects with evidence of hepatitis B or C virus infection, unless their hepatitis is 
considered to have been cured. (Note that subjects with prior hepatitis B virus [HBV] 
infection must have HBV viral load [VL] <100 IU/mL before study enrollment, and must 
be treated according to local standards; hepatitis C virus [HCV] infection must have, before 
study enrollment, no detectable VL and must be treated according to local standards). 
13. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis). 
14. History of primary immunodeficiency. 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure according to New York Heart Association (NYHA) 
Functional Classification ≥ 3, uncontrolled hypertension, unstable angina pectoris, cardiac 
arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/social situations 
that would limit compliance with study requirements, substantially increase risk of 

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incurring AEs from toripalimab, or compromise the ability of the subject to give written 
informed consent.  
16. Symptomatic or untreated central nervous system metastases requiring concurrent 
treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids.  Subjects 
with previously treated brain metastases may participate provided they are clinically stable 
for at least 4 weeks prior to study entry, have no evidence of new or enlarging metastases, 
and are off steroids.  
17. Receipt of live attenuated vaccination within 4 weeks prior to study entry or within 4 weeks 
of receiving toripalimab. 
18. Any condition that, in the opinion of the investigator or sponsor, would interfere with 
evaluation of toripalimab or interpretation of subject safety or study results. 
19. Pregnant or breastfeeding women. 
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION 
Toripalimab is a humanized, IgG4κ monoclonal antibody specific for PD-1.  Toripalimab will 
be administered IV over a minimum of 60 minutes in Cycle 1.  In subsequent cycles, the 
infusion time may be reduced to a minimum of 30 minutes depending upon subject tolerance.  
The infusion duration may be increased at any time at the discretion of the investigator.  
Refer to Section 3.1.7.3 Management of Toripalimab-related Toxicities.  
STATISTICAL ANALYSIS  
Statistical Considerations: All statistical analyses will be performed using SAS Version 9.3 
or higher, unless otherwise noted.  In general, analysis of categorical variables will include 
counts and percentage of subjects in each category observed.  For continuous variables, the 
sample size (n), mean, standard deviation (SD), mean, median, minimum, and maximum will 
be presented.  No formal comparisons among dose groups (escalation) or treatment cohorts(in 
Part B expansion cohorts) are planned.  Missing data will not be imputed unless otherwise 
stated.  Subject demographics, baseline characteristics, and disposition will be characterized 
using descriptive statistics.  PK data will be presented descriptively, with accompanying 
figures.  
No formal interim analysis is planned for this study.  However, a review of safety data and 
available PK data will be performed after completion of each dose escalation cohort.  In 
addition to ongoing safety data review in Part B, a periodic cumulative review of safety will 
be performed.  A statistical analysis plan (SAP) will fully describe the planned analyses for 
this study. 
Sample Size Considerations: It is assumed that 3 cohorts will be required to determine the 
MTD or the MFD; therefore, up to 18 subjects will be enrolled in the dose escalation (Part A) 
portion of the study.  Up to 280 subjects will be enrolled in the expansion phase (Part B) at a 
dose determined from the safety, clinical responses, PK and pharmacodynamics found in Part 
A and other pertinent data, for a total of up to approximately 298 subjects.  Assuming a 10% 
drop out rate, a total of up to approximately 327 subjects are expected to be enrolled.  Six 
expansion cohorts may include 5 disease-specific cohorts and, at the discretion of the 
Sponsor, another tumor cohort, to a maximum of 40 subjects enrolled in each cohort with the 
exception of the sarcoma cohort in which a maximum of 80 subjects can be enrolled. After 40 

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TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................ 23 
1.1 
Disease Background ........................................................................................... 23 
1.2 
Toripalimab Background .................................................................................... 24 
1.3 
Summary of Nonclinical Experience ................................................................. 24 
1.4 
Summary of Clinical Experience ....................................................................... 26 
1.4.1Summary of Safety from Trials Performed in China ................................. 26 
1.4.2Safety Summary of Phase 1 Study in the United States (TAB001-01; 
NCT03474640 ) ........................................................................ 27 
1.4.3Summary of Pharmacokinetic Analyses ..................................................... 31 
1.4.4Immunogenicity of toripalimab .................................................................. 32 
1.4.5Pharmacodynamics study of toripalimab in NCT03316144 ...................... 33 
1.5 
Rationale for the current Study .......................................................................... 33 
1.6 
Rationale for Tumor Selection ........................................................................... 34 
1.7 
Rationale for Dose .............................................................................................. 38 
2 
OBJECTIVES AND ENDPOINTS .............................................................................. 40 
2.1 
Objectives ........................................................................................................... 40 
2.1.1Primary Objectives ..................................................................................... 40 
2.1.2Secondary Objectives ................................................................................. 40 
 
2.2 
Study Endpoints ................................................................................................. 41 
2.2.1Primary Endpoint ....................................................................................... 41 
2.2.2Secondary Endpoints .................................................................................. 41 
 
3 
STUDY DESIGN .......................................................................................................... 42 
3.1 
Description of the Study ..................................................................................... 42 
3.1.1Overview…………… ................................................................................ 42 
3.1.2Part A – Dose Escalation ............................................................................ 42 
3.1.3Part B – Dose Expansion ............................................................................ 42 
3.1.4Treatment Regimen .................................................................................... 43 
3.1.5Treatment Regimen .................................................................................... 44 
3.1.6Dose-escalation Design .............................................................................. 45 
3.1.7Management of Study Related Toxicities .................................................. 48 
3.1.8Study Stopping Criteria .............................................................................. 55 
4 
MATERIALS AND METHODS .................................................................................. 56 
4.1 
Subjects .............................................................................................................. 56 
4.1.1Number of Subjects .................................................................................... 56 
4.1.2Inclusion Criteria ........................................................................................ 56 

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4.1.3Exclusion Criteria ....................................................................................... 59 
4.1.4Subject Enrollment ..................................................................................... 61 
4.1.5Withdrawal Criteria .................................................................................... 61 
4.1.6Replacement of Subjects ............................................................................ 63 
4.1.7Withdrawal of Informed Consent for Data and Biological Samples .......... 63 
4.2 
Schedule of Study Procedures ............................................................................ 64 
4.2.1Enrollment/Screening Period ..................................................................... 64 
4.2.2Treatment Period ........................................................................................ 65 
4.2.3Part A and Part B Unscheduled and Follow-up Periods ............................ 83 
4.3 
Description of Study Procedures ........................................................................ 86 
4.3.1Efficacy 
 .................................................................................................. 86 
4.3.2Medical History and Physical Examination, Electrocardiogram, and 
Vital Signs ................................................................................ 97 
4.3.3Clinical Laboratory Tests ........................................................................... 98 
4.3.4Pharmacokinetic Evaluation and Methods ............................................... 100 
4.3.5Immunogenicity Evaluation and Methods ............................................... 101 
4.4 
Biomarker Evaluation and Methods ................................................................. 101 
4.4.1Pharmacodynamic Measurements ............................................................ 101 
4.4.2Predictive Biomarkers .............................................................................. 102 
4.5 
Archival Tumor Samples and Tumor Biopsies ................................................ 102 
4.5.1Archival Tumor Samples .......................................................................... 102 
4.5.2Tumor Biopsies ........................................................................................ 102 
4.6 
Estimate of Volume of Blood to Be Collected ................................................. 103 
4.7 
Study Suspension or Termination .................................................................... 104 
4.8 
Investigational Products ................................................................................... 105 
4.8.1Identity of Investigational Product(s) ....................................................... 105 
4.8.2Additional Study Medications .................................................................. 108 
4.8.3Labeling………. ....................................................................................... 109 
4.8.4Storage…………. ..................................................................................... 109 
4.8.5Treatment Compliance ............................................................................. 109 
4.8.6Accountability .......................................................................................... 109 
4.9 
Treatment Assignment and Blinding ................................................................ 109 
4.9.1Methods for Assigning Treatment Groups ............................................... 109 
4.9.2Methods for Ensuring Blinding ................................................................ 109 
4.10 Restrictions During the Study and Concomitant Treatment(s) ........................ 110 
4.10.1Permitted Concomitant Medications ...................................................... 110 
4.10.2Prohibited Concomitant Medications ..................................................... 112 
4.11 Statistical Evaluation ........................................................................................ 112 

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4.11.1General Considerations .......................................................................... 112 
4.11.2Sample Size ............................................................................................ 113 
4.11.3Safety Analysis ....................................................................................... 113 
4.11.4Efficacy Analyses ................................................................................... 113 
4.11.5Analysis of Immunogenicity .................................................................. 114 
4.11.6Analysis of Pharmacokinetics ................................................................ 114 
4.11.7Analysis of Pharmacodynamics ............................................................. 114 
 
4.11.9Interim Analysis ..................................................................................... 115 
5 
ASSESSMENT OF SAFETY ..................................................................................... 115 
5.1 
Definition of Adverse Events ........................................................................... 115 
5.2 
Definition of Serious Adverse Events .............................................................. 115 
5.3 
Definition of Adverse Events of Special Interest ............................................. 116 
5.3.1Adverse event(s) of special interest .......................................................... 116 
5.4 
Recording of Adverse Events ........................................................................... 117 
5.4.1Time Period for Collection of Adverse Events ........................................ 117 
5.5 
Follow-up of Unresolved Adverse Events ....................................................... 118 
5.6 
Reporting of Serious Adverse Events .............................................................. 118 
5.7 
Other Events Requiring Immediate Reporting ................................................. 119 
5.7.1Dose-limiting Toxicity ............................................................................. 119 
5.7.2Overdose  ................................................................................................ 119 
5.7.3Hepatic Function Abnormality ................................................................. 120 
5.7.4Pregnancy………… ................................................................................. 120 
6 
STUDY AND DATA MANAGEMENT .................................................................... 121 
6.1 
Training of Study Site Personnel ...................................................................... 121 
6.2 
Monitoring of the Study ................................................................................... 121 
6.2.1Source Data .............................................................................................. 122 
6.2.2Archiving of Study Documents ................................................................ 123 
6.3 
Study Timetable and End of Study ................................................................... 123 
6.4 
Data Management ............................................................................................. 123 
7 
ETHICAL AND REGULATORY REQUIREMENTS .............................................. 123 
7.1 
Ethical Conduct of the Study ............................................................................ 123 
7.2 
Subject Data Protection .................................................................................... 124 
7.3 
Ethics and Regulatory Review ......................................................................... 124 
7.4 
Informed Consent ............................................................................................. 125 
7.5 
Changes to the Protocol and Informed Consent Form ..................................... 126 
7.6 
Audits and Inspections ..................................................................................... 126 
8 
REFERENCES ........................................................................................................... 128 

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9 
APPENDIX ................................................................................................................. 134 
9.1 
Appendix 1: Additional Safety Guidance ........................................................ 134 
9.2 
Appendix 2: National Institute of Allergy and Infectious Diseases and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis .............................................................................................. 136 
9.3 
Appendix 3: Eastern Cooperative Oncology Group Performance Status ........ 137 
9.4 
Appendix 4: Cockcroft-Gault Formula ............................................................ 138 
9.5 
Appendix 5: Measured Creatinine Clearance Formula (Adjusted for Body 
Surface Area) ........................................................................................ 139 
9.6 
New York Heart Association (NYHA) Functional Classification ................... 140 
 
LIST OF IN-TEXT TABLES 
Table 1.4.2-1: TEAEs Reported in ≥10% of Subjects in Phase I Studies in the United States
 ............................................................................................................. 29 
Table 1.4.2-2: Treatment Related Serious Adverse Events in a Phase 1 Trial Conducted in the 
United States (N=109) ......................................................................... 30 
Table 1.4.3-1: Summary of PK Parameters after Multiple Intravenous Infusions of 
Toripalimab ......................................................................................... 31 
Table 3.1.7-1: Toripalimab Dose Modification Due to Toxicity ............................................ 48 
Table 3.1.7-2:  Management of Immune-related Adverse Events ........................................... 52 
Table 3.1.7-3:  Management of Gastrointestinal irAEs. .......................................................... 52 
Table 3.1.7-4:  Management of Hepatic irAEs. ....................................................................... 52 
Table 4.1.2-1  Highly Effective Methods of Contraception .................................................... 59 
Table 4.2.1-1  PART A and Part B Schedule of Evaluations: Screening ................................ 64 
Table 4.2.2-1  Part A Schedule of Evaluations: Cycle 1 ......................................................... 67 
Table 4.2.2-2: Part A Schedule of Evaluations: Cycles 2, 4, 5, 6 and 7 (Cycle 3 is in Table 
4.2.2-3) ................................................................................................ 69 
Table 4.2.2-3  PART A Schedule of Evaluations: Cycle 3 ..................................................... 71 
Table 4.2.2-4  PART A Schedule of Evaluations: Cycle 8 and Beyond ................................. 73 
Table 4.2.2-5  PART B Schedule of Evaluations Cycle 1 ....................................................... 75 
Table 4.2.2-6  PART B Schedule of Evaluations: Cycles 2, 4, 5, 6 and 7 (Cycle 3 is in Table 
4.2.2-7) ................................................................................................ 77 
Table 4.2.2-7  PART B Schedule of Evaluations: Cycle 3 ..................................................... 79 
Table 4.2.2-8  PART B Schedule of Evaluations: Cycle 8 and Beyond ................................. 81 
Table 4.2.3-1  Part A and PART B Schedule of Evaluations: Unscheduled and Follow-up 
Procedures ........................................................................................... 84 
Table 4.3.1-1  Time point overall response: patients with target (+/- non-target) lesions ...... 93 
Table 4.3.1-2  Best Overall Response when CR and PR confirmation is required per RECIST 
v 1.1 ..................................................................................................... 94 
Table 4.3.1-3  Table Derivation of irRC Overall Responses .................................................. 97 
Table 4.5.2-1  Blood Draw Volumes – Part A ...................................................................... 103 
Table 4.5.2-2  Blood Draw Volumes – Part B ...................................................................... 104 
Table 4.8.1-1  Identification of Investigational Products ...................................................... 105 

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Table 4.8.1-2  Toripalimab, 0.9% NaCl and Total Deliverable Volume .............................. 106 
 
 

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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ADA 
anti-drug antibodies 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibody 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASPS 
alveolar soft part sarcoma 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC(0-inf) 
AUC to time infinity 
AUC(0-t) 
AUC to time of last measurable concentration 
AUC(t-inf) 
AUC from time of last measurable concentration to time infinity 
AUC(t-inf)% 
percentage of AUC(t-inf) of AUC(0-inf) 
AUC TAU 
AUC to the end of the dosing period 
BOR 
best overall response 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
Cavg 
average observed concentration 
CBC 
complete blood count 
CI 
confidence interval 
CL 
Clearance 
CLss 
clearance at steady state 
cm 
centimeter 
CM 
concomitant medications 
Cmax 
maximum observed concentration 
CPK 
creatine phosphokinase 
CR 
complete response 
CrCl 
calculated creatinine clearance 
CRO 
Clinical Research Organization 
CT 
computed tomography 

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Abbreviation or 
Specialized Term 
Definition 
DC 
disease control 
DCO 
data cutoff 
DCR 
disease control rate 
dL 
deciliter 
DLT 
dose-limiting toxicity 
dMMR 
mismatch repair deficient 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
EC50 
half-maximal effective concentration 
EC 
esophageal cancer 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EOI 
end of infusion 
ETBR 
endothelin-B receptor 
FAAN 
Food Allergy and Anaphylaxis Network 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
g 
gram 
G-CSF 
granulocyte colony-stimulating factor 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEC 
gastroesophageal junction cancer 
γ-GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GMP 
Good Manufacturing Practice 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCG 
Human chorionic gonadotropin 
HCT 
hematocrit 
HCV 
hepatitis c virus 

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Abbreviation or 
Specialized Term 
Definition 
HED 
human equivalent dose 
HepB cAb 
hepatitis B core antibody 
HepB SA 
hepatitis B surface antigen 
HepC Ab 
hepatitis C antibody 
HepC RNA 
hepatitis C ribonucleic acid 
HGB 
hemoglobin 
HIV 
human immunodeficiency virus 
HR 
hour or heart rate 
IB 
Investigator’s Brochure 
IBW 
ideal body weight 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDO 
dioxygenase 
IEC 
Independent Ethics Committee 
IgG4K 
Immunoglobulin gamma 4, kappa 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 
ILD 
Interstitial lung disease 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IP 
intraperitoneal 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
irBOR 
immune-related best overall response 
irCR 
immune-related complete response 
irNE 
immune-related NE 
ir-NN 
irNon-CR/Non-PD 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irRC 
immune-related Response Criteria 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
irSD 
immune-related stable disease 
IU 
international units 
IV 
intravenous 
IWG 
International Working Group 

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Abbreviation or 
Specialized Term 
Definition 
kDa 
kilodalton 
Kel 
elimination rate constant from the central compartment 
Kg 
kilogram 
L 
liter 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantitation 
µg 
microgram 
mAb 
monoclonal antibody 
MABEL 
minimally-anticipated biological effect level 
mDOR 
median duration of overall response 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
maximum feasible dose 
mg 
milligram 
mL 
milliliter 
mm 
millimeter 
MMR 
mismatch repair 
MOA 
mechanism of action 
mPFS 
median progression free survival 
MRI 
magnetic resonance imaging 
MRSD 
maximum recommended safe dose 
MRTinf 
mean residence time extrapolated to infinity 
MSI 
microsatellite instability 
MSI-H 
microsatellite instability-high 
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
n 
sample size 
NAb 
neutralizing antibody 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NET 
neuroendocrine tumor 
ng 
Nanogram 
NHP 
non-human primate 
NIAID 
National Institute of Allergy and Infectious Diseases 
NK 
natural killer 
NKT  
natural killer T 
nM 
nanomolar 

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Abbreviation or 
Specialized Term 
Definition 
NOAEL 
no-observed-adverse-effect level 
NPC 
nasopharyngeal carcinoma 
NS 
no sample 
NSCLC 
non-small cell lung carcinoma 
NYHA 
New York Heart Association 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed death ligand 1 
PD-L2 
programmed death ligand 2 
PEF 
peak expiratory flow 
PET 
positive emission tomography 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PPS 
per-protocol set 
PR 
partial response 
PT 
prothrombin time 
Q1W 
every 1 week 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
Q9W 
every 9 weeks 
Q12W 
every 12 weeks 
QTcF 
QT interval corrected by Fridericia’s formula 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
RES 
Response Evaluation Criteria in Solid Tumors 
response-evaluable set 
RNA 
ribonucleic acid 
RO 
receptor occupancy 
RP2D 
recommended phase 2 dose 

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Abbreviation or 
Specialized Term 
Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
Scr 
serum creatine 
SD 
study day, stable disease or standard deviation 
SID 
subject identification number 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
terminal half-life 
t1/2z 
terminal elimination half-life 
T4 
thyroxine 
TEAE 
treatment emergent adverse event  
Tmax 
time to observed maximum serum concentration 
Tmin 
total collection time 
TMB 
tumor mutational burden 
TMTB 
total measured tumor burden 
TNF 
tumor necrosis factor 
TNFa 
tumor necrosis factor alpha 
Treg 
regulatory T cells 
TSH 
thyroid stimulating hormone 
TTR 
time to response 
Ucr 
urine creatinine 
ULN 
upper limit of normal 
UPS 
undifferentiated pleomorphic sarcoma 
U.S. 
United States 
Uvol 
urine volume 
Vd 
volume of distribution 
VEGF 
vascular endothelial growth factor 
VL 
viral load 
Vss 
apparent volume of distribution at equilibrium determined after 
intravenous administration 
Vz 
volume of distribution during terminal phase after intravenous 
administration 
WBC 
white blood cell 
WBDC 
web based data capture 
w/v 
Weight per volume 

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1 
INTRODUCTION 
1.1 
Disease Background 
Genetic and epigenetic changes occurring in cancer cells result in tumor-associated antigens 
that can be recognized by the immune system (Pardoll 2012).  To produce immunity against 
tumors, three major steps are important (Mellman, et al., 2011).  First, to initiate the immune 
response, dendritic cells need to encounter antigens, such as protein products of mutated 
genes, from the tumor, and process them.  Second, in lymphoid organs, the dendritic cells 
that are processing the antigens have to generate T-cell responses, such as the production of 
CD8+ effector cells with cytotoxic capabilities.  In addition, the dendritic cells may evoke 
antibody responses, or natural killer (NK) or natural killer T (NKT) cell responses.  Third, 
tumor-specific T cells must enter the tumor environment and attack the tumor.  However, 
tumors have multiple means of evading the immune response.  Among these are that tumors 
may facilitate a local increase in regulatory T cells (Treg) that suppress the activity of 
effector T cells, decrease expression of MHC class I molecules on the surface of tumor cells, 
decrease expression of tumor antigens targeted by the immune system, or express molecules, 
such as programmed death ligand 1 (PD-L1) or programmed death ligand 2 (PD-L2), on their 
surfaces that interact with molecules on the surface of activated T cells.  The latter results in 
T-cell exhaustion or anergy.  Tumors may also produce molecules such as 2,3-dioxygenase 
(IDO) that suppress T cell function.  Myeloid-derived cells entering the tumor may also 
produce molecules that suppress effector T cell function.  Hypoxia may result in production 
of CCL28 that facilitates movement of Treg cells into the tumor.  Tumor stroma cells may 
block proliferation and function of effector T cells and tumor vascular cells may inhibit T 
cell adhesion and thereby interfere with homing of such cells into tumors, partly mediated by 
vascular endothelial growth factor (VEGF) and endothelin-B receptor (ETBR). 
An important mechanism by which tumors thwart immune resistance is through immune 
checkpoint pathways, which normally mediate tolerance and lessen collateral tissue damage.  
Immune checkpoints may be stimulatory or inhibitory (Mellman, et al., 2011, Pardoll 2012, 
Ribas 2012).  The potential T cells targets for immunoregulatory treatments with monoclonal 
antibodies include those that stimulate activating receptors and those that block the action of 
inhibitory receptors.  Activating receptors on the T cell include: HVEM, CD27, CD137, 
GITR, OX40, and CD28.  Inhibitory receptors include: LAG-3, VISTA, BTLA, TIGIT, TIM-
3, PD-1, and CTLA-4.   

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1.2 
Toripalimab Background 
Toripalimab is briefly described below. Refer to the current Toripalimab Investigator’s 
Brochure (IB) for details.  
Toripalimab injection (also known as JS001 and TAB001) is a humanized IgG4K 
(immunoglobulin gamma 4, kappa) monoclonal antibody (mAb) specific for human 
programmed death-1 (PD-1), a co-inhibitory receptor expressed on T cells and is being 
evaluated for the treatment of cancer.  Toripalimab contains serine228 to proline substitution 
to minimize Fab arm exchange. 
As with other anti-PD-1 antibodies, toripalimab has a high affinity and blocks interaction 
between PD-1 and its ligand, PD-L1.  However, toripalimab differs from other such 
antibodies in that the binding to PD-1 is more prolonged, as measured by the dissociation 
coefficient.  Based on the results of nonclinical pharmacology studies performed to date, 
toripalimab binds to human PD-1, and blocks the interaction between PD-1 and its ligands.  
Toripalimab inhibits the inhibitory signaling cascade that is triggered by interactions between 
PD-1 and its ligands.  In primary cell-based assays using cells obtained from healthy donors 
and cancer patients, toripalimab increases T cell proliferation, effector cytokine production, 
and survival following stimulation with a variety of antigens. 
1.3 
Summary of Nonclinical Experience 
Toripalimab binds both human and cynomolgus monkey PD-1 with similar affinity by 
enzyme-linked immunosorbent assay (ELISA) and flow cytometry, but does not bind mouse 
or rat PD-1.  The cynomolgus monkey is thus selected because it is a relevant toxicology 
species.  
Single, 4-week repeat-dose (every 2 weeks over 4 weeks [total of 3 doses]) and 26-week 
pivotal  repeat-dose (every week over 26 weeks [total of 27 doses]) toxicology studies of 
toripalimab was performed in cynomolgus monkeys.   
Following a single intravenous (IV) infusion of toripalimab for 30 minutes at doses up to 203 
mg/kg to male and female cynomolgus monkeys (Smithers Avanza study no. 2352-13085), 
there was no effect on mortality, physical examinations, cageside observations, body 
weights, body weight changes, food consumption, or clinical pathology (clinical chemistry, 
hematology, coagulation, and urinalysis). 
The terminal half-life (t1/2) of toripalimab following the single IV dose was approximately 
108 and 116 hours in male and female monkeys, respectively, dosed with 1 mg/kg and 256 
hours in a female monkey dosed with 203 mg/kg toripalimab.  At Study Day (SD) 28, all 

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animals had antibodies to toripalimab and a confirmatory assay showed antibodies in all 
animals except a high dose female.  The presence of antibodies did not appear to affect the 
serum toripalimab levels as t1/2 was long in all animals. 
The no-observed-adverse-effect level (NOAEL) is 203 mg/kg when administered once via IV 
infusion for 30 minutes to male and female cynomolgus monkeys. 
Following 30 minute IV infusions every 2 weeks (Q2W) over four weeks (total of three 
doses) of toripalimab at doses up to 100 mg/kg to male and female cynomolgus monkeys 
(Smithers Avanza study no. 2352-13086), there was no effect on mortality, physical 
examinations, cageside observations, body weights, body weight changes, food consumption, 
ophthalmic examination findings, electrocardiogram (ECG) evaluations, clinical pathology 
(clinical chemistry, hematology, coagulation, and urinalysis), gross pathology findings, 
absolute and relative organ weights, and histopathology findings.  Serum concentration-time 
profiles of toripalimab were characterized by a bi-phasic decline with time.  The serum 
concentration of toripalimab declined very slowly from serum following dosing, both on SD 
1 and 29.  No gender difference was observed in the rate of decline; however, a dose-
dependent slowing was observed with mostly higher maximum observed concentrations 
(Cmax) values on SD 15 and 29 indicating some accumulation at the higher doses from 
multiple dosing, consistent with higher residual serum concentrations in samples collected 
prior to dosing on SD 15 and SD 29.  Anti-drug antibodies (ADA) were observed in most 1 
and 10 mg/kg monkeys and persisted to the end of recovery while antibodies were only 
observed in 2/10 monkeys at 100 mg/kg and did not persist to recovery.  The NOAEL of 
toripalimab in male and female cynomolgus monkeys is 100 mg/kg when administered via 
30 minute IV infusions Q2W over four weeks (total of three doses). 
Following IV infusions once a week over 26 weeks (total of 27 doses) of toripalimab at doses 
of 10, 30,  and 100 mg/kg to male and female cynomolgus monkeys (InnoStar study no. 
1348RD2), there was no toripalimab-related adverse effects on in-life parameters, ophthalmic 
examination findings, safety pharmacology, clinical pathology (clinical chemistry, 
hematology, coagulation, urinalysis and analysis and fecal occult blood test), immune 
function parameters (immune-phenotype, complements, immunoglobulin and immune 
histological examination of the kidney), hormone analysis, macroscopic and microscopic 
findings. At 100 mg/kg level, the mean Cmax and AUC0-168h following the 26th dosing phase 
were 4.4 mg/mL and 431 mg•h/mL for males, and 5.03 mg/mL and 602 mg•h/mL for 
females, respectively. The dose of 100 mg/kg (every 1 week [Q1W] for 27 doses, mean 
AUC0-168.5h = 525944 μg•h/mL) was considered the NOAEL. The Maximum Recommended 
Safe Dose (MRSD) is considered to be 10 mg/kg (1/10 of NOAEL). The proposed human 
starting dose is 80 mg, about 1 mg/kg given an 80 kg average body weight of a patient, a 

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dose that is 10-fold lower than the MRSD. Furthermore, two FDA approved PD-1 blocking 
mAbs, Pembrolizumab (KEYTRUDA®) and Nivolumab (Opdivo®), were included as a 
positive control and compared with toripalimab in binding affinity assays and cytokine 
release assays. The study results showed none of the three agents induced cytokine release in 
unstimulated and pre-activated human peripheral blood mononuclear cells (PBMCs), 
indicating a possible comparable safety profile.  
1.4 
Summary of Clinical Experience 
As of December 16, 2019, toripalimab has been administered to approximately 1241 subjects 
participating in a total of 27 Phase I-III clinical trials in China. In the United States, 
toripalimab has been administered to 109 subjects in 1 Phase I clinical trial. Refer to Section 
5 of the IB for information on the effect of toripalimab in humans. 
Toripalimab was approved in China on 17 December 2018 for the treatment of patients with 
locally progressive or metastatic melanoma that have progressed after receiving standard 
treatment. The approved dose is 3 mg/kg Q2W. 
This update is based on the currently available pharmacokinetic (PK), efficacy and safety 
data of toripalimab, as well as on the types of adverse drug reactions (ADRs) obtained from 
summarization of safety data. This update covers the latest experience in clinical use of 
toripalimab to support its further clinical development.  
Clinical trials of subjects with advanced solid tumors are ongoing or have been completed in 
China and include those for progressive or metastatic melanoma, mucosal melanoma, gastric 
adenocarcinoma, esophageal squamous carcinoma, nasopharyngeal carcinoma (NPC) and 
head-and-neck squamous cell carcinoma, recurrent refractory malignant lymphoma, NSCLC, 
triple-negative advanced breast cancer,  locally progressive or metastatic urothelial bladder 
carcinoma, advanced renal carcinoma, advanced neuroendocrine neoplasms, and high-risk 
recurrent hepatic carcinoma after radical surgery.   
Several trials are also investigating combination therapy with toripalimab and: GP regimen 
(gemcitabine and cisplatin) in the treatment of advanced NPC; axitinib in subjects with 
advanced renal carcinoma and melanoma who failed standard care; pemetrexed and 
carboplatin for treating advanced or recurrent non-small-cell lung carcinoma. For further 
details see the IB. 
1.4.1 Summary of Safety from Trials Performed in China 
Summary of the safety of monotherapy in Chinese subjects was based on 12 company 
sponsored studies. There were a total of 985 subjects, including melanoma (N=322), 
nasopharyngeal cancer (N=200), urothelial carcinoma (N=160), esophageal squamous cell 
carcinoma (N=65), adenocarcinoma gastric (N=63), squamous cell carcinoma of head and 

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neck (N=34), non-small cell lung cancer (N=33), triple negative breast cancer (N=20), 
malignant lymphoma (N=24), soft tissue sarcoma (N=12), renal carcinoma (N=6), 
neuroendocrine tumor (N=40), pancreatic cancer (N=2) and other types of tumors (N=4). The 
administered doses were: 0.3 mg/kg (N=3), 1 mg/kg (N=39), 3 mg/kg (N=851), 10 mg/kg 
(N=31) and 240 mg (N=61).  
In the 985 subjects, 964 subjects (97.9%) had at least one adverse event (AE), 928 subjects 
(94.2%) had study related AEs (if judged by investigators as positively related, probably 
related, possibly related or possibly unrelated, the causal relationship of the AE/serious 
adverse event [SAE] with the study drug was classified as related). The majority of subjects 
reported AEs of CTCAE grade 1-2. The study drug related AEs with the reporting rate ≥10% 
were anemia, elevated alanine aminotransferase (ALT), elevated aspartate aminotransferase 
(AST), fever, hypothyroidism, weakness, elevated thyroid stimulating hormone (TSH), 
cough, rash, decreased appetite, pruritus, increased blood glucose, decreased white blood cell 
count and urine protein detected. The reporting rate of the AEs leading to termination of 
study drug was 13.6% (134 subjects), and 15.6% (154 subjects) for AEs leading to dose 
interruption of study drug. The reporting rate of Common Terminology Criteria for Adverse 
Events (CTCAE)≥ grade 3 AE was 40.3%; 302 subjects (30.7%) had CTCAE≥ grade 3 AE 
related to the study drug, where the reporting rate ≥1% was seen in anemia, hyponatremia, 
pulmonary infection and abnormal hepatic function. The reporting rate of SAEs was 22.9%; 
161 subjects (16.3%) had study drug related SAEs, where the reporting rate ≥1% was seen in 
pulmonary infection and abnormal hepatic function.  
In the 985 subjects, systematic immune-related adverse events (irAE) adjudication had been 
made in the 741 subjects receiving the recommended therapeutic dose (3 mg/kg or 240 mg) 
(not including CT8, CT14 and CT17). In the 741 subjects, 236 subjects (31.8%) had at least 
one category of irAE, the majority of which were grade 1-2. The most common irAE was 
hypothyroidism that occurred in 13.6% subjects. 1 subject died of interstitial pneumonia. 
Overall, the AEs observed in the pooled safety data were mainly abnormalities in various 
examinations, mostly grade 1-2 in severity, or consistent with the characteristics of 
underlying disease. The irAE profile was consistent with that reported for similar products 
and showed good tolerability. Overall, the AEs were manageable.  
Refer to IB for detailed safety and clinical efficacy data on studies performed in China as 
well as the summary table of ADRs determined by company.  
1.4.2 
Safety Summary of Phase 1 Study in the United States (TAB001-01; 
NCT03474640 ) 
Currently, one phase I study is ongoing for toripalimab in the United States (U.S.) (TAB001-
01: a multicenter, open label, phase I clinical study to evaluate the safety, tolerability and 
pharmacokinetics (PK) of TAB001 in the subjects with advanced malignancies). The study 
includes two parts. Part A, the dose escalation phase, has been completed. A total of three 

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dose groups of 80 mg (3 subjects), 240 mg (8 subjects) and 480 mg (7 subjects) IV Q2W 
were set up, 18 subjects were enrolled, and 1 dose-limiting toxicity (DLT) event (grade 3 
myocarditis) occurred; Part B is the dose extension phase using the therapeutic dose of 
240 mg IV Q3W, 280 subjects are expected to be enrolled. A total of 109 subjects were 
enrolled in Part A and Part B by 16 December 2019.  
The DLT of myocarditis was also an SAE.  A blood test showing elevated troponin T was 
consistent with myocarditis.  The subject had received 2 doses of 480 mg toripalimab, the 
highest dose in the study. Magnetic resonance imaging (MRI) of the heart showed no 
evidence of myocarditis and a heart muscle biopsy did not show inflammation. The event 
was considered to be immune related and possibly related to toripalimab. 
Summary of safety from the phase I study in the U.S. was based on the 109 subjects who had 
received at least one dose of toripalimab. 104 (95.4%) subjects reported at least one AE 
during treatment, and 59 (54.1%) subjects reported AEs that were related to study drug. 56 
(51.4%) subjects reported AEs with CTCAE ≥ grade 3, of which 17 (15.6%) were related to 
the study drug. For 5 (4.6%) subjects, the investigational product was interrupted due to an 
AE. For treatment emergent adverse events (TEAE) reported in ≥10% of subjects, see Table 
1.4.2-1. 

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Table 1.4.2-1: TEAEs Reported in ≥10% of Subjects in Phase I Studies in the United 
States 
Preferred Term (PT) 
Frequency (%) 
Frequency (%) 
All CTCAE grades 
CTCAE ≥ Grade 3 
Subjects reporting at least 1 TEAE (N=109) 
104 (95.4) 
56 (51.4) 
Fatigue 
29 (26.6) 
4 ( 3.7) 
Nausea 
23 (21.1) 
3 ( 2.8) 
Constipation 
20 (18.3) 
2 ( 1.8) 
Anemia 
19 (17.4) 
8 ( 7.4) 
Diarrhea 
19 (19.3) 
0 
Dyspnoea 
18 (16.5) 
5 ( 4.6) 
Abdominal pain 
17 (15.6) 
3 ( 2.8) 
Blood alkaline phosphatase increased 
15 (13.8) 
4 ( 3.7) 
Decreased appetite 
15 (13.8) 
0 
AST increased 
14 (12.8) 
1 ( 0.9) 
ALT increased 
13 (11.9) 
1 ( 0.9) 
Peripheral edema 
13 (11.9) 
0 
Pyrexia 
13 (11.9) 
2 ( 1.8) 
Vomiting 
13 (11.9) 
4 ( 3.7) 
Hyponatremia 
12 (11.0) 
8 ( 7.4) 
Upper respiratory tract infection 
12 (11.0) 
0 
Hypokalaemia 
11 (10.1) 
4 ( 3.7) 
Cough 
11 (10.1) 
1 ( 0.9) 
82 treatment emergent SAEs were reported in 47 (43.1%) subjects of which 9 (8.3%) were 
considered related to the study drug (see Table 1.4.2-2). 5 (4.6%) subjects reported SAEs 
with death outcome. 
 

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Table 1.4.2-2: Treatment Related Serious Adverse Events in a Phase 1 Trial Conducted 
in the United States (N=109) 
System Organ ClassSystem Organ Class 
Preferred Term 
CTCAE All  
Incidence (%) 
CTCAE ³ Grade 3 
Incidence (%) 
Cardiac disorders 
1 (0.9) 
1 (0.9) 
Myocarditis 
1 (0.9) 
1 (0.9) 
Gastrointestinal disorders 
2 (1.8) 
2 (1.8) 
Large intestine preforation 
1 (0.9) 
1 (0.9) 
Vomiting 
1 (0.9) 
1 (0.9) 
General disorders and administration site conditions 
2 (1.8) 
1 (0.9) 
Asthenia 
1 (0.9) 
1 (0.9) 
Pyrexia 
1 (0.9) 
0 
Immune system disorders 
2 (1.8) 
2 (1.8) 
Immune-mediated adverse reaction 
1 (0.9) 
1 (0.9) 
Serum sickness 
1 (0.9) 
1 (0.9) 
Respiratory, thoracic and mediastinal disorders 
1 (0.9) 
0 
Pneumonitis 
1 (0.9) 
0 
Vascular disorders 
1 (0.9) 
1 (0.9) 
Orthostatic hypotension 
1 (0.9) 
1 (0.9) 
The spectrum of AEs for toripalimab, including SAEs, is generally similar to approved drugs 
in the same class without novel safety signals. The incidence of AEs does not appear to be 
dose related. The subjects will be continuously treated and monitored for safety and efficacy 
readouts (duration of response [DoR] and progression free survival[PFS]) until disease 
progression or intolerable toxicity. 
In addition to the specific risks identified in the current toripalimab studies in China and the 
United States, trials of other immune checkpoint inhibitors most frequently report iRAEs of 
the gastrointestinal tract (e.g., colitis), endocrine glands (e.g., autoimmune thyroid and 
adrenal disease), hypophysitis, skin, and liver (e.g., autoimmune hepatitis) (Postow, et al., 
2018).  To a lesser extent,  iRAEs involve the central nervous system (e.g., aseptic 
meningitis, transverse myelitis) and cardiovascular (e.g., myocarditis), pulmonary (e.g., 
pneumonitis), musculoskeletal (e.g., myositis and myasthenia gravis), and hematologic 
systems are involved (Postow, et al., 2018; Spain, et al., 2019). Because of the number of 
systems that may be involved, it is important to maintain a high index of suspicion for iRAEs 
and to refer subjects to the relevant specialists, such as a pulmonologist, cardiologist, 
endocrinologist, dermatologist, or rheumatologist. 
 

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Refer to IB for detailed safety data from the TAB001-01 study performed in the U.S.  
1.4.3 Summary of Pharmacokinetic Analyses 
A pooled PK analysis was performed by pooling the sample data of toripalimab in various 
dose groups (doses 0.3-10 mg/kg, as well as a fixed dose of 240 mg, Q2W) in three phase I 
dose- escalation clinical studies (CT1, CT2 and CT3). See Table 1.4.3-1 for the detailed 
parameters. The study results showed that after IV infusion of 1, 3 and 10 mg/kg to the 
clinical subjects, toripalimab basically presented linear PK characteristics and that after the 
dose increased to 10 mg/kg, the drug presented certain non-linear PK characteristics. 
The study results revealed that toripalimab showed an obvious "long-acting" characteristic 
of antibody drugs, with the plasma drug concentrations basically reaching a steady state after 
about 3 to 4 consecutive IV infusions of toripalimab to the clinical subjects, with mean half-
life of 222.98±61.92 hours (9.29±2.58 days), Cmax of 77.17±47.3 μg/mL, and AUC(0-t) of 
11635.89±7204.64, respectively, after multiple administrations in the 3 mg/kg group (n=37). 
Table 1.4.3-1: Summary of PK Parameters after Multiple Intravenous Infusions of 
Toripalimab 
PK 
Parameters 
 
 
 
 
 
Toripalimab 
 
 
 
 
 
Units 
0.3 mg/kg 
 
1 mg/kg 
3 mg/kg
 
10 mg/kg 
 
240 mg / 
subject 
Kel 
1/hr 
0.004±0.000 
n=2 
0.003 
±0.001 
n=14 
0.002 
±0.001 
n=27 
0.002 
±0.001 
n=10 
0.001 
n=1 
t1/2 
hr 
188.322 
±4.934 
n=2 
242.52 
±42.69 
n=14 
302.91 
±88.48 
n=27 
430.3 
±193.82 
n=10 
525.106 
n=1 
Tmax 
hr 
0-2 
n=2 
2 
(0.5, 12) 
n=14 
2 (0.5, 24) 
n=27 
2 (0, 24) 
n=10 
0 
n=1 
Cmax 
μg/mL 
6.577 
±2.193 
n=2 
30.42 
±11.03 
n=14 
93.31 
±30.55 
n=27 
305.97 
±97.01 
n=10 
152.628 
n=1 
AUC(0-t) 
hr*μg/mL 
1099.367 
±448.421 
n=2 
4538.23 
±1541.22 
n=14 
18180.89 
±6101.07 
n=27 
62833.57 
±24694.62 
n=10 
34212.001 
n=1 
AUC(0-inf) 
hr*μg/mL 
1583.594 
±717.532 
n=2 
7895.14 
±2051.06 
n=14 
34529.42 
±12671.64 
n=27 
157946.58 
±81099.1 
n=10 
95199.868 
n=1 
AUC(t-inf)% 
% 
29.785 
±3.498 
n=2 
37.87 
±6.88 
n=14 
46.09±9.07 
n=27 
54.72 
±13.45 
n=10 
64.063 
n=1 
Vd 
mL/kg 
57.017 
±24.486 
n=2 
66.58 
±18.73 
n=14 
54.1 
±27.26 
n=27 
69.64 
±54.5 6 
n=10 
1909.836 
n=1 
CL 
mL/hr/kg 
0.211 
±0.096 
n=2 
0.19 
±0.05 
n=14 
0.13 
±0.06 
n=27 
0.12 
±0.08 
n=10 
2.521 
n=1 
MRTinf 
hr 
264.836 
±11.921 
n=2 
341.12 
±58.95 
n=14 
435.8 
±125.05 
n=27 
609.1 
±259.74 
n=10 
755.415 
n=1 
Kel = elimination rate constant from the central compartment; t1/2 = terminal half-life; Tmax = time to observed maximum serum 
concentration; Cmax = maximum observed concentration; AUC(0-t) = area under the curve (AUC) to time of last measurable 
concentration; AUC(0-inf) = AUC to time infinity; AUC(t-inf)% = percentage of AUC(t-inf) of AUC(0-inf); vd = volume of distribution; CL 
= clearance; MRTinf = mean residence time extrapolated to infinity 
The minimum steady-state plasma concentration was about 20~40 μg/ml when toripalimab 
was administered IV at 3 mg/kg Q2W. In vitro experiments demonstrated that when the 

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plasma concentration of toripalimab was >20 nM or 3 μg/ml, PD-1 receptors on the surface 
of T-cells could be saturated, and that given the limitation of the antibody’s macromolecules 
to enter the tumor microenvironment, the concentration of toripalimab in the peripheral blood 
was maintained at 20 μg/ml in order to ensure complete occupancy of lymphocyte PD- 1 in 
the tumor microenvironment. All Phase I studies showed that complete occupancy of PD-1 
receptors could be maintained during the whole course of treatment in different dosage 
groups (0.3, 1, 3 and 10 mg/kg Q2W). The results of PK studies mentioned above and the 
resulting receptor occupancy (RO) data supported 3 mg/kg IV Q2W to be selected as the 
dose for the CT4 phase II key study (see Section 5.4 of the IB detailed information about the 
safety and efficacy of toripalimab). Two early studies explored a fixed dose of 240 mg IV 
every 3 weeks (Q3W). Of these two studies, a preliminary PK study involving 14 subjects 
revealed the peak steady-state plasma concentration and minimum steady-state plasma 
concentration at the dose of 240 mg Q3W (85 µg/mL and 21 µg/mL, respectively) are similar 
with those of 3 mg/kg Q2W (77 µg/mL and 25 µg/mL), which showed similar drug exposure 
and steady concentration and sufficient PD-1 RO. Those above results of toripalimab’s 
PK/RO and Phase II key studies about melanoma, support the fixed dose of toripalimab 240 
mg IV Q3W to be used as the recommended dose in Part B of this study and in Phase III 
clinical studies. 
1.4.4 Immunogenicity of toripalimab 
Use of any recombinant protein is associated with potential induction of local and systemic 
immune responses. Additional tests, for example, autoimmune serology or biopsies, should 
be used to monitor the production of ADA carefully to determine the probability of possible 
immunogenicity and the effect on subjects.  
As of 1 May 2018, the pooled analysis on 518 subjects had shown the observation of ADA in 
subjects at the dose of 0.3-10 mg/kg and individual ADA positive rate of 15.4% in the 
subjects. The ADA positive rate observed was 18% in the 128 subjects with melanoma who 
received 3 mg/kg toripalimab injection. In accordance with PK and exposure-effect analysis, 
currently no evidence of loss of efficacy, change in the toxicity profile, or change in the PK 
profile was observed in the presence of ADA. No difference was observed in the efficacy and 
safety profile between the subjects with positive and negative ADA test results.  
Based on the guideline for immunogenicity released by the U.S. FDA in January 2019, the 
serum matrix before administration from the subjects in the two phase II registration clinical 
studies for nasopharyngeal carcinoma (CT-5) and urothelial carcinoma (CT-12) and the 
blank matrix in humans constructed by the previous ADA test to validate the ADA positive 
threshold using analytical procedure were statistically analyzed in September 2019. The 
results showed a statistically significant difference in the response value between the two 
populations, thus the ADA positive threshold was reset for the serum matrix from the tested 

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subjects prior to administration in October 2019, and all the tested samples for relevant items 
were analyzed.  
As of March 2020, in accordance with the new method for setting the ADA threshold, the 
ADA positivity rate observed in 190 subjects with nasopharyngeal carcinoma who received 3 
mg/kg toripalimab injection was 3.7% and the ADA positivity rate was 6.6% in 151 subjects 
with urothelial carcinoma. The pooled analysis showed an ADA positivity rate of 5.0% in the 
341 subjects with nasopharyngeal carcinoma and urothelial carcinoma who received 3 mg/kg 
toripalimab injection. Currently, from the PK and exposure-effect analysis, no evidence of 
loss of efficacy, change in toxicity profile or change in the PK profile was observed in the 
presence of ADA, and no difference was observed in the efficacy and safety between the 
subjects with positive and negative ADA test results.  
A neutralizing antibody (NAb) assay is currently being developed to evaluate the neutralizing 
activity of ADA positive samples. 
1.4.5 Pharmacodynamics study of toripalimab in NCT03316144 
The pharmacodynamic effect of toripalimab was evaluated by PD-1 RO on the target cell over 
the course of treatment using the flow cytometry analysis. Toripalimab bound to the target 
molecule PD-1 on activated T lymphocytes (CD3+ CD45RA-) with full occupancy in all 
subjects from three cohorts after the initial dose. The full RO (>80% RO) was maintained in 
all subjects throughout the study period of 84 days. 
1.5 
Rationale for the current Study 
A brief summary of the rationale for targeting PD-1 in oncology is provided below.  For a 
more comprehensive review of toripalimab pharmacology, PK, and toxicology data, please 
refer to the toripalimab IB. 
Blockade of the interaction between PD-1/PD-L1 has been demonstrated in non-clinical and 
clinical studies to enhance specific responses against tumors.  In murine studies of 
melanoma, breast, ovarian, lung, liver, pancreatic and colon cancers, blockade of PD-1/PD-
L1 reduced tumor burden and improved survival (Blank, et al., 2004; Curiel, et al., 2004; 
Hirano, et al., 2005).  In humans, such blockade enhanced T cell responses against melanoma 
and leukemia (Fourcade, et al., 2010; Norde, et al., 2011).  A number of clinical trials have 
demonstrated that monoclonal anti-PD-1 antibodies show evidence of efficacy and adequate 
safety in melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and 
mismatch repair deficient tumors, including colorectal cancer (Ansell, et al., 2015; Asaoka, et 
al., 2015; Berger, et al., 2008; Borghaei, et al., 2015; Brahmer, et al., 2010; Brahmer, et al., 
2015; Le, et al., 2015; Garon, et al., 2015; Hamid, et al., 2013; Larkin, et al., 2015; Motzer, et 

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al., 2015; Nghiem, et al., 2016; Robert, et al., 2015; Topalian, et al., 2012; Wolchok, et al., 
2013).   
While toripalimab has a high affinity and blocks interaction between PD-1 and its ligand, 
PD-L1, it differs from other such antibodies by demonstrating more prolonged binding to 
PD-1 (Refer to the IB for more details).  This raises the possibility of prolonged action of the 
drug in the tissues.  
1.6 
Rationale for Tumor Selection 
Blockade of PD-1 pathway by mAbs has been demonstrated in non-clinical and clinical 
studies to enhance specific T cell responses against a broad spectrum of human malignancies. 
Solid tumors have thus been selected for this dose-escalation study on the basis of unmet 
medical need. Selected cancer patients, including but not limited to advanced gastric cancer 
(GC), esophageal cancer (EC), cholangiocarcinoma, hepatocellular cancer (HCC), sarcomas, 
both chondrosarcoma  and soft tissue sarcoma (excluding leiomyosarcoma and including 
angiosarcoma, undifferentiated pleomorphic sarcoma and alveolar soft part sarcoma), 
neuroendocrine tumors (NETs) (excluding lung derived NET), NPC, or with the agreement 
of the Sponsor, other tumors will be enrolled for the expansion phase of the study, because of 
unmet medical need and evidence supporting the potential benefits to anti-PD-1 treatment. 
Patients with GC, EC, or gastroesophageal junction cancer (GEC) often present with 
advanced and metastatic stage disease, which has poor prognosis, limited treatment options 
and represent an important unmet medical need. 
Preliminary data from the phase I/II open-label study NCT01928394 for patients with 
GC/GEC receiving nivolumab monotherapy revealed an objective response rate of 12% (n = 
7/58; 1 CR, 6 PR) and 12 patients (21%) with SD  demonstrating antitumor activity in these 
disease settings. (http://meetinglibrary.asco.org/content/160127-173).  Subsequent 
publication of the trial results confirmed the response rate: “Of 160 treated patients (59 with 
nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior 
therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% 
confidence interval [CI], 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 
19%) in the three groups, respectively” (Jainjigian YY, et al., 2019).  Since toripalimab 
differs from other such antibodies in that the binding to PD-1 is more prolonged, as measured 
by the dissociation coefficient, GC/GEC continues to be investigated to gather more 
experience in the U.S. and is planned in Europe. 

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NETs are heterogeneous and show diverse biologic and clinical behaviors, reflect primary 
tumor origin, type of neuroendocrine cell, and pathologic features (Kim, et al., 2016). NETs 
in the GI tract appear to be associated with different anatomical distributions in Western 
versus Eastern populations of the world. Most commonly NETs in the GI tract in the U.S. 
involve small intestine (38%), followed by the rectum (34%), colon (16%), stomach (11%), 
and unknown sites (1%). The average annual incidence of GI NETs in the U.S. is 2.5 cases 
per 100 000 per year, and an apparent recent increase in incidence may reflect increased 
identification of gastric and rectal NET cases. In Korea, the rectum (48%) is the most 
common location of GI tract NETs, followed by stomach (15%), pancreas (9%), colon (8%), 
small intestine (8%), liver (7%), appendix (3%), and biliary tract (2%). Everolimus, 
mammalian target of rapamycin (mTOR) inhibitor, and sunitinib, a multiple receptor tyrosine 
kinase (RTK) inhibitor were approved for treatment of advanced, progressive, well-
differentiated pNETs in 2011 (Liu, et al., 2016). In 2016. for everolimus, the indication  was 
expanded to encompass advanced, well-differentiated, non-functional gastrointestinal and 
lung NETs. Ongoing trials for NETs continue to investigate the clinical activity and 
therapeutic potential of other drugs, including other RTK and mTOR pathway inhibitors, and 
immune checkpoint inhibitors. Evidence from several clinical trials suggests some response 
to anti-PD-1 monotherapy in terms of Karnofsky Functional Status (KFS) scores and stable 
disease, and a number of trials are investigating combination therapies (Chauhan, et al., 
2017). A trial of toripalimab (Title: A Trial of JS001 in Patients with Advanced 
Neuroendocrine Tumors; ClinicalTrials.gov Identifier: NCT03167853) enrolled 
chemotherapy refractory NET patients in China (Lu M, et al., 2020). Of 40 patients, 8 partial 
responses and 6 with stable disease were observed with a 20% objective response rate (ORR) 
and a 35% disease control rate (DCR). The median DOR was 15.2 months. Patients with PD-
L1 expression (≥10%) or high tumor mutational burden (TMB) had better ORR than PD-L1 
<10% (50.0% vs. 10.7%, P ¼ 0.019) and TMB-low patients (75.0% vs. 16.1%, P ¼ 0.03). 
Three of 8 (37.5%) responders had ARID1A mutations, whereas only 1 of 27 nonresponders 
had mutations (P ¼ 0.03). Notably, 1 exceptional responder with TMB-L, microsatellite 
stable (MSS), and PD-L1–negative had multiple genomic arrangements with high prediction 
score for neoantigens. The authors concluded that toripalimab showed antitumor activity and 
had acceptable safety in treating recurrent or metastatic NETs. Patients with positive PD-L1 
expression, TMB-H (top 10%), and/or microsatellite instability (MSI-H) might preferentially 
benefit from the treatment. The genomic mutation of ARID1A and high genomic 
rearrangements might be correlated with clinical benefit. 
Based on some evidence of response to anti-PD-1 monotherapy, the results of the clinical 
trial in China and differences in the spectrum of disease in Asia versus the U.S., and the 
sparsity of data for the treatment of NETs further investigation is planned with toripalimab.  

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Hepatobiliary malignancies represent 13% of cancers worldwide, and 3% of cancer mortality 
in the United States. Cholangiocarcinoma is the second most common primary hepatic cancer 
and the most frequent among biliary tract cancers and has a very poor prognosis (Blechacz, 
2017).  Only surgery appears to have the potential curative outcomes, but the disease tends to 
be diagnosed late, and recurrences are frequent after resection.  Liver transplantation alone is 
not recommended because of high recurrence rates and 20% survival rate, but neoadjuvant 
radiation and chemotherapy decreases recurrence rates and increases 5 year survival.  While 
cholangiocarcinoma has tended to be considered resistant to chemotherapy, the addition of 
cisplatin and erlotinib to gemcitabine therapy has been associated with better responses.  
Immune checkpoint inhibitors are being investigated as treatments for cholangiocarcinoma, 
and pembrolizumab has been approved for all refractory mismatch repair (MMR)–deficient 
cancers, including cholangiocarcinoma (Le, et al., 2017).  In the KEYNOTE 028 study, 
cholangiocarcinomas showed a 17% response rate with a median response duration of 40 
weeks.  While there is a high unmet medical need for treatments for cholangiocarcinoma, 
data on immune checkpoint inhibitors for this disease are still sparse, and further 
investigations are warranted to clarify the role of anti-PD-1 therapy.   
HCC is a major health problem and worldwide is the second leading cause of cancer-related 
death.  Immunotherapy seems suitable as a possible treatment for HCC since it is seen in the 
setting of chronic hepatic inflammation, such as in individuals infected with hepatitis B or C 
and those with non-alcoholic fatty liver disease (Brown, et al., 2017). This inflammation 
encourages oncogenesis and often results in immunogenic lesions. Specific gene mutations 
result in the expression of tumor-associated antigens and neo-antigens which become targets 
for the immune system.  Several clinical trials showed that immune checkpoint inhibitors 
have promise in the treatment of HCC. Adverse events from checkpoint inhibitors are 
associated with induction of autoimmunity, including hepatitis and transaminitis. Although 
patients with HCC treated with immune checkpoint inhibitors show increased AST/ALT in 
comparison with melanoma and NSCLC patients, a safety study by Brown, et al., found that 
this was not associated with patients discontinuing therapy or deaths attributed to drug 
toxicity.  
Patients with unresectable, recurrent, and/or metastatic high grade soft-tissue sarcoma and 
chondrosarcoma who progress after systemic therapy have limited treatment options. In the 
phase II open-label study NCT02301039, sarcoma patients received pembrolizumab after 
failure of prior systemic therapy (Tawbi, et al., 2017).  In this 86-patient single-arm study, 
there were two cohorts, soft-tissue sarcoma or bone sarcoma.  In each cohort, pembrolizumab 
which is a mAb to target PD-1 was received by 42 patients of whom 40 were evaluable. 
Median follow-up was 17·8 months (IQR 12·3-19·3). Of 40 patients with soft-tissue 
sarcoma, 7 (18%) showed an OR, including 4 (40%) of 10 patients with undifferentiated 

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pleomorphic sarcoma, 2 (20%) of 10 patients with liposarcoma, and 1 (10%) of 10 patients 
with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an OR. Of 40 patients 
with bone sarcoma, 2 (5%) had an OR, including 1 (5%) of 22 patients with osteosarcoma 
and 1 (20%) of 5 patients with chondrosarcoma. Of 13 patients with Ewing's sarcoma, none 
had an OR. The authors concluded that while the primary endpoint of overall response was 
not met for either cohort, pembrolizumab appeared to show activity in patients with 
undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.  In addition, as seen 
for leiomyosarcoma in the above study by Tawbi, et al., in a phase 2, single center, single 
agent study of 12 patients, nivolumab which is a human immunoglobulin G4 (IgG4) 
monoclonal antibody to target PD-1 did not demonstrate benefit in a cohort of previously 
treated advanced uterine leiomyosarcoma patients (Ben-Ami, et al., 2017).  
As of May 2020, in the current TAB001-01 study, responses for `undifferentiated 
pleomorphic sarcomas and to a greater extent angiosarcoma have been encouraging.  Of 6 
subjects with angiosarcoma, 5 were evaluable, and the best responses for 3 of those subjects 
were partial response (PR) (60%).  Four subjects with undifferentiated pleomorphic sarcoma 
were evaluable and 1 had an initial PR (25%) and was still in follow up.  Angiosarcoma is 
rare, accounts for less than 2% of all soft tissue sarcomas, and mainly affects adult and 
elderly patients (Cao J, et al., 2019). It is an aggressive malignant tumor that arises from 
lymphatic or vascular endothelial cells. Angiosarcomas most frequently occur as cutaneous 
lesions (about 60% of cases), particularly the head and neck, may present within the soft 
tissues, visceral organs, bone and retroperitoneum. Angiosarcoma has a high rate of local 
recurrence and metastasis. Advanced/metastatic disease at presentation occurs in 16 to 44% 
of patients, and overall survival (OS) ranges from 6 to 16 months.  Risk factors include 
chronic lymphoedema, history of radiation, environmental carcinogens and certain familial 
syndromes. Conventional options of treatment include surgery, radiotherapy and 
chemotherapy. Targeted therapeutic agents and immunotherapy have been studied as 
promising treatments of angiosarcoma. 
A Phase 1 clinical trial of toripalimab conducted in China, included 12 patients with chemo-
refractory advanced alveolar soft part sarcoma (ASPS) and responses were promising (Yang, 
et al., 2020).  Of these patients, 1 showed a complete response (CR), 2 showed PRs, and 8 
showed SD.  The ORR was 25.0% (3/12) and the DCR was 91.7% (11/12). The responses 
were durable, as the median progression free survival (PFS) and the median overall survival 
(OS) were 11.1 month and 34.7 month, respectively. Alveolar soft part sarcoma is rare 
(Jaber, et al., 2015).  Mostly it arises in lower limb soft tissues in adults and in children in the 
head and neck region. Usually it presents as a slowly growing mass or as metastatic disease. 
ASPS is a rare neoplasm, about 0.2% to 0.9% of all soft tissue sarcomas occurring mostly in 
those between ages 15 to 35 years; it is rare in patients less than 5 years of age those older 

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than 50 years. Females are more frequently affected than males with a 2:1 ratio in the first 3 
decades of life but after that a slight male predominance is seen (Jaber, et al., 2015). 
ASPS has a high frequency of metastasis that may occur before the primary tumor is noted 
(Jaber, et al., 2015). In 20% to 30% of patients the tumor recurs locally. Prognosis depends 
on whether the initial presentation is localized or metastatic, as well as age and tumor size. 
The 5-year survival rate for localized disease at presentation is 71%, compared with 20% for 
patients with metastatic disease at time of diagnosis. Large tumors are most likely to be 
associated with metastasis at the time of diagnosis. 
Given the safety profile of toripalimab is similar to that of other anti-PD-1 monoclonal 
antibodies, the responses seen for angiosarcoma and undifferentiated pleomorphic sarcomas 
in the current trial and the promising results of another toripalimab clinical trial showing a 
high response rate for subjects with ASPS, the sarcoma cohort was expanded to enroll an 
additional 40 subjects focusing on these sarcoma subtypes.  In addition, there is a high unmet 
medical need for treatments of these rare tumors.  
Patients with unresectable and/or recurrent NPC who progress after radiation therapy have 
limited treatment options and represent an important unmet medical need. NPC patients have 
been reported to have a high percentage of PD-L1 expression (>60%) by multiple studies, 
indicating potential implication of PD-1 blockade in treating these patients (Zhang, et al., 
2015; Chang, et al., 2017; Zhang, et al., 2008).  
As a result, patients with GC, EC, cholangiocarcinoma, NETs (excluding lung derived NET), 
sarcomas, both chondrosarcoma and soft tissue sarcoma (excluding leiomyosarcoma and 
including angiosarcoma, undifferentiated pleomorphic sarcoma and ASPS), HCC, and NPC, 
as well as other indications where PD-1 is thought to play a role in tumor immune evasion, 
may be enrolled in this toripalimab clinical trial. 
1.7 
Rationale for Dose 
The rationale for the proposed Phase 1 starting dose has taken into account all relevant 
preclinical pharmacology and toxicology data, including calculated and experimentally 
measured receptor occupancy, dose-response in human cell-based assays, and 
pharmacodynamic evaluations conducted in conjunction with the toxicology studies, as well 
as the safety profiles and Food and Drug Administration (FDA) approved clinical dose of 
similar drugs targeting the same molecule.  
As a starting point, the guidelines presented in the FDA Guidance for Industry Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers were used.  The NOAEL determined in the Good Laboratory Practice (GLP)-

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compliant repeat-dose toxicology study in cynomolgus monkeys was 100 mg/kg (the highest 
dose level tested).  Toripalimab is not pharmacologically active in rodent species and 
therefore rodent toxicology studies were not performed.  Since toripalimab is a protein 
administered IV with a molecular weight > 100 kDa, mg/kg scaling was used, and the 
human-equivalent dose (HED) was determined to be 100 mg/kg.  A default safety factor of 
10 is appropriate, as there are no considerations indicating a safety concern that warrants 
increasing the safety factor.  Based on this analysis, the MRSD is considered to be 10 mg/kg 
(1/10 of NOAEL). The proposed human starting dose is 80 mg, about 1 mg/kg given an 
average patient weight of 80 kg, a dose that is 10-fold lower than the MRSD.  
Furthermore, commercially purchased Pembrolizumab (KEYTRUDA®) and Nivolumab 
(Opdivo®) had been included as positive controls and compared with toripalimab in binding 
affinity assays and in vitro cytokine release assays. The study results showed none of the 
three agents induced cytokine release in unstimulated and pre-activated human PBMCs, 
indicating a possible comparable safety profile.  
Based on literature reports and data obtained from other anti-PD-1 products, there is no clear 
relationship between body size and PK or efficacy/safety at the therapeutic dose. Given the 
clinical experience, the proposed starting dose of 80 mg, about 1 mg/kg, would not pose 
unreasonable risk on patients. We therefore propose a flat starting dose of 80 mg in this 
study.   
Toripalimab has been administered to humans in 26 trials in China and 1 trial (TAB001-01) 
in the United States as of Dec 2019. One phase I study (NCT03316144) conducted at 
Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science, 
was a 3+3 dose-escalation study treating Malignant Lymphoma. The dose-escalation cohorts 
are 1, 3 and 10 mg/kg biweekly (Q2W) via IV infusion. Any dose-escalation cohort that did 
not exceeded the MTD could be expanded up to a maximum of 3 subjects at each dose level 
for further evaluation of safety, PK, pharmacodynamics, and efficacy. The first subject was 
enrolled on 5 Sep 2017 and last subject enrolled on 2 Dec 2017.  The study has enrolled a 
total of 13 subjects, 4 subjects in the 1 mg/kg cohort, 3 subjects in the 3 mg/kg cohort and 6 
subjects in the 10 mg/kg cohort.  See Section 1.4 for details regarding study NCT03316144. 
From the Phase I toripalimab dose escalation study (NCT03316144), toripalimab was well 
tolerated in up to 10 mg/kg Q2W. No DLT or death has occurred. 100% of subjects had 
TEAEs, but the majority of AEs were of Grade 1 or 2. The spectrum of AEs is similar to 
approved drugs in the same class without novel safety signals. The observed serum half-life 
of toripalimab was 16.4 to 18.1 days after five consecutive Q2W doses of 1, 3, or 10 mg/kg. 
1 out of 13 subjects had an ADA positive sample(s) identified after dosing. The trough 
concentration of toripalimab after 6 doses were 10.08±5.69, 40.09±26.95 and 209.24±23.73 

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ug/mL for 1, 3 and 10 mg/kg cohorts respectively. Previous in vitro study has shown that the 
saturation binding and blocking effect on PD-1 was achieved when toripalimab concentration 
was no less than 2.9 µg/mL (See IB, page 30 for details). Consistent with the in vitro 
blocking study, toripalimab bound to the target molecule PD-1 on PBMC with full 
occupancy in all subjects from three cohorts after the initial dose. The full receptor 
occupancy (>80% RO) was maintained in all subjects throughout the study period of 84 days, 
indicating the PD-1 receptor was fully saturated in three dose cohorts.  
Additionally, objective clinical response was observed in all three cohorts. The incidence of 
AEs or clinical response does not appear to be dose related.  Given the favorable safety and 
efficacy profile of the Phase I toripalimab study NCT03316144 and observed long half-life 
of toripalimab, upon the completion of the current dose escalation study (TAB001-01) at 80 
mg, 240 mg and 480 mg fixed dose Q2W, we plan to explore the intermediate dose of 240 
mg Q3W in the expansion phase for further safety and efficacy evaluation. 
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objectives 
• Dose-escalation phase: To assess the safety and tolerability of multiple doses of 
toripalimab and define the MTD or the maximum feasible dose (MFD) (highest protocol-
defined dose of toripalimab in the absence of exceeding the MTD) in subjects with 
advanced malignancies. 
• Dose-expansion phase: To further characterize the safety profile of toripalimab in 
subjects with selected advanced malignancies, and to evaluate the recommended Phase 2 
Dose (RP2D). 
2.1.2 
Secondary Objectives 
• To describe the PK profile of toripalimab  
• To evaluate antitumor activity of toripalimab  
• To determine the immunogenicity of toripalimab 
• To evaluate OS 
2.1.3 
 
 
 

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3 
STUDY DESIGN 
3.1 
Description of the Study 
3.1.1 Overview
 
This Phase 1, open-label, 2-part (Part A = dose-escalation, Part B = dose-expansion) study to 
evaluate the safety, tolerability, PK, immunogenicity, and antitumor activity of toripalimab 
administered IV on a Q2W (Part A) or Q3W (Part B) dosing schedule in adult subjects with 
advanced solid malignancies that are refractory to standard therapy or for which no standard 
therapy exists.  In Part A, a cycle is 28 days (4 weeks) which includes toripalimab being 
administered IV Q2W. In Part B, a cycle is 42 days (6 weeks) which includes toripalimab 
being administered IV Q3W. 
3.1.2 Part A – Dose Escalation 
Part A will use a 3+3 design and will enroll cohorts of 3-6 subjects sequentially at escalating 
doses of 80 mg, 240 mg and 480 mg.  Subjects will receive their assigned dose Q2W (± 2 
days) in the absence of confirmed progressive disease, unacceptable toxicity, withdrawal of 
consent, intercurrent illness preventing further administration of toripalimab, or the 
investigator considers it in the best interest of a subject to discontinue study treatment. A 
protocol amendment will be submitted to the FDA if there are any changes in dose levels and 
dosing frequency. 
Dose escalation will continue up to a flat dose of 480 mg or until identification of a MTD or 
the MFD. Up to a total of 18 immunotherapy-naïve subjects (no prior exposure to 
immunotherapy such as but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 
antibodies excluding vaccines) may be enrolled in Part A.   
3.1.3 Part B – Dose Expansion 
In Part B, up to 280 subjects with solid tumors including but not limited to esophageal or 
gastric carcinoma, cholangiocarcinoma, NETs (excluding lung derived NET), sarcomas, both 
chondrosarcoma and soft tissue sarcoma (excluding leiomyosarcoma and including 
angiosarcoma, undifferentiated pleomorphic sarcoma and ASPS), or with agreement of the 
Sponsor, other tumors, including NPC and HCC, that have been treated with at least one line 
of therapy in the metastatic setting will be enrolled. Patients with microsatellite instability-
high (MSI-H)/ mismatch repair deficient (dMMR) tumors are eligible to enroll. 
The dose(s) to be evaluated in Part B will be 240 mg administered IV Q3W after review of 
safety, PK and pharmacodynamic data from subjects treated with TAB001. A maximum of 
40 subjects can be enrolled in each cohort with the exception of the sarcoma cohort, in which 

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a maximum of 80 subjects can be enrolled.  Enrollment will consist of solid tumors that may 
include but will not be limited to esophageal and gastric carcinoma, cholangiocarcinoma, 
NETs (excluding lung derived NET), sarcomas, both chondrosarcoma and soft tissue 
sarcoma (excluding leiomyosarcoma and including angiosarcoma, undifferentiated 
pleomorphic sarcoma and ASPS), or with agreement of the Sponsor, other tumors, including 
NPC and HCC, that have been treated with at least one line of therapy in the metastatic 
setting. After 40 subjects have been enrolled in the sarcoma cohort, a further 40 subjects will 
be enrolled and will be limited to angiosarcoma, undifferentiated pleomorphic sarcoma and 
alveolar soft part sarcoma. Patients with MSI-H/dMMR tumors are eligible to enroll. 
Subjects will receive their assigned dose IV Q3W until confirmed disease progression, 
unacceptable toxicity, withdrawal of consent, intercurrent illness preventing further 
administration of toripalimab, or the investigator considers it in the best interest of a subject 
to discontinue study therapy. 
3.1.4 Treatment Regimen 
All subjects will be evaluated regularly, and their clinical status classified according to 
RECIST v1.1 and irRECIST (http://www.irrecist.com/).  If feasible, all subjects will be 
followed for PFS and OS (Part B only) until the end of the study, defined as the date of the 
last protocol-specified visit/assessment (including telephone contact), or the date the study is 
closed by the sponsor, whichever comes first. AEs and SAEs will be followed from the start 
of the first dose of toripalimab through 90 days after the last dose of toripalimab. For subjects 
who receive another experimental or anticancer therapy, only related AE/SAEs will be 
collected through 90 days after the last dose of study drug. 
In Part A, radiological assessment of tumor response status must be performed approximately 
every 8 weeks (± 10 days) for the first 12 months and approximately every 12 weeks (± 10 
days) thereafter, unless the Investigator determines it is more appropriate to continue the 
radiological assessments on an approximately 8 week frequency. 
In Part B, radiological assessment of tumor response status must be performed approximately 
every 9 weeks (± 10 days) for the first 12 months and approximately every 18 weeks (± 10 
days) thereafter, unless the Investigator determines it is more appropriate to continue the 
radiological assessments on an approximately 9 week frequency. 
Subjects will be monitored for safety, PK, anti-toripalimab antibodies and clinical activity as 
outlined in Section 4.2.  Serum samples will be collected to screen for changes in markers of 
immune response and determine whether changes in serum markers are predictive of 
response and/or reflective of pharmacodynamic response.  In Part A, fresh pre-treatment 
biopsies will be requested from subjects with safely accessible lesions.  For subjects who 

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cannot provide a fresh pre-treatment biopsy, an archival specimen will be required.  In Part 
B, fresh pre-treatment biopsies will be required from all subjects with safely accessible 
lesions.  Archival specimens will be requested. Biopsies results from materials specifically 
obtained for the study will not affect eligibility.  However, the biopsy report upon which the 
diagnosis was based should be in the subject’s medical record. 
The study will be conducted at up to 30 centers in the U.S.. 
3.1.5 Treatment Regimen 
Subjects will be treated in either Part A or Part B of the study.  Subjects will receive 
toripalimab IV Q2W (Part A) or Q3W (Part B) until confirmed disease progression, 
unacceptable toxicity, withdrawal of consent, intercurrent illness preventing further 
administration of toripalimab, or the investigator considers it in the best interest of a subject 
to discontinue study therapy. 
Toripalimab will be administered IV over a minimum of 60 minutes.  In subsequent cycles, 
the infusion time may be reduced to a minimum of 30 minutes depending upon subject 
tolerance.  The infusion duration may be increased at any time at the discretion of the 
investigator. 
Refer to Section 4.8 for a description of toripalimab dose calculation, preparation, and 
administration. 
Toripalimab may be administered in the setting of progressive disease (PD) as long as all of 
the following criteria are met: 
• Absence of clinical symptoms or signs indicating clinically significant disease 
progression 
• No decline in Eastern Cooperative Oncology Group (ECOG) performance status from 
baseline 
• Absence of rapid disease progression or threat to vital organs or critical anatomical sites 
(e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention; no significant, 
unacceptable or irreversible toxicities related to study treatment.  
These subjects would continue on to the next regulatory scheduled visit and thereafter as per 
the Schedule of Evaluations.  However, a repeat scan to assess for true disease progression in 
4 weeks ± 2 days in Part A and in 6 weeks ± 2 days in Part B is required. It is also required 
that any subject with pending organ compromise be discontinued from the toripalimab 
treatment.  

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If feasible, all subjects will be followed for PFS and OS (Part B only) until the end of the 
study, defined as the date of the last protocol-specified visit/assessment (including telephone 
contact), or the date the study is closed by the sponsor, whichever comes first.  
3.1.6 Dose-escalation Design 
3.1.6.1 General Dose Escalation and De-escalation Rules  
Rules for dose escalation and de-escalation are as follows: 
1. A minimum of 3 subjects will be enrolled in each dose cohort. 
2. The administration of toripalimab to the first and second subjects of each cohort will be 
separated by at least 24 hours.  
3. All safety data will be reviewed by a study-specific dose-escalation committee 
(including, but not limited to, the sponsor medical monitor or designee, and participating 
principal investigator’s or designees) before proceeding with an escalation or de-
escalation decision.  All decisions from the committee will be documented and shared 
with each participating principal investigator. 
4. A 3+3 dose-escalation design will be followed as summarized below: 
a. If 0 out of the 3 subjects in a dose cohort experience a DLT during the DLT 
evaluation period, dose escalation may proceed to the next planned cohort with 
approval of the dose-escalation committee.  
b. If 1 of the 3 subjects in any dose cohort experiences a DLT during the DLT 
evaluation period, that dose cohort will be expanded to a total of 6 subjects.  If no 
more than 1 of 6 subjects in the dose cohort experiences a DLT, dose escalation may 
proceed to the next planned dose cohort(s) with the approval of the dose-escalation 
committee. 
c. If 2 or more subjects in a dose cohort experience a DLT during the DLT evaluation 
period, the MTD will have been exceeded and no further subjects will be enrolled 
into that dose cohort.  A previous lower-dose cohort or an intermediate-dose cohort 
may be explored based on the recommendation of the dose-escalation committee. 
5. Any cohort that has not exceeded the MTD can be expanded up to a maximum of 
10 subjects for further evaluation of safety and efficacy. 
6. Intrasubject dose escalation will not be allowed. 

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3.1.6.2 Dose-limiting Toxicity 
DLTs will be evaluated in each cohort in Part A.  The period for evaluating DLTs will be 
defined as the time period starting with the first dose of toripalimab until the planned 
administration of the third dose of toripalimab.  Subjects are considered evaluable for DLT if 
they receive the protocol-assigned dose(s) of toripalimab and complete the safety follow-up 
through the end of the DLT evaluation period, or experience a DLT during the DLT 
evaluation period.  Any subject who experiences a DLT will receive no further toripalimab 
(see Section 4.1.5 Withdrawal Criteria).  Subjects who do not remain on the study up to this 
time for reasons other than DLT will be replaced with another subject at the same dose level.  
Grading of DLTs will be according to the National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v4.03. 
A DLT will be defined as all Grade 3 or higher adverse events that occur during the DLT 
evaluation period that are at least possibly related to toripalimab, including but not limited to: 
• Neutropenic fever, regardless of grade 
• Grade 4 neutropenia lasting > 7 days 
• Increase in ALT or AST to > 3 x ULN with concurrent increase in bilirubin to > 2 x ULN 
• Any Grade ≥ 3 enterocolitis 
• Grade 4 thrombocytopenia of any duration 
• Grade 3 thrombocytopenia associated with bleeding 
• Any Grade 4 irAE or non-irAE irrespective of duration  
• Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration 
• Any Grade 3 irAE including rash, pruritus, or diarrhea that does not downgrade to 
≤ Grade 2 within 7 days after onset of the event despite maximal supportive care 
including systemic corticosteroids 
• Any ≥ Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 14 days of the 
initiation of maximal supportive care 
The definition excludes the following conditions:  
• Grade 3 fatigue or nausea for ≤ 7 days 

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• Grade 3 decrease in lymphocyte count that downgrades to ≤ Grade 2 within 7 days after 
onset of the event and resolves to ≤ Grade 1 or baseline within 14 days, unless not 
clinically significant (e.g., fungal nail infections or thrush) 
• Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy 
and/or hormone replacement therapy and the following criterion is met: 
◦ 
The subject is asymptomatic 
• Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) that resolve to  
≤ Grade 1 within 30 days 
While the rules for adjudicating DLTs in the context of dose escalation/cohort expansion are 
specified above, an AE not listed above, or an AE meeting the DLT criteria above but 
occurring outside of the DLT period may be defined as a delayed DLT following the 
procedures outlined below. 
Delayed DLTs will be evaluated on a case-by-case basis upon consultation between the 
sponsor and the PI.  At minimum, a review and discussion of potential delayed DLTs will 
take place at each safety review prior to a dose escalation decision (i.e., approximately every 
6-8 weeks).  Factors taking into account whether these AEs constitute a delayed DLT include 
the emerging safety profile of toripalimab, whether the AE meets the definition of a DLT as 
defined above including duration of the event and response to intervening therapy, and clear 
determination of whether there is a well-documented alternative explanation for the toxicity 
observed.  In the event that the delayed DLT constitutes a laboratory based toxicity not 
associated with clinical signs or symptoms, confirmation of the laboratory results will be 
obtained and DLT determination will be evaluated in light of the clinical benefit of 
toripalimab to the subject. 
Once the documented AE has been designated a delayed DLT, by the sponsor and PI, the 
same rules of reporting as that for DLTs described in Section 5.7.1 will be followed. 
The impact of a delayed DLT on the dose-escalation cohort will follow the rules outlined in 
Section 3.1.6.  If a higher dose is under evaluation (relative to the dose cohort where a 
delayed DLT was noted), further enrollment in the higher dose cohort will be held pending 
outcome of the evaluation of the lower dose cohort.  Subjects who are tolerating study drug 
at the higher dose level may be allowed to continue treatment provided the PI believes there 
is a favorable benefit-risk and there is agreement with the sponsor. 
All subjects will be evaluated regularly, and their clinical status classified according to 
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followed for PFS and OS (Part B only) until the end of the study, defined as the date of the 
last protocol-specified visit/assessment (including telephone contact), or the date the study is 
closed by the sponsor, whichever comes first.  AEs and SAEs will be followed from the start 
of the first dose of toripalimab through 90 days after the last dose of toripalimab unless a 
subject receives another experimental or anticancer therapy, at which time only related 
AE/SAEs will be collected through 90 days after the last dose of toripalimab.  The endpoints 
to be measured in this study are described in Section 2.2. 
3.1.7 Management of Study Related Toxicities 
Management of study related toxicities will be the same for Part A and Part B of this study. 
3.1.7.1 Toripalimab Dose Modifications 
Following the first dose of toripalimab, subsequent administration of toripalimab can be 
modified based on toxicities observed as described in Table 3.1.7-1.  All toxicities will be 
graded according to NCI-CTCAE v4.03.  
Dose modifications will not be required for AEs that are clearly not attributed to toripalimab 
(such as an accident) or for laboratory abnormalities that are not deemed to be clinically  
Table 3.1.7-1: Toripalimab Dose Modification Due to Toxicity 
Severity 
Immune-related Adverse Events (irAEs) a 
All Other Events b 
Grade 1 
None 
For infusion-related reactions: 
• 
The infusion rate of toripalimab may be 
decreased by 50% or temporarily 
interrupted until resolution of the event  
• 
Acetaminophen and/or antihistamines 
may be administered per institutional 
standard at the discretion of the 
investigator  
• 
Refer to Section 4.10.1.2 for use of 
corticosteroids 
• 
Consider premedication prior to 
subsequent doses 
All other AEs: 
No dose adjustment is required 

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Severity 
Immune-related Adverse Events (irAEs) a 
All Other Events b 
Grade 2 
For endocrinopathy: 
• 
Hold toripalimab dose 
• 
When endocrinopathy is controlled, resume 
toripalimab dosing 
For dermatologic irAEs: 
• 
Do not hold toripalimab dose 
For pneumonitis: 
• 
Hold toripalimab until resolution to ≤ Grade 
1 
• 
If resolution to ≤ Grade 1 occurs within 3 
days of the initiation of maximal supportive 
care (including corticosteroids), resume 
toripalimab administration at next 
scheduled dose. Otherwise, discontinue 
toripalimab 
For all other irAEs:  
• 
Hold toripalimab until resolution to ≤ Grade 
1 
• 
If resolution to ≤ Grade 1 does not occur 
within 30 days, discontinue toripalimab 
For infusion-related reactions: 
• 
The infusion rate of toripalimab may be 
decreased by 50% or temporarily 
interrupted until resolution of the event 
• 
Acetaminophen and/or antihistamines 
may be administered per institutional 
standard at the discretion of the 
investigator  
• 
Refer to Section 4.10.1.2 for use of 
corticosteroids 
• 
Consider premedication prior to 
subsequent doses 
All other AEs: 
• 
Hold toripalimab until resolution to 
≤ Grade 1 or baseline 
• 
If resolution to ≤ Grade 1 does not occur 
within 30 days, discontinue toripalimab 

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Severity 
Immune-related Adverse Events (irAEs) a 
All Other Events b 
Grade 3 
For endocrinopathy: 
• 
Hold toripalimab dose. 
• 
When endocrinopathy is controlled, resume 
toripalimab) administration at next 
scheduled dose 
For dermatologic irAEs:  
• 
Hold toripalimab until resolution to ≤ Grade 
1 or baseline 
• 
If resolution to ≤ Grade 1 or baseline does 
not occur within 30 days, discontinue 
toripalimab 
For elevations in transaminases: 
• 
For elevations in transaminases ≤ 8 × upper 
limit of normal (ULN), hold toripalimab 
until resolution to ≤ Grade 1 or baseline  
• 
If elevations downgrade to ≤ Grade 2 within 
7 days or resolve to ≤ Grade 1 or baseline 
within 14 days, resume toripalimab 
administration at next scheduled dose. 
Otherwise, discontinue toripalimab 
• 
For elevations in transaminases > 8 × ULN, 
discontinue toripalimab 
For elevations in total bilirubin: 
• 
For elevations in total bilirubin ≤ 5 × ULN, 
hold toripalimab until resolution to ≤ Grade 
1 or baseline 
• 
If elevations downgrade to ≤ Grade 2 
(< 3 × ULN) within 7 days or resolve to 
≤ Grade 1 or baseline within 14 days, 
resume toripalimab administration at next 
scheduled dose. Otherwise, discontinue 
toripalimab 
• 
For elevations in total bilirubin > 5 × ULN, 
discontinue toripalimab 
For all other irAEs:  
• 
Discontinue toripalimab 
For hypersensitivity and infusion-related 
reactions: 
• 
Discontinue toripalimab  
All other AEs: 
• 
Hold toripalimab until resolution to 
≤ Grade 1 or baseline 
• 
For AEs that downgrade to ≤ Grade 2 
within 7 days or resolve to ≤ Grade 1 or 
baseline within 14 days, resume 
toripalimab administration at next 
scheduled dose. Otherwise, discontinue 
toripalimab 
Grade 4 
• 
Discontinue toripalimab 
• 
Discontinue toripalimab 
a. Management of irAEs may require administration of immunosuppressive 
medications (and/or hormone replacement therapy for endocrinopathies; see 
Section 3.1.7.2 for management of irAEs). Resolution of irAEs managed in this 
manner in the timeframes specified is acceptable.  
b 
See Section 3.1.7.3 for management of toripalimab-related toxicities. 
 

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3.1.7.2 Management of Immune-related Adverse Events 
Based on the mechanism of action (MOA) of toripalimab leading to T-cell activation and 
proliferation, there is the possibility of observing irAEs during the conduct of this study. 
Optimal strategies to monitor the immune related toxicities are evolving, and therefore, 
subjects receiving toripalimab should be carefully monitored for signs and symptoms of 
irAEs.  In the absence of alternate etiology (e.g., infection or PD), signs or symptoms of 
enterocolitis, pneumonitis, transaminitis, dermatitis, hepatitis, and endocrinopathies should 
be considered immune-mediated.  
The management guidelines summarized in Table 3.1.7-2, Management of Immune-related 
Adverse Events will provide guidance to investigators on the management and recommended 
interventions to prevent morbidity and mortality of these rare immune-related toxicities.  
Immune-Related Colitis 
Toripalimab can cause immune-mediated colitis, defined as requiring use of corticosteroids 
with no clear alternate etiology. Immune-related colitis shares some characteristics with 
inflammatory bowel disease but with little specificity. Signs and symptoms of colitis may 
include diarrhea (loose stools) or more bowel movements than usual, blood in stools or dark, 
tarry, sticky stools.  
The investigator will handle AEs (diarrhea and colitis) according to local standard procedure 
or follow the recommendations listed in Table 3.1.7-3.  
Immune-Related Hepatitis 
Toripalimab can cause immune-mediated hepatitis, defined as requiring use of 
corticosteroids and no clear alternate etiology. Signs and symptoms of hepatitis may include 
transaminase elevation, total bilirubin elevation, jaundice, severe nausea or vomiting, right 
upper quadrant abdominal pain, drowsiness, dark urine (tea colored), bleeding or bruising 
more easily than normal, and decreased appetite. The investigator will handle immune-
related hepatic AEs according to local standard procedure or follow the recommendations 
listed in Table 3.1.7-4.  
The administration of any recombinant protein has the potential to induce local and systemic 
immunologic reactions. Subjects will be carefully monitored for the formation of ADA. 

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Table 3.1.7-2:  Management of Immune-related Adverse Events 
1 
Subject evaluation to identify any alternative etiology 
2 
In the absence of a clear alternative etiology, all events of an inflammatory nature should be 
considered to be immune-related 
3 
Symptomatic and topical therapy should be considered for low-grade event 
4 
Systemic corticosteroids (e.g., prednisone or IV equivalent should be considered for a persistent low-
grade event or for a severe event) 
5 
If symptoms recur of worsen during corticosteroid tapering, increase the corticosteroid dose until 
stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate 
6 
More potent immunosuppressives – tumor necrosis factor (TNF) antagonist class (e.g., infliximab) or 
mycophenylate should be considered for events not responding to systemic steroids after discussion 
with the medical monitor 
 
Table 3.1.7-3:  Management of Gastrointestinal irAEs. 
Grade 1 
• 
Symptomatic treatment (for example, loperamide) according to institutional standards; 
• 
Close monitoring; instruct subject to report worsening immediately and treat as Grade ³2 
Grade 2 
• 
£5 days: Symptomatic treatment according to institutional standards 
• 
>5 days or recurrence: 0.5–1.0 mg/kg/d methylprednisolone; consider prophylactic 
antibiotics; 
• 
Persistence or worsening despite steroids >3 days: treat as Grade 3/4 
• 
Improvement to £Grade 1: taper steroids over at least 4 weeks, consider prophylactic 
antibiotics for opportunistic infections, resume study therapy per protocol 
Grade 3-4 
Should 
discontinuatio
n from 
treatment be 
warranted 
• 
Immediately: 1.0–2.0 mg/kg/d methylprednisolone IV; consider prophylactic antibiotics 
and lower colonoscopy 
• 
Persistence >3 days or recurrence: add infliximab 5 mg/kg (if no contraindication such as 
perforation or sepsis) 
• 
Improvement to £Grade 2 within £3 days: taper steroids over at least 4 weeks 
 
Table 3.1.7-4:  Management of Hepatic irAEs. 
Grade 1 
• 
Continue liver function monitoring 
• 
If worsens: Treat as Grade ³2  
Grade 2 
• 
Monitor every 3 days; 
• 
Returning to baseline: resume per protocol monitoring 
• 
LFT elevation >5 days or worsening: 0.5-1.0 mg/kg/d methylprednisolone IV or oral 
equivalent; consider prophylactic antibiotics 
• 
LFT return to £Grade 1 or baseline: taper steroids over at least 4 weeks; resume routine 
monitoring and resume study treatment per protocol 
Grade 3-4 
Should 
discontinuatio
n from 
treatment be 
warranted 
• 
Monitor every £2 days; 
• 
Immediately: 1.0-2.0 mg/kg/d methylprednisolone IV or IV equivalent; start prophylactic 
antibiotics; consult gastroenterologist 
• 
Persistence >3 days or recurrence: add mycophenolate mofetil 1g bid; if no response 
within £5 days, consider other immunosuppressants per local guidelines 
• 
LFT return to Grade 2: stop immunosuppressants 
• 
LFT return to £Grade 1: taper steroids over at least 4 weeks 
 

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3.1.7.3 Management of Toripalimab-related Toxicities 
Infusion-related Reactions 
Infusion-related reactions may manifest with symptoms such as fever, chills, rigors, 
headache, rash, pruritus, arthralgia, hypo- or hypertension, bronchospasm, or other 
symptoms.  
In order to promptly treat infusion-related reactions, it is recommended that treatment 
medications be prepared prior to the start of the infusion and placed within easy access of the 
bedside along with standing orders for the treatment of infusion related reactions. 
Once symptoms of an infusion reaction occur (e.g., sense of feeling cold, chills, rigors, fever, 
neck pain, nausea), the infusion should be interrupted, and the subject should be assessed for 
other signs or symptoms (e.g., hypotension, hypoxia, wheezing, urticaria) suggestive of a 
more serious reaction. 
Medications used to treat an infusion reaction will be at the discretion of the investigator. 
Sites should follow the guidelines in Table 3.1.7-1 for medical management of the actual 
infusion (i.e., reducing the infusion rate or stopping the infusion based on symptoms the 
subject is eliciting). 
As with any antibody, allergic reactions to dose administration are possible.  Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. See Table 3.1.7-1 for management guidelines by event severity. 
Liver Chemistry Testing Procedures 
The procedures listed below are to be followed if a subject meets the criteria for treatment 
discontinuation based on elevations in transaminases or total bilirubin as defined in Table 
3.1.7-1 or any of the other criteria defined below.  They do not apply if a subject develops 
liver chemistry abnormalities as a result of progressive disease. 
Medical Management of Liver Chemistry Event 
If a subject meets any of the criteria for treatment discontinuation based on elevations in 
transaminases or total bilirubin as defined in Table 3.1.7-1, do the following: 
• Immediately withdraw the subject from further administration of toripalimab.  
• Within 24 hours of learning of its occurrence, report the event to TopAlliance 
Biosciences Patient Safety representative as a SAE, notify the medical monitor of the 

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abnormality, confirm the subject has discontinued toripalimab, and appropriate follow-up 
has been arranged. 
• Complete the Liver Event Follow-up Assessments listed below, especially the 
autoimmune work-up. 
• Upon completion of the safety follow-up, permanently withdraw the subject from 
treatment and do not rechallenge with toripalimab.  
• Follow procedures for stopping the study (See Section 3.1.8). 
In addition, for subjects experiencing ALT ≥ 3 × ULN and bilirubin ≥ 2 × ULN (> 35% 
direct bilirubin) (or ALT ≥ 3 × ULN and international normalized ratio (INR) > 1.5) that was 
not present at baseline because of existing liver metastases or HCC which allow for ALT≤5) 
and is not attributable to tumor progression: 
• Make every reasonable attempt to have subjects return to the clinic within 24 hours for 
repeat liver chemistries and additional testing. 
• Close monitoring including specialist or hepatology consultation is recommended.  
• Monitor subjects until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) 
resolve, stabilize or return to within baseline values. 
Liver Event Follow-up Assessments 
For subjects that meet study stopping criteria based on liver function abnormalities (Section 
3.1.8), make every attempt to carry out the liver event follow-up assessments described 
below: 
• Anti-nuclear antibody (ANA), anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies. 
• Obtain viral hepatitis serology testing including: 
◦ 
Hepatitis A Immunoglobulin M (IgM) antibody 
◦ 
Hepatitis B surface antigen and Hepatitis B core antibody (IgM) 
◦ 
Hepatitis C ribonucleic acid (RNA) 
• Assess eosinophilia 
• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease. 

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In addition to the above, for subjects meeting any of the study stopping criteria, make every 
attempt to carry out the following additional liver event follow-up assessments described 
below: 
• Viral hepatitis serology including: 
◦ 
Cytomegalovirus IgM antibody 
◦ 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing) 
◦ 
Hepatitis E IgM antibody (if subject resides outside the U. S. or Canada, or has 
traveled outside the U.S. or Canada in past 3 months) 
• All End of Treatment Central Laboratory Assessments (PK and pharmacodynamic blood 
draws) should be collected as described in Sections 4.3.4, and 4.4. 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin ³ 2 × ULN. 
• Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, jaundice, 
fever, or rash as relevant on the AE electronic case report form (eCRF). 
• Record use of concomitant medications, acetaminophen, herbal remedies, other over the 
counter medications, or putative hepatotoxins on the Concomitant Medications (CM) 
eCRF. 
• The Liver Imaging and/or Liver Biopsy reports are also to be provided to the Sponsor if 
these tests are performed. 
3.1.8 
Study Stopping Criteria 
If the following occurs, administration of toripalimab will be stopped and no additional 
subjects will be entered into the study: 
• Any safety finding assessed as related to toripalimab that, in the opinion of the sponsor in 
consultation with the medical monitor and investigator(s), contraindicates further dosing 
of study subjects.  
• Refer to Section 3.1.7.3 Management of toripalimab-related toxicities 
If any such safety findings occur, further administration of toripalimab will be stopped and 
no further subjects will be entered into the study.  Thereafter the regulatory authorities and 

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Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) will be notified 
and a prompt cumulative review of safety data and the circumstances of the event in question 
will be conducted.  The findings will be shared with the regulatory authorities and the 
IRBs/IECs.  If it is deemed appropriate by the sponsor after review by the medical monitor 
and investigator(s), justification for stopping the study will be sent to the regulatory 
authorities and the IRBs/IECs as required.  
Any subjects who have already received toripalimab and are currently in the study at the time 
study-stopping criteria are met will continue to be followed through 90 days after the last 
dose of toripalimab unless a subject receives another experimental or anticancer therapy, at 
which time only related AE/SAEs will be collected through 90 days after the last dose of 
toripalimab. 
Withdrawal criteria for individual subjects are provided in Section 4.1.5. 
4 
MATERIALS AND METHODS 
4.1 
Subjects 
4.1.1 Number of Subjects 
This study is expected to enroll up to 18 subjects (not including replacement subjects) in Part 
A.  Additional subjects may be enrolled depending on the number of dose levels and toxicity 
profile observed. Part B will enroll up to 280 subjects, maximum of 80 subjects in a sarcoma 
cohort and 40 subjects for the other 5 cohorts. After 40 subjects have been enrolled in the 
sarcoma cohort, a further 40 subjects will be enrolled and will be limited to angiosarcoma, 
undifferentiated pleomorphic sarcoma and alveolar soft part sarcoma. Men and women, 
18 years or older, with advanced malignancies that are evaluable by RECIST v1.1 and 
irRECIST, that are refractory to standard treatment or for which no standard therapy exists 
may be enrolled.  
Additional subjects may be required, depending on the number of dose levels explored and 
toxicity profile observed. 
4.1.2 Inclusion Criteria 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects.  If there is a question about the inclusion/exclusion criteria listed below, the 
principal investigator should contact the medical monitor or designee before enrolling the 
subjects. 
Subjects must meet all of the following criteria:  

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1. Signed Informed Consent Form 
2. Age ≥ 18 years 
3. Subject meets the following corresponding requirements for the part of the study they will 
enroll into: 
During Part A, subjects must have a histologically or cytologically documented, incurable 
or metastatic solid tumor that has progressed on (or they have been intolerant to) standard 
systemic therapy options for their tumor type in the metastatic setting or must have a tumor 
type for which no such standard systemic option exists. 
During Part B, subjects must have a histologically or cytologically documented diagnosis 
of gastric cancer, esophageal cancer,  cholangiocarcinoma, NETs (excluding lung derived 
NET), NPC, HCC, sarcomas, both chondrosarcoma  and soft tissue sarcoma (excluding 
leiomyosarcoma and including angiosarcoma, undifferentiated pleomorphic sarcoma and 
alveolar soft part sarcoma), or with agreement of the Sponsor, other tumors that have been 
treated with at least one line of standard systemic therapy for their respective tumor type 
in the metastatic setting with progressive locally advanced or metastatic disease that is not 
amenable to definitive local therapy with curative intent. Patients with MSI-H/dMMR 
tumors are eligible to enroll. 
a. Subjects with nasopharyngeal cancer must have received (or been intolerant) to a 
platinum-based combination as part of their prior therapy for advanced/metastatic 
disease.  
b. Subjects with soft tissue sarcoma and chondrosarcoma must have radiographic 
evidence of progression within the previous 6 months and must have received at 
least 1 line of systemic therapy. 
c. Subjects with esophageal cancer must have received (or been intolerant to) a 
platinum-based combination as part of their prior therapy for advanced/metastatic 
disease. 
d. Subjects with gastric cancer must have received (or been intolerant to) a 
fluoropyrimidine-platinum combination as part of their prior therapy for 
advanced/metastatic disease. 
e. Subjects with HCC must have received (or been intolerant to) sorafenib as part of 
their prior therapy for advanced/metastatic disease.  
4. Measurable disease per RECIST v1.1 and irRECIST   
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
 

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6. Adequate organ and marrow function, as defined below: 
a. Hemoglobin ³ 8.0 g/dL within first 2 weeks prior to first dose of toripalimab 
b. Absolute neutrophil count (ANC) ³ 1.2 × 109/L (1,200/mm3) 
c. Platelet count ³ 75 × 109/L (75,000/mm3) 
d. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) except subjects with 
documented Gilbert’s syndrome who must have a baseline total bilirubin ≤ 3.0 
mg/dL 
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × 
ULN; for subjects with hepatic metastases, ALT and AST ≤ 5 × ULN 
f. Serum creatinine ≤ 1.5 × ULN OR calculated creatinine clearance (CrCl) or 24-hour 
urine CrCl ≥ 40 mL/minute 
g. Cockcroft-Gault formula will be used to calculate CrCl.(Section 9.4); 24-hour urine 
CrCl will be derived using the measured creatinine clearance formula (9.5) 
h. International normalized ratio (INR) and activated partial thromboplastin time 
(aPTT) ≤ 1.5 ×ULN; applies only to subjects who do not receive therapeutic 
anticoagulation; subjects receiving therapeutic anticoagulation (such as low-
molecular weight heparin or warfarin) should be on a stable dose. 
7. Willingness to provide consent for biopsy samples (In Part A, fresh pre-treatment biopsies 
will be requested from subjects with safely accessible lesions.  For subjects who cannot 
provide a fresh pre-treatment biopsy, an archival specimen will be required.  In Part B, 
fresh pre-treatment biopsies will be required from subjects with safely accessible lesions.  
Archival specimens will be requested). 
8. Females of childbearing potential who are sexually active with a nonsterilized male partner 
must use effective contraception from time of screening, and must agree to continue using 
such precautions for 90 days after the final dose of toripalimab; cessation of birth control 
after this point should be discussed with a responsible physician.  Periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of birth control. 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as at least 12 months with no menses confirmed by follicle-
stimulating hormone [FSH] levels.  FSH testing will be conducted at the Screening visit to 
confirm post-menopausal status). 
Subjects must use effective contraception as described in Table 4.1.2-1. 

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9. Nonsterilized males who are sexually active with a female partner of childbearing potential 
must use effective contraception (see Table 4.1.2-1) from Day 1 and for 90 days after 
receipt of the final dose of toripalimab. 
Table 4.1.2-1  Highly Effective Methods of Contraception 
Barrier Methods 
Hormonal Methods 
• 
Male condom plus spermicide 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing intrauterine system 
(e.g., Mirena®) a 
• 
Implants 
• 
Hormone shot or injection 
• 
Combined pill 
• 
Minipill 
• 
Patch 
a This is also considered a hormonal method. 
 
4.1.3 Exclusion Criteria 
Any of the following would exclude the subject from participation in the study:  
1. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study. 
2. Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic therapy for 
cancer treatment.  Concurrent use of hormones for non-cancer-related conditions (e.g., 
insulin 
for 
diabetes 
and 
hormone 
replacement 
therapy) 
is 
acceptable. 
NOTE: Local treatment of isolated lesions for palliative intent is acceptable (e.g., by local 
surgery or radiotherapy). 
3. Receipt of any investigational anticancer therapy within 4 weeks prior to the first dose of 
toripalimab. 
4. Current or prior use of immunosuppressive medication within 2 weeks prior to the first 
dose of toripalimab, with the exception of intranasal and inhaled corticosteroids or systemic 
corticosteroids not to exceed 10 mg/day of prednisone or equivalent.  
5. In Part A: Prior exposure to immunotherapy such as but not limited to other anti-CTLA-4, 
anti-PD-1, or anti-PD-L1 antibodies excluding vaccines.  In Part B: Exclusion of prior 
immunotherapy exposure will be limited to anti-PD-1, anti-PD-L1, or anti-PD-L2. 
6. Prior allogeneic bone marrow transplantation or prior solid organ transplantation. 
7. Major surgery (as defined by the investigator) within 4 weeks prior to first dose of 
toripalimab or still recovering from prior surgery. 
8. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
baseline or to NCI-CTCAE v4.03 Grade 0 or 1, or to levels dictated in the inclusion / 
exclusion criteria with the exception of alopecia.  Subjects with irreversible toxicity that is 

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not reasonably expected to be exacerbated by toripalimab may be included (e.g., hearing 
loss) after consultation with the medical monitor. 
9. Active or prior documented autoimmune disease within the past 2 years.  
NOTE: Subjects with vitiligo, Grave’s disease not requiring systemic treatment other than 
thyroid hormone replacement (within the past 2 years), or psoriasis not requiring systemic 
treatment are not excluded. Subjects with a history of autoimmune hypothyroidism 
requiring only thyroid hormone replacement therapy will not be excluded. 
10. Known history of tuberculosis. 
11. Subjects who are known to be human immunodeficiency virus (HIV) positive.  
12. Subjects with evidence of hepatitis B or C virus infection, unless their hepatitis is 
considered to have been cured. (Note that subjects with prior hepatitis B virus (HBV) 
infection must have HBV viral load (VL) <100 IU/mL before study enrollment, and must 
be treated according to local standards; hepatitis C virus (HCV) infection must have, before 
study enrollment, no detectable viral load and must be treated according to local standards). 
13. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis). 
14. History of primary immunodeficiency. 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure according to New York Heart Association (NYHA) 
Functional Classification≥3, uncontrolled hypertension, unstable angina pectoris, cardiac 
arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/social situations 
that would limit compliance with study requirements, substantially increase risk of 
incurring AEs from toripalimab, or compromise the ability of the subject to give written 
informed consent.  
16. Symptomatic or untreated central nervous system metastases requiring concurrent 
treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids.  
Subjects with previously treated brain metastases may participate provided they are 
clinically stable for at least 4 weeks prior to study entry, have no evidence of new or 
enlarging metastases, and are off steroids.  
17. Receipt of live attenuated vaccination within 4 weeks prior to study entry or within 4 weeks 
of receiving toripalimab. 
18. Any condition that, in the opinion of the investigator or sponsor, would interfere with 
evaluation of toripalimab or interpretation of subject safety or study results. 
19. Pregnant or breastfeeding women. 

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4.1.4 Subject Enrollment  
Study participation begins (i.e., a subject is “enrolled”) once a subject receives the first dose 
of study drug.  Once informed consent is obtained, a screening number will be assigned by 
the site and the screening evaluations may begin to assess study eligibility (inclusion / 
exclusion) criteria.  Once a subject is enrolled, a subject identification number (SID) will be 
assigned by 
.  
A master log of all consented subjects will be maintained at the site and will document all 
screen failures (i.e., subjects who are consented but do not meet study eligibility criteria), 
including the reason(s) for screen failure. 
Once subjects are screened and determined by the PI to be eligible, the investigational site 
will complete an enrollment form and forward the completed document to 
 to 
request enrollment into the study.  
 will designate the part of the study the 
subject will enroll into (Part A [dose-escalation] or Part B [expansion]) and the cohort 
number.  The medical monitor may request to review the subject’s medical chart to ensure 
they meet the inclusion/exclusion criteria. 
Subjects who fail to meet the inclusion/exclusion criteria (i.e., screen failures) may be 
rescreened and will maintain their same screening number. Subjects can be rescreened 3 
times. 
TAB001-01 is a competitive enrollment study. Up to 30 sites will be participating in 
TAB001-01 in the United States and up to 15 sites will be participating in TAB001-01 in 
Europe. The anticipated accrual per site is approximately 6 subjects; however, given the 
tumor types of interest, the actual enrollment rate per site will vary. 
4.1.5 Withdrawal Criteria 
Permanent discontinuation of toripalimab: In Part A and Part B, an individual subject will 
not receive any further toripalimab if any of the following occur in the subject in question: 
• Withdrawal of consent from the study 
• Withdrawal of consent from further treatment with toripalimab 
• Lost to follow-up  
• An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing  
• Any AE that meets criteria for discontinuation as defined in Section 3.1.7 
• Dose-limiting toxicity (see Section 3.1.6.2 for definition of a DLT) 

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• Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing toripalimab might constitute a safety risk  
• Pregnancy or intent to become pregnant  
• Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (e.g., refusal to adhere to scheduled visits) 
• Initiation of alternative anticancer therapy including another investigational agent 
Subjects who are permanently discontinued from further receipt of toripalimab, regardless of 
the reason (withdrawal of consent, due to an AE, other), will be identified as having 
permanently discontinued treatment.  Subjects who permanently discontinue treatment may 
either be considered to have completed the study or not to have completed the study 
(see Section 6.3). 
Subjects who are permanently discontinued from receiving toripalimab will continue on 
study to complete their End of Treatment and 90-day Post Treatment visits and will be 
followed for safety per Section 5.4.1 and Section 5.5, including the collection of any 
protocol-specified blood specimens, unless consent is withdrawn or the subject is lost to 
follow-up or enrolled in another clinical study.  If feasible, all subjects will be followed for 
progression free survival.  
A subject who receives another experimental or anticancer therapy will not continue on the 
study. All visits will cease.  Only related AEs/SAEs will be collected through 90 days after 
the last dose of toripalimab, as noted in Section 5.4.1. 
Withdrawal of consent: If consent is withdrawn, the subject will not receive any further 
toripalimab or further study observation.  Note that the subject may be offered additional 
tests to withdraw safely. 
Lost to follow-up: Subjects will be considered lost to follow-up only if no contact has been 
established by the time the study is completed (as defined in Section 6.3), such that there is 
insufficient information to determine the subject’s status at that time. 
Note: Subjects who refuse continuing participation in the study, including phone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.”  Subjects 
would be considered lost to follow-up after 3 documented unsuccessful attempts in 3 months. 
Investigators should document attempts to re-establish contact with missing subjects.  If 
contact with a missing subject is re-established, the subject should not be considered lost to 
follow-up. If the interruption was < 4 weeks, the subject may resume therapy in the next 
cycle and any evaluations should resume according to the protocol. If the interruption is ³ 4 

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weeks, the end of treatment visit should be conducted followed by the 90-day post treatment 
visit if applicable. 
4.1.6 Replacement of Subjects 
Subjects are considered evaluable if they complete the first imaging evaluation or they 
discontinue toripalimab due to a DLT.  Nonevaluable subjects may be replaced in the same 
dose cohort.  
4.1.7 Withdrawal of Informed Consent for Data and Biological Samples 
4.1.7.1 Biological Samples Obtained for the Main Study 
Study data are protected by the use of an SID number, which is a number specific to the 
subject.  The investigator is in control of the information that is needed to connect a study 
sample to a subject.  A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator.  If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor the safety of the subject. 
4.1.7.2 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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Footnotes for Table 4.2.1-1  Schedule of Evaluations: Screening 
a  
Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and 
surgical treatment.  Date of last prior cancer treatment must be documented.  Radiographic studies 
performed prior to study entry may be collected for review by the investigator.   
b  
Vital signs are to be obtained in the seated or supine position after the subject has been resting for at 
least 5 minutes. 
c  
All ECGs will be obtained in triplicate (all 3 within a 5-minute time period at least 1 minute apart) after 
10 minutes of supine rest.  Record HR, PR interval, QRS interval, QT interval, QTcF interval and 
results. 
d  
Document complete medication history taken within 30 days prior to the Screening Visit. 
e  
Disease assessments include: computerized tomography (CT) or magnetic resonance imaging (MRI) 
scan of the chest, abdomen, and pelvis.  The preferred method of disease assessment is CT with contrast.  
If CT with contrast is contraindicated, CT without contrast is preferred over MRI.  The same method is 
preferred for all subsequent tumor assessments. 
f  
Viral load to only be obtained from subjects with history of hepatitis B virus (HBV) or hepatitis C virus 
(HCV). 
g  
Serum pregnancy testing obtained from females of childbearing potential only. 
h  
FSH should be obtained from females who are postmenopausal for < 12 months to confirm 
postmenopausal status. 
i  
Collection of archival tumor tissue for purpose of biomarker analysis.  In Part A, archival tumor tissue 
will be required from subjects in which a fresh pre-treatment biopsy is not safely accessible. In Part B, 
archival tumor tissue will be requested.  See Laboratory Manual for tissue collection, processing, and 
shipment. 
j 
In Part A, fresh pre-treatment biopsies will be requested from subjects with safely accessible lesions.  In 
Part B, fresh pre-treatment biopsies will be required from subjects with safely accessible lesions.    See 
Laboratory Manual for tissue collection, processing, and shipment.  
 
 
4.2.2 Treatment Period 
In Part A, procedures to be conducted during Cycle 1 are presented in Table 4.2.2-1, for 
Cycles 2, 4, 5, 6 and 7 in Table 4.2.2-2.  Procedures to be conducted in Cycle 3 are presented 
in Table 4.2.2-3, for Cycles 8 and beyond in Table 4.2.2-4.   
In Part B, procedures to be conducted during Cycle 1 are presented in Table 4.2.2-5, for 
Cycles 2, 4, 5, 6 and 7 in Table 4.2.2-6. Procedures to be conducted in Cycle 3 are presented 
in Table 4.2.2-7, for Cycles 8 and beyond in Table 4.2.2-8.   
In Part A and Part B, procedures to be conducted during an unscheduled Visit or during the 
Follow-up Visit are presented in Table 4.2.3-1. 
Whenever vital signs, 12-lead ECGs (in triplicate), and blood draws are scheduled for the 
same nominal time, the assessments should occur in the following order: 12-lead ECG, vital 
signs, and then blood draws.  The timing of the first two assessments should be such that it 
allows the blood draw (e.g., PK blood sample) to occur at the exact nominal time. 
Refer to the Laboratory Manual for complete details on central laboratory collections. 

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If toripalimab is infused peripherally, PK blood draws must be taken from the contra-lateral 
arm or from a central line.  If toripalimab is infused via a central line, PK blood draws must 
be obtained peripherally.

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Footnotes for Table 4.2.2-1 PART A Schedule of Evaluations: Cycle 1 
a On dosing days, vital signs (temperature, blood pressure, heart rate, & respiratory rate) will be measured within 30 min (-30 min) prior to start of toripalimab infusion, every 
15 min (±5 min) during infusion, at end of infusion (EOI) (±5 min), 30 minutes (±15 min) and 4 hours (±15 min) post EOI. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion. Exam to be completed if subject is experiencing AEs.  Exam to be directed to the 
symptoms causing the AE. 
c All ECGs will be obtained in triplicate (all 3 within a 5-min time period at least 1 min apart) after 10 minutes of supine rest. Record HR, PR interval, QRS interval, QT 
interval, QTcF interval and results. Obtained on dosing days (Days 1 & 15), obtain ECGs within 60 minutes prior to start of infusion and within ±15 min post EOI. 
d AE collection begins at the start of the first infusion of toripalimab. AEs will be graded per NCI-CTCAE version 4.03. If an AE does not have a CTCAE grade, refer to 
protocol Appendix 1 (Section 9.1) for grading criteria. 
e Laboratory results must be reviewed prior to infusion. May be obtained 48 hrs prior to infusion. 
f Urine or serum pregnancy testing obtained from females of childbearing potential only. 
g Refer to the Laboratory Manual for more detail about collection and processing of pharmacodynamic samples to include PD-1 RO & T cell subsets. 
h See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and 
that the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
 
 
 
 

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Footnotes for Table 4.2.2-2 PART A Schedule of Evaluations: Cycles 2, 4, 5, 6 and 7 
a On dosing days in Cycles 2 & 4, vital signs (T, BP, HR, RR) will be measured within 30 min (-30 min) prior to start of toripalimab infusion, every 30 min (±5 min) during 
infusion, and at EOI (±5 min). On dosing days in Cycles 5, 6 & 7, vital signs will be measured within 30 min (-30 min) prior to start of toripalimab infusion, and at EOI (±5 
min).  Vital signs are to be obtained in the seated or supine position after the subject has been resting for at least 5 minutes. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion. Exam to be completed if subjects is experiencing AEs.  Exam to be directed to 
the symptoms causing the AE. 
e All ECGs will be obtained in triplicate (all 3 within a 5-min time period at least 1 min apart after 10 minutes of supine rest. Record HR, PR interval, QRS interval, QT 
interval, QTcF interval and results. Obtained on dosing days (Days 1 & 15), obtain ECGs within 60 minutes prior to start of infusion and within ±15 min post EOI. 
d AEs will be graded per NCI-CTCAE version 4.03. If an AE does not have a NCI-CTCAE grade, refer to protocol Appendix 1 (Section 9.1)for grading criteria. 
e Disease assessments include: CT or MRI scan of the chest, abdomen, and pelvis.  The preferred method of disease assessment is CT with contrast.  If CT with contrast is 
contraindicated, CT without contrast is preferred over MRI.  The same method is preferred for all subsequent tumor assessments. 
f  Laboratory results must be reviewed prior to infusion. Samples may be obtained 48 hrs prior to infusion. 
g Urine or serum pregnancy testing obtained from females of childbearing potential only. 
h Pharmacodynamic sample collected pre-dose on Day 1 of Cycles 2, 4, 5 and 6. Refer to the Laboratory Manual for more detail about collection, processing, and shipment of 
pharmacodynamic samples to include PD-1 RO & T cell subsets. 
i Post-treatment tumor biopsy at the PIs discretion at the occurrence of progressive disease, pseudoprogression or partial response. Biopsy to be taken from same baseline 
lesion. See Laboratory Manual for tissue collection, processing, and shipment. 
j See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and 
that the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
 
 
 
 
 

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Footnotes for Table 4.2.2-3  PART A Schedule of Evaluations: Cycle 3 
a On dosing days, vital signs (T, BP, HR, RR) will be measured within 30 min (-30 min) prior to start of toripalimab infusion, every 30 min (±5 min) during infusion, and at 
EOI (±5 min).  Vital signs are to be obtained in the seated or supine position after the subject has been resting for at least 5 minutes. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion. Exam to be completed if subjects is experiencing AEs.  Exam to be directed to 
the symptoms causing the AE. 
c All ECGs will be obtained in triplicate (all 3 within a 5-min time period at least 1 min apart after 10 minutes of supine rest.  Record HR, PR interval, QRS interval, QT 
interval, QTcF interval and results. Obtained on dosing days (Days 1 & 15), obtain ECGs within 60 minutes prior to start of infusion and within ±15 min post EOI. 
d AEs will be graded per NCI-CTCAE version 4.03.  If an AE does not have a NCI-CTCAE grade, refer to protocol Appendix 1 (Section 9.1)for grading criteria. 
e Disease assessments include: CT or MRI scan of the chest, abdomen, and pelvis.  The preferred method of disease assessment is CT with contrast.  If CT with contrast is 
contraindicated, CT without contrast is preferred over MRI.  The same method is preferred for all subsequent tumor assessments. 
f Laboratory results must be reviewed prior to infusion. May be obtained 48 hrs prior to infusion. 
g Urine or serum pregnancy testing obtained from females of childbearing potential only. 
h Pharmacodynamic sample collected pre-dose on Day 1 of Cycle 3, Refer to the Laboratory Manual for more detail about collection, processing, & shipment of 
pharmacodynamic samples to include PD-1 RO & T cell subsets. 
i Post-treatment tumor biopsy at the PIs discretion at the occurrence of progressive disease, pseudoprogression or partial response.  Biopsy to be taken from same baseline 
lesion. See Laboratory Manual for tissue collection, processing, and shipment. 
j See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and 
that the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
 
 
 
 

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Footnotes for Table 4.2.2-4  PART A Schedule of Evaluations: Cycle 8 and Beyond 
a Vital signs (temperature, blood pressure, heart rate, & respiratory rate) will be measured within 30 min (-30 min) prior to start of toripalimab infusion and at end of infusion 
(EOI) (±5 min).  Vital signs are to be obtained in the seated or supine position after the subject has been resting for at least 5 minutes. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion.  Exam to be completed if subjects is experiencing AEs.  Exam to be directed to 
the symptoms causing the AE. 
c AE collection begins at the start of infusion of toripalimab.  AEs will be graded per NCI-CTCAE version 4.03. If an AE does not have a NCI-CTCAE grade, refer to protocol 
Appendix 1 (Section 9.1) for grading criteria. 
d Disease assessments include: CT or MRI scan of the chest, abdomen, and pelvis.  The preferred method of disease assessment is CT with contrast.  If CT with contrast is 
contraindicated, CT without contrast is preferred over MRI.  The same method is preferred for all subsequent tumor assessments. 
e Laboratory results must be reviewed prior to infusion.  May be obtained 48 hrs prior to infusion. 
f Refer to the Laboratory Manual for more detail about collection, processing, & shipment of pharmacodynamic samples to include PD-1 RO & T cell subsets. 
g Post-treatment tumor biopsy at the PIs discretion at the occurrence of progressive disease, pseudoprogression or partial response.  Biopsy to be taken from same baseline 
lesion. See Laboratory Manual for tissue collection, processing, and shipment. 
h See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and 
that the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
 
 
 
 

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Footnotes for  Table 4.2.2-5  PART B Schedule of Evaluations Cycle 1 
a On dosing days (Days 1 & 22), vital signs (temperature, blood pressure, heart rate, & respiratory rate) will be measured within 30 min (-30 min) prior to start of toripalimab 
infusion, every 15 min (±5 min) during infusion, at end of infusion (EOI) (±5 min), 30 minutes (±15 min) and 4 hours (±15 min) post EOI. Vital signs are to be obtained in 
the seated or supine position after the subject has been resting for at least 5 minutes. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion. Exam to be completed if subject is experiencing AEs.  Exam to be directed to the 
symptoms causing the AE. 
c All ECGs will be obtained in triplicate (all 3 within a 5-min time period at least 1 min apart) after 10 minutes of supine rest. Record HR, PR interval, QRS interval, QT 
interval, QTcF interval and results. On Days 1 & 22, obtain ECGs within 60 minutes prior to start of infusion and within ±15 min post EOI. 
d AE collection begins at the start of the first infusion of toripalimab. AEs will be graded per NCI-CTCAE version 4.03. If an AE does not have a CTCAE grade, refer to 
protocol Appendix 1 (Section 9.1) for grading criteria. 
e Laboratory results must be reviewed prior to infusion. May be obtained 48 hrs prior to infusion. 
f Urine or serum pregnancy testing obtained from females of childbearing potential only. 
g Full PK collection to be obtained on the first 20 subjects enrolled. Once the number of subjects for full PK collection is met, sites will be notified that the remaining subjects 
will only have trough and EOI PK as noted in the Schedule of Evaluations. Day 3 and 4 visits are only for the first 20 subjects enrolled in Part B.  
h  Following enrollment of the 20th subject in Part B, only trough and EOI PK samples are to be obtained as noted in the Schedule of Evaluations. Day 3 & 4 visit are not 
required for subjects beyond the first 20 enrolled. 
i  Refer to the Laboratory Manual for more detail about collection and processing of pharmacodynamic samples to include 
 
j  Day 3 and 4 visits are only for the first 20 subjects enrolled in Part B. 
k See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and that 
the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
l    Screening labs obtained within 48 hours prior to Cycle 1 Day 1 will suffice as Cycle 1 Day 1 pre-dose labs.  
 
 
 
 

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Footnotes for Table 4.2.2-6  PART B Schedule of Evaluations: Cycles 2, 4, 5, 6 and 7 (Cycle 3 is in Table 4.2.2-7) 
a On dosing day in Cycles 2 & 4, vital signs (T, BP, HR, RR) will be measured within 30 min (-30 min) prior to start of toripalimab infusion, every 30 min (±5 min) during 
infusion, and at EOI (±5 min). On dosing days in Cycles 5, 6 & 7, vital signs will be measured within 30 min (-30 min) prior to start of toripalimab infusion, and at EOI (±5 
min).  Vital signs are to be obtained in the seated or supine position after the subject has been resting for at least 5 minutes. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion. Exam to be completed if subjects is experiencing AEs.  Exam to be directed to 
the symptoms causing the AE. 
c All ECGs will be obtained in triplicate (all 3 within a 5-min time period at least 1 min apart after 10 minutes of supine rest. Record HR, PR interval, QRS interval, QT 
interval, QTcF interval and results. On Days 1 & 22 of Cycles 2, 4, 5 & 6, obtain ECGs within 60 minutes prior to start of infusion and within ±15 min post EOI. 
d AEs will be graded per NCI-CTCAE version 4.03. If an AE does not have a NCI-CTCAE grade, refer to protocol Appendix 1 (Section 9.1) for grading criteria. 
e Disease assessments include: CT or MRI scan of the chest, abdomen, and pelvis.  The preferred method of disease assessment is CT with contrast.  If CT with contrast is 
contraindicated, CT without contrast is preferred over MRI.  The same method is preferred for all subsequent tumor assessments. 
f Laboratory results must be reviewed prior to infusion. Samples may be obtained 48 hrs prior to infusion. 
g Urine or serum pregnancy testing obtained from females of childbearing potential only. 
h Peak and trough PK to be collected on Days 1 and 22 from the first 20 subjects enrolled in Part B as outlined in the Schedule of Evaluations. 
i  Peak and trough PK to be collected on Day 1 only for subjects enrolled beyond the first 20 in Part B. 
j  Immunogenicity and pharmacodynamic sample collected pre-dose on Day 1 of even Cycles (i.e.; Cycles 2, 4, 6, 8 and every 4 cycles thereafter: Cycles 12, 16, 20, etc.). Refer 
to the Laboratory Manual for more detail about collection, processing, and shipment of pharmacodynamic samples to include 
. 
k Post-treatment tumor biopsy at the PIs discretion at the occurrence of progressive disease, pseudoprogression or partial response. Biopsy to be taken from same baseline 
lesion. See Laboratory Manual for tissue collection, processing, and shipment. 
l See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and 
that the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
 
 
 
 

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Footnotes for Table 4.2.2-7 PART B  Schedule of Evaluations: Cycle 3 
a On dosing days (Days 1 & 22), vital signs (T, BP, HR, RR) will be measured within 30 min (-30 min) prior to start of toripalimab infusion, every 30 min (±5 min) during 
infusion, and at EOI (±5 min).  Vital signs are to be obtained in the seated or supine position after the subject has been resting for at least 5 minutes. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion. Exam to be completed if subjects is experiencing AEs.  Exam to be directed to 
the symptoms causing the AE. 
c All ECGs will be obtained in triplicate (all 3 within a 5-min time period at least 1 min apart after 10 minutes of supine rest.  Record HR, PR interval, QRS interval, QT 
interval, QTcF interval and results. Obtained on dosing days (Days 1 & 22), obtain ECGs within 60 minutes prior to start of infusion and within ±15 min post EOI. 
d AEs will be graded per NCI-CTCAE version 4.03.  If an AE does not have a NCI-CTCAE grade, refer to protocol Appendix 1 (Section 9.1) for grading criteria. 
e Disease assessments include: CT or MRI scan of the chest, abdomen, and pelvis.  The preferred method of disease assessment is CT with contrast.  If CT with contrast is 
contraindicated, CT without contrast is preferred over MRI.  The same method is preferred for all subsequent tumor assessments. 
f Laboratory results must be reviewed prior to infusion. May be obtained 48 hrs prior to infusion. 
g Urine or serum pregnancy testing obtained from females of childbearing potential only. 
h Full PK collection to be obtained on the first 20 subjects enrolled.  
i Once the first 20 subjects for full PK collection are enrolled, sites will be notified that the remaining subjects will only have trough and EOI PK as noted in the Schedule of 
Evaluations. Subsequently enrolled subjects (after the first 20) will not be required to attend Days 23, 24, 25, 29 and 36. 
j Post-treatment tumor biopsy at the PIs discretion at the occurrence of progressive disease, pseudoprogression or partial response.  Biopsy to be taken from same baseline 
lesion. See Laboratory Manual for tissue collection, processing, and shipment. 
k Once the first 20 subjects are enrolled for full PK collection, the remaining subjects will not be required to attend Days 23, 24, 25, 29 and 36. 
l See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and 
that the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
 
 
 
 

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Footnotes for Table 4.2.2-8  PART A Schedule of Evaluations: Cycle 8 and Beyond 
a Vital signs (temperature, blood pressure, heart rate, & respiratory rate) will be measured within 30 min (-30 min) prior to start of toripalimab infusion and at end of infusion 
(EOI) (±5 min).  Vital signs are to be obtained in the seated or supine position after the subject has been resting for at least 5 minutes. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion.  Exam to be completed if subjects is experiencing AEs.  Exam to be directed to 
the symptoms causing the AE. 
c AE collection begins at the start of infusion of toripalimab.  AEs will be graded per NCI-CTCAE version 4.03. If an AE does not have a NCI-CTCAE grade, refer to protocol 
Appendix 1 (Section 9.1) for grading criteria. 
d Disease assessments include: CT or MRI scan of the chest, abdomen, and pelvis.  The preferred method of disease assessment is CT with contrast.  If CT with contrast is 
contraindicated, CT without contrast is preferred over MRI.  The same method is preferred for all subsequent tumor assessments. 
e Laboratory results must be reviewed prior to infusion.  May be obtained 48 hrs prior to infusion. 
f Refer to the Laboratory Manual for more detail about collection, processing, & shipment of pharmacodynamic samples to include 
. 
g Post-treatment tumor biopsy at the PIs discretion at the occurrence of progressive disease, pseudoprogression or partial response.  Biopsy to be taken from same baseline 
lesion. See Laboratory Manual for tissue collection, processing, and shipment. 
h See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and 
that the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
 
 
 
 
 

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4.2.3 Part A and Part B Unscheduled and Follow-up Periods 
Table 4.2.3-1 shows all procedures to be conducted during unscheduled delays and follow-up 
periods.  
Whenever vital signs, 12-lead ECGs (in triplicate), and blood draws are scheduled for the 
same nominal time, the assessments should occur in the following order: 12-lead ECG, vital 
signs, and then blood draws.  The timing of the first two assessments should be such that it 
allows the blood draw (e.g., PK blood sample) to occur at the exact nominal time. 
Refer to the Laboratory Manual for complete details on central laboratory collections. 

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Footnotes for Table 4.2.3-1  PART A and  PART B Schedule of Evaluations: Unscheduled and Follow-up Procedures 
a Vital signs are to be obtained in the seated or supine position after the subject has been resting for at least 5 minutes. 
b Abbreviated symptom driven physical examination obtained at the investigator’s discretion.  Exam to be completed if subjects is experiencing AEs.  Exam to be directed to 
the symptoms causing the AE. 
c All ECGs will be obtained in triplicate (all 3 within a 5-minute time period at least 1 minute apart).  Record HR, PR interval, QRS interval, QT interval, QTcF interval and 
results. 
d AE collection begins at the start of infusion of toripalimab.  AEs will be graded per NCI-CTCAE version 4.03. If an AE does not have a NCI-CTCAE grade, refer to protocol 
Appendix 1 (Section 9.4) for grading criteria.  
e Disease assessments include: CT or MRI scan of the chest, abdomen, and pelvis.  The preferred method of disease assessment is CT with contrast.  If CT with contrast is 
contraindicated, CT without contrast is preferred over MRI.  The same method is preferred for all subsequent tumor assessments. CT/MRI to be performed at PI discretion at 
the onset of dyspnea, cough, chest pain or discomfort, and other respiratory symptoms. 
g Urine pregnancy testing obtained from females of childbearing potential only. 
h End of treatment tumor biopsy at the PIs discretion at the occurrence of progressive disease, pseudoprogression or partial response. Biopsy to be taken from same baseline 
lesion if possible.  See Laboratory Manual for tissue collection, processing, and shipment. 
i See section 4.3.3.1 for whole blood/serum samples to be obtained if a subject experiences symptoms associated with irAEs and at the onset of any SAE, irAEs, during any 
suspected infusion related reaction, and at time of progression when a subject is taken off study, so long as the investigator believes the readouts would be informative, and 
that the collection would not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid panel, PK, ADA, ANA, serum and blood collection for 
pharmacodynamic analysis. 
 
 
 

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4.3 
Description of Study Procedures 
4.3.1 Efficacy 
4.3.1.1 Disease Assessment 
Tumor assessments will be based on RECIST v1.1 and irRECIST guidelines, and will be 
performed during screening and treatment according to the schedule presented in Section 4.2.  
As far as possible, for consistency, the same medically qualified staff person who has been 
trained in RECIST and irRECIST should evaluate and measure lesions at each disease 
assessment. For those subjects who discontinue toripalimab as a result of confirmed PD, 
disease evaluation will be performed at the end of treatment visit if clinically appropriate 
(i.e., in the absence of rapidly deteriorating clinical status).  Additional disease assessments 
may be performed as clinically indicated.  In addition, when available, scans performed after 
disease progression in subjects who permanently discontinue toripalimab will be obtained, 
when possible, to determine if there was any delayed activity, unless consent is withdrawn, 
or the subject is lost to follow-up or starts receiving another experimental or anticancer 
therapy.  
Sites will be required to store electronic copies of all scans and the sponsor may arrange for 
possible centralized storage of all imaging data.  The centralized storage of imaging data 
would allow for possible independent centralized review of disease assessments. 
The initial post treatment tumor assessment performed approximately 8 weeks (± 10 days) 
(Part A) or approximately every 9 weeks (± 10 days) (Part B) after Cycle 1, Day 1 will not be 
used to make decisions regarding continued subject participation in the study unless observed 
disease progression is accompanied by rapidly deteriorating clinical status.  Subjects may 
continue to receive toripalimab Q2W (± 2 days) (Part A) or Q3W (Part B) in the setting of 
progressive disease (PD) when all the following criteria described in Section 3.1.5 are met: 
• Absence of clinical symptoms or signs indicating clinically significant disease 
progression 
• No decline in Eastern Cooperative Oncology Group (ECOG) performance status from 
baseline 
• Absence of rapid disease progression or threat to vital organs or critical anatomical sites 
(e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention; no significant, 
unacceptable or irreversible toxicities related to study treatment. 

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◦ 
20 mm by chest X-ray. 
◦ 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
◦ 
Lytic or mixed lytic-blastic lesions with a measurable soft tissue component ≥10 mm 
can be selected as target lesions. 
• Nonmeasurable Lesion Definitions – Non-target lesions will include: 
• Measurable lesions not selected as target lesions. 
• All sites of non-measurable disease, such as neoplastic masses that are too small to 
measure because their longest uninterrupted diameter is <10 mm (or < two times the 
axial slice thickness). i.e., the longest perpendicular diameter is ≥10 and <15 mm. 
• Other types of lesions that are confidently felt to represent neoplastic tissue, but are 
difficult to measure in a reproducible manner.  These include bone metastases, 
leptomeningeal metastases, malignant ascites, pleural or pericardial effusions, ascites, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, ill-defined 
abdominal masses, skin lesions, etc. 
• Pathological nodes (those with a 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. 
Special considerations regarding lesion measurability – Bone lesions, cystic lesions, and 
lesions previously treated with local therapy require particular comment: 
Bone lesions: 
• Bone scan, (positive emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
• Regardless of the imaging modality, blastic bone lesions are non-measurable and 
therefore will not be selected as target lesions. 

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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• “Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non cystic lesions are present in the same patient, these are preferred for 
selection as target lesions.  
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.   
Assessment of overall tumor burden and measurable disease per RECIST v1.1 
• To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurement.  Measurable disease is defined by the presence of at least one measurable 
lesion. 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
• When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline (this means in instances where patients have only one or two 
organ sites involved, a maximum of two and four lesions respectively will be recorded). 
• Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition, should be those that 
lend themselves to reproducible repeated measurements. 
• A sum of 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. 
• All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare 

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cases ‘unequivocal progression’.  It is possible to record multiple non-target lesions 
involving the same organ as a single item on the case record form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
• Assessment of overall tumor burden and measurable disease per irRECIST Target 
Lesions - 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.  
Occasionally, the largest lesion may not lend itself to reproducible measurement in which 
case the next largest lesion which can be measured reproducibly should be selected. 
• Non-target Lesions - All lesions or sites of disease not recorded as target lesions should 
be recorded as non-target lesions at baseline.  There is no limit to the number of non-
target lesions that can be recorded at baseline. 
Follow-up: Recording of Target and New Measurable Lesion Measurements 
• The longest diameters of non-nodal target and new non-nodal measurable lesions, and 
short axis of nodal target and new nodal measurable lesions will be recorded.  
Together they determine the TMTB at follow-up. 
Follow-up: Definition of Measurable New Lesions 
• In order to be selected as new measurable lesions (≤2 lesions per organ, ≤5 lesions 
total, per timepoint), new lesions must meet criteria as defined for baseline target 
lesion selection and meet the same minimum size requirements of 10 mm in the long 
diameter and minimum 15 mm in the short axis for new measurable lymph nodes.  
New measurable lesions shall be prioritized according to size, and the largest lesions 
shall be selected as new measured lesions. 
Follow-up: Non-Target Lesion Assessment 
The RECIST 1.1 definitions for the assessment of non-target lesions apply. 
 
The response of non-target lesions primarily contributes to the overall response assessments 
of irCR and irNon-CR/Non-PD (irNon). Non-target lesions do not affect irPR and irSD 
assessments. Only a massive and unequivocal worsening of non-target lesions alone, even 
without progression in the TMTB is indicative of irPD. 
Response Criteria 
Evaluation of tumors based upon RECIST v1.1 (Eisenhauer et al, 2009) 

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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 diameters of target lesion, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note: the appearance of one 
or more new lesions is also considered progression). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Special notes on the assessment of target lesions  
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of <10 
mm. 
Target lesions that become ‘too small to measure’:  While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2 mm).  However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small 
to measure’.  When this occurs, it is important that a value be recorded on the CRF.  If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded at 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.  This default value is derived from the 5 
mm CT slice thickness.  The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 

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measurement error.  However, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum.  Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion.  If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
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). 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.  (Note: 
the appearance of one or more new lesions is also considered 
progression). 
Special notes on the assessment of target lesions  
When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
‘increase’ in size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare. 
New lesions 
The appearance of new malignant lesions denotes disease progression.  The finding of a new 
lesion should be unequivocal: i.e. not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than tumor. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.   
 

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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation.   
At each time point of tumor evaluation, an overall response will depend on the findings of 
both target and non-target disease and will also take into consideration the appearance of new 
lesions (Table 4.3.1-1). The overall response will be assessed by the investigator based on 
target lesions, non-target lesions and new lesions assessed. The confirmation of CR and PR is 
required; and a response of CR or PR at one time point must be confirmed by subsequent 
tumor assessment no less than 4 weeks after first response criteria are met.  
Table 4.3.1-1  Time point overall response: patients with target (+/- non-target) lesions 
Target lesions 
Non-Target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable (NE) 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
The best overall response (BOR) will be derived from overall responses at different time 
points, and defined as Table 4.3.1-2 (RECIST 1.1, Eisenhauer EA, et al, 2009).   
 
 

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Table 4.3.1-2  Best Overall Response when CR and PR confirmation is required per 
RECIST v 1.1  
Overall 
Response 
First Time Point 
Overall response  
Subsequent Time 
Point 
Best Overall response 
CR 
CR 
CR 
CR 
PR 
PR 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
SD 
SD 
SD provided minimum criteria for SD duration 
met, otherwise NE 
SD 
PD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
SD 
NE/Not done 
SD provided minimum criteria for SD duration 
met, otherwise NE 
PD 
Not Applicable 
PD 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable. 
Note: For this study, minimum criteria for SD duration is 4 weeks.  
 
• 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 objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy. 
• In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
 

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Confirmatory Measurement/Duration of Response per RECIST v1.1 
Confirmation 
• The main goal of confirmation of objective response (CR/PR) is to avoid overestimating 
the response rate observed.  In cases where confirmation of response is not feasible, it 
should be made clear when reporting the outcome of such studies that the responses are not 
confirmed. 
• To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met.  Longer intervals as determined by the study protocol may also be 
appropriate. 
• In the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general not less than 6-8 weeks) that is defined in the study 
protocol. 
Duration of overall response 
• The duration of overall response is measured from the time measurement criteria are first 
met from CR/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 on study). 
• The duration of overall complete response is measured from the time measurement criteria 
are first met for CR until the first date that recurrent 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 sum on study (if the baseline sum is the smallest, 
this is the reference for calculation of PD). 
Evaluation of tumors based upon the irRECIST (http://www.irrecist.com/). 
Overall Tumor Assessments 
• Immune-related Complete Response (irCR) – Complete disappearance of all 
measurable and non-measurable lesions.  Lymph nodes must decrease to < 10 mm in 
short axis.  Confirmation of response is not necessary.  
Immune-related Partial Response (irPR) - Decrease of ≥ 30% TMTB relative to 
baseline, non-target lesions are irNN, and no unequivocal progression of new non-
measurable lesions. 

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• Immune-related Stable Disease (irSD) - Failure to meet criteria for irCR or irPR in the 
absence of irPD. 
• Immune-related NN (irNN) – No target disease was identified at baseline and at follow-
up the patient fails to meet criteria for irCR or irPD. 
• Immune-relate Progressive Disease (irPD) – Minimum 20% increase and minimum 5 
mm absolute increase in TMTB compared to nadir, or irPD for non-target or new non-
measurable lesions.  Confirmation of progression is recommended minimum 4 weeks 
after the first irPD assessment. 
• Immune-related NE (irNE) – used in exception cases where insufficient data exists. 
Additional Guidance per irRECIST: 
Total Measured Tumor Burden (TMTB) 
Baseline-selected target lesions and new measurable lesions should NOT be assessed 
separately. Measurements of those lesions should be combined into the TMTB to provide 
combined assessment. 
New Measurable Lesions 
Criteria for unidimensional lesion measurement apply to both target and new measurable 
lesions:  
A minimum of 10 mm in the longest diameter for non-nodal lesions, and a minimum 15 mm 
in the short axis for lymph nodes.  But smaller lesions of the non-target or new non-
measurable tumor burden do not get measured.  
irPR if not Target Lesions 
If new measurable lesions appear in patients with no target lesions at baseline, irPD will be 
assessed.  That irPD timepoint will be considered a new baseline, and all subsequent 
timepoints will be compared to it for response assessment.  irPR is possible if the TMTB of 
new measurable lesions decreased by ≥30% compared to the first irPD documentation. 
Non-Target Lesions 
Baseline selected non-target lesions can never convert to measurable lesions, not even if they 
increase in size at subsequent timepoints and become measurable.  Only true new lesions can 
be measured and contribute to the TMTB. 
irPD Based on Non-Target Lesions 
A substantial and unequivocal increase of non-target lesions is indicative of progression. 

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irPD Based on New Non-Measurable Lesions 
The reviewer may assign irPD for the patient with multiple new lesions of 9 mm if they are 
considered to be a sign of unequivocal, massive worsening. 
irPD Confirmation 
Progression confirmation no less than 4 weeks after the initial irPD assessment is 
recommended especially in the case of marginal disease growth and if the first irPD 
assessment is within the compound-specific tumor flare window. 
Best Overall Response (irBOR) 
The immune-related overall responses at each time point of tumor assessment will be 
evaluated based on measurable and non-measurable lesions by investigator using criteria in 
Table 4.3.1-3 (Wolchock et al., 2009). The confirmation of irCR and irPR is not required.  
However, per irRECIST, the confirmation of irPD is recommended by using the subsequent 
tumor evaluation at least 4 weeks after the first irPD.  
Table 4.3.1-3  Table Derivation of irRC Overall Responses 
 
 
 
Best overall response (irBOR) will be derived from overall responses at different time points 
for a subject. The order of irBOR is irCR, irPR, irSD and irPD.   
4.3.2 
Medical History and Physical Examination, Electrocardiogram, and Vital 
Signs 
A complete physical examination and an abbreviated symptom-driven physical examination 
will be conducted according to the schedule presented in Section 4.2.  Note that “physical 
examination” implies that a licensed independent healthcare provider (i.e., physician, 
physician’s assistant, or licensed nurse practitioner) will perform the exam, and this is the 
requirement for this study; “physical assessment” or “health assessment” should not be used. 

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Vital signs (oral temperature, blood pressure, heart rate, and respiratory rate) will be assessed 
according to the schedule presented in Section 4.2.  At any time, if an infusion reaction 
occurs, obtain vital signs every 15 minutes until symptoms resolve.  Vital signs are to be 
obtained in the seated or supine position after the subject has been resting for at least 
5 minutes. 
Twelve (12)-lead ECGs will be obtained after 10 minutes of supine rest and recorded for all 
subjects according to the schedule presented in Section 4.2.  All ECGs recorded during the 
study will be obtained in triplicate (all 3 within a 5-minute time period at least 1 minute 
apart).  The same method of assessment should be used for each subject throughout the 
study.  Date and time settings should be checked at the start of each study day and aligned 
with an official timekeeper for all machines used in the study.  Skin preparation should be 
thorough and electrode positions should be according to standard 12-lead ECG placement.  
The following variables will be reported: heart rate, RR, PR, QRS, QT and QTcF intervals.  
Additional 12-lead ECGs may be added by the investigator if clinically indicated, e.g., in the 
event of a cardiac AE. 
4.3.3 Clinical Laboratory Tests 
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study.  
Clinical laboratory safety tests will be performed in a licensed clinical laboratory.  Urine 
pregnancy tests may be performed at the site using a licensed test (dipstick).  Clinically 
significant abnormal laboratory results should be repeated as soon as possible (preferably 
within 24 to 48 hours).  
Where performing serum safety laboratory tests is not locally available or obtaining them 
would present a hardship for the subject, plasma tests may be used. 
The following clinical laboratory tests will be performed (see Section 4.2 for the schedule of 
tests):  
Serum Chemistry (Local Laboratory) 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Sodium 
• 
Total protein 
• 
Potassium 
• 
Albumin 
• 
Chloride 
• 
Alkaline phosphatase (ALP) 
• 
Blood urea nitrogen (BUN) 
• 
Total bilirubin 
• 
Creatinine 
• 
Direct bilirubin (obtain anytime total bilirubin is 2 × ULN) 
• 
Calcium 
• 
Alanine transaminase (ALT) 
• 
Magnesium 
• 
Aspartate transaminase (AST) 

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• 
Phosphorous 
• 
Amylase 
• 
Lipase 
 
Note for serum chemistries: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently 
and assessed concurrently.  
Where performing serum safety laboratory tests is not locally available or obtaining them would present a 
hardship for the subjects, plasma tests may be used. 
Thyroid Panel (Local Laboratory) 
• 
Thyroid-stimulating hormone (TSH) 
• 
Free thyroxine (Free T4) 
 
Coagulation Panel (Local Laboratory) 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 
• 
Activated partial thromboplastin time (aPTT) 
 
Virology (Local Laboratory) 
• 
Hepatitis B surface antigen (HepB SA) 
• 
Reflex Hepatitis C RNA (HepC RNA) 
• 
Hepatitis B core antibody (HepB cAb) 
• 
Human immunodeficiency virus (HIV) 
• 
Hepatitis C antibody (HepC Ab) 
• 
Viral Load (VL) 
 
Hematology (Local Laboratory) 
• 
Red blood cell (RBC) count 
• 
White blood cell (WBC) count 
• 
Hemoglobin (Hgb) 
• 
Automated white blood cell differential 
• 
Hematocrit (Hct) 
• 
Neutrophils (absolute) 
• 
MCV 
• 
Lymphocytes (absolute) 
• 
MCH 
• 
Eosinophils (absolute) 
• 
MCHC 
• 
Monocytes (absolute) 
• 
RDW 
• 
Platelet count 
 
Urinalysis (Local Laboratory) 
• 
pH 
• 
Ketone 
• 
Specific gravity 
• 
WBC 
• 
Color 
• 
Blood 
• 
Clarity 
• 
Protein 
• 
Nitrate 
• 
Glucose 
 
Testing for pregnancy or ability to become pregnant (Local Laboratory) 
• 
Urine human chorionic gonadotropin (hCG) 
Follicle Stimulating Hormone (FSH) 
• 
Serum beta-hCG (at screening only) 
 
 
Autoantibody Testing (Local Laboratory) 
• 
Anti-nuclear antibody (ANA) 
 

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Complement Studies (Central Laboratory)a 
• 
CH50 
C4 
• 
C3 
 
 
Immune Complex Assays (Central Laboratory)a 
• 
C1q binding assay 
Raji cell assay 
a Refer to Section 4.3.3.1 for guidance on safety tests related to Serum Sickness 
4.3.3.1 Other Safety Tests 
Safety will be determined by reporting of AEs; by findings on physical exams; and by vital 
signs, ECG, and laboratory tests to include CBC, chemistry, thyroid panel and urinalysis.  
The severity of AEs, laboratory abnormalities, or other abnormal clinical assessments will be 
graded based on the NCI-CTCAE v4.03.  
Special attention will be given to monitor any instance of irAEs such as dermatitis, colitis, 
pneumonitis or pulmonary toxicities.  
Whole blood and serum samples should be obtained in the event subjects experience 
symptoms associated with irAEs and at the onset of any SAE, irAEs, during any suspected 
infusion related reaction, and at time of progression when a subject is taken off study, so long 
as the investigator believes the readouts would be informative, and that the collection would 
not pose an undue risk to the subject.  These samples may include chemistry, CBC, thyroid 
panel, PK, ADA, ANA, serum and blood collection for pharmacodynamic analysis. 
In the event of a serum sickness like reaction (see NCI-CTCAE), with symptoms such as 
fever, rash, and arthritis, the following laboratory tests should be obtained at the time of 
evaluation: CBC with differential, serum chemistry including BUN, creatinine and liver 
function tests, complement studies including CH50, C3, C4, C1q binding assay, Raji cell 
assay (if the complement and C1q binding assays are not definitive but serum sickness is still 
suspected), and urinalysis to detect urine protein and blood and rule out possible infection. 
4.3.4 Pharmacokinetic Evaluation and Methods 
Measurement of toripalimab in serum will be performed using a validated capture ELISA 
method.  
Blood samples for measurement of toripalimab concentrations in serum will be collected 
according to the schedule presented in Section 4.2.  

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Extensive time points will be collected during Cycles 1 (Part A and Part B [first 20 subjects]) 
and Cycle 3 (Part A and Part B [first 20 subjects]), after which peak (end of infusion [EOI]) 
and trough levels will be collected with each dose through Cycle 6 and every 4th cycle on 
Day 1 beginning in Cycle 8 (Part A and first 20 subjects in Part B).  In Part B, after the first 
20 subjects are enrolled, PK for the subsequently enrolled subjects will be obtained at peak 
(EOI) and trough on Day 1 of Cycles 1 and 2, on Day 1 of every even cycle through Cycle 6, 
and every 4th cycle on Day 1 beginning in Cycle 8. Additional PK samples may be collected 
at the discretion of the principal investigator and the onset of any SAE or irAE, and when the 
subject is taken off study.  Details for collection, aliquoting, storage, and shipment of serum 
samples for PK evaluations are presented in a separate Laboratory Manual. 
If toripalimab is infused peripherally, PK blood draws must be taken from the contralateral 
arm or from a central line.  If toripalimab is infused via a central line, PK blood draws must 
be obtained peripherally.  If the infusion was interrupted, the reason for interruption must be 
documented on the eCRF.  
4.3.5 Immunogenicity Evaluation and Methods 
Presence of ADA will be assessed in samples obtained according to the schedule presented in 
Section 4.2.  Samples will be measured for the presence of ADA using a validated 
immunoassay.  
4.4 
Biomarker Evaluation and Methods 
Blood and tumor samples for pharmacodynamic analyses will be obtained according to the 
schedule presented in Section 4.2.  Details for collection, storage, and shipment of biologic 
samples are presented in a separate Laboratory Manual. 
4.4.1 Pharmacodynamic Measurements 
Pharmacodynamic measurements using [whole blood, serum and/or plasma] samples include 
PD-1 RO assays to measure target engagement and lymphocyte subset analysis.  TopAlliance 
Biosciences will also conduct additional pharmacology studies, to further characterize the 
activity of toripalimab. 
Pharmacokinetic results will be correlated with pharmacodynamic outcomes where possible.  
Pharmacodynamic measurements using paired, pre and post treatment biopsies may also be 
performed.  Samples will be processed to enable immunohistochemistry (IHC) and/or gene 
expression analysis to evaluate the immunologic status of the tumor microenvironment and 
assess the impact of toripalimab treatment within the tumor microenvironment.  

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4.4.2 Predictive Biomarkers 
Candidate biomarkers for subject selection will be assessed to determine whether these 
biomarkers predict which subjects are most likely to respond to treatment with toripalimab. 
Pembrolizumab is an approved agent for the treatment of unresectable or metastatic MSI-H 
or dMMR solid tumors that have progressed following prior treatment and who have no 
satisfactory alternative treatment options or colorectal cancer that has progressed following 
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. MSI and/or MMR status 
information of all patients enrolled will be collected when available. 
 
 
4.5 
Archival Tumor Samples and Tumor Biopsies 
4.5.1 Archival Tumor Samples 
Archival tumor samples are required for all subjects not providing fresh pre-treatment 
biopsies, and adequate tissue for biomarker analysis must be deemed available during the 
screening period.  For subjects who have provided fresh pre-treatment biopsies, archival 
specimens will also be requested.  Formalin fixed paraffin embedded (FFPE) tumor samples 
will be collected for IHC and additional correlative markers (e.g., tumor mutation analysis, 
RNA analysis, and immunodiversity).  If a tumor block cannot be provided for this study, 
then only freshly prepared unstained sections should be provided as described in the 
Laboratory Manual. 
4.5.2 Tumor Biopsies 
Fresh pre-treatment tumor biopsies that are safely accessible will be requested from all 
subjects in Part A and required from all subjects in Part B.  Image-guided core needle tumor 
biopsy will be performed according to institutional practice during screening.   
Following initiation of toripalimab, post-treatment tumor biopsies will be at the PIs 
discretion at the occurrence of progressive disease, pseudoprogression or partial response.  
Tumor lesions used for biopsy should not be lesions used as RECIST/irRECIST target 
lesions, unless there are no other lesions suitable for biopsy.  If a RECIST/irRECIST target 
lesion is used for biopsy the lesion must be ≥ 2 cm in longest diameter.  Additional tumor 
biopsies are permitted as clinically indicated (e.g., for mixed responses or upon PD), and as 
long as the additional biopsy does not pose unacceptable medical risk to a subject as 
determined by the investigator.  

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For all fresh biopsies, if clinically practical, at each time point, subjects will provide 4 core 
biopsies, but a minimum of at least 3 core biopsies are required.  The first and third core 
biopsies will be placed in formalin and processed for FFPE at the central laboratory, while 
the second and fourth core biopsies (fourth biopsy, if available) will be immediately stored in 
RNA Later. 
Tumor biopsies will be stored at an appropriate vendor selected by TopAlliance Biosciences. 
Core and punch biopsies may be used for correlative studies such as IHC, tumor mutation 
analysis, RNA analysis, proteomic analysis, and immunodiversity.  Additional details for 
sample collection, processing, storage, and shipment will be provided in the Laboratory 
Manual. 
4.6 
Estimate of Volume of Blood to Be Collected 
Dose-escalation and Dose-Expansion Phases 
Blood draw volumes at screening and during each cycle are provided in Table 4.5.2-1 (Part 
A) and Table 4.5.2-2 (Part B).  The total volume to be collected will depend on the number 
of doses administered and the length of follow-up. 
Table 4.5.2-1  Blood Draw Volumes – Part A 
Timepoint 
Blood Draw Volume Volume Equivalent 
Screening 
27mL 
Approximately 1 ounce 
Cycle 1 
132mL 
Approximately 5 ounces 
Cycles 2, 4, & 6 
60mL 
Approximately 2 ounces 
Cycle 3 
89mL 
Approximately 3 ounces 
Cycle 5 
48mL 
Approximately 1.5 ounces 
Cycle 7 & 10 
24mL 
Approximately 1 ounce 
Cycle 8 
35mL 
Approximately 1 ounce 
Cycles 9, 11, 13, 14, 15, 17, 18, & 19 
20mL 
Approximately 4 teaspoons 
Cycle 12, 16, & 20 
31mL 
Approximately 1 ounce 
End of Treatment & 90 Days Post Treatment 
16mL 
Approximately 1 tablespoon 
Unscheduled Visit 
20mL 
Approximately 4 teaspoons 
 
 
 

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Table 4.5.2-2  Blood Draw Volumes – Part B 
Timepoint 
Blood Draw Volume Volume Equivalent 
Screening 
37mL 
Approximately 7 teaspoons 
Cycle 1 
125mL 
Approximately 4 ounces 
Cycles 2, 4, & 6 
53mL 
Approximately 2 ounces 
Cycle 3 
65mL 
Approximately 2 ounces 
Cycle 5 
36mL 
Approximately 7 teaspoons 
Cycle 7 
24mL 
Approximately 1 ounce 
Cycles 8, 12, 16, & 20 
41mL 
Approximately 8 teaspoons 
Cycles 9, 10, 11, 13, 14, 15, 17, 18, & 19 
24mL 
Approximately 4 teaspoons 
End of Treatment & 90 Days Post Treatment 
15mL 
Approximately 1 tablespoon 
Unscheduled Visit 
19mL 
Approximately 4 teaspoons 
 
4.7 
Study Suspension or Termination 
The sponsor reserves the right to temporarily suspend or terminate this study at any time.  
The reasons for temporarily suspending or terminating the study may include but are not 
limited to the following:  
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects 
• Subject enrollment is unsatisfactory 
• Non-compliance that might significantly jeopardize the validity or integrity of the 
study  
• Sponsor decision to terminate development 
• Sponsor decision to terminate the study based on a planned futility analysis 
If TopAlliance Biosciences determines that temporary suspension or termination of the study 
is required, TopAlliance Biosciences will discuss the reasons for taking such action with all 
participating investigators (or head of the medical institution, where applicable).  When 
feasible, TopAlliance Biosciences will provide advance notice to all participating 
investigators (or head of the medical institution, where applicable) of the impending action. 

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Once the container closure integrity of the vial has been breached, toripalimab must be fully 
infused within 4 hours. 
Toripalimab Preparation 
 
The toripalimab dose to be administered to the subject will be diluted in 0.9% NaCl.  The 
toripalimab volume, 0.9% NaCl volume, and total deliverable volume for each dose level is 
captured in Table 4.8.1-2. 
Table 4.8.1-2  Toripalimab, 0.9% NaCl and Total Deliverable Volume 
Dose Level 
(mg) 
Toripalimab 
Volume 
(mL) 
0.9% NaCl 
Volume 
(mL) 
Total Deliverable 
Volume 
(mL) 
80 
2 
98 
100 
240 
6 
94 
100 
480 
12 
88 
100 
 
 
Note that empty IV bags should be used and filled with the appropriate volume of 0.9% NaCl 
and toripalimab (e.g.; for the 80mg dose level, add to the empty IV bag, 98mLs of 0.9% 
NaCl followed by 2mLs of toripalimab).  
Dose Preparation Steps 
No incompatibilities between toripalimab in diluent and plastics passing compatibility tests 
(i.e., polyolefin and polyvinylchloride IV bags; polycarbonate syringe) have been observed.  
Toripalimab does not contain preservatives and any unused portion must be discarded.  
Preparation of toripalimab is to be performed aseptically.  Total in-use storage time from 
removal of toripalimab from the refrigerator and diluent to completion of administration 
should not exceed 4 hours at room temperature.  If storage time exceeds these limits, a new 
dose must be prepared from new vials. 
Dose should be prepared in an IV bag for IV infusion.  An empty IV bag must be used (i.e., 
empty bag provided from manufacturer).  To prepare the IV bag, first determine the volume 
of toripalimab and 0.9% NaCl required based upon the assigned Dose Level (Table 4.8.1-2).  
Second, add the required volume of 0.9% NaCl to the IV bag as appropriate for the intended 
dose.  Third, add the required dose volume of toripalimab to the IV bag.  Gently mix the 
solution in the bag or syringe by inverting up and down.  Avoid shaking the IV bag to 
prevent foaming. 
Following preparation of the dose, the entire contents of the IV bag should be administered 
as an IV infusion at a constant rate.  See Section 4.8.1.2 for treatment administration. 

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Investigational Product Inspection 
Each vial selected for dose preparation should be carefully inspected.  Toripalimab is 
supplied as a sterile liquid dosage form filled in a glass vial configuration.  The products 
must be stored refrigerated at 2°C to 8°C until ready to use.  
Toripalimab drug product container closure system is a particle-free, pyrogen-free, sterile 6 
mL glass vial, with 20 mm stoppers (butyl rubber) and 20 mm aluminum crimp.  The label is 
white. 
If there are any defects noted with toripalimab, the Investigator and Site Monitor should be 
notified immediately.  Refer to the Section 4.8.1.4 for further instructions. 
4.8.1.2 Treatment Administration 
The first day of dosing is considered Day 1.  In Part A, toripalimab will be administered by 
IV infusion on Day 1 and Day 15 of a 28-day treatment cycle.  In Part B, toripalimab will be 
administered by IV infusion on Day 1 and Day 22 of a 42-day treatment cycle. Cycles may 
be repeated every 28 days (± 2d) (Part A) or every 42 days (± 2d) (Part B) in the absence of 
confirmed PD, clinical deterioration, and if investigators consider that subjects continue to 
receive benefit from treatment. 
The final solution containing toripalimab will be infused IV via a volumetric syringe pump or 
infusion pump at a constant rate.  A 0.22 or 0.2-μm in-line filter should be used for IV 
infusion. toripalimab will be administered IV over a minimum of 60 minutes in Cycle 1.  
After Cycle 1, the infusion duration may be decreased to infuse over a minimum of 30 
minutes depending upon subject tolerance and occurrence of AEs.  Slowly infusing the study 
drug will allow sufficient time to interrupt the infusion in the case of infusion reactions.  The 
infusion time may be extended at any time to reduce infusion reactions.  Flush the IV line 
with a volume of normal saline equal to the priming volume of the infusion set used after the 
contents of the IV bag are fully administered. 
4.8.1.3 Monitoring of Dose Administration  
Vital signs to include temperature, blood pressure, heart rate, and respiratory rate will be 
monitored during and after infusions as follows: 
Part A: Cycle 1, Days 1 & 15: 
Within 30 minutes (± 30 minutes) prior to start of toripalimab infusion, every 15 minutes 
(± 5 minutes) during infusion, at the end of infusion (± 5 minutes), and 30 minutes 
(± 5 minutes) and 4 hours (± 15 minutes) post end of infusion of toripalimab, followed by 
a 2-hour (± 15 minute) period of observation (Cycle 1 only). 

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All cycles beyond Cycle 1, Days 1 & 15: 
Within 30 minutes (± 30 minutes) prior to start of toripalimab infusion, every 30 minutes 
(± 5 minutes) during infusion, and at the end of infusion (± 5 minutes) of toripalimab. 
Part B: Cycle 1 Day 1: 
Within 30 minutes (± 30 minutes) prior to start of toripalimab infusion, every 15 minutes 
(± 5 minutes) during infusion, at the end of infusion (± 5 minutes), and 30 minutes 
(± 5 minutes) and 4 hours (± 15 minutes) post end of infusion of toripalimab, followed by 
a 2-hour (± 15 minute) period of observation. 
Cycles 2, 3 and 4: 
Within 30 minutes (± 30 minutes) prior to start of toripalimab infusion, every 30 minutes 
(± 5 minutes) during infusion and at end of infusion (± 5 minutes). 
Cycles 5 and beyond: 
Within 30 minutes (± 30 minutes) prior to start of toripalimab infusion and at end of 
infusion (± 5 minutes). 
Refer to Section 4.2 and Section 4.3.2 for more information regarding assessment of vital 
signs.  Refer to Section 3.1.7.3 for information on the management of toripalimab related 
toxicities. 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The study 
site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit subjects to an intensive care unit if necessary. 
4.8.1.4 Reporting Product Complaints 
Any defects with toripalimab must be reported immediately to TopAlliance Biosciences by 
the site with further notification to the site monitor.  During the investigation of the product 
complaint, all toripalimab must be stored at labeled conditions unless otherwise instructed. 
TopAlliance Biosciences contact information for reporting product complaints: 
Email: 
productcomplaints@topalliancebiosciences.com 
Email subject line should include: “Toripalimab Product Complaint” 
4.8.2 Additional Study Medications 
No other study medications are specified for use in this clinical protocol. 

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4.8.3 Labeling
 
Labels for toripalimab will be prepared in accordance with Good Manufacturing Practice 
(GMP) and local regulatory guidelines.  The label will fulfill GMP Annex 13 requirements 
for labeling.  If applicable, label text will be translated into local languages, as required. 
4.8.4 Storage
 
Store toripalimab between 2°C to 8°C. 
4.8.5 Treatment Compliance 
Toripalimab is administered by study site personnel, who will monitor compliance.  The 
study monitor will evaluate treatment compliance during monitoring visits. 
4.8.6 Accountability 
The investigator’s or site’s designated toripalimab manager is required to maintain accurate 
toripalimab accountability records.  Upon completion of the study, copies of toripalimab 
accountability records will be returned to TopAlliance Biosciences or their designee.  All 
unused toripalimab will be returned to an TopAlliance Biosciences-authorized depot or 
disposed of upon authorization by TopAlliance Biosciences. 
4.9 
Treatment Assignment and Blinding 
4.9.1 Methods for Assigning Treatment Groups 
A designated form will be used for enrollment to a cohort and assignment of unblinded 
toripalimab.  A subject is considered enrolled into the study when the investigator notifies the 
Clinical Research Organization (CRO) of the subject’s eligibility and the CRO assigns the 
part (A or B) of the study the subject will be enrolled into.  The CRO will also assign the 
cohort into which the subject will be enrolled.  
All subjects will receive toripalimab.  
If there is a delay in the administration of toripalimab such that it will not be administered 
within the timeframe specified on the Enrollment Form, the study monitor must be notified 
immediately. 
4.9.2 Methods for Ensuring Blinding 
This study is not blinded. 

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4.10 Restrictions During the Study and Concomitant Treatment(s) 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening through 90 days post last dose of toripalimab.  Subjects may continue their 
baseline medication(s) as long as the medications are not prohibited as outlined in 
Section 4.10.2.  The daily dose of each medication should be maintained throughout the 
study, if possible.  Any concomitant medication(s), including herbal preparations, taken 
during the study will be recorded in the eCRF.  The eCRFs will capture the medication(s), 
dosage, route of administration, start and stop dates, and the indication for which it was 
given. 
4.10.1 Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.10.2.  Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, 
anti-emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines. 
4.10.1.1 
Prophylactic Pre-Medications 
Primary prophylaxis against infusion-related reactions is not permitted during this study in 
order to avoid obscuring potential safety signals and enable a future assessment regarding 
whether premedications should be required for all subjects in future studies.  However, at the 
discretion of the investigator, secondary prophylaxis (i.e., prevention of infusion-related 
reaction following initial episode) is appropriate and will be permitted with the following 
recommended regimen: acetaminophen (e.g., 650 to 1000 mg) and diphenhydramine (e.g., 
12.5 to 25 mg) may be administered approximately 30 minutes prior to the start of the 
toripalimab infusion.  Consideration can be given to premedicating with non-sedating anti-
histamines (e.g., cetrizine) instead of diphenhydramine for subjects with recurrent infusion 
related reactions. 
At the discretion of the investigator, administer intravenous doses of meperidine (e.g., 10 to 
25 mg) and promethazine (e.g., 12.5 to 25 mg) or their equivalents just prior to the start of 
the toripalimab infusion.   
NOTE: Pre-treatment medications may need to be repeated during the course of the infusion; 
therefore, this should be taken into consideration when deciding on the dosage of the 
pre-treatment medications. 

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4.10.1.2 
Corticosteroids 
The following corticosteroids are permitted while on study: 
• Intranasal or inhaled corticosteroids or systemic corticosteroids at physiologic doses not 
to exceed 10 mg/day of prednisone or equivalent.  
• Systemic corticosteroids required for the control of infusion reactions or irAEs must be 
tapered and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or 
equivalent) for at least 2 weeks before the next study drug administration.  For irAEs that 
are Grade 2 (moderate), prednisone 0.5 mg/kg/day or equivalent should be initiated if 
symptoms persist beyond a week.  For Grade 3 (severe) or Grade 4 (life threatening) 
irAEs, prednisone 1-2 mg/kg/day or equivalent should be given until symptoms have 
improved to Grade 1 (mild) or less, then tapered slowly over a month or more.  Note that 
approximate equivalent doses for prednisone 5 mg are: methylprednisolone 4 mg; 
dexamethasone 0.75 mg; and hydrocortisone 20 mg.  Note that for the irAE of diarrhea, if 
corticosteroids are not effective after about 3 days, treatment with the TNF inhibitor 
infliximab in a dose of 5 mg/kg should be considered, but should be avoided in patients 
with immune-mediated hepatitis.   
• Corticosteroids as prophylactic treatment for subjects with contrast allergies to diagnostic 
imaging contrast dyes will be permitted. 
4.10.1.3 
Vaccination 
The use of live, attenuated vaccines within 4 weeks prior to receiving a toripalimab dose is 
prohibited.  After treatment with toripalimab, it is best to wait until at least 4 weeks have 
transpired or until recovery of immune responses (e.g., B lymphocytes) before giving live, 
attenuated vaccines.  However, the use of killed vaccines for the prevention of influenza is 
permitted at the discretion of the investigator.  The use of killed vaccines for the prevention 
of any infectious disease may be permitted on a case-by-case basis and must be discussed 
with the medical monitor prior to its use.  All vaccinations administered during the study 
must be recorded in the eCRF. 
4.10.1.4 
Prophylactic Therapies 
Palliative/therapeutic therapies such as radiotherapy for pain, thoracentesis or paracentesis 
for comfort may be administered after consultation with the medical monitor. 
4.10.1.5 
Treatment of Isolated Lesions 
Treatment of isolated/symptomatic lesions by local surgery or radiation therapy is permitted 
for palliative or potentially curative management at any time during the study, provided that 

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the isolated lesion is not the only target lesion being assessed.  All interventions should be 
discussed in advance with the medical monitor.  Radiation therapy should be scheduled to 
minimize treatment delays.  
4.10.2 Prohibited Concomitant Medications 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
The following medications are considered exclusionary during the study.  The sponsor must 
be notified if a subject receives any of these during the study. 
• Any investigational anticancer therapy. 
• Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for 
cancer treatment.  Concurrent use of hormones for noncancer-related conditions (e.g., 
insulin for diabetes and hormone replacement therapy) is acceptable.  
• Live attenuated vaccines 
• Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses beyond 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and tumor necrosis factor alpha (TNF-α) blockers.  Use of immunosuppressive 
medications for the management of toripalimab related AEs in subjects with contrast 
allergies is acceptable.  In addition, use of inhaled and intranasal corticosteroids or 
systemic corticosteroids are permitted at physiologic doses not to exceed 10 mg/day 
of prednisone or equivalent.  
NOTE: Local treatment of isolated lesions for palliative intent is acceptable (e.g., by 
local surgery or radiotherapy). 
4.11 Statistical Evaluation 
4.11.1 General Considerations 
There will be no formal hypothesis testing.  All statistical analyses will be performed using 
SAS Version 9.3 or higher, unless otherwise noted.  In general, analysis of categorical 
variables will include counts and percentage of subjects in each category observed.  For 
continuous variables, the sample size (n), mean, standard deviation (SD), mean, median, 
minimum, and maximum will be presented.  Missing data will not be imputed unless 
otherwise stated.  Subject demographics, baseline characteristics, and disposition will be 
characterized using descriptive statistics.   

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No formal interim analysis is planned for this study.  However, a review of safety data and 
available PK data will be performed after completion of each dose escalation cohort.  A 
statistical analysis plan (SAP) will fully describe the planned analyses for this study. 
4.11.2 Sample Size 
The sample size will include up to 18 subjects in escalation phase plus approximately 280 
subjects in expansion phase for a total of up to approximately 298 subjects.  Assuming a 10% 
drop out rate, a total of up to approximately 327 subjects are expected to be enrolled.  
Expansion cohorts may include 5 disease-specific cohorts, and at the discretion of the 
Sponsor, another tumor cohort, to a maximum of 80 subjects in a sarcoma cohort (minimum 
of 40 subjects with either angiosarcoma, undifferentiated pleomorphic sarcoma or alveolar 
soft part sarcoma) and 40 subjects for the other 5 cohorts. The indications initially pursued in 
the expansion phase will be decided based on responses in the escalation phase, and other 
considerations. 
4.11.3 Safety Analysis 
4.11.3.1 
MTD Evaluation 
Maximum tolerated dose evaluation will be based on the DLT evaluable subjects. DLT 
events will be summarized descriptively. 
4.11.3.2 
Analysis of Safety Endpoints 
The results from AEs, CMs, vital signs, ECGs, safety lab results, and physical examinations 
will be provided in listings.  AEs and medical history will be coded using the MedDRA 
version 19.1 or higher.  CMs will be coded using WHODrug version September 2016 or 
higher.  Safety summaries will include the Safety Population, i.e. subjects receiving any 
amount of toripalimab.  Summaries of AEs and other parameters will be provided in 
summary tables to assess frequency of incidence.  Shift tables for AEs, ECGs, and other 
Safety parameters will be generated to assess changes from baseline.  A list of preferred 
terms designated as AESIs will be provided in the SAP. 
4.11.4 Efficacy Analyses 
Efficacy analyses will include all subjects who received study drug.  ORR and DCR will be 
presented for each dose cohort in Part A and expansion cohort in Part B.  For the expansion 
phase, PFS will be presented for each expansion cohort.  For PFS and OS, subjects not 
achieving the endpoint will be censored at the time of last endpoint assessment. If a subject 
receives alternate therapy prior to PD (or irPD, respectively) or death without PD, this 
subject will be censored at the date of their last radiological assessment prior to start of 

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4.11.9 Interim Analysis 
No formal interim analysis will be performed. 
5 
ASSESSMENT OF SAFETY 
5.1 
Definition of Adverse Events 
The International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as: 
Any untoward medical occurrence in a patient or 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 a 
medicinal product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition.  An abnormal laboratory finding (including ECG finding) that requires an 
action or intervention by the investigator, or a finding judged by the investigator to represent 
a change beyond the range of normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of toripalimab) 
or nontreatment emergent.  A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received toripalimab.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious).  An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE unless the investigator deems the event to be related to 
the use of the study drug. 
Progression of disease is considered an efficacy outcome parameter, and for AE/SAE 
reporting purposes, is excluded from the definition of an AE and SAE.  Similarly, death from 
progressive disease will not be considered an AE or SAE. 
5.2 
Definition of Serious Adverse Events 
An SAE is any AE that: 
• Results in death 

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• Is immediately life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect in offspring of the subject 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
◦ 
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation.  Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalizations; or development 
of drug dependency or drug abuse. 
5.3 
Definition of Adverse Events of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of toripalimab and may require close monitoring and rapid communication 
by the investigator to the sponsor.  An AESI may be serious or nonserious.  The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this toripalimab. 
5.3.1 Adverse event(s) of special interest  
Adverse events that are considered AESIs and require immediate reporting are listed below: 
• Hepatic function abnormality meeting the definition of Hy’s law. See Section 5.7.3 for 
the definition and reporting of AESIs of hepatic function abnormality.  
• ≥ Grade 3 endocrinopathy (e.g., hypophysitis, thyroiditis, adrenal insufficiency) 
• ≥ Grade 3 dermatologic AE 
• ≥ Grade 3 pneumonitis 
• ≥ Grade 3 enterocolitis 
• ≥ Grade 3 serum sickness (see Section 4.3.3.1) 
AESIs ≥ Grade 3 are required to be reported within 24 hours of knowledge of the event to 
TopAlliance Biosciences Patient Safety representative (
) using the SAE/AESI 

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Report Form, even if the event is considered to be nonserious (see Section 5.6 for contact 
information). 
5.4 
Recording of Adverse Events 
Adverse events will be recorded on the eCRF using a recognized medical term or diagnosis 
that accurately reflects the event.  Adverse events will be assessed by the investigator for 
severity, relationship to toripalimab, possible etiologies, and whether the event meets criteria 
of an SAE and therefore requires immediate notification to TopAlliance Biosciences Patient 
Safety representative (
).  See Section 5.2 for the definition of SAEs and 9.1 
for guidelines for assessment of severity and relationship.  If an AE evolves into a condition 
that meets the regulatory definition of “serious,” it will be reported on the SAE Report Form. 
Infusion of biological products is commonly associated with infusion related reactions.  
Anaphylaxis and infusion related reactions have some common manifestations and may be 
difficult to distinguish from each other.  Infusion related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic monoclonal antibodies delivered 
through intravenous infusion.  These reactions are less common following subsequent 
exposures. Unlike infusion related reactions, anaphylaxis is a rare event, usually occurring 
after subsequent exposure to an antigen, and it is most commonly accompanied by severe 
systemic skin and or mucosal reactions.  The Investigator is advised to carefully examine 
symptoms of adverse reactions observed during or shortly after exposure to toripalimab, and 
consider the above mentioned facts prior to making a final diagnosis.  Reactions occurring at 
the time of or shortly after subsequent infusions of toripalimab are to be judged by the 
investigator at his/her own discretion.  For the Investigator’s convenience and in order to 
facilitate consistency in judgments, a copy of the National Institute of Allergy and Infectious 
Diseases (NIAID) and Food Allergy and Anaphylaxis Network (FAAN) guidance for 
anaphylaxis diagnosis is provided in Section 9.2. 
5.4.1 Time Period for Collection of Adverse Events 
AEs and SAEs will be collected from the start of the first dose, throughout the treatment 
period, and through the 90 days post last dose of toripalimab. 
All AEs or other clinically significant AEs occurring up to 90 days after administration of the 
last dose of study drug will be collected for subjects continuing in the study.  For subjects 
who discontinue from the study within 90 days after the administration of the last dose of 
study drug: 

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• Study drug-related AE information will be collected and should be followed to resolution 
/ stabilization. 
• AEs that lead to the discontinuation should be followed to resolution / stabilization. 
• A telephone contact for the safety update would be acceptable if the subject cannot 
manage an office visit. 
Only study drug-related serious or other clinically significant (e.g., late emerging irAEs that 
are not serious) AEs will be collected for all subjects > 90 days after the administration of the 
last dose of study drug.   
A nonserious AE is an AE that does not have a classification of serious.  The collection of 
nonserious AE information should begin at initiation of study drug and should conclude 90 
days after last dose of study drug.  Nonserious AEs should be followed to resolution or 
stabilization, or reported as SAEs if they become serious (see Section 5.2).  Follow-up is also 
required for nonserious AEs that cause interruption or discontinuation of study drug, or those 
that are present at the end of study treatment as appropriate. All identified nonserious AEs 
must be recorded and described on the nonserious AE page of the eCRF. 
5.5 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved by End of study visit are followed up by the investigator for as 
long as medically indicated, but without further recording in the eCRF.  TopAlliance 
Biosciences retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
5.6 
Reporting of Serious Adverse Events 
Within 24 hours of identifying an SAE, regardless of the presumed relationship to 
toripalimab, the investigator or qualified designee must complete the SAE/AESI Report 
Form and fax or email it to TopAlliance Biosciences Patient Safety representative 
(PAREXEL International Medical Services). 
Patient Safety representative contact information:  
Name:  
 
Email: 
 
  
Fax:   
 
 

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The sponsor is responsible for reporting certain SAEs as expedited safety reports to 
applicable regulatory authorities, ethics committees, and participating investigators, in 
accordance with ICH Guidelines and/or local regulatory requirements.  The sponsor may be 
required to report certain SAEs to regulatory authorities within 7 calendar days of being 
notified about the event; therefore, it is important that investigators submit additional 
information requested by the sponsor as soon as it becomes available. 
Investigators should provide all available information at the time of SAE/AESI Report Form 
completion.  Investigators should not wait to collect additional information to fully document 
the event before notifying TopAlliance Biosciences Patient Safety representative of an SAE.  
When additional information becomes available, investigators should submit a follow-up 
SAE Report Form.  Any follow-up information to an SAE also needs to be provided to 
TopAlliance Biosciences Patient Safety representative within 24 hours of learning of the new 
information.  
5.7 
Other Events Requiring Immediate Reporting 
5.7.1 Dose-limiting Toxicity 
Dose-limiting toxicities are defined in Section 3.1.6.2.  Any subject who the principal 
investigator believes has experienced a toxicity that meets the DLT criteria should be 
reported within 24 hours of knowledge of the event to 
Medical Monitor so 
that the sponsor can confirm the occurrence of a DLT and notify all of the other 
investigators. 
5.7.2 Overdose 
An overdose is defined as a subject receiving a dose of toripalimab in excess of that specified 
in the IB, unless otherwise specified in this protocol. 
Any overdose of a study subject with the toripalimab, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to 
 
Medical Monitor.  If the overdose results in an AE, the AE must also be recorded on the AE 
eCRF (see Section 5.4).  Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the event is 
serious and must be reported as an SAE (Section 5.6).  TopAlliance Biosciences does not 
recommend specific treatment for an overdose.  The investigator will use clinical judgment to 
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5.7.3 Hepatic Function Abnormality 
Adverse events of hepatic function abnormality of special interest to the sponsor are defined 
as any increase in ALT or AST to greater than 3 × ULN and concurrent increase in bilirubin 
to greater than 2 × ULN and no reason exists other than exposure to the study drug (i.e., Hy’s 
law cases).  Concurrent findings are those that derive from a single blood draw or from 
separate blood draws taken within 8 days of each other. In the event of hepatic function 
abnormality where the etiology is unknown, timely follow-up investigations and inquiries 
should be initiated by the investigational site, based on medical judgment, to make an 
informed decision regarding the etiology of the event.  
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease such as primary or metastatic malignancy), the diagnosis 
should be recorded as an AE/SAE. 
If the underlying diagnosis for the hepatic function abnormality remains unknown, the term 
“hepatic function abnormal” should be used to report the AE/SAE. 
Hepatic function abnormality of unknown etiology, or which is considered attributable to 
toripalimab, is required to be reported as “hepatic function abnormal” within 24 hours of 
knowledge of the event to TopAlliance Biosciences Patient Safety representative using the 
SAE/AESI Report Form, even if the event is considered to be non-serious (see Section 5.6 
for contact information).  The investigator will review the data with the medical monitor.  
The investigator should then use clinical judgment to establish the cause based on local 
standard of care and follow the subject by conducting testing as clinically indicated. 
If, after appropriate workup, in the opinion of the investigator, the underlying diagnosis for 
the abnormality remains unexplained, or is considered attributable to toripalimab, permanent 
discontinuation of dosing for the study subject should be considered.  
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor.  
5.7.4 Pregnancy
 
Pregnancy in a female subject who has received toripalimab is required to be reported within 
24 hours of knowledge of the event to TopAlliance Biosciences Patient Safety representative 
using the Pregnancy Notification Form (see Section 5.6 for contact information).   
Subjects who become pregnant during the treatment period and prior to their first follow up 
visit must not receive additional doses of toripalimab but will not be withdrawn from the 
study.  The reporting period for the occurrence of a pregnancy is through 90 days after the 
last dose of toripalimab.  The pregnancy will be followed for outcome of the mother and 

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child (including any premature terminations) and should be reported to TopAlliance 
Biosciences Patient Safety representative after outcome. 
Pregnancy in a female clinical trial subject is not an SAE per se. Complications of such 
pregnancies, for example, spontaneous abortion, may qualify as an SAE and should be 
reported as an SAE even if they occur greater than 90 days past the last dose of toripalimab.  
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received toripalimab, this should be reported within 24 hours of knowledge of the 
event to TopAlliance Biosciences Patient Safety representative using the Pregnancy 
Notification Form (see Section 5.6 for contact information).  The sponsor will endeavor to 
collect follow-up information on such pregnancies provided the partner of the study subject 
provides consent.  
6 
STUDY AND DATA MANAGEMENT 
6.1 
Training of Study Site Personnel 
Before the first subject is entered into the study, a TopAlliance Biosciences representative 
will review and discuss the requirements of the Clinical Study Protocol and related 
documents with the investigational staff and also train them in any study-specific procedures 
and system(s) utilized. 
The principal investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
6.2 
Monitoring of the Study 
During the study, a TopAlliance Biosciences representative will have regular contacts with 
the study site, including visits to: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team are adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
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• Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects.  This will 
require direct access to all original records for each subject (e.g., clinic charts). 
• Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject. 
The TopAlliance Biosciences representative will be available between visits if the 
investigator(s) or other staff at the center needs information and advice about the study 
conduct. 
6.2.1 Source Data 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  Data reported in the eCRF derived from source documents should be 
consistent with the source documents. 
The primary source document for this study will be the subject’s medical record.  If the 
investigator(s) maintain separate research records, both the medical record and the research 
records will be considered the source documents for the purposes of auditing the study. 
The anonymity of subjects must be maintained.  Subjects will be identified by their initials 
and an assigned subject number on eCRFs and other documents submitted to the sponsor.  
Documents that identify the subject beyond initials and subject number will not be submitted 
to the sponsor (e.g., the signed informed consent document) and must be maintained in strict 
confidence by the investigator, except to the extent necessary to allow auditing by the 
regulatory authorities, study monitor, or sponsor representatives. 
Data recorded on source documents will be entered into eCRFs.  The investigator must 
promptly review the completed eCRFs for each subject.  A study monitor representing the 
sponsor will review the source documents against the eCRF on a regular basis through the 
study period.  
The principal investigator at each/the center should comply with all the terms, conditions, 
and obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of 
any inconsistency between this clinical study protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail. 

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Agreements between TopAlliance Biosciences and the principal investigator must be in place 
before any study-related procedures can take place, or subjects are enrolled. 
6.2.2 Archiving of Study Documents 
The investigator follows the principles outlined in the Clinical Study Agreement. 
6.3 
Study Timetable and End of Study 
An individual subject will be considered to have completed the study if the subject was 
followed through the last protocol-specified visit/assessment (including telephone contact), 
regardless of the number of doses of toripalimab that was received.   
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.5). 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. 
6.4 
Data Management 
Data management will be performed by a CRO according to the study specific Data 
Management Plan. 
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The investigator will ensure that data are recorded on the eCRFs as specified in the 
study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement.  The 
investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site. 
7 
ETHICAL AND REGULATORY REQUIREMENTS 
7.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements. 

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7.2 
Subject Data Protection 
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
The anonymity of subjects must be maintained.  Subjects will be identified by their initials 
and an assigned subject number on eCRFs and other documents submitted to the sponsor.  
Documents that identify the subject beyond initials and subject number will not be submitted 
to the sponsor (e.g., the signed ICF) and must be maintained in strict confidence by the 
investigator, except to the extent necessary to allow auditing by the regulatory authorities, 
study monitor, or sponsor representatives. 
TopAlliance Biosciences will not provide individual genotype results to subjects, any 
insurance company, any employer, their family members, general physician or any other 
third party, unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the subject.  In exceptional circumstances, however, certain individuals 
might see both the genetic data and the personal identifiers of a subject.  For example, in the 
case of a medical emergency, a TopAlliance Biosciences medical monitor or an investigator 
might know a subject’s identity and also have access to his or her genetic data.  Also, 
Regulatory authorities may require access to the relevant files, though the subject’s medical 
information and the genetic files would remain physically separate. 
7.3 
Ethics and Regulatory Review 
An IRB/IEC should approve the final study protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the subjects.  The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff. 
The opinion of the IRB/IEC should be given in writing.  The investigator should submit the 
written approval to TopAlliance Biosciences or designee before enrollment of any subject 
into the study.  
The IRB/IEC should approve all advertising used to recruit subjects for the study. 
TopAlliance Biosciences or designee should approve any modifications to the ICF that are 
needed to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually. 

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Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
TopAlliance Biosciences will handle the distribution of any of these documents to the 
national regulatory authorities. 
TopAlliance Biosciences will provide Regulatory Authorities, IRB/IEC and principal 
investigators with safety updates/reports according to local requirements, including suspected 
unexpected serious adverse reactions (SUSARs), where relevant. 
Each principal investigator must inform the IRB/IEC of: 
• Changes in informed consent 
• Revisions of other documents originally submitted for review 
• Serious and/or unexpected adverse events occurring during the study  
• New information that may adversely affect the safety of subjects or the conduct of the 
study 
• Annual update and/or request for re-approval 
• Study completion 
7.4 
Informed Consent 
A copy of the proposed informed consent document must be submitted to the sponsor for 
review and comment prior to submission to the reviewing IRB/IEC.  The consent form must 
be approved by the IRB/IEC and contain all elements required by national, state, local and 
institutional regulations or requirements.  
The principal investigator(s) at each center will: 
• Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
• Ensure each subject is notified that they are free to discontinue from the study at any time 
• Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 
• Ensure each subject voluntarily provides signed and dated informed consent before 
conducting any procedure specifically for the study 

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• Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
• Ensure a copy of the signed ICF is given to the subject 
• Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC 
7.5 
Changes to the Protocol and Informed Consent Form 
Protocol revisions will be prepared and approved by TopAlliance Biosciences and the 
medical monitor. Minor revisions will be submitted as administrative changes.  If there are 
any substantial changes to the study protocol, then these changes will be documented in a 
study protocol amendment and where required in a new version of the study protocol. 
All protocol amendments will be signed by the principal investigator and approved by the 
relevant IRB/IEC and if applicable, also the national regulatory authority approval, before 
implementation. Local requirements are to be followed for revised protocols.  Documentation 
of IRB/IEC approval must be forwarded to the sponsor 
TopAlliance Biosciences or their designee will distribute any subsequent amendments and 
new versions of the protocol to each principal investigator(s).  For distribution to IRB/IEC 
see Section 7.3. 
If a protocol amendment alters the study design, increases potential risk to the subject or 
otherwise affects statements in the ICF, the ICF must be revised accordingly and submitted 
to TopAlliance Biosciences and the IRB/IEC for review and approval before the revised ICF 
is used.  The approved consent form must be used to obtain informed consent from new 
subjects prior to enrollment and must be used to obtain ICF subjects already enrolled if they 
are affected by the amendment.  
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC. 
7.6 
Audits and Inspections 
Authorized representatives of TopAlliance Biosciences, a regulatory authority, or an 
IRB/IEC may perform audits or inspections at the clinical sites, including source data 
verification.  The purpose of an audit or inspection is to systematically and independently 
examine all study-related activities and documents, to determine whether these activities 

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were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP, guidelines of the ICH, and any applicable regulatory requirements.  The 
investigator will contact TopAlliance Biosciences immediately if contacted by a regulatory 
agency about an inspection at the site. 
 
 

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8 
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9 
APPENDIX 
9.1 
Appendix 1: Additional Safety Guidance 
Assessment of Severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs.  Severity will be graded according to the NCI-CTCAE v4.03 as provided 
below.  The determination of severity for all other events not listed in the NCI-CTCAE 
should be made by the investigator based upon medical judgment and the severity categories 
of Grade 1 to 5 as defined below. 
• Grade 1 (mild): 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living. 
• Grade 2 (moderate): An event that is usually alleviated with additional specific 
therapeutic intervention.  The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
• Grade 3 (severe): An event that requires intensive therapeutic intervention.  The event 
interrupts usual activities of daily living, or significantly affects the clinical status of the 
subject. 
• Grade 4 (life threatening): An event, and/or its immediate sequelae, that is associated 
with an imminent risk of death or with physical or mental disabilities that affect or limit 
the ability of the subject to perform activities of daily living (eating, ambulation, 
toileting, etc.). 
• Grade 5 (fatal): 
Death (loss of life) as a result of an event. 
It is important to distinguish between serious criteria and severity of an AE.  Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2.  A Grade 3 
AE need not necessarily be considered an SAE.  For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE. 
The NCI-CTCAE v4.03 will be provided in the Study Procedure Manual, and can be 
downloaded from the Cancer Treatment Evaluation Program (CTEP; 
http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). 

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Assessment of Relationship 
Relationship to toripalimab 
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
toripalimab. 
An event will be considered “not related” to use of the toripalimab if any of the following are 
met: 
• An unreasonable temporal relationship between administration of the toripalimab and 
the onset of the event (e.g., the event occurred either before, or too long after, 
administration of toripalimab for it to be considered product-related). 
• A causal relationship between the toripalimab and the event is biologically 
implausible (e.g., death as a passenger in an automobile accident). 
• A clearly more likely alternative explanation for the event is present (e.g., typical 
adverse reaction to a concomitant drug and/or typical disease-related event). 
Individual AE/SAE reports will be considered “related” to use of toripalimab if the “not 
related” criteria are not met.  
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (i.e., there are facts, evidence, or arguments to suggest possible 
causation). 
 
 
 

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9.2 
Appendix 2: National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis 
The National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and 
Anaphylaxis Network (FAAN) Network Guidance for Anaphylaxis define anaphylaxis as a 
serious allergic reaction that is rapid in onset and may cause death (Sampson et al, 2006). 
They recognize 3 categories of anaphylaxis, with criteria designated to capture from 80% of 
cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 categories).  
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia). 
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence). 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula). 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia). 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence). 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting). 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP. 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline. 
 

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9.3 
Appendix 3: Eastern Cooperative Oncology Group Performance 
Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair 
5 
Dead 
(Oken et al, 1982)  
 
 
 

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9.4 
Appendix 4: Cockcroft-Gault Formula 
Estimated creatinine clearance, or glomerular filtration rate =  
[(140-Age) × Mass (in kg)] \ [72 × Serum creatinine (in mg/dL)]  
If the patient is female, multiply the above by 0.85  
If the subject is obese (> 30% over ideal body weight), use ideal body weight in calculation 
of estimated creatinine clearance. 
 
Calculation of Ideal Body Weight  
Ideal Body Weight (IBW) in kg 
Males = 50 + [2.3 × each inch over 5 ft] 
 
or 50 + [2.3 kg × (each cm over 152.4/2.54)] 
Females = 45.5 + [2.3 × each inch over 5 ft] 
 
or 45.5 + [2.3 kg × (each cm over 152.4/2.54)] 
 
Calculation for Obesity  
[(actual weight - IBW)/IBW] × 100%.  If this value is > 30% then the person is obese.  
Example: 
Subject weight = 160.  Subject ideal weight = 120 
160-120 = 40 
40 / 120 = 0.33 
0.33 × 100% = 33% 
 
 

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9.5 
Appendix 5: Measured Creatinine Clearance Formula (Adjusted for 
Body Surface Area) 
Creatinine Clearance = CrCl (measured) × 1.73/body surface area (BSA) 
where CrCl (measured) = Ucr × Uvol) / (Scr × Tmin) 
And BSA (m2) = ([Height(cm) × Weight(kg)] / 3600)½ (Mosteller, 1987) 
Ucr: Urine creatinine (mg/dL) 
Uvol: Urine volume collected (mL) 
Scr: Serum creatine (mg/dL) 
Tmin: Total collection time (minutes) 
 
 
 

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9.6 
New York Heart Association (NYHA) Functional Classification 
NYHA 
CLASS 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, e.g. no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20-100m). 
Comfortable at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 
(Little, Brown & Co., 1994)