A Phase III, Randomized, Placebo Controlled, Multicenter, Double-Blind Study Comparing Toripalimab Injection (JS001) Combined With Chemotherapy Versus Placebo Combined With Chemotherapy for Recurrent or Metastatic Nasopharyngeal Cancer
Phase: PHASE3
Conditions: Recurrent or Metastatic NPC
Sponsor: Shanghai Junshi Bioscience Co., Ltd.

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JS001- Shanghai Junshi Biosciences Co., Ltd. 
JS001-015-III-NPC, Version 6.0 
 
Clinical Study Protocol 
Protocol Title:  
A PHASE III, RANDOMIZED, 
PLACEBO-CONTROLLED, MULTICENTER, 
DOUBLE-BLIND STUDY COMPARING 
TORIPALIMAB INJECTION（JS001） COMBINED 
WITH CHEMOTHERAPY VERSUS PLACEBO 
COMBINED WITH CHEMOTHERAPY FOR 
RECURRENT OR METASTATIC 
NASOPHARYNGEAL CANCER 
Protocol Number: 
JS001-015-III-NPC 
Test Product: 
Toripalimab Injection (JS001) 
Study Phase: 
Phase III 
Sponsor: 
Shanghai Junshi Biosciences Co., Ltd. 
Floor 13, Building 2, No. 36/58, Haiqu Road, Pudong New 
Area, Shanghai,200120, P.R.China 
Medical Monitor: 
Weihua Wang, Medical Director 
Principal Investigator: 
Prof. Ruihua Xu 
Version number:                                    6.0 
Version date:                                          2020-Oct-14 
Previous version:                                   1.0 (2018-Mar-02） 
2.0 (2018-Sep-17） 
3.0 (2019-May-28) 
4.0 (2020-May-15) 
4.1 (2020-May-26) 
5.0 (2020-Aug-18) 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or consultant for review by you, 
your staff, and the applicable Institutional Review Board/Independent Ethics Committee. Your acceptance of this 
document constitutes agreement that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 
 
 

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Table of Contents 
Table of Contents .......................................................................................................................................... 2 
List of Tables ................................................................................................................................................ 6 
List of Figures ............................................................................................................................................... 6 
List of Figures ............................................................................................................................................... 6 
Protocol Approval Form ............................................................................................................................... 8 
PROTOCOL ACCEPTANCE FORM .......................................................................................................... 9 
Protocol synopsis ........................................................................................................................................ 10 
List of Abbreviations and Definitions of Terms ......................................................................................... 20 
1 Introduction .............................................................................................................................................. 24 
1.1 Background information ................................................................................................................... 24 
1.2 Rationale ........................................................................................................................................... 27 
1.2.1 Rationale for the trial and selected subject population .............................................................. 27 
1.2.2 Rationale for dose selection ....................................................................................................... 28 
1.3 Hypothesis......................................................................................................................................... 29 
1.4 Benefit and risk assessment .............................................................................................................. 29 
2 Objectives and Endpoints ........................................................................................................................ 30 
2.1 Primary objectives ............................................................................................................................ 30 
2.2 Secondary objectives ........................................................................................................................ 30 
2.3 Exploratory objectives ...................................................................................................................... 31 
3 Study Design ............................................................................................................................................ 31 
3.1 Description of the study .................................................................................................................... 31 
3.2 End of study and length of study ...................................................................................................... 33 
4 Materials and Methods ............................................................................................................................. 34 
4.1 Patients .............................................................................................................................................. 34 
4.1.1 Inclusion criteria ........................................................................................................................ 34 
4.1.2 Exclusion criteria ....................................................................................................................... 36 
4.1.3 Other eligibility criteria consideration ....................................................................................... 38 
4.1.4 Patient restrictions ...................................................................................................................... 39 
4.2 Method of treatment assignment and blinding .................................................................................. 39 
4.3 Study treatment ................................................................................................................................. 41 
4.3.1 Formulation, packaging, and handling ....................................................................................... 41 

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4.3.2 Dosage, administration, and compliance ................................................................................... 42 
4.3.3 Investigational medicinal product accountability ...................................................................... 44 
4.3.4 Post-trial access to toripalimab injection (JS001) ...................................................................... 44 
4.4 Concomitant therapy ......................................................................................................................... 45 
4.4.1 Permitted therapy ....................................................................................................................... 45 
4.4.2 Prohibited therapy ...................................................................................................................... 46 
4.5 Study assessments ............................................................................................................................. 47 
4.5.1 Informed consent forms and screening log ................................................................................ 47 
4.5.2 Medical history and demographic data ...................................................................................... 48 
4.5.3 Physical examinations ................................................................................................................ 48 
4.5.4 Vital signs .................................................................................................................................. 48 
4.5.5 Tumor and response evaluations ................................................................................................ 48 
4.5.6 Laboratory, biomarker, and other biological samples ................................................................ 49 
4.5.7 Tumor tissue samples ................................................................................................................. 51 
4.5.8 Electrocardiograms and echocardiogram ................................................................................... 52 
4.5.9 Patient-reported outcomes (PRO) .............................................................................................. 52 
4.5.10 Timing of assessment ............................................................................................................... 52 
4.6 Patient, Treatment, Study, and Site Discontinuation ........................................................................ 54 
4.6.1 Patient Discontinuation .............................................................................................................. 54 
4.6.2 Study Treatment Discontinuation .............................................................................................. 54 
4.6.3 Study and Site Discontinuation .................................................................................................. 55 
5 Assessment of Safety ............................................................................................................................... 56 
5.1 Safety plan ........................................................................................................................................ 56 
5.2 Risks associated with toripalimab injection (JS001) ........................................................................ 57 
5.3 Risks associated with gemcitabine .................................................................................................... 57 
5.3.1 Risk associated with cisplatin .................................................................................................... 57 
5.3.2 General plan to manage safety concerns .................................................................................... 58 
5.3.3 Toripalimab injection (JS001) /placebo dosage modification and management of specific 
adverse events ..................................................................................................................................... 58 
5.3.4 Gemcitabine and cisplatin dose modification and management of specific adverse events ...... 60 
5.4 Safety parameters and definitions ..................................................................................................... 63 
5.4.1 Adverse events ........................................................................................................................... 64 

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5.4.2 Serious adverse events (immediately reportable to the sponsor) ............................................... 64 
5.4.3 Adverse events of special interest (immediately reportable to the sponsor) .............................. 65 
5.5 Methods and timing for capturing and assessing safety parameters ................................................. 65 
5.5.1 Adverse event reporting period .................................................................................................. 66 
5.5.2 Eliciting adverse event information ........................................................................................... 66 
5.5.3 Assessment of severity of adverse events .................................................................................. 66 
5.5.4 Assessment of causality of adverse events................................................................................. 67 
5.5.5 Procedures for recording adverse events .................................................................................... 68 
5.6 Immediate reporting requirements from investigator to sponsor ...................................................... 73 
5.6.1 Reporting requirements for serious adverse events ................................................................... 74 
5.6.2 Reporting requirements for pregnancies .................................................................................... 75 
5.7 Follow-up of patients after adverse events ....................................................................................... 76 
5.7.1 Investigator follow-up ................................................................................................................ 76 
5.7.2 Sponsor follow-up ...................................................................................................................... 76 
5.8 Post-study adverse events ................................................................................................................. 76 
5.9 Expedited reporting to health authorities, investigators, institutional review boards, and ethics 
committees .............................................................................................................................................. 77 
6 Statistical Considerations and Analysis Plan ........................................................................................... 77 
6.1 Determination of Sample Size .......................................................................................................... 78 
6.2 Summaries of conduct of study ......................................................................................................... 78 
6.3 Summaries of treatment group comparability ................................................................................... 78 
6.4 Efficacy analyses .............................................................................................................................. 78 
6.4.1 Primary efficacy endpoint .......................................................................................................... 78 
6.4.2 Secondary efficacy endpoints .................................................................................................... 79 
6.4.3 Exploratory efficacy endpoints .................................................................................................. 81 
6.5 Safety analyses .................................................................................................................................. 81 
6.6 Immunogenicity analyses .................................................................................................................. 82 
6.7 Biomarker analyses ........................................................................................................................... 82 
6.8 Interim analysis ................................................................................................................................. 83 
7 Data Collection and Management ............................................................................................................ 83 
7.1 Data quality assurance ...................................................................................................................... 83 
7.2 Electronic case report forms ............................................................................................................. 84 

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7.3 Source data documentation ............................................................................................................... 84 
7.4 Use of computerized systems ............................................................................................................ 85 
7.5 Retention of records .......................................................................................................................... 85 
8 Ethical Considerations ............................................................................................................................. 85 
8.1 Compliance with laws and regulations ............................................................................................. 85 
8.2 Informed consent .............................................................................................................................. 86 
8.3 Institutional review board or ethics committee ................................................................................. 87 
8.4 Confidentiality .................................................................................................................................. 87 
8.5 Financial Disclosure .......................................................................................................................... 88 
9 Study Documentation, Monitoring, and Administration.......................................................................... 88 
9.1 Study documentation ........................................................................................................................ 88 
9.2 Protocol deviations ............................................................................................................................ 88 
9.3 Site inspections ................................................................................................................................. 89 
9.4 Administrative structure .................................................................................................................... 89 
9.5 Publication of data and protection of trade secrets ........................................................................... 89 
9.6 Protocol amendments ........................................................................................................................ 90 
10 Independent data monitoring committee ................................................................................................ 90 
11 References .............................................................................................................................................. 90 
12 Appendix ................................................................................................................................................ 93 
12.1 Appendix 1 Schedule of Activities ................................................................................................. 93 
12.2 Appendix 2 Schedule of Biomarker and Anti-drug Antibody Samples .......................................... 98 
12.3 Appendix 3 Eastern Cooperative Oncology Group Performance Status ........................................ 99 
12.4 Appendix 4 The Response Evaluation in Solid Tumors (RECIST version 1.1) Guidelines ......... 100 
12.5 Appendix 5 Immuno-Related Response Evaluation in Solid Tumors (irRECIST) ...................... 104 
12.6 Appendix 6 New York Heart Association Cardiac Function Classification ................................. 109 
12.7 Appendix 7 Body Surface Area Calculation Formula .................................................................. 110 
12.8 Appendix 8 Method for Calculation of Creatinine Clearance Rate .............................................. 111 
12.9 Appendix 9 EORTC QLQ-C30 (version 3) .................................................................................. 112 
12.10 Appendix 10 EORTC QLQ - H&N35 ........................................................................................ 115 
12.11 Appendix 11 Preexisting Autoimmune Diseases ........................................................................ 118 
12.12 Appendix 12 Anaphylaxis Precautions ....................................................................................... 120 
12.13 Appendix 13 Management of Immune-related Adverse Events ................................................. 121 

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List of Tables 
Table 1 Toripalimab Injection (JS001) and Placebo Formulations .............................................. 41 
Table 2 Administration of First and Subsequent Infusions of JS001/Placebo*............................ 43 
Table 3 Dose Modification Guidelines for Hematological Toxicities on Day 1 of Gemcitabine 60 
Table 4 Dose Modification Guidelines for Hematological Toxicities on Day 8 of Gemcitabine 60 
Table 5 Gemcitabine Dose Modification Guidelines for Non-Hematological Toxicities ............ 61 
Table 6 Cisplatin Dose Modification for Hematologic Toxicities ................................................ 62 
Table 7 Cisplatin Dose Modification for Non-Hematologic Toxicities (Excluding Neurotoxicity)
....................................................................................................................................................... 62 
Table 8 Cisplatin Dose Modification for Associated Neurotoxicity ............................................ 63 
Table 9 Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE ......................................................................................................................................... 66 
Table 10 Timing and Stopping Boundary of PFS Analyses ......................................................... 82 
 
 
 
 
 
 
List of Figures 
Figure 1 Study Schema ................................................................................................................. 33 
 
 
 
List of Appendix 
Appendix 1 Schedule of Activities............................................................................................ 93 
Appendix 2 Schedule of Biomarker and Anti-drug Antibody Samples .................................... 98 
Appendix 3 Eastern Cooperative Oncology Group Performance Status .................................. 99 

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Appendix 4 The Response Evaluation in Solid Tumors (RECIST version 1.1) Guidelines ... 100 
Appendix 5 Immuno-Related Response Evaluation in Solid Tumors (irRECIST) ................ 104 
Appendix 6 New York Heart Association Cardiac Function Classification ........................... 109 
Appendix 7 Body Surface Area Calculation Formula ............................................................ 110 
Appendix 8 Method for Calculation of Creatinine Clearance Rate ........................................ 111 
Appendix 9 EORTC QLQ-C30 (version 3) ............................................................................ 112 
Appendix 10 EORTC QLQ - H&N35..................................................................................... 115 
Appendix 11 Preexisting Autoimmune Diseases .................................................................... 118 
Appendix 12 Anaphylaxis Precautions ................................................................................... 120 
Appendix 13 Management of Immune-related Adverse Events ............................................. 121 
 
 
 
 

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PROTOCOL ACCEPTANCE FORM 
TITLE: 
A PHASE III, RANDOMIZED, 
PLACEBO-CONTROLLED, MULTICENTER, 
DOUBLE-BLIND STUDY COMPARING TORIPALIMAB 
INJECTION (JS001) COMBINED WITH 
CHEMOTHERAPY VERSUS PLACEBO COMBINED 
WITH CHEMOTHERAPY FOR RECURRENT OR 
METASTATIC NASOPHARYNGEAL CANCER 
PROTOCOL NUMBER: 
JS001-015-III-NPC 
VERSION NUMBER: 
6.0 
TEST PRODUCT: 
Toripalimab Injection (JS001) 
MEDICAL MONITOR: 
Weihua Wang, Medical Director    
SPONSOR: 
Shanghai Junshi Biosciences Co., Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy to the contact 
provided below. 
 
Name     _________________________________________________ 
 
 
Address  _________________________________________________ 
 
 

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Protocol synopsis 
Name of Sponsor/Company: 
Shanghai Junshi Biosciences Co., Ltd. 
Test Product: 
Toripalimab Injection (JS001 or TAB001) 
Name of Active Ingredient: 
Recombinant humanized anti-PD-1 monoclonal antibody 
Title of Study:  
A Phase III, Randomized, Placebo-Controlled, Multicenter, Double-Blind Study 
Comparing Toripalimab Injection (JS001) Combined with Chemotherapy versus Placebo 
Combined with Chemotherapy for Recurrent or Metastatic Nasopharyngeal Cancer 
Protocol No: 
 
JS001-015-III-NPC 
Indication: 
Nasopharyngeal Cancer 
Primary 
Investigator: 
Prof. Ruihua Xu 
Study center(s): 
Approximately 40 sites in China mainland, Taiwan, Singapore. 
Phase: 
III 
Objectives: 
Primary: 
• 
To evaluate the efficacy of Toripalimab Injection (JS001) plus chemotherapy compared with placebo 
plus chemotherapy，as measured by independent review committee (IRC)-assessed progression free 
survival (PFS) according to RECIST v1.1 in all patients. 
Secondary: 
• 
To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus chemotherapy, as 
measured by overall survival (OS).  
• 
To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus chemotherapy, as 
measured by investigator- and IRC-assessed overall response rate (ORR), duration of response (DoR), 
and disease control rate (DCR) according to RECIST v1.1.  
• 
To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus chemotherapy, as 
measured by investigator-assessed PFS according to RECIST v1.1. 
• 
To evaluate the IRC- and investigator-assessed PFS rate at 1 and 2 years in each treatment arm. 
• 
To evaluate the OS rate at 1 and 2 years in each treatment arm.  
• 
To assess disease-related symptoms and health related quality of life (HRQoL) in patients treated with 
JS001 plus chemotherapy compared with placebo plus chemotherapy using the EORTC QLQ-C30, 
EORTC QLQ-H&N35 and ECOG performance status assessments. 

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• 
To evaluate the safety and tolerability of JS001 plus chemotherapy compared with placebo plus 
chemotherapy. 
• 
To evaluate the incidence and titers of ADAs against JS001 and to explore the potential relationship of 
the immunogenicity response with pharmacokinetics, safety and efficacy. 
• 
To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus chemotherapy，as 
measured by investigator- and IRC-assessed PFS, ORR, DoR and DCR according to irRECIST. 
Exploratory: 
• 
To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers (including but not 
limited to PMBC, PD-L1, PD-1, tumor mutation burden and others) in archival and/or fresh tumor tissue 
and blood and their association with disease status, mechanisms of resistance, and/or response to JS001.  
• 
To evaluate the utility of biopsy at the time of apparent disease progression to distinguish apparent 
increases in tumor volume related to the immunomodulatory activity of JS001 (i.e., pseudoprogression 
and tumor immune infiltration) from true disease progression.  
Study design: 
This is a randomized, placebo-controlled, multi-center, double blinded, Phase III study to determine the efficacy 
and safety of Toripalimab Injection (JS001) in combination with gemcitabine/cisplatin compared with placebo in 
combination with gemcitabine/cisplatin as first-line treatment in patients with histological/cytological 
confirmation of recurrent or metastatic nasopharyngeal carcinoma (NPC).  Patients who fulfill all of the 
inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 ratio according to the following 
stratification scheme:  
• 
ECOG performance status (0 versus 1) 
• 
Disease stage (recurrent versus metastatic)  
Patients will be randomized in a 1:1 ratio to receive treatment every 3 weeks (Q3W) with JS001 plus 
gemcitabine/cisplatin (Arm A) or placebo plus gemcitabine/cisplatin chemotherapy (Arm B) in the ‘during 
chemotherapy’ phase. During the ‘post-chemotherapy’ phase, patients randomized to Arm A or Arm B will 
continue treatment with JS001 or placebo as maintenance therapy Q3W until excessive toxicity or progressive 
disease, withdrawal of consent or Investigator’s judgement or a maximum of 2 years. Patients may continue 
treatment with JS001 (Arm A) or placebo (Arm B) beyond radiographic progression by the Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.1, provided they are experiencing clinical benefit, as assessed by 
the Investigator in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease 
progression, as determined by the sponsor medical monitor or designee and treating physician after an integrated 
assessment of radiographic data and clinical status.  
Tumor evaluation scans will be performed at screening (as baseline) then every 6weeks in the first 12 months 
then every 9 weeks thereafter until objective disease progression. 
This is a double blinded, one interim efficacy analysis of PFS is planned and pre-defined stopping boundary is 
set for two-sided p-value. The iDMC will provide the recommendation as to whether to unblind the study or not 
according to the data of interim analysis and the iDMC charter if the stopping boundary is crossed. If the 
Sponsor accepted the recommendation and unblind the study, JS001 will be provided to the patients who were 
randomized to arm A and still on JS001 treatment until the treatment discontinuation criteria are met according 
to protocol, the placebo treatment will be terminated for the patients who were randomized to arm B. After the 

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study is unblinded, the tumor evaluation, survival follow-up, safety information, and so on information 
collection should be performed as required by the protocol.  
Planned number of patients: 
Expected median PFS time is about 7 months for standard chemotherapy. 
With an expected enrollment of 14 months, 280 patients (140 per arm) are 
needed to observe 200 PFS events at approximately 25 months after the 
first patient is randomized in order to detect the PFS improvement of 
HR=0.67 with 80% power at a 2-sided significance level of 0.05, 
assuming the dropout rate is 5% over 12 months for PFS. 
Inclusion criteria: 
To be eligible to participate in the study, patients must meet all of the 
following Inclusion Criteria: 
1. Age ≥ 18 years and ≤75 years. 
2. An archival tumor specimen or fresh tumor biopsy sample is 
available. 
3. Histological/cytological confirmation of NPC. 
4. Primarily metastatic (stage IVB as defined by the International Union 
against Cancer and American Joint Committee on Cancer staging 
system for NPC, eighth edition) or recurrent NPC after curative 
treatment, which is not amenable for local regional treatment or 
curative treatment. No previous systemic chemotherapy was given for 
metastatic or recurrent disease 
5. For the recurrent NPC after curative treatment (including radiotherapy 
and/or induction, concurrent or adjuvant chemotherapy), the interval 
between recurrence and the last dose of previous radiotherapy or 
chemotherapy must be more than 6 months. 
6. At least 1 measurable lesion according to RECIST version 1.1. 
7. Life expectancy ≥ 3 months. 
8. Performance status 0 or 1 according to the Eastern Cooperative 
Oncology Group (ECOG) criteria (Appendix 3). 
9. Adequate organ function: 
• 
Hematologic: leucocytes ≥ 4.0 × 109/L, Absolute Neutrophil 
Count ≥ 2.0 × 109/L, hemoglobin ≥ 90 g/L, and platelets ≥ 100.0 
× 109/L. 
• 
Hepatic: bilirubin ≤ 1.5 × upper limit of normal (ULN)(patients 
with known Gilbert’s disease who have serum bilirubin level ≤  3 
× ULN may be enrolled), AST and ALT ≤ 3 × ULN (AST/ALT 
≤ 5 × ULN if liver metastases), with alkaline phosphatase ≤ 3 × 
ULN (ALP ≤ 5 × ULN if liver or bone metastases); albumin ≥ 3 
g/dL;  

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• 
International Normalized Ratio (INR) or Prothrombin Time (PT) 
or Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN. 
• 
Renal: serum creatinine ≤ 1.5 ULN and creatinine clearance ≥ 60 
mL/min according to Cockcroft-Gault formula (Appendix 8) 
10. Toxicities from any prior therapy, surgery, or radiotherapy must have 
resolved to Grade 0 or 1 as per the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE 5.0), 
excluding any grade alopecia. 
11. Willingness and ability to comply with scheduled visits, treatment 
plans, laboratory tests and other study procedures. 
12. Female patients are eligible to enter and participate in the study if they 
are of: 
• 
Non-childbearing potential (i.e., physiologically incapable of 
becoming pregnant), including any female who 
o 
Has had a hysterectomy, 
o 
Has had a bilateral oophorectomy (ovariectomy), 
o 
Has had a bilateral tubal ligation, or 
o 
Is post-menopausal (total cessation of menses for ≥ 1 year). 
• 
Childbearing potential, has a negative serum pregnancy test at 
screening (within 7 days of the first investigational product 
administration), and uses adequate contraception before study 
entry and throughout the study until 60 days after the last 
investigational product administration. Adequate contraception, 
when used consistently and in accordance with both the product 
label and the instructions of the physician, are defined as follows: 
o 
Any intrauterine device with a documented failure rate of less 
than 1% per year. 
o 
Double barrier contraception defined as condom with 
spermicidal jelly, foam, suppository, or film; OR diaphragm 
with spermicide; OR male condom and diaphragm. 
Exclusion criteria 
Patients will be excluded from the study, if any of the following criteria is 
met: 
1. History of severe hypersensitivity reactions to other mAbs or any 
ingredient of Toripalimab Injection (JS001). 
2. Active or untreated CNS metastases (e.g., brain or leptomeningeal), as 
determined on CT or magnetic resonance imaging (MRI) evaluation 
during screening and prior radiographic assessments. Patients who 
have prior therapies for brain or leptomeningeal metastasis and has 
been stabilized for ≥ 2 months and has discontinued systemic steroids 

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therapy (> 10 mg/day prednisone or equivalent) > 4 weeks prior to 
randomization could be included. 
3. Spinal cord compression not definitively treated with surgery and/or 
radiation or previously diagnosed and treated spinal cord compression 
without evidence that disease has been clinically stable for  2 weeks 
prior to randomization 
4. Patients with necrotic lesions have potential risk of massive 
hemorrhage at the discretion of investigator. 
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring 
recurrent drainage procedures 
Patients with indwelling catheters (e.g., PleurX® catheter) are 
allowed. 
6. Uncontrolled tumor-related pain  
Patients requiring pain medication must be on a stable regimen at 
study entry. 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be 
treated prior to enrollment. 
Asymptomatic metastatic lesions whose further growth would likely 
cause functional deficits or intractable pain (e.g., epidural metastasis 
that is not presently associated with spinal cord compression) should 
be considered for loco-regional therapy, if appropriate, prior to 
enrollment. 
7. Uncontrolled or symptomatic hypercalcemia ( 1.5 mmol/L ionized 
calcium or Ca  12 mg/dL or corrected serum calcium greater than the 
ULN) 
8. Malignancies other than NPC within 5 years prior to randomization, 
with the exception of those with a negligible risk of metastasis or 
death (e.g., expected 5-year OS  90%) treated with expected curative 
outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous cell skin cancer, localized prostate cancer treated 
with curative intent, ductal carcinoma in situ treated surgically with 
curative intent) 
9. Prior therapy targeting PD-1 receptor, or its ligand PD-L1, or 
cytotoxic T-lymphocyte-associated protein 4 (CTLA4) receptor. 
10. Use of antineoplastic traditional herbal medicine within 4 weeks 
before randomization. 
11. Major surgical procedure other than for diagnosis of NPC within 28 
days prior to randomization or anticipation of need for a major 
surgical procedure during the study. 

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12. History of autoimmune disease, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
vascular thrombosis associated with antiphospholipid syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain -Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see 
Appendix 11 for a more comprehensive list of autoimmune diseases) 
Patients with a history of autoimmune-related hypothyroidism on a 
stable dose of thyroid-replacement hormone may be eligible for this 
study. Patients with controlled Type I diabetes mellitus on a stable 
insulin regimen are eligible for this study. 
13. Treatment with systemic immunostimulatory agents (including, but 
not limited to, interferons or IL-2) within 4 weeks or five half-lives of 
the drug, whichever is shorter, prior to randomization 
14. Treatment with systemic corticosteroids (> 10 mg daily prednisone 
equivalents) or other systemic immunosuppressive medications 
(including, but not limited to, prednisone, dexamethasone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [anti-TNF] agents) within 2 weeks prior to 
randomization. Use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids is allowed. 
Patients who have received acute, low-dose, systemic 
immunosuppressant medications (e.g., a one-time dose of 
dexamethasone for nausea) may be enrolled in the study after 
discussion with and approval by the Medical Monitor. 
Patients with history of allergic reaction to IV contrast requiring 
steroid pre-treatment should have baseline and subsequent tumor 
assessments performed on MRI. 
The use of inhaled corticosteroids for chronic obstructive pulmonary 
disease, mineralocorticoids (e.g., fludrocortisone) for patients with 
orthostatic hypotension, and low-dose supplemental corticosteroids 
for adrenocortical insufficiency is allowed. 
15. Patients with prior allogeneic bone marrow transplantation or prior 
solid organ transplantation 
16. History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans), idiopathic 
pneumonitis, or evidence of active pneumonitis on screening chest CT 
scan. 
17. History of hypersensitivity to gemcitabine or cisplatin or to any of the 
excipients. 

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18. Use of any live vaccines (e.g., against infectious diseases such as 
influenza, varicella, etc.) within 4 weeks (28 days) before 
randomization. 
19. Active infection including tuberculosis (clinical evaluation that 
includes clinical history, physical examination and radiographic 
findings, and TB testing in line with local practice), hepatitis B 
(known positive HBV surface antigen (HBsAg) result and HBV DNA 
detected by study site lab ≥ 1000 cps/mLor the lower limit of the local 
lab), hepatitis C, or human immunodeficiency virus (positive HIV 
antibodies).  
Patients with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [anti-HBc] and absence of 
HBsAg) are eligible only if they are negative for HBV DNA (HBV 
DNA detected by study site lab ˂ 1000 cps/mL or the lower limit of 
the local lab).  
Patients positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
20. Underlying medical conditions with clinical significance (such as 
dyspnea, pneumonitis, pancreatitis, uncontrollable diabetes, active or 
uncontrollable infection, drug or alcohol abuse, or psychiatric 
conditions), which in the Investigator’s opinion can affect the 
administration of study drugs and protocol compliance. 
21. Presence of a significant neurological or psychiatric disease, including 
dementia and seizures. 
22. Have NCI-CTCAE ≥ Grade 2 peripheral neuropathy. 
23. Female patients who are at pregnancy or lactation. 
24. Significant cardiovascular disease, such as New York Heart 
Association cardiac disease (Class II or greater, Appendix 6), 
myocardial infarction within 3 months prior to randomization, 
unstable arrhythmias, or unstable angina.  
Patients with known coronary artery disease, congestive heart failure 
not meeting the above criteria, or left ventricular ejection fraction 
 50% must be on a stable medical regimen that is optimized in the 
opinion of the treating physician, in consultation with a cardiologist if 
appropriate. 
Investigational product, dose, 
schedule and mode of 
administration: 
Test product: Toripalimab Injection (JS001)   
JS001 will be administered at the dose of 240 mg Q3W, as an intravenous 
(IV) infusion over 60 minutes followed by a 60-minute observation period 
(only required in the first 2 cycles). If no infusion-related reactions have 
occurred, subsequent infusions will be administered over 30 minutes.  

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In the during-chemotherapy phase, JS001 will be given before 
gemcitabine and cisplatin. 
After up to 6 cycles of chemotherapy, during the post-chemotherapy 
phase, JS001 and best supportive care (BSC) can be continued Q3W until 
excessive toxicity or progressive disease, withdrawal of consent, at the 
discretion of the Investigator or for a maximum of 2 years.  
Reference product, dose, 
schedule and mode of 
administration:  
Reference product (comparator): matching placebo. 
Placebo will be administered Q3W, as an IV infusion over 60 minutes 
followed by a 60-minute observation period (only required in the first 2 
cycles). If no infusion-related reactions have occurred, subsequent 
infusions will be administered over 30 minutes. 
In the during-chemotherapy phase, the matching placebo will be given 
before gemcitabine and cisplatin.  
After up to 6 cycles of chemotherapy, placebo and BSC can be continued 
Q3W until excessive toxicity or progressive disease, withdrawal of 
consent, at the discretion of the Investigator or for a maximum of 2 years. 
Associated products dose, 
schedule and mode of 
administration 
Associated products: gemcitabine and cisplatin  
In Arm A & B: 60 minutes after the end of Toripalimab Injection (JS001)  
or placebo infusion (only required in the first 2 cycles), gemcitabine 
1000 mg/m² IV over 30 minutes are given on Days 1 & 8, and cisplatin 
80 mg/m² IV over 4  hours are given on Day 1 of each cycle. 
Chemotherapy is given Q3W for up to 6 cycles according to drug label 
and to local standards for premedication and other prophylactic 
medications. 
Assessment Parameter and Criteria: 
Primary Endpoint: 
Progression-free survival defined as the time from randomization to the time of first documented IRC-assessed 
disease progression per RECIST v1.1  or death due to any cause (whichever occur first).  
Secondary Endpoints: 
• 
Clinical response according to RECIST version 1.1 to evaluate ORR, DoR, and DCR. 
o 
ORR, defined as the proportion of patients with best overall response of complete or partial 
response 
o 
DoR, defined as the time between first documentation of a response and first evidence of 
progressive disease 
o 
DCR, defined as the proportion of patients with best response of CR or PR or SD. 
• 
Clinical response according to irRECIST. In cases the Investigator suspects progressive disease 
corresponds to a pseudo-progression, such as an increase in tumor burden (including the appearance of 
small new lesions in new non vital areas), in the absence of significant deterioration of performance 

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status and laboratory values, treatment continuation is allowed until confirmation of progression with 
repeat imaging at least 4 weeks later or at the next regularly scheduled imaging time point.  
• 
Survival Endpoints: 
o 
PFS rate at 1 and 2 years, defined as the proportion of patients with no documented progression 
according to RECIST version 1.1 and alive at 1 and 2 years after randomization 
o 
OS, defined as time from randomization to death due to any cause. Kaplan-Meier methods will be 
used to estimate median OS 
o 
OS rate at 1 and 2 years, defined as the proportion of patients alive at 1, 2 years after randomization. 
• 
Safety and tolerability assessed throughout the study by the incidence of serious adverse events (SAE), 
the incidence and severity of adverse events (AEs) (coded to preferred term and system organ class 
using the Medical Dictionary for Regulatory Activities [MedDRA] and graded according to NCI-
CTCAE version 5.0, physical examination, vital signs, electrocardiograms (ECG), and laboratory tests 
classified for severity using NCI-CTCAE version 5.0. Given the mechanism of action of JS001, which 
involves immune regulatory function, particular guidance should be given to immune-related adverse 
events (irAEs), Details please refer to IB. 
• 
Serum level of (neutralizing) ADA against JS001 and trough concentration measured every 4 cycles in 
first year then after measured every 8 cycles until disease progression to explore the potential 
relationship of the immunogenicity response with pharmacokinetics, safety and efficacy. 
• 
Quality of Life assessed by the EORTC QLQ-C30, EORTC QLQ-H&N35 questionnaire and ECOG 
performance status assessments. 
Exploratory endpoints: 
• 
To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers (including but not 
limited to PBMC, PD-L1, PD-1, tumor mutation burden and others) in archival and/or fresh tumor tissue 
and blood and their association with disease status, mechanisms of resistance, and/or response to JS001.  
To evaluate the utility of biopsy at the time of apparent disease progression to distinguish apparent increases in 
tumor volume related to the immunomodulatory activity of JS001 (i.e., pseudoprogression and tumor immune 
infiltration) from true disease progression. 
Statistical methods: 
Sample size determination 
The sample size calculation is based on the primary endpoint PFS. Patients will be randomized in a 1:1 ratio. 
Expected median PFS time is about 7 months for standard chemotherapy. With an expected enrollment of 14 
months, 280 patients (140 per arm) are needed to observe 200 PFS events at approximately 25 months after the 
first patient is randomized in order to detect the PFS improvement of HR = 0.67 with 80% power at a 2-sided 
significance level of 0.05, assuming the dropout rate is 5% over 12 months for PFS. 
Analysis populations 
The intent-to-treat set (ITT) will include all patients randomized. Patients will be analyzed according to the study 
arm to which they are randomized.   

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All patients receiving any amount of JS001 or placebo will be included in the safety analysis set (SS). Patients in 
the SS will be analyzed according to the treatment they actually received. The SS will be the primary analysis set 
for safety, immunogenicity, pharmacokinetics, and biomarker analyses.  
The Per-Protocol Analysis Set (PPS) will include all ITT patients who do not have any major protocol violations 
which have significant impact on the primary outcome measures, and have valid baseline and primary output 
measures. Patients will be analyzed according to the study arm to which they are randomized. Major protocol 
violations will be defined and inclusion of subjects in the PPS population will be finalized prior to study 
unblinding. The PPS population will be used for some secondary/exploratory analysis as well as sensitivity 
analysis of the primary efficacy endpoints. 
Efficacy analysis 
The primary objective is to compare PFS as assessed by the IRC in ITT population (all randomized patients). The 
non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each treatment arm. The 
treatment difference in PFS will be assessed by the stratified log-rank test. A stratified Cox proportional hazard 
model will be used to assess the magnitude of the treatment difference (i.e. HR) between the treatment arms. The 
HR and its 95% confidence interval from the stratified Cox model will be reported. The same stratification factors 
used for randomization will be applied to both the stratified log-rank test and the stratified Cox model. 
Secondary analyses will be performed for PFS rates at 1 year and 2 years after randomization, and OS rates at 1 
year and 2 years after randomization. The number and proportion of patients with best overall response of CR or 
PR or SD or progressive disease will be summarized. Objective response rate and DCR will be determined along 
with 95% CI. Kaplan-Meier curve will be used to estimate median DoR and OS along with 95% CI in each arm. 
Safety analysis 
Extent of exposure to each study drug will be summarized descriptively as the number of cycles received 
(number and proportion of patients), duration of exposure (days), cumulative total dose received per patient (mg), 
dose intensity, and relative dose intensity. The number (proportion) of patients requiring dose reduction, 
interruption, dose delay, and drug discontinuation due to AEs will be summarized for each study drug. Frequency 
of the above dose adjustments and discontinuation will be summarized by category. Patient data listings will be 
provided for all dosing records and for calculated summary statistics. 
Adverse events will be coded using MedDRA version 20.0 or higher. For each study treatment, numbers of 
events and incidence rates will be tabulated by preferred term and system organ class. Serious adverse events, 
AEs leading to death, and AEs leading to withdrawal of patients will be tabulated for each arm. Commonly 
occurring AEs, i.e. those which occur in 5% or more of the patients in each arm, will be summarized using 
descriptive statistics. 
All laboratory test results, physical examination results, vital signs measurements, weight, ECOG performance 
status, and 12-lead ECG results will be summarized for each arm using descriptive statistics at each visit for raw 
numbers and change from baseline. 
Interim analysis 
An iDMC will be set up to evaluate safety data on an ongoing basis. One interim efficacy analysis of PFS is 
planned when approximately 130 PFS events in the ITT population have been observed.  This is expected to 
occur approximately 18 months after the first patient is randomized, while the exact timing of the interim analysis 
will depend on the actual occurrence of PFS events.  
 
 

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List of Abbreviations and Definitions of Terms 
 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
ADA 
Anti-drug antibody 
AE 
AESI 
Adverse event 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BSC 
Best supportive care 
C-RT 
Chemo-radiotherapy 
CBC 
Complete blood cell 
CI 
Confidence interval 
CR 
Complete response 
CRO 
Contract research organization 
CT 
Computed tomography 
CTLA4 
cytotoxic T-lymphocyte-associated protein 4 
DCT 
Disease control rate 
DLT 
Dose limiting toxicity  
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 

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Abbreviation 
Definition 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
EQ-5D-5L 
European Quality of Life 5-dimensons 5 Level Questionnaire 
FDA 
Food and Drug Administration 
G-CSF 
Granulocyte-colony stimulating factor 
GCP 
good clinical practice 
GLP 
good laboratory practice 
HBV 
Hepatitis B virus 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus  
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HR 
Hazard ratio 
IA 
Interim analysis 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
iDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 

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Abbreviation 
Definition 
INR 
International normalized ratio 
irAE 
Immune-related adverse events 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IRR 
Infusion-related reactions 
irRECIST 
Immune-related Response Evaluation Criteria In Solid Tumors 
ITT 
Intent-to-treat set 
IV 
intravenous 
IWRS 
Interactive Web response system 
LOCF 
Last observation carried forward 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NOAEL 
no-observed-adverse-effect level 
NPC 
Nasopharyngeal carcinoma 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Pharmacodynamic(s) 
PD-1 
Programmed cell death-1 

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Abbreviation 
Definition 
PD-L1 
Programmed cell death-ligand 1 
PFS 
Progression-free survival 
PK 
pharmacokinetics 
PPS 
Per-protocol analysis set 
PR 
Partial response 
PT 
Prothrombin time 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
QoL 
Quality of life 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SS 
Safety analysis set 
SD 
Stable disease 
SOP 
Standard operating procedures 
TEAE 
Treatment-emergent adverse event 
UC 
Urothelial carcinoma 
ULN 
Upper limit of normal 
 
 
 

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1 Introduction 
1.1 Background information 
Toripalimab Injection (JS001) is a humanized IgG4K (gamma 4, kappa) monoclonal antibody 
(mAb) specific for human programmed cell death-1 (PD-1), a co-inhibitory receptor expressed 
on T-cells and is being evaluated for the treatment of cancer. JS001 contains serine228 to proline 
substitution to minimize Fab arm exchange1. As with other anti-PD-1 antibodies, JS001 has a 
high affinity and blocks interaction between PD-1 and its ligand, programmed cell death-ligand 1 
(PD-L1; B7-H1 or CD274). However, JS001 differs from other such antibodies in that the 
binding to PD-1 is more prolonged, as measured by the dissociation constant.   
Based on the results of nonclinical pharmacology studies performed to date, JS001 binds to 
human PD-1, blocks the interaction between PD-1 and its ligands. JS001 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 patients with cancer, JS001 increases 
T-cell proliferation and effector cytokine production following stimulation with a variety of 
antigens. However, in the absence of antigen or T-cell receptor engagement by a CD3 antibody, 
JS001 does not induce any significant cytokine release by unstimulated or pre-stimulated human 
T-cells in comparison with Nivolumab (Opdivo® [BMS]), Pembrolizumab  (Keytruda® 
[Merck])or control IgG4 antibody, indicating a low risk of inducing cytokine storm. 
The binding of JS001 to its target receptor, PD-1, has been characterized using enzyme-linked 
immunosorbent assay (ELISA)-based binding to plate-immobilized PD-1 fusion protein, flow 
cytometry based binding to cell surface PD-1, and Biacore based binding affinity analysis. An 
ELISA-based binding assay demonstrated specific interaction of JS001 with recombinant human 
and cynomolgus monkey PD-1 extracellular domain fusion proteins, but not with mouse or rat 
PD-1 fusion proteins. A Flow Cytometry-based binding assay demonstrates the binding of JS001 
to human and cynomolgus monkey CD4 and CD8 T-cells. JS001 was confirmed to block 
interactions between PD-1 and its ligands, PD-L1 and PD-L2. Half-maximal inhibitory 
concentrations (IC50) of JS001 were determined to be 0.8 nM for PD-L1 and 1.3 nM for PD-L2. 
JS001 increases T-cell proliferative response and interferon-gamma production in tetanus toxoid 
and Cytomegalovirus/Epstein-Barr virus (EBV)/Flu peptide recall assays. In addition, JS001 
promotes nuclear factor of activated T-cells activation in a Jurkat Reporter System.  
JS001 binds to PD-1 expressed on activated and memory T-cells to promote their response to 
antigenic stimulation. IgG4 heavy chain was selected over other heavy chain isotypes for JS001 
to minimize immune effector function against the target cells.  
JS001 treatment as well as Nivolumab increased CD3+/CD4+/CD8+ human T-cell counts 
compared with IgG4 treatment. In addition, JS001 treatment leads to complete tumor remission 
in MC-38 syngeneic tumor model in human PD-1 knock in mice. 

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Following a single intravenous (IV) infusion of JS001 for 30 minutes at doses up to 203 mg/kg 
to male and female cynomolgus monkeys, 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 serum 
concentration of JS001 was quantifiable through 648 hours post-infusion in 3 animals and 
through 240 hours in 1 (female dosed with 1 mg/kg) animal. At study day 28, all animals had 
antibodies to JS001 which were not neutralizing as indicated by the long half-life. The no-
observed-adverse-effect level (NOAEL) of JS001 was 203 mg/kg when administered once via IV 
infusion for 30 minutes to male and female cynomolgus monkeys.  
In a good laboratory practice (GLP)-compliant repeat dose toxicology study, following 
30 minute IV infusions every 2 weeks over 4 weeks (total of 3 doses) of JS001 at doses up to 
100 mg/kg to male and female cynomolgus monkeys, there were no adverse effects on in-life 
parameters, ophthalmic examination findings, electrocardiogram (ECG) evaluations, clinical 
pathology (clinical chemistry, hematology, coagulation, and urinalysis), cytokine production, 
immune phenotype, gross pathology findings, absolute and relative organ weights, and 
histopathology findings. Although anti-drug antibodies (ADA) were observed in 2/10 monkeys 
in the 100 mg/kg group, 8/10 animals in the 100 mg/kg group maintained drug exposure during 
the course of the study. Thus, the NOAEL of JS001 in this study was 100 mg/kg when 
administered every 2 weeks over 4 weeks (total of 3 doses) via 30-minute IV infusion to male 
and female cynomolgus monkeys. 
No unexpected tissue cross-reactivity was observed with JS001 in a GLP-compliant human 
tissue cross-reactivity study. JS001 produced plasma membrane and cytoplasmic staining of 
mononuclear cells in most human lymphoid tissues (including the lymph node, thymus, and 
tonsil, as well as gut-associated lymphoid tissue in the colon and bronchus-associated lymphoid 
tissue in the lung) and select non-lymphoid tissues (including in the esophagus, kidney, and 
cervix [cytoplasm only]).  This staining was expected based on literature reports of PD-1 
expression in mononuclear cell types, including T-cells, B-cells, and other myeloid cells2,3. 
Refer to the Investigator’s Brochure for more detailed information about the non-clinical 
pharmacology, PK, and toxicology of JS0014.  
Based on analysis of all relevant preclinical pharmacology and toxicology parameters, 1 mg/kg 
has been selected as a starting dose, which is predicted to have partial receptor occupancy in the 
tumor tissue at 14 days post-dose. The selected starting dose is 1/100 of the NOAEL. In the 
absence of dose-limiting toxicity (DLT), the maximum dose will be 10 mg/kg; this dose level is 
predicted to provide sustained full receptor occupancy and represents 1/10 of the NOAEL on a 
mg/kg basis. 
An initial dose escalation Phase I study with 3+3 design was performed in patients with 
advanced solid tumors (melanoma, urothelial carcinoma [UC], and renal cell carcinoma [RCC]) 

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followed by a dose expansion phase to evaluate the safety, tolerability, pharmacokinetics (PK), 
immunogenicity, and anti-tumor activity of JS001 administered with 1 mg/kg, 3 mg/kg, or 10 
mg/kg IV once every 2 weeks (Q2W) dosing schedule5. A total of 36 patients were enrolled. The 
safety and tolerability results showed that no DLT was observed and no maximum tolerated dose 
(MTD) was reached. The most common treatment-related adverse events (AEs) were Grade 1 or 
2 in intensity and the emergence of AEs was not dose related. The clinical activity results 
showed that in 35 evaluable patients, an objective response rate (ORR) of 23% was reached, 
including complete response (CR) in 1 melanoma patient and partial response (PR) in 7 patients 
(3 melanoma, 2 UC, and 2 RCC). In addition, 10 patients achieved stable disease (SD) with a 
disease control rate (DCR) of 51%. The average time to response was 85 days. Four out of 8 
patients with objective responses still had ongoing responses as of 24 May 2017, including 1 
RCC patient. Pharmacokinetic (PK) analysis showed a dose-dependent linear exposure with the 
elimination half-life of 6 to 12 days and 6 out of 64 (9.4%) antidrug antibody (ADA) samples 
were positive. Using the flow cytometry method of assessing receptor occupancy, JS001 bound 
to the target molecule PD-1 on activated T lymphocytes with full occupancy in all patients in all 
cohorts after first dose of JS001. The full receptor occupancy was maintained in most patients 
during the study (332 day). The Phase I clinical trial data indicate that JS001 exhibits a favorable 
safety profile in humans. Treatment-related AEs were in line with those from approved drugs of 
the same class. JS001 has demonstrated promising anti-tumor activity, especially in previously 
under-evaluated acral and mucosal melanomas. Phase II/III clinical trials in selected indications 
are therefore desirable and currently ongoing. 
A multi-center, open-label, Phase II registration study (CT4) was designed to evaluate safety and 
efficacy of JS001 in advanced melanoma patients who had failed systemic treatment. JS001 
monotherapy was given at 3 mg/kg IV  Q2W  until  disease  progression  or  intolerable  toxicity.  
The primary endpoint was ORR assessed by IRC pursuant to RECIST 1.1. The secondary 
endpoints included DOR, PFS and OS assessed by IRC. A total of 128 melanoma patients were 
enrolled, by March 15, 2018, 127 evaluable patients of FAS (Full analysis set) had been followed 
up for at least six months, One complete  response，21  partial  responses  and 51 stable diseases 
were observed, representing an ORR of 17.3% and a DCR of 57.5%.In the subset of chronic UV 
exposure induced cutaneous melanoma subgroup, ORR and DCR was 31.03% and 65.52% 
respectively. There was no treatment-related death occurred in the study. The most common 
treatment-related adverse events were grade 1-2, including proteinuria (25%), ALT increase 
(25%), rash (22%), hyperglycemia (20%), amylase increase (18%), leukopenia (17%), anemia 
(16%), vitiligo (16%), AST increase (16%), pruritus (14%) and hypothyroidism (13%). 
Treatment-related adverse events of grade 3-4 occurred in 18% of patients. Therefore, at 3 mg/kg 
Q2W, JS001 had similar safety profile and comparable clinical efficacy with marketed PD-1 
antibodies in treating metastatic melanoma. which have been filed for NDAs to the CFDA 
recently.  

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A Phase Ib/II study in patients with advanced gastric adenocarcinoma, esophageal squamous cell 
carcinoma, nasopharyngeal carcinoma (NPC), and head and neck squamous cell carcinoma is 
ongoing to evaluate the preliminary efficacy and safety of JS001 as monotherapy. The interim 
data showed that as of 31 Aug, 2017, 56 NPC patients (81.8% patients failed at least 2 lines of 
previous treatment) were enrolled into this study, 50 patients have been evaluated for clinical 
efficacy. Among these patients, 12 PR (partial response) and 13 SD (stable disease) were 
observed (ORR 24.0%, DCR 50.0%). 
Refer to the Investigator’s Brochure for more detailed information about the ongoing clinical 
trials of JS001. 
 
1.2 Rationale 
1.2.1 Rationale for the trial and selected subject population 
Nasopharyngeal carcinoma (NPC), is a rare malignancy in most parts of the world with < 1 new 
cases/100,000 while it is endemic in a few countries6. In Southern China, and Southeast Asia, the 
estimated annual incidence of NPC is 25-50 new cases/100,0006. The major cause of NPC is 
Epstein-Barr virus (EBV) infection in conjunction with a high risk human leukocyte antigen 
(HLA) allotype (mainly HLA-A*11:01 and HLA-A*02:27) populations and environmental 
factors7,8,9.  For advanced stage disease, overall survival (OS) at 5 years is < 10%10. 
At time of first diagnosis, according to the stage of disease, surgery, radiotherapy and 
chemo-radiotherapy (C-RT) are the standard treatments11. At time of tumor relapse, or in patients 
with metastatic disease at first diagnosis, standard first line chemotherapy consists of platinum 
based regimens. Targeting of epidermal growth factor receptor is also under exploration. 
Recently, the combination of gemcitabine and cisplatin was shown to be superior to that of 
cisplatin and 5-fluorouracil (5-FU) in terms of progression-free survival (PFS) with an increase 
from 5.6 months to 7.0 months and hazard ratio (HR) of 0.55, thus establishing that regimen as 
the standard of care12.  
Since EBV induces a high level of PD-L1 expression by cancer cells, and EBV antigens aid in 
immune escape, there is a good rationale to explore the role of anti-PD1 antibodies in advanced 
NPC13. Preliminary data with anti-PD-1 antibodies used alone in refractory disease have shown 
activity in early phase clinical studies, and randomized studies against chemotherapy are 
underway. The tolerability was as expected for this class of agent with Grade 3-5 treatment-
related AEs including hepatitis, pneumonitis, anemia, facial pain, increase blood creatinine 
phosphokinase, proteinuria and sepsis, with one treatment-related death due to sepsis14.  
However, for the first line patients, a combination of chemotherapy with a PD-1 blocker can 
produce immunogenic cell death and yield synergistic efficacy. Such a dramatic increase in 

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survival is reported in other tumor types such as lung cancer (PFS HR 0.53 with the addition of 
pembrolizumab to chemotherapy as first line therapy). 
Toripalimab Injection (JS001) is a humanized anti-PD-1 mAb. Preliminary efficacy of JS001 as 
monotherapy in an ongoing Phase Ib/II study in patients with advanced gastric adenocarcinoma, 
esophageal squamous cell carcinoma, NPC and head and neck squamous cell carcinoma has 
shown encouraging efficacy with 4/10 PRs in the subset of patients with NPC. In that study, 
JS001 monotherapy was well tolerated with no safety signal for unexpected drug-related AEs. 
The trial will also explore the safety and tolerability of the combination of JS001 with 
gemcitabine and cisplatin to support the conduct of this study. Exploratory biomarker analyses 
including PD-L1 level of expression as well as additional potential predictive biomarkers will be 
explored in this study, if applicable. 
 
1.2.2 Rationale for dose selection 
The serum trough concentration of JS001 plateaued after 3-4 consecutive doses, with the mean 
steady state trough concentration (Cmin) at 20~40 μg/mL in the 3 mg/kg Q2W dose group (n = 
37). In vitro binding study has showed that JS001 was able to fully saturate PD-1 receptors on T 
cell surface when its concentration was higher than 20 nM or 3 μg/mL. Given the penetration for 
antibody into tumor microenvironment, the concentration of JS001 in the peripheral blood is 
targeted at 25 μg/mL to ensure PD-1 receptor full occupancy on T lymphocytes in the tumor 
microenvironment. Results from Phase I studies showed all dose groups of 0.3, 1.0, 3.0, and 10.0 
mg/kg JS001 Q2W maintained PD-1 receptor full occupancy during the entire course of 
treatment. Based on the PK and receptor occupancy results, 3 mg/kg Q2W was selected as the 
recommended Phase II dose. In the registration trial NCT03013101 in advanced melanoma 
(CT4), at 3 mg/kg Q2W, JS001 had similar safety profile and comparable clinical efficacy with 
marketed PD-1 antibodies in treating metastatic melanoma refractory to standard therapy 
(Section 1.1).  
A fixed dose of 360 mg JS001 Q3W was also explored in two early phase trials. The PK 
comparison of two dosing regimens, 3 mg/kg Q2W (N = 11) and 360 mg Q3W(N = 9), showed 
that the steady state peak concentration of 360 mg Q3W dosing was 153% of  3 mg/kg Q2W 
dosing (166.53 μg/mL: 95% CI 121.0 to 212.0 vs 108.83 μg/mL: 95% CI 87.5 to 130.0); the 
steady state trough concentration of 360 mg Q3W dosing was 133% of 3 mg/kg Q2W dosing 
(47.92 μg/mL: 95% CI 31.8 to 64.0 vs 36.09 μg/mL: 95% CI 27.7 to 44.5); the estimated AUC 
0-Day85 of 360 mg Q3W dosing was 138% of 3 mg/kg Q2W dosing (164993 μg/mL*hr vs 
119814 μg/mL*hr). PK model extrapolation predicts the 240 mg Q3W regimen having a similar 
steady state trough concentration (~ 32 μg/mL) and drug exposure with the 3 mg/kg Q2W 
regimen. Based on the preliminary PK results and extrapolation from PK model, the results from 
RO and Phase II registration trial in melanoma, 240 mg Q3W is therefore selected as the 
recommended Phase III dose for subsequent clinical studies. 

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1.3 Hypothesis 
The hypothesis of the study is that Toripalimab Injection (JS001) in combination with 
chemotherapy shows superiority compared with placebo in combination with chemotherapy in 
terms of PFS. 
 
1.4 Benefit and risk assessment 
Chemotherapy with gemcitabine plus cisplatin is now recognized as the standard of care for 
patients with recurrent or metastatic NPC. In a Phase III, multicenter, randomized, open-label 
trial, the median PFS was 7.0 months (95% confidence interval [CI]: 4.4-10.9 months) in patients 
who received gemcitabine plus cisplatin and 5.6 months (95% CI: 3.0-7.0 months) in patients 
who received 5-FU plus cisplatin treatment (HR 0.55 [95% CI: 0.44-0.68], p<0.0001).12 The 
preliminary clinical benefit of Toripalimab Injection (JS001)  as monotherapy in patients with 
NPC has been shown in a Phase Ib/II study and is consistent with the benefit that can be 
expected with PD-1 blockers in highly immunogenic tumors. Four out of 10 patients with NPC 
had PRs, and JS001 was tolerated well (data not published). In this study, chemotherapy will be 
given to all patients to ensure the standard of care is received and the additional clinical benefit 
of JS001 will be explored by comparing PFS after JS001 in combination with chemotherapy 
versus PFS after placebo in combination with chemotherapy. Benefits in terms of ORR, duration 
of response (DoR), DCR, and OS will also be evaluated. 
The safety profile of chemotherapy with gemcitabine plus cisplatin is well established. In the 
Phase III, multicenter, randomized, open-label trial in patients with recurrent or metastatic NPC, 
the most common (> 10%) drug-related AEs for patients treated with gemcitabine plus cisplatin 
were leucopenia, neutropenia, anemia, thrombocytopenia, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, fatigue, weight loss, decreased appetite, 
nausea, and vomiting. A total of 68 (38%) and 9 (5%) patients experienced Grade 3 and Grade 4 
drug-related AEs. The most common (> 10%) Grade 3-4 drug-related AEs included leucopenia, 
neutropenia, and thrombocytopenia. No Grade 5 drug-related AEs occurred during the study.12 
Based on the known biology of the PD-1 pathway and its importance in immune function, the 
most likely class of JS001 toxicities are immune-related adverse events (irAE). The frequency 
and type of irAE manifestations have varied across clinical trials, depending on the treatment 
targets, patient populations, and the type and dosage of the drug. These symptoms led to 
dermatitis, enterocolitis, hepatitis, and endocrinopathies (hypophysitis, thyroiditis, adrenal 
insufficiency), and less often uveitis, nephritis, arthritis, and inflammatory myopathy.15,16 
Treatment with anti-PD-1 agents is commonly associated with diarrhea, although colitis, 
endocrinopathies, skin toxicity, fatigue and flu-like symptoms (such as fever and myalgias) are 
less common.17 Eligibility criteria need to be established to exclude patients with a history of 

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autoimmune disease. In a Phase I study of JS001 as monotherapy in patients with advanced solid 
tumors (melanoma, UC, and RCC), no DLT was observed and no MTD was reached at dose 
levels of 1 mg/kg, 3 mg/kg, and 10 mg/kg Q2W. The most common (> 10%) treatment-related 
Grade 1-2 AEs were rash, fever, leukopenia, elevated lipase, hypothyroidism, hyperthyroidism, 
elevated AST, hyperglycemia, anorexia, neutropenia, elevated amylase, pruritus, elevated ALT, 
elevated direct bilirubin, elevated total bilirubin, elevated indirect bilirubin, elevated creatine 
kinase, and fatigue. Six out of 36 (17%) patients were reported to have Grade 3 AEs and they 
included proteinuria, elevated lipase, elevated amylase, and elevated direct bilirubin. Serious 
adverse events were reported in 7 patients but they were all unrelated to JS001.5 The interim 
analysis of the Phase Ib/II study in patients with advanced gastric adenocarcinoma, esophageal 
squamous cell carcinoma, NPC, and head and neck squamous cell carcinoma showed that as of 
Dec 30, 2017, the clinical database contained preliminary safety data from 213 patients (58 
patients with GC, 59 patients with ESCC, 62 patients with NPC and 34patients with HNCC) who 
had received doses of JS001. Of the 213 treated patients, 95.5% experienced an adverse event 
regardless of attribution to JS001. Of the adverse events, 57.9% were Grade 1 or 2 in maximum 
severity graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.03 (NCI CTCAE v4.03).  The most frequently observed adverse 
events (occurring in ≥ 10% of treated patients) included ALT increased, weight decreased, blood 
bilirubin increased, Platelet count decreased, nausea, abdominal pain, constipation, vomiting, 
diarrhea, hyponatremia, decreased appetite, asthenia, proteinuria. Treatment-related adverse 
events (per investigator’s assessment of causality) were reported in 67.3% of patients. 
 
2 Objectives and Endpoints 
2.1 Primary objectives 
The primary objective of the study is to evaluate the efficacy of Toripalimab Injection (JS001) 
plus chemotherapy compared with placebo plus chemotherapy, as measured by IRC-assessed 
PFS according to RECIST v1.1 in patients with histological/cytological confirmation of recurrent 
or metastatic NPC. 
 
2.2 Secondary objectives 
The secondary objectives of the study are: 
• 
To evaluate the efficacy of Toripalimab Injection (JS001) plus chemotherapy compared 
with placebo plus chemotherapy, as measured by OS.  
• 
To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus 
chemotherapy, as measured by investigator- and IRC-assessed ORR, DoR, and DCR 
according to RECIST v1.1.  

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• 
To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus 
chemotherapy, as measured by investigator-assessed PFS according to RECIST v1.1. 
• 
To evaluate the IRC- and investigator-assessed PFS rate at 1 and 2 years in each 
treatment arm. 
• 
To evaluate the OS rate at 1 and 2 years in each treatment arm. 
• 
To assess disease-related symptoms and HRQoL in patients treated with JS001 plus 
chemotherapy compared with placebo plus chemotherapy using the EORTC QLQ-C30, 
EORTC QLQ-H&N35 and ECOG performance status assessments. 
• 
To evaluate the safety and tolerability of JS001 plus chemotherapy compared with 
placebo plus chemotherapy. 
• 
To evaluate the incidence and titers of ADAs against JS001 and to explore the potential 
relationship of the immunogenicity response with pharmacokinetics, safety, and efficacy.  
• 
To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus 
chemotherapy, as measured by investigator- and IRC-assessed PFS, ORR, DoR and DCR 
according to irRECIST. 
 
2.3 Exploratory objectives 
The exploratory objectives of the study are: 
• 
To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers 
(including but not limited to PMBC, PD-L1, PD-1, tumor mutation burden and others) in 
archival and/or fresh tumor tissue and blood and their association with disease status, 
mechanisms of resistance, and/or response to Toripalimab Injection (JS001).  
• 
To evaluate the utility of biopsy at the time of apparent disease progression to distinguish 
apparent increases in tumor volume related to the immunomodulatory activity of JS001 
(i.e., pseudoprogression and tumor immune infiltration) from true disease progression. 
 
3 Study Design 
3.1 Description of the study 
This is a randomized, placebo-controlled, multi-center, double blinded, Phase III study to 
determine the efficacy and safety of Toripalimab Injection (JS001) in combination with 
gemcitabine/cisplatin compared with placebo in combination with gemcitabine/cisplatin as first-
line treatment in patients with histological/cytological confirmation of recurrent or metastatic 
NPC. The primary endpoint is PFS in all patients. The availability of an archival or fresh tumor 
biopsy sample is mandatory for histological confirmation of NPC, PD-L1 expression level and 

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for correlative analyses (i.e., PD-L1 expression). Follow-up optional tissue and/or liquid biopsies 
will be collected for exploratory PD tests.  
Approximately 280 patients who fulfill all of the inclusion criteria and none of the exclusion 
criteria will be randomized in a 1:1 ratio to one of the two treatment arms according to the 
following stratification factors:  
• 
ECOG performance status (0 versus 1) 
• 
Disease stage (recurrent versus metastatic)  
After stratification, patients will be randomly assigned by Interactive Web Response System 
(IWRS) to the combination of JS001 (Arm A) or placebo (Arm B) with gemcitabine and 
cisplatin given every 3 weeks (Q3W) in 3-week cycles. Day 1 (baseline) will be defined as the 
first day a patient receives study medication. Patients will receive JS001 (Arm A) or placebo 
(Arm B) on Day 1 of each 3-week cycle. In Arms A & B, patients will receive gemcitabine on 
Days 1 & 8 and cisplatin on Day 1 of each cycle. The chemotherapy will continue until 
progressive disease, excessive toxicity, noncompliance, withdrawal of consent, or a maximum of 
6 cycles, whichever occurs first in the ‘during chemotherapy’ phase. During the ‘post-
chemotherapy’ phase, patients randomized to Arm A or Arm B will continue treatment with 
JS001 or placebo as maintenance therapy Q3W until excessive toxicity or progressive disease, 
withdrawal of consent or Investigator’s judgement or a maximum of 2 years. Patients may 
continue treatment with JS001 (Arm A) or placebo (Arm B) beyond radiographic progression by 
the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, provided they are 
experiencing clinical benefit, as assessed by the Investigator in the absence of unacceptable 
toxicity or symptomatic deterioration attributed to disease progression, as determined by the 
Investigator after an integrated assessment of radiographic data and clinical status. Patients will 
be permitted by sponsor medical monitor or designee and treating physician to continue 
JS001/placebo after RECIST v1.1 criteria for progressive disease are met if they meet all of the 
criteria detailed in Section 4.6.2. 
Study treatment doses and regimens are described in Section 5. Tumor evaluation scans will be 
performed at screening (as baseline) then every 6weeks in the first 12 months then every 9 weeks 
thereafter until objective disease progression. The management of patients will be based solely 
upon the results of the tumor evaluation scans conducted by the Investigator.  
The Review Committee (IRC), consisting of independent experts will review all radiologic scans 
and derive the PFS, ORR, DoR and DCR, according to RECIST 1.1 and irRECIST. Details will 
be provided in a separate charter. 
To take into account the specificities of imaging after an immuno-modulating agent, both the 
RECIST version 1.1 and irRECIST will be used to evaluate tumor response. To date, it is 
considered that a 2-year period of therapy is adequate to yield the maximum effect of 
immunotherapeutics. Therefore, after the during chemotherapy phase, responding or stabilized 

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patients will be offered to continue with JS001 or placebo as maintenance therapy over a 
maximum of 2 years. Thereafter, patients can continue on BSC or start a new therapy as 
indicated in case of relapse.  
This is a double blinded, one interim efficacy analysis of PFS is planned and pre-defined 
stopping boundary is set for two-sided p-value. The iDMC will provide the recommendation as 
to whether to unblind the study or not according to the data of interim analysis and the iDMC 
charter if the stopping boundary is crossed. If the Sponsor accepted the recommendation and 
unblind the study, JS001 will be provided to the patients who were randomized to arm A and still 
on JS001 treatment until the treatment discontinuation criteria are met according to protocol, the 
placebo treatment will be terminated for the patients who were randomized to arm B. After the 
study is unblinded, the tumor evaluation, survival follow-up, safety information, and so on 
information collection should be performed as required by the protocol. 
The study will be conducted according to the national and international ethical standards and 
GCP. The protocol will be approved by the Research Ethics Committees of the participating 
sites. 
The study design is presented in Figure 1. 
A schedule of activities is provided in Appendix 1. 
 
Figure 1 Study Schema 
Abbreviations: BSC=best supportive care; PD=disease progression; Q3W=every 3 weeks 
 
3.2 End of study and length of study 
The final analysis of the primary efficacy endpoint will be performed when approximately 200 
IRC-assessed PFS events in the intent-to-treat (ITT) population have occurred or when the last 
patient has been randomized, whichever occurs last. It is expected to occur at approximately 25 
months after the first patient is randomized. The planned interim analysis of PFS will be treated 

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as the definitive efficacy analysis if the stopping boundary for the interim analysis is crossed; the 
interim analysis is expected to occur at approximately 18 months after the first patient is 
randomized (see Section 6.8 for details of the PFS interim analysis plan). If the stopping 
boundary is crossed and the study is unblinded, patients remaining on the experimental arm who 
have not progressed will be provided with toripalimab, whereas patients on the placebo arm will 
have placebo discontinued.  
The end of study is defined as the date of the last visit of the last patient, or the date of the last 
data point required for efficacy analyses or safety follow-up, whichever occurs first. In addition, 
the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 32 months. 
At the time of end of study, sponsor will continuously provide investigational product to patients 
who still are under treatment in accordance with local regulations. 
 
4 Materials and Methods 
4.1 Patients 
Approximately 280 patients with recurrent or metastatic nasopharyngeal cancer will be enrolled 
in this study. 
 
4.1.1 Inclusion criteria 
A signed informed consent form must be obtained before the start of any study specific 
procedure. To be eligible to participate in the study, patients must meet all of the following 
Inclusion Criteria: 
1. Age ≥ 18 years and ≤ 75 years. 
2. An archival tumor specimen or fresh tumor biopsy sample is available. 
3. Histological/cytological confirmation of NPC. 
4. Primarily metastatic (stage IVB as defined by the International Union against Cancer and 
American Joint Committee on Cancer staging system for NPC, eighth edition) or recurrent 
NPC after curative treatment, which is not amenable for local regional treatment or curative 
treatment. No previous systemic chemotherapy was given for the recurrent or metastatic 
disease. 
5. For the recurrent NPC after curative treatment (including radiotherapy and/or induction, 
concurrent or adjuvant chemotherapy), the interval between recurrence and the last dose of 
previous radiotherapy or chemotherapy must be more than 6 months. 

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6. At least 1 measurable lesion according to RECIST version 1.1. 
7. Life expectancy ≥ 3 months. 
8. Performance status 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) 
criteria (Appendix 3). 
9. Adequate organ function: 
• 
Hematologic: leucocytes ≥ 4.0 × 109/L, Absolute Neutrophil Count ≥ 2.0 × 109/L, 
hemoglobin ≥ 90 g/L, and platelets ≥ 100.0 × 109/L. 
• 
Hepatic: bilirubin ≤ 1.5 × upper limit of normal (ULN) (patients with known Gilbert’s 
disease who have serum bilirubin level ≤ 3 × ULN may be enrolled), AST and ALT ≤ 3 × 
ULN (AST/ALT ≤ 5 × ULN if liver metastases), with alkaline phosphatase ≤ 3 × 
ULN(ALP ≤ 5 × ULN if liver or bone metastases); albumin ≥ 3 g/dL;  
• 
International Normalized Ratio (INR) or Prothrombin Time (PT) or Activated Partial 
Thromboplastin Time (aPTT) ≤ 1.5 × ULN. 
• 
Renal: serum creatinine ≤ 1.5 ULN and creatinine clearance ≥ 60 mL/min according to 
Cockcroft-Gault formula (Appendix 8) 
10. Toxicities from any prior therapy, surgery, or radiotherapy must have resolved to Grade 0 or 
1 as per the National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE), excluding any grade alopecia. 
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and 
other study procedures. 
12. Female patients are eligible to enter and participate in the study if they are of: 
• 
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), 
including any female who 
o Has had a hysterectomy, 
o Has had a bilateral oophorectomy (ovariectomy), 
o Has had a bilateral tubal ligation, or 
o Is post-menopausal (total cessation of menses for ≥ 1 year). 
• 
Childbearing potential, has a negative serum pregnancy test at screening (within 7 days of 
the first investigational product administration), and uses adequate contraception before 
study entry and throughout the study until 60 days after the last investigational product 
administration. Adequate contraception, when used consistently and in accordance with 
both the product label and the instructions of the physician, are defined as follows: 
o Any intrauterine device with a documented failure rate of less than 1% per year.  

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o Double barrier contraception defined as condom with spermicidal jelly, foam, 
suppository, or film; OR diaphragm with spermicide; OR male condom and 
diaphragm. 
 
4.1.2 Exclusion criteria 
Patients will be excluded from the study, if any of the following criteria is met: 
1. History of severe hypersensitivity reactions to other mAbs or any ingredient of Toripalimab 
Injection (JS001). 
2. Active or untreated CNS metastases (e.g., brain or leptomeningeal), as determined on CT or 
magnetic resonance imaging (MRI) evaluation during screening and prior radiographic 
assessments. Patients who have prior therapies for brain or leptomeningeal metastasis and 
has been stabilized for ≥ 2 months and has discontinued systemic steroids therapy 
(>10 mg/day prednisone or equivalent) > 4 weeks prior to randomization could be included. 
3. Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for ≥ 2 weeks prior to randomization 
4. Patients with necrotic lesions have potential risk of massive hemorrhage at the discretion of 
investigator. 
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures. Patients with indwelling catheters (e.g., PleurX® catheter) are allowed. 
6. Uncontrolled tumor-related pain  
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases 
causing nerve impingement) should be treated prior to enrollment. 
Asymptomatic metastatic lesions whose further growth would likely cause functional deficits 
or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord 
compression) should be considered for loco-regional therapy, if appropriate, prior to 
enrollment. 
7. Uncontrolled or symptomatic hypercalcemia ( 1.5 mmol/L ionized calcium or Ca  12 
mg/dL or corrected serum calcium greater than the ULN) 
8. Malignancies other than NPC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year OS  90%) treated 
with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 

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basal or squamous cell skin cancer, localized prostate cancer treated with curative intent, 
ductal carcinoma in situ treated surgically with curative intent) 
9. Prior therapy targeting PD-1 receptor, or its ligand PD-L1, or cytotoxic 
T-lymphocyte-associated protein 4 (CTLA4) receptor. 
10. Use of antineoplastic traditional herbal medicine within 4 weeks before randomization. 
11. Major surgical procedure other than for diagnosis of NPC within 28 days prior to 
randomization or anticipation of need for a major surgical procedure during the study. 
12. History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener 
granulomatosis, Sjögren syndrome, Guillain -Barré syndrome, multiple sclerosis, vasculiti s, 
or glomerulonephritis (see Appendix 11 for a more comprehensive list of autoimmune 
diseases). 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-
replacement hormone may be eligible for this study. 
Patients with controlled Type I diabetes mellitus on a stable insulin regimen are eligible for 
this study. 
13. Treatment with systemic immunostimulatory agents (including, but not limited to, interferons 
or IL-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to 
randomization. 
14. Treatment with systemic corticosteroids (> 10 mg daily prednisone equivalents) or other 
systemic immunosuppressive medications (including, but not limited to, prednisone, 
dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor [anti-TNF] agents) within 2 weeks prior to randomization. Use of topical, 
ocular, intra-articular, intranasal, and inhalational corticosteroids is allowed.  
Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., 
a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion 
with and approval by the Medical Monitor.  
Patients with history of allergic reaction to IV contrast requiring steroid pre-treatment should 
have baseline and subsequent tumor assessments performed on MRI.  
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency is allowed. 
15. Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation. 

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16. History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia 
(i.e., bronchiolitis obliterans), idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan. 
17. History of hypersensitivity to gemcitabine or cisplatin or to any of the excipients. 
18. Use of any live vaccines (e.g., against infectious diseases such as influenza, varicella, etc.) 
within 4 weeks (28 days) before randomization. 
19. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local practice), 
hepatitis B (known positive HBV surface antigen (HBsAg) result and HBV DNA detected by 
study site lab > 1000 cps/mL or the lower limit of the local lab), hepatitis C, or human 
immunodeficiency virus (positive HIV 1/2 antibodies).  
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [anti-HBc] and absence of HBsAg) are eligible only if they are negative for HBV 
DNA (HBV DNA detected by study site lab ˂ 1000 cps/mL or the lower limit of the local 
lab).  
Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
20. Underlying medical conditions with clinical significance (such as dyspnea, pneumonitis, 
pancreatitis, uncontrollable diabetes, active or uncontrollable infection, drug or alcohol 
abuse, or psychiatric conditions), which in the Investigator’s opinion can affect the 
administration of study drugs and protocol compliance. 
21. Presence of a significant neurological or psychiatric disease, including dementia and 
seizures. 
22. Have NCI-CTCAE ≥ Grade 2 peripheral neuropathy. 
23. Female patients who are at pregnancy or lactation. 
24. Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater, Appendix 6), myocardial infarction within 3 months prior to 
randomization, unstable arrhythmias, or unstable angina.  
Patients with known coronary artery disease, congestive heart failure not meeting the above 
criteria, or left ventricular ejection fraction  50% must be on a stable medical regimen that 
is optimized in the opinion of the treating physician, in consultation with a cardiologist if 
appropriate. 
 
4.1.3 Other eligibility criteria consideration 

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To assess any potential impact on patient eligibility with regards to safety, the Investigator must 
refer to the IB for detailed information regarding warnings, precautions, contraindications, AEs, 
and other significant data pertaining to the investigational product being used in this study.  
Re-screening under limited conditions should be allowed after consultation with the Sponsor, 
e.g. when a patient narrowly misses a lab criterion and it’s correctable and not due to rapidly 
deteriorating condition or progressive disease. Multiple attempts should not be allowed for re-
screening. 
 
4.1.4 Patient restrictions 
The following restrictions may affect patient participation in this study: 
• 
Availability to attend visits according to the protocol. 
• 
Concomitant medication restrictions as described in Section 4.4. 
• 
Women of child-bearing potential must use a double-barrier method of contraception 
during the study and for at least 60 days following the last dose of study drug and male 
patients must use appropriate contraception methods (total abstinence or condom with 
spermicide) for at least 60 days after the last dose of study drug.  
• 
Male patients with a female partner of childbearing potential 
o Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from screening through 60 days 
after receipt of the final dose of Toripalimab Injection (JS001) /placebo in 
combination chemotherapy or 60 days after receipt of the final dose of JS001/placebo 
monotherapy.  Not engaging in sexual activity is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. 
o Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (the same request with 
female patients). 
• 
Strenuous exercise should be avoided up to 72 hours before planned study visits. 
 
4.2 Method of treatment assignment and blinding 
This is a randomized, double-blind, placebo-controlled study with limited access to the 
randomization code. Toripalimab Injection (JS001) and placebo will be identical in physical 
appearance. The treatment each patient will receive will not be disclosed to the Investigator, 
study center staff, patient, Sponsor, CRO or the IRC. The treatment codes will be held by the 

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Clinical Supplies Department of the Sponsor. After written informed consent has been obtained 
and eligibility has been established, personnel at the study site will enter demographic and 
baseline characteristics in the IWRS. For patients eligible for enrollment, the study site will 
obtain the patient’s randomization number and treatment assignment from the IWRS.  
Randomization to one of the two treatment arms will occur in a 1:1 ratio. 
Permuted-block randomization will be applied to ensure a balanced treatment assignment with 
respect to the prespecified stratification factors as follows: 
• 
ECOG performance status (0 versus 1) 
• 
Disease stage (recurrent versus metastatic)  
Patients should receive their first dose of study treatment on the day of randomization if possible. 
If this is not possible, the first dose should occur within 3 calendar days after randomization. 
While ADA and trough concentration samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, ADA and trough 
concentration assay results for these patients are generally not needed for the safe conduct or 
proper interpretation of this trial.  Sponsor personnel or designee responsible for performing 
ADA and trough concentration assays will be unblinded to patients’ treatment assignments to 
identify appropriate ADA and trough concentration samples to be analyzed. Samples from 
patients assigned to the comparator arm will not be analyzed except by request (e.g., to evaluate 
a possible error in dosing). 
The Sponsor will offer post-trial access to the study drug Toripalimab (JS001) free of charge to 
eligible patients that was assigned to Arm A after 2 years of treatment. For the patients who 
intent to receive study drug after completing the study will be unblinded. Only patients who are 
found to be randomized to Arm A may continue to receive Toripalimab (JS001) rechallenge 
(more details refer to section 4.3.4). 
The process for breaking the blind will be handled through the IWRS. Investigators are strongly 
discouraged from requesting the blind be broken for an individual patient. If unblinding is 
necessary for patient management (e.g., in the case of a serious adverse event for which patient 
management might be affected by knowledge of treatment assignment), the investigator will be 
able to break the treatment code by contacting the IWRS. Treatment codes should not be broken 
except in emergency situations. If the investigator wishes to know the identity of the study drug 
for any other reason, he or she should contact the Medical Monitor directly.   
The investigator should document and provide an explanation for any premature unblinding 
(e.g., accidental unblinding, unblinding due to a serious adverse event). Any site that breaks the 
blind under inappropriate circumstances may be asked to discontinue its participation in the 
study.  

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The Sponsor and CRO must be notified immediately if a patient and/or Investigator is unblinded 
during the course of the study. Pertinent information regarding the circumstances of unblinding 
of a patient’s treatment code must be documented in the patient’s source documents and 
electronic case report forms (eCRFs). 
For regulatory reporting purposes, and if required by local health authorities, the Sponsor will 
break the treatment code for all serious, unexpected suspected adverse reactions (see Section 5.9) 
that are considered by the investigator or Sponsor to be related to study drug. 
At the time of end of study, patients who still are under treatment will be unblinded. Only 
patients who are found to be randomized to the JS001 arm may continue to receive JS001 
treatment.  
Before the end of study, all the patients would be unblinded in advance if the pre-defined 
stopping boundary is crossed and the Sponsor accepted the recommendation of unblind the study 
recommended by iDMC. JS001 will be provided to the patients who were randomized to JS001 
arm and still under JS001 treatment until the treatment discontinuation criteria are met according 
to protocol, the placebo treatment will be terminated for the patients who were randomized to 
placebo arm. The tumor evaluation, survival follow-up, and safety information, and so on 
information collection should be performed as required by the protocol. 
 
4.3 Study treatment 
4.3.1 Formulation, packaging, and handling 
4.3.1.1 Toripalimab injection (JS001) /placebo 
JS001 is a humanized modified IgG4κ mAb specific against human PD-1. JS001 contains the 
complementarity-determining regions of a murine antibody that binds to human PD-1 and human 
framework regions with limited back-mutations to the parental murine sequence. A serine to 
proline substitution was introduced at amino acid 228 to minimize Fab arm exchange. JS001 is 
produced by recombinant DNA technology in a Chinese Hamster Ovary mammalian cell 
expression system (LONZA). JS001 has a predicted molecular weight of approximately 147 
kDa, and it is composed of two 452 amino acid heavy chains and two 219 amino acid light 
chains. JS001 contains an N-linked glycosylation site at heavy chain amino acid 302. The 
isoelectric point of JS001 is between 6.4 and 7.4. The JS001 drug product is a 6 mL sterile liquid 
form filled in a glass vial configuration (West Flurotec® stopper and aluminum crimp) to be 
administered IV. The JS001 drug product formulation is shown in Table 1 and should be stored 
at 2-8°C.  
Placebo formulation is also shown in Table 1 and should be stored at 2-8°C.  
Table 1 Toripalimab Injection (JS001) and Placebo Formulations 

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Test/reference drug 
Manufacturer 
Concentration and formulation as supplied 
Toripalimab 
Injection (JS001) 
Suzhou Union 
Biopharm. Co. Ltd. 
Supplied as a sterile liquid containing 240 mg JS001. 
JS001 is formulated at a nominal concentration of 40 
mg/mL in 20 mM Sodium Citrate, 2.5% (w/v) 
Mannitol, 50 mM NaCl, 0.02% (w/v) Polysorbate 80, 
pH 6.0. Each vial contains 6 mL of available volume. 
Placebo 
Suzhou Union 
Biopharm. Co. Ltd. 999 
Longqiao Rd,Suzhou, 
Jiangsu, 215200, China 
Supplied as a sterile liquid containing 20 mM Sodium 
Citrate, 2.5% (w/v) Mannitol, 50 mM NaCl, 0.02% 
(w/v) Polysorbate 80, pH 6.0. Each vial contains 6 mL 
of available volume. 
NaCl  sodium chloride. 
 
The JS001 drug product or placebo is aseptically filled in a 6 mL glass vial configuration (West 
Flurotec ® stopper and aluminum crimp) and supplied to sites in separate multi-patient cartons. 
Each carton contains 1 vial. White labels will be applied to cartons and vials containing JS001 or 
placebo. No other coding will be included.  
The primary labeling on the vials contains the following information: protocol number, content 
and quality of JS001 or placebo, batch number, expiry date, storage instruction, and 
administration instructions. The content of the label will be in accordance with Good 
Manufacture Practice and local regulatory requirement. If applicable, label text will be translated 
into local languages, as required. 
JS001/placebo will be supplied by the sponsor. 
 
4.3.1.2 Gemcitabine and cisplatin 
The associated products in this study include gemcitabine and cisplatin. Each drug will be used 
in the commercially available formulation and will be provided by the Sponsor.  
For information on the formulation, packaging, and handling of gemcitabine and cisplatin, see 
the local prescribing information for each drug. 
 
4.3.2 Dosage, administration, and compliance 
4.3.2.1 Toripalimab injection (JS001) /placebo in combination with gemcitabine 
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Patients will receive 240 mg JS001/placebo administered by IV infusion Q3W in a monitored 
setting where there is immediate access to trained personnel and adequate equipment/medicine to 
manage potentially serious reactions. JS001/placebo will be administered in 100-mL 0.9% NaCl 
IV infusion bags at the dose of 240 mg as an intravenous infusion (IV) over 60 ( 15) minutes 
followed by a 60-minute observation period (only required in the first 2 cycles).   If no clinically 
significant infusion reactions are observed during or after the first 2 cycles, JS001/placebo will 
be administrated as a 30-minute IV infusion (±10 minutes is permitted). JS001 /placebo is given 
first on Day 1 of each cycle. 
JS001/placebo infusions will be administered per the instructions outline in Table 2.  
Table 2 Administration of First and Subsequent Infusions of JS001/Placebo* 
First Infusion 
Subsequent Infusions 
 
No pre-medication is allowed. 
 
Infuse JS001/placebo over 60 ( 15) minutes 
 
Record patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) at 60 ( 10) 
minutes after the infusion. 
 
Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed to 
contact their study physician if they develop such 
symptoms. 
 
If patient experienced infusion-related reaction 
during any previous infusion, pre-medication with 
antihistamines may be administered for Cycles  2 
at the discretion of the treating physician.  
 
Record patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) 60 min 
( 10) after the second infusion.  
 
Record patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) during the 
infusion if clinically indicated or patient 
experienced symptoms during the previous 
infusion.  
 
If no reaction occurs during the first 2 infusions, 
continue subsequent infusions 30 minutes (±10 
minutes is permitted) without following 60-minute 
observation period.  
 
If an infusion-related reaction occurred during a 
previous infusion, subsequent infusions should be 
administered over at least 2 hours and patients 
should be observed post-infusion. Vital signs 
should be obtained during and post-infusion. 
* Refer to most recent version of the Investigator’s Brochure and Appendix 13 concerning the management of an 
infusion-related reaction.   
Gemcitabine and cisplatin are given according to drug label and to local standards for 
premedication and prophylactic medications. gemcitabine 1000 mg/m2 over 30 minutes IV is 
given on Days 1 and 8, and cisplatin 80 mg/m2 IV over 4 hours is given on Day 1, in 3-week 
cycles for up to 6 cycles. The formula for body surface area calculation is provided in Appendix 
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The chemotherapy will continue until progressive disease, excessive toxicity, noncompliance, 
withdrawal of consent, or a maximum of 6 cycles, whichever occurs first in the ‘during 
chemotherapy’ phase. During the ‘post-chemotherapy’ phase, patients A will continue treatment 
with JS001/placebo as maintenance therapy Q3W until excessive toxicity or progressive disease, 
withdrawal of consent or Investigator’s judgement or a maximum of 2 years. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Section 5.3.3. 
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration Electronic Case Report Form (eCRF).  Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded on the Adverse Event 
eCRF. 
 
4.3.3 Investigational medicinal product accountability 
The investigational medicinal products (IMP) for this study are Toripalimab Injection (JS001) 
and placebo. Depending on local classification, in this study, gemcitabine and cisplatin are 
considered a non-investigational medicinal product (NIMP). All IMPs and NIMPs required for 
completion of this study (JS001/placebo, gemcitabine and cisplatin) will be provided by the 
Sponsor.  
The study site will acknowledge receipt of IMPs with use of IWRS to confirm shipment 
condition and content. Any damaged shipments will be replaced. 
IMPs and NIMPs either will be disposed of at the study site according to the study site’s 
institutional standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation. The site’s method of IMP/NIMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP/NIMP is destroyed, 
and IMP/NIMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs and NIMPs received at, dispensed from, returned to, and disposed 
of by the study site should be recorded on the Drug Inventory Log. 
 
4.3.4 Post-trial access to toripalimab injection (JS001) 
The Sponsor will offer post-trial access to the study drug JS001 free of charge to eligible patients 
that was assigned to Arm A after 2 years of treatment, as outlined below. 
A patient will be eligible to receive study drug JS001 after completing the study if all of the 
following conditions are met: 
• 
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• 
At investigator’s discretion, the patient will derive benefit from JS001 rechallenge. 
• 
The patient has a life-threatening or severe medical condition and requires continued 
study drug JS001 treatment for his or her well-being.  
• 
There are no appropriate alternative treatments available to the patient. 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug JS001 after completing the study if any of the 
following conditions are met: 
• 
The study drug JS001 is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't otherwise 
create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug JS001 or data suggest that 
the study drug JS001 is not effective for recurrent or metastatic NPC. 
• 
The Sponsor has reasonable safety concerns regarding the study drug JS001 as treatment 
for recurrent or metastatic NPC.  
• 
Provision of study drug JS001 is not permitted under the laws and regulations of the 
patient's country. 
 
4.4 Concomitant therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient from 7 
days prior to initiation of study drug to the treatment discontinuation visit (within 30 days after 
the last dose of study drugs or the actual day of the treatment discontinuation visit, whichever 
occurs first). All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF, all the concomitant medication administrated for the 
management of AE/SAE (refer to section 5.5.1) occurred after the treatment discontinuation visit 
should be recorded on the Concomitant Medications eCRF. 
 
4.4.1 Permitted therapy 
Premedication with antihistamines may be administered for any Toripalimab Injection (JS001) 
infusions after Cycle 1. 
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• 
Anticonvulsants: Cisplatin may lower the serum levels of anticonvulsants. Subjects 
receiving anticonvulsants should undergo frequent assessments of their serum levels to 
ensure that a therapeutic concentration is maintained. 
• 
Oral contraceptives 
• 
Hormone-replacement therapy 
• 
Prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin or warfarin at a stable dose level) 
• 
Palliative radiotherapy (e.g., treatment of known bony metastases) if the lesion to be 
irradiated is not the only site of disease as that would render the patient not evaluable for 
response by tumor assessments according to RECIST v1.1, but patient will remain 
evaluable for progression 
• 
Inactive influenza vaccinations during influenza season ONLY 
• 
Megestrol administered as an appetite stimulant  
• 
Inhaled corticosteroids for chronic obstructive pulmonary disease 
• 
Mineralocorticoids (e.g., fludrocortisone) 
• 
Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, as per local standards. Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, 
and/or famotidine or another H2 receptor antagonist as per standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress should be managed with 
supportive therapies as clinically indicated (e.g., supplemental oxygen and 2-adrenergic 
agonists; see Appendix 12). 
All medications must be recorded on the Concomitant Medications Electronic Case Report Form 
(eCRF). 
 
4.4.2 Prohibited therapy 
Any concomitant therapy intended for the treatment of cancer, whether health authority 
approved or experimental, is prohibited for various time periods prior to starting study 
treatment, depending on the anti-cancer agent (see Section 4.1.2), and during study treatment 
until disease progression is documented and patient has discontinued study treatment.  This 

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includes but is not limited to chemotherapy, hormonal therapy, immunotherapy, radiotherapy, 
investigational agents, or herbal therapy.  
The following medications are prohibited while on study, unless otherwise noted: 
• 
Traditional herbal medicines as their use may result in unanticipated drug-drug 
interactions that may cause or confound assessment of toxicity 
• 
Denosumab; patients who are receiving denosumab prior to enrollment must be willing 
and eligible to receive a bisphosphonate instead while on study.  
• 
Any live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to randomization or at 
any time during the study  
• 
Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in such 
patients, MRIs of the nasopharynx, neck, abdomen with a non-contrast CT scan of the 
chest must be performed.  
• 
Prophylactic G-CSF are not allowed before the first cycle. Thereafter, they must be 
administered curatively and preventively according to the severity of neutropenia. 
 
4.5 Study assessments 
Flowcharts of scheduled study assessments are provided in Appendix 1. 
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient. 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. 
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend that 
precludes the visit, the visit should be scheduled on the nearest following feasible date, with 
subsequent visits rescheduled accordingly. 
 
4.5.1 Informed consent forms and screening log 
Written informed consent for participation in the study must be obtained before performing any 
study-specific screening tests or evaluations and may be obtained within 28 days before initiation 
of study treatment. 
Informed Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
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All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all patients pre-screened and/or screened and to confirm eligibility or record reasons 
for screening failure, as applicable. 
Patients who are treated with IMPs and who show apparent radiographic progression at a tumor 
response evaluation and have alternative anti-cancer therapies available to them must sign 
consent at that time to acknowledge deferring these treatment options before continuing 
treatment JS001/placebo, and to have a biopsy of the progressing lesion is strongly 
recommended. 
 
4.5.2 Medical history and demographic data 
Medical history includes clinically significant diseases, surgeries, non-NPC cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, use of 
alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 7 days prior 
to the screening visit. 
NPC cancer history will include prior cancer therapies, procedures.  
Demographic data will include age, sex, and self-reported race/ethnicity. 
 
4.5.3 Physical examinations 
A complete physical examination, according to local practice, should be performed at screening.  
Any abnormality identified at screening should be recorded on the General Medical History and 
Baseline Conditions eCRF. 
At subsequent visits, limited, symptom-directed physical examinations should be performed.  
Changes from baseline abnormalities should be recorded in patient notes. New or worsened 
clinically significant abnormalities should be recorded as adverse events on the Adverse Event 
eCRF. 
 
4.5.4 Vital signs 
Vital signs will include measurements of pulse rate, respiratory rate, systolic and diastolic blood 
pressures while the patient is in a seated position, and temperature. 
 
4.5.5 Tumor and response evaluations 

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Screening assessments must include CT scans (with oral/IV contrast unless contraindicated) or 
MRIs of the nasopharynx, neck, chest and abdomen. A CT (with contrast) or MRI scan of the 
head must be done at screening to evaluate CNS metastasis in all patients.  An MRI scan of the 
brain is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of 
an equivocal scan.  Patients with active or untreated CNS metastases are not eligible for this 
study. 
If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast diagnostic 
CT scan. 
Bone scans should also be performed if clinically indicated.  At the investigator’s discretion, 
other methods of assessment of measurable disease as per RECIST v1.1 may be used. 
Tumor assessments performed as standard of care prior to obtaining informed consent and within 
28 days of Cycle 1, Day 1 may be used rather than repeating tests.  All known sites of disease 
must be documented at screening and re-assessed at each subsequent tumor evaluation.  The 
same radiographic procedure used to assess disease sites at screening should be used throughout 
the study (e.g., the same contrast protocol for CT scans).  Response will be assessed by the 
investigator using RECIST v1.1 (see Appendix 4) and irRECIST (see Appendix 5).  Assessments 
should be performed by the same evaluator, if possible, to ensure internal consistency across 
visits. Results must be reviewed by the investigator before dosing at the next cycle. 
Tumor assessments will be performed every 6 weeks ( 7 days) for 12 months following Cycle 
1, Day 1 and then every 9 weeks ( 7 days) thereafter, regardless of treatment delays, until 
disease progression per RECIST v1.1 (for patients in both treatment arms), loss of clinical 
benefit (for patients who continue treatment after disease progression according to RECIST v1.1) 
withdrawal of consent, initiation of new anti-cancer therapy, death, or study termination by the 
Sponsor, whichever occurs first.  At the investigator’s discretion, CT scans should be repeated at 
any time if progressive disease is suspected. 
Patients who are treated with Toripalimab Injection (JS001) /placebo who continue to experience 
clinical benefit, despite evidence of radiographic progression, will continue tumor assessments as 
per the schedule listed above. 
Scans will be submitted for central review to an IRC. 
 
4.5.6 Laboratory, biomarker, and other biological samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory for 
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• 
Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count) 
• 
Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, magnesium, 
chloride, calcium, phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, LDH, 
total protein, and albumin) 
• 
Coagulation (INR, PT, aPTT) 
• 
Serum pregnancy test should only be conducted at screening period for women of 
childbearing potential, including women who have had a tubal ligation; urine pregnancy 
tests will be performed at each cycle during treatment.  A serum pregnancy test must be 
performed if the urine pregnancy test is positive.  
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/or bilateral oophorectomy or not being postmenopausal ( 12 months 
of amenorrhea).  
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood), dipstick permitted; 
and microscopic examination (sediment, RBCs, WBCs). 
• 
Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4) 
• 
HBV serology (HBsAg, antibodies against HBsAg, hepatitis B core antigen [anti-HBc]) 
• 
HBV DNA should be obtained prior to randomization if patient has positive serology for 
anti-HBc Ab. 
• 
HCV serology (anti-HCV) 
• 
HIV testing 
All patients will be tested for HIV prior to the inclusion into the study and HIV-positive 
patients will be excluded from the clinical trial. 
A central laboratory will coordinate the sample collection of tissue and blood samples for 
research-related testing at central laboratories or at the Sponsor. Instruction manuals and 
supply kits will be provided for all central laboratory assessments. Samples for the 
following laboratory tests will be sent to one or several central laboratories for analysis: 
• 
Epstein-Barr virus serology 
• 
PD-L1 assays 
• 
ADA and trough concentration assays (patients assigned to Arm A only) 
Serum samples will be assayed for the presence of ADAs to JS001 and trough 
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• 
Biomarker assays in blood samples 
Blood samples will be obtained for biomarker evaluation (including but not limited to 
biomarkers that are related to NPC or tumor immune biology) from all eligible patients 
according to the schedule in Appendix 2.  Samples will be processed to obtain plasma 
and serum for the determination of changes in blood-based biomarkers (e.g., ctDNA, 
cytokines).  Whole blood samples may be processed to obtain peripheral blood 
mononuclear cells and their derivatives (e.g., RNA and DNA) and may be evaluated for 
immune-related, tumor typerelated, and other exploratory biomarkers (e.g., alterations 
in gene expression or single nucleotide polymorphisms). 
Any remaining samples collected for biomarker assays, ADAs and trough concentration 
may be used for exploratory biomarker profiling, identification, and additional safety 
assessments as appropriate. 
See the laboratory manual for additional details on laboratory assessments and sample handling. 
 
4.5.7 Tumor tissue samples 
A central laboratory will coordinate the sample collection of tissue samples for research-related 
testing at central laboratories or at the Sponsor.  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
See the laboratory manual for additional details on tissue sample handling. 
 
4.5.7.1 Archival or freshly collected tumor tissue samples at screening 
A pre-treatment tumor tissue (archival or freshly obtained) sample should be submitted before or 
within 4 weeks after enrollment. This specimen must be accompanied by the associated 
pathology report.  Although any available tumor tissue sample can be submitted, it is strongly 
encouraged that the sites submit representative tumor specimens in paraffin blocks (preferred) or 
8 (or more) serial, freshly cut, unstained slides exploratory biomarker analysis (including, but not 
limited to, markers related to immune or NPC biology, such as PD-L1expression, tumor 
mutation burden and tumor infiltration CD8+ lymphocyte).  
The preferred sample types include: resections, core needle, excisional, incisional, punch, or 
forceps biopsies. Tumor tissue should be of good quality based on total and viable tumor content.  
Tumor tissue from bone metastases that is subject to decalcification is not advisable. 
 
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Patients in all treatment arms can undergo an optional tumor biopsy to obtain a tumor sample at 
the time of radiographic disease progression (preferably within 40 days of radiographic 
progression or prior to start of the next anti-cancer treatment, whichever is sooner) if they have 
provided consent for Optional Biopsy.   
The preferred sample types include:  resections, core needle, excisional, incisional, punch, or 
forceps biopsies.  If such specimens are not available, any type of specimens including fine-
needle aspiration, cell pellet specimens (e.g., from pleural effusion and lavage samples) can also 
be submitted. 
 
4.5.8 Electrocardiograms and echocardiogram 
A twelve-lead ECG is required at screening and as clinically indicated. ECGs should be obtained 
on the same machine whenever possible.  Lead placement should be as consistent as possible.  
ECG recordings should be performed after the patient has been resting in a supine position. 
An echocardiogram to assess left ventricular ejection fraction (LVEF) will be conducted at 
screening and then if clinically indicated thereafter until discontinuation of study drug. The 
patients should also be examined using the same machine and operator whenever possible. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings 
and echocardiogram report.  Paper copies of ECG tracings and echocardiogram report will be 
kept as part of the patient's permanent study file at the site.  Any morphologic waveform changes 
or other ECG abnormalities and echocardiogram abnormalities must be documented on the 
eCRF. 
 
4.5.9 Patient-reported outcomes (PRO) 
PRO data will be collected via the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires 
to more fully characterize the clinical profile of Toripalimab Injection (JS001). 
The questionnaires will be translated as required in the local language.  To ensure instrument 
validity and that data standards meet health authority requirements, questionnaires scheduled for 
administration during a clinic visit will be completed in their entirety by the patient prior to the 
performance of non-PRO assessments which will relate to disease status assessment, and the 
administration of study treatment. 
 
4.5.10 Timing of assessment 
4.5.10.1 Screening/baseline assessment 

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Screening tests and evaluations will be performed within 28 days prior to Cycle 1, Day 1. 
Pregnancy test and key lab tests will be obtained within 7 days prior to Cycle 1, Day 1 ( See 
Appendix 1). Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to Cycle 1, Day 1 may be used; such tests do not need 
to be repeated for screening. 
See Appendix 1 for the schedule of screening assessments and Appendix 2 for the schedule of 
ADA, trough concentration, and biomarker sampling. 
 
4.5.10.2 Assessments during treatment 
All treatment visits must occur within  3 days from the scheduled date unless otherwise noted 
(see Appendix 1).  All procedures, tests and assessments will be performed on the day of the 
specified visit unless a time window is specified. Assessments scheduled on the day of study 
treatment administration (Day 1) of each cycle should be performed prior to study treatment 
infusion unless otherwise noted. 
If scheduled dosing and study assessments are precluded because of a holiday, weekend, or other 
event, then dosing may be postponed to the soonest following date, with subsequent dosing and 
visits continuing on a 21-day schedule. If treatment was postponed for fewer than 3 days, the 
patient can resume the original schedule.  
See Appendix 1 and Appendix 2 for the schedule of treatment period. 
 
4.5.10.3 Assessment at treatment discontinuation visit 
Patients who discontinue study treatment will return to the clinic for a treatment discontinuation 
visit within 30 days after the last dose of study treatment.  The visit at which a response 
assessment shows progressive disease according to RECIST v1.1 or loss of clinical benefit may 
be used as the treatment discontinuation visit. If the study drug infusion delayed and 
discontinued subsequently, and the interval between last dose of study treatment and decision of 
treatment discontinuation probably is near or longer than 30 days, the investigator should 
complete Treatment Discontinuation Visit as early as they can after patients formally withdrawal 
from study treatment. 
See the study flowcharts provided in Appendix 1 and Appendix 2 for assessments 
to be performed at the treatment discontinuation visit. 
Patients who discontinue study treatment must be followed according to the follow-up visit 
schedule for progression and/or survival until death, loss to follow-up, or withdrawal of consent, 
which will be defined as study discontinuation. 
 

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4.5.10.4 Follow-up assessment 
After the Treatment Discontinuation Visit, adverse events should be followed as outlined in 
Section 5.5.1. 
For patients who discontinue study treatment for any reason other than progressive disease, 
tumor assessments should continue at the same frequency as would have been followed if the 
patient had remained on study treatment until disease progression, loss of clinical benefit, 
initiation of new anti-cancer therapy, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first. 
See the study flowcharts provided in Appendix 1 and Appendix 2 for assessments 
to be performed during Follow-Up visits. 
 
4.5.10.5 Assessment at unscheduled visits 
Assessments for unscheduled visits related to a patient’s underlying diseases, study treatment, or 
adverse events should be performed as clinically indicated and entered into Unscheduled Visit 
eCRFs. 
 
4.6 Patient, Treatment, Study, and Site Discontinuation 
4.6.1 Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In 
addition, the investigator has the right to withdraw a patient from the study at any time.  Reasons 
for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance 
Every effort should be made to obtain information on patients who withdraw from the study. The 
primary reason for withdrawal from the study should be documented on the appropriate eCRF. 
However, patients will not be followed for any reason after consent has been withdrawn.  
Patients who withdraw from the study will not be replaced. 
 
4.6.2 Study Treatment Discontinuation 
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• 
Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and clinical 
status  
• 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable given 
the individual patient’s potential response to therapy and severity of the event 
• 
Any medical condition that may jeopardize the patient’s safety if he or she continues on 
study treatment 
• 
Use of another non-protocol anti-cancer therapy (see Section 4.4.2) 
• 
Pregnancy 
• 
Radiographic disease progression per RECIST v1.1  
Exception:  Patients will be permitted by sponsor medical monitor or designee and treating 
physician to continue Toripalimab Injection (JS001) /placebo after RECIST v1.1 criteria for 
progressive disease are met if they meet all of the following criteria: 
• 
Evidence of clinical benefit as assessed by the investigator 
• 
Absence of symptoms and signs (including worsening of laboratory values [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status that can be attributed to disease progression  
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) 
that cannot be readily managed and stabilized by protocol-allowed medical interventions 
prior to repeat dosing 
• 
Patients must provide written consent to acknowledge deferring any standard treatment 
options that may exist in favor of continuing JS001/placebo treatment at the time of 
initial progression.  
Patients who experience second progression (taking as reference the smallest sum after first 
progression) according to RECIST v1.1 should permanently discontinue JS001/placebo 
treatment. 
In during chemotherapy phase, if patients experience progressive disease according to 
RECIST v1.1 criteria, chemotherapy must be discontinued without exception. 
The primary reason for study drug discontinuation should be documented on the appropriate 
eCRF. 
 
4.6.3 Study and Site Discontinuation 

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The Sponsor has the right to terminate this study at any time.  Reasons for terminating the study 
may include but are not limited to the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may include but 
are not limited to the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been fulfilled) 
 
5 Assessment of Safety  
JS001 has been approved for the treatment of patients with unresectable or metastatic melanoma 
with disease progression on or after previous systemic treatment on the basis of a single arm trial 
in December 2018 in China. The indications for nasopharyngeal carcinoma are currently in 
clinical development. Human experience is currently limited and the entire safety profile is not 
known at this time. The following information is based on results from nonclinical and clinical 
studies and published data on similar molecules. 
 
5.1 Safety plan 
Measures will be taken to ensure the safety of patients participating in this trial, including the use 
of stringent inclusion and exclusion criteria (see Sections 4.1.1 and 4.1.2) and close monitoring 
(as indicated below and in Section 4.5).  See Section 5.5 for complete details regarding safety 
reporting for this study. 
Administration of Toripalimab Injection (JS001)/placebo will be performed in a monitored 
setting where there is immediate access to trained personnel and adequate equipment/medicine to 
manage potentially serious reactions. All adverse events and serious adverse events will be 
recorded during the trial and for up to 60 days after the last dose of study treatment.  
Investigators are instructed to report all serious adverse events considered related to study 

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treatment regardless of time after study. The potential safety issues anticipated in this trial, as 
well as measures intended to avoid or minimize such toxicities, are outlined in the following 
sections. 
 
5.2 Risks associated with toripalimab injection (JS001)  
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may 
increase the risk of immune-mediated adverse events, specifically the induction or enhancement 
of autoimmune conditions. Adverse events with potentially immune-mediated causes, including 
interstitial lung disease, hypothyroidism and hyperthyroidism, liver function disorder, 
pancreatitis and hyperglycemia, have been observed in previous clinical studies which 
investigated safety and efficacy of JS001 in solid tumors. For further details regarding clinical 
safety, see the JS001 Investigator’s Brochure. 
Suggested workup procedures for suspected immune-mediated AEs are provided in Section 5.3.3 
and Appendix 13. 
 
5.3 Risks associated with gemcitabine 
Infusion times of gemcitabine longer than 60 minutes and more frequent than weekly dosing 
have been shown to increase toxicity. 
Pulmonary toxicity has been reported with the use of gemcitabine.  In cases of severe lung 
toxicity, gemcitabine therapy should be discontinued immediately and appropriate supportive 
care measures instituted. 
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia has been reported 
with gemcitabine as a single agent or in combination with other cytotoxic drugs. Monitor for 
myelosuppression should occur prior to each cycle. 
Hemolytic-uremic syndrome (HUS) and/or renal failure have been reported following one or 
more doses of gemcitabine.  Renal failure leading to death or requiring dialysis, despite 
discontinuation of therapy, has been rarely reported.  The majority of the cases of renal failure 
leading to death were due to HUS. 
Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients 
receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs. 
Use caution in patients with pre-existing renal impairment or hepatic insufficiency. 
For more details regarding the safety profile of gemcitabine, see the appropriate Package Insert. 
 
5.3.1 Risk associated with cisplatin 

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Cisplatin is known to cause myelosuppression, ototoxicity, and nephrotoxicity.  Cisplatin-based 
chemotherapy is considered to be moderately emetogenic.  Patients will be monitored for 
cisplatin-related adverse events. 
For more details regarding the safety profile of cisplatin, refer to the appropriate package insert 
or national prescribing information as needed. 
 
5.3.2 General plan to manage safety concerns 
5.3.2.1 Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and nonserious 
adverse events defined and graded according to NCI CTCAE v5.0.  Patients will be assessed for 
safety (including laboratory values) according to the schedule in Appendix 1.  Laboratory values 
must be reviewed prior to each infusion. 
General safety assessments will include serial interval histories, physical examinations, and 
specific laboratory studies, including serum chemistries and blood counts (see Appendix 1 and 
Appendix 2 for the list and timing of study assessments). 
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection. 
All serious adverse events will be reported in an expedited fashion (see Section 5.4.2).  In 
addition, the iDMC and Medical Monitor will review and evaluate observed adverse events on a 
regular basis. 
Patients will be followed for safety for 60 days following their last dose of study drug. 
Patients who have an ongoing study treatmentrelated adverse event upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline grade, the 
event is assessed by the investigator as stable, the patient is lost to follow-up, the patient 
withdraws consent, or it has been determined that study treatment or participation is not the 
cause of the adverse event. 
 
5.3.3 Toripalimab injection (JS001) /placebo dosage modification and management of 
specific adverse events 
5.3.3.1 Dose modification 
There will be no dose reduction for JS001/placebo in this study. Patients may temporarily 
suspend study treatment for up to 56 days beyond the last dose if they experience an adverse 
event that requires a dose to be held. If because of adverse events JS001/placebo is held for up to 

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56 days beyond the last dose, then the patient will be discontinued from treatment and will be 
followed for safety and efficacy as specified in Section 5.4.1. 
If a patient must be tapered off steroids used to treat adverse events, JS001/placebo may be held 
for additional time beyond 56 days (but not more than 12 weeks) from the last dose until steroids 
are discontinued or reduced to ≤ 10 mg/day of prednisone or equivalent dose. 
In during chemotherapy phase, for patients who suspend JS001/placebo, if the adverse event was 
clearly related to JS001/placebo alone, chemotherapy could continue after consulting sponsor 
Medical Monitor, if fulfill appropriate organ function. If the chemotherapy should be suspended 
due to the chemotherapy-related adverse events based on investigators’ judgement, the  
JS001/Placebo administration may be adjusted or not be adjusted accordingly. JS001/placebo 
may be continued if the adverse event was clearly related to chemotherapy alone. Overlapping 
toxicities that may be due to either chemotherapy or JS001/placebo (e.g., pulmonary, renal, or 
hepatic toxicity) should result in temporary discontinuation of both chemotherapy and 
JS001/placebo. 
5.3.3.2 Management of toripalimab injection (JS001)/placebo specific adverse 
events 
Toxicities associated or possibly associated with JS001/placebo treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, should be used to determine a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of JS001/placebo may not have an 
immediate therapeutic effect and, in severe cases, immune-mediated toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, mycophenolate, or TNF- 
inhibitors. 
The investigator should consider the benefit-risk balance a given patient may be experiencing 
prior to further administration of JS001/placebo. Adverse events that require temporary 
discontinuation of JS001/placebo must resolve to Grade 0-1 and the subject must be on < 10 
mg/d of prednisone or equivalent dose prior to resumption of dosing. JS001/placebo should be 
permanently discontinued in patients with life-threatening immune-mediated adverse events. 
The most common irAEs are: fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, 
dyspnea, musculoskeletal pain, constipation, and nausea.  
Refer to most recent version of Investigator Brochure or Appendix 13 concerning the irAEs 
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5.3.4 Gemcitabine and cisplatin dose modification and management of specific adverse 
events 
At the start of each cycle, the ANC must be ≥ 1.5 × 109/L and the platelet count must be 
≥ 100.0×109/L. Treatment should be delayed for up to 42 days to allow sufficient time for 
recovery. Upon recovery, dose adjustments at the start of a subsequent cycle will be made on the 
basis of the lowest platelet and neutrophil values from the previous cycle. Additionally, 
manufacturer’s instructions as well as local hospital or clinical practice will also be followed.  
Please note that chemotherapy dose modifications are permanent; once the dose of any agent has 
been reduced it will remain reduced or be further reduced in subsequent cycles. No more than 2 
dose reductions are allowed. 
 
5.3.4.1 Gemcitabine dose modification and management of specific adverse events 
5.3.4.1.1 Hematologic toxicity 
Dose adjustments for hematologic toxicity may be required for gemcitabine. The gemcitabine 
doses may be either administered at full dose (in the absence of toxicity) or at a reduced dose, as 
described in Table 3 and Table 4. Patient receiving gemcitabine should be monitored prior to 
each dose with a CBC, including differential and platelet counts. If marrow suppression is 
detected, therapy should be modified or suspended according to the guidelines in Table 3 and 
Table 4 . Administration of D8 gemcitabine due to hematological toxicity, it can be delayed up 
to D15 to allow recovery, otherwise this dose should be omitted.  
 
Table 3 Dose Modification Guidelines for Hematological Toxicities on Day 1 of 
Gemcitabine  
Toxicity a 
Gemcitabine Dose 
ANC  0.5 × 109/L and platelets ≥ 50.0 × 109/L 
75% of previous dose 
Platelets  50.0 × 109/L, regardless of ANC 
75% of previous dose 
Platelets  50.0 × 109/L with Grade ≥ 2 bleeding, regardless of ANC 
50% of previous dose 
ANC  1.0 × 109/L plus fever of ≥ 38.5°C  
75% of previous dose 
a 
Nadir prior cycle. 
 
Table 4 Dose Modification Guidelines for Hematological Toxicities on Day 8 of 
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Absolute Neutrophil Count 
(× 109/L) 
 
Platelet Count 
(× 109/L) 
Gemcitabine 
% of previous dose (Day 1 of the cycle) 
≥ 1.0 
and 
≥ 100.0 
100% 
≥ 0.5, and < 1.0 
or 
≥ 50.0, and < 100.0 
75% 
 0.5 
or 
 50.0 
Hold 
 
5.3.4.1.2 Dose modifications guidelines of non-hematological toxicity 
In general, for severe (Grade 3 or 4) non-hematological toxicity, including nausea/vomiting, 
therapy with gemcitabine should be held or dose reduced by 50% depending on the judgment of 
the investigator, detailed dose modifications refer to Table 5 Gemcitabine Dose Modification 
Guidelines for Non-Hematological Toxicities or local standards.  
Permanently discontinue gemcitabine for any of the following: 
• 
Unexplained dyspnea or other evidence of severe pulmonary toxicity 
• 
Severe hepatic toxicity 
• 
Hemolytic-uremic syndrome 
• 
Capillary-leak syndrome 
• 
Posterior reversible encephalopathy syndrome 
Table 5 summarizes dose modifications guidelines for non-hematologic toxicities based on 
grade and severity. 
Table 5 Gemcitabine Dose Modification Guidelines for Non-Hematological Toxicities  
 
Grade 2 
Grade 3 
Grade 4 
First appearance  
Interrupt treatment until 
resolved to Grade 01 then 
continue at same dose with 
prophylaxis where possible  
Interrupt treatment until 
resolved to Grade 01, then 
continue at 75 % of original 
dose with prophylaxis where 
possible 
Discontinue treatment unless 
investigator considers it to 
be in the best interest of the 
patient to continue at 50% of 
original dose, once toxicity 
has resolved to Grade 01 
(after approval by the 
Sponsor) 
Second appearance of 
same toxicity  
Interrupt treatment until 
resolved to Grade 01, then 
continue at 75% of original 
dose 
Interrupt treatment until 
resolved to Grade 01, then 
continue at 50 % of original 
dose  
 

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Third appearance of 
same toxicity  
Interrupt treatment until 
resolved to Grade 01, then 
continue at 50 % of original 
dose 
Discontinue treatment 
permanently  
 
Fourth appearance of 
same toxicity 
Discontinue treatment 
permanently  
 
 
 
5.3.4.2 Cisplatin dose modification and management of specific adverse events 
Treatment with cisplatin should be discontinued if a patient experiences any hematologic or non-
hematologic Grade 3 or 4 toxicity after two dose reductions or immediately if a Grade 3 or 4 
neurotoxicity is observed. 
 
5.3.4.2.1 Hematologic toxicity 
The cisplatin doses may be either administered at full dose (in the absence of toxicity) or at a 
reduced dose, as described in Table 6. 
Table 6 Cisplatin Dose Modification for Hematologic Toxicities 
Toxicity a 
Cisplatin Dose 
ANC  0.5 × 109/Land platelets ≥ 50.0 × 109/L 
75% of previous dose 
Platelets  50.0 × 109/L, regardless of ANC 
75% of previous dose 
Platelets  50.0 × 109/L with Grade ≥ 2 bleeding, regardless of ANC 
50% of previous dose 
ANC  1.0 × 109/L plus fever of ≥ 38.5°C  
75% of previous dose 
a 
Nadir prior cycle. 
 
5.3.4.2.2 Non-hematologic toxicity 
If a patient develops a Grade ≥ 3 non-hematologic toxicity (excluding alopecia, which does not 
warrant treatment discontinuation, and neurotoxicity), cisplatin should be withheld until 
resolution to less than the patient’s pre-treatment value.  Treatment should be resumed according 
to the guidelines in Table 7. 
Table 7 Cisplatin Dose Modification for Non-Hematologic Toxicities (Excluding 
Neurotoxicity) 
Toxicity 
Cisplatin Dose  

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Any Grade 3 or 4 toxicity 
75% of previous dose 
Any diarrhea requiring hospitalization (irrespective of grade) or Grade 3 or 
4 diarrhea that occurs on adequate anti-diarrhea medication 
75% of previous dose 
 
5.3.4.2.2.1 Nephrotoxicity 
Impairment of renal function has been reported with cisplatin as single agent or in combination 
with other cytotoxic agents. CrCl must be ≥ 60 mL/min prior to the start of any cycle.  If there is 
a drop in CrCl between cycles, but the CrCl is still ≥ 60 mL/min at time of next cycle, the 
treating physician should use his/her clinical judgment regarding continuing cisplatin, dose 
reduction, or delaying the cycle. If a patient’s CrCl value has not returned to ≥ 60 mL/min within 
42 days following last cycle D1 chemotherapy administration, the patient must be discontinued 
from chemotherapy. 
 
5.3.4.2.2.2 Ototoxicity 
Ototoxicity has been observed with cisplatin as single agent or in combination with other 
cytotoxic agents. If the patient develops ototoxicity, subsequent doses of cisplatin should not be 
given until an audiometric analysis indicates that auditory acuity is within normal limits 
(http://www.drugs.com/pro/platinol.html). 
 
5.3.4.2.2.3 Neurotoxicity 
In the event of neurotoxicity, the recommended dose adjustment for cisplatin is documented in 
Table 8.  Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed. 
Table 8 Cisplatin Dose Modification for Associated Neurotoxicity 
Toxicity 
Cisplatin Dose 
Grade 0–1 neurotoxicity 
100% of previous dose 
Grade 2 neurotoxicity 
50% of previous dose 
Grade 3 or 4 neurotoxicity 
Permanent discontinuation 
 
5.4 Safety parameters and definitions 
Safety assessments will consist of monitoring and recording adverse events, including serious 
adverse events, performing protocol-specified safety laboratory assessments, measuring 

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protocol-specified vital signs, and conducting other protocol-specified tests that are deemed 
critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 5.6. 
 
5.4.1 Adverse events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution. An adverse event can therefore be any of the following: 
• 
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 
• 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition), except as described in Section 5.5.5.9. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 
5.4.2 Serious adverse events (immediately reportable to the sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe form or was 
allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.5.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
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• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes listed 
above) 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE]; see Section 5.5.3); the event 
itself may be of relatively minor medical significance (such as severe headache without any 
further findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded on 
the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.6.1 for reporting 
instructions). 
 
5.4.3 Adverse events of special interest (immediately reportable to the sponsor) 
Non-serious adverse events of special interest are required to be reported by the investigator to 
the Sponsor immediately (i.e., no more than 24 hours after learning of the event), no need to 
report to HA. Adverse events of special interest for this study include the following:  
• 
Suspected immune-related myocarditis: an increase in myocardial enzymes associated 
with changes in the electrocardiogram or clinical symptoms. 
• 
Abnormal liver function which meet the criteria of Hy’s law: elevated ALT or AST (> 3 
× ULN) in combination with either an elevated total bilirubin (> 2 × ULN) or clinical 
jaundice in the absence of cholestasis or other causes of hyperbilirubinemia. 
 
5.5 Methods and timing for capturing and assessing safety parameters 
The investigator is responsible for ensuring that all adverse events (see Section 5.4.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Sections 5.6 to 5.8. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.4.2 for seriousness criteria), severity (see Section 5.5.3), 
and causality (see Section 5.5.4).   
 

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5.5.1 Adverse event reporting period 
Investigators will seek information on adverse events at each patient contact. All adverse events, 
whether reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only serious 
adverse events caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported (see Section 5.6.2 for instructions 
for reporting serious adverse events). 
After initiation of study drug, all adverse events, regardless of relationship to study drug, will 
be reported until 60 days after the last dose of study drug. After this period, the investigator 
should report any serious adverse events that are believed to be related to prior study drug 
treatment (see Section 5.8). 
 
5.5.2 Eliciting adverse event information 
A consistent methodology of non-directive questioning should be adopted for eliciting adverse 
event information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.5.3 Assessment of severity of adverse events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for assessing 
adverse event severity. Table 9 will be used for assessing severity for adverse events that are not 
specifically listed in the NCI CTCAE. 
Table 9 Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
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Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate 
instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily 
living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using 
the toilet, and taking medications, as performed by patients who are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious adverse event (see 
Section 5.6.2 for reporting instructions), per the definition of serious adverse event in Section 5.4.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.6.2 for reporting instructions), 
per the definition of serious adverse event in Section 5.4.2. 
 
5.5.4 Assessment of causality of adverse events 
Investigators should use their knowledge of the patient, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether an adverse event is 
considered to be related to the study drug, indicating "yes" or "no" accordingly.  The following 
guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
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• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
 
5.5.5 Procedures for recording adverse events 
Investigators should use correct medical terminology/concepts when recording adverse events on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event eCRF. 
 
5.5.5.1 Infusion-related reactions 
Adverse events that occur during or within 24 hours after study drug administration and are 
judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction") on the Adverse Event module. If possible, avoid ambiguous 
terms such as "systemic reaction."  Associated signs and symptoms should be recorded on the 
dedicated Infusion-Related Reaction module. If a patient experiences both a local and systemic 
reaction to the same dose of study drug, each reaction should be recorded separately on the 
Adverse Event module, with signs and symptoms also recorded separately on the dedicated 
Infusion-Related Reaction module. 
 
5.5.5.2 Diagnosis versus signs and symptoms 
For adverse events other than infusion-related reactions (see Section 5.5.5.1), diagnoses (if 
known) should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms.  For example, if a patient has pain in the leg that is eventually diagnosed as being a 
symptom of deep vein thrombosis, then only deep vein thrombosis should be entered as an 
adverse event.  For example, if a patient is hospitalized with shortness of breath, and pulmonary 
embolism, pneumonia or pneumonitis are differential diagnoses, report the appropriate adverse 
event term following confirmation of the diagnosis.  Prior to obtaining the confirmed diagnosis, 
it is sufficient to report the symptoms.  Once the diagnosis is subsequently established, all 
previously reported adverse events based on signs and symptoms should be nullified and 
replaced by the adverse event(s) representing the diagnosis. 
5.5.5.3 Adverse events that are secondary to other events 
In general, adverse events that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or serious 

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secondary events.  A medically significant secondary adverse event that is separated in time from 
the initiating event should be recorded as an independent event on the Adverse Event eCRF.  For 
example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be reported 
separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF. 
All adverse events should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
 
5.5.5.4 Persistent or recurrent adverse events 
A persistent adverse event is one that extends continuously, without resolution, between patient 
evaluation timepoints.  The initial severity (intensity or grade) of the event will be recorded at 
the time the event is first reported.  If a persistent adverse event becomes more severe, the most 
extreme intensity should also be recorded on the Adverse Event eCRF.  Details regarding any 
increases or decreases in severity will be captured on the Adverse Event Intensity or Grade 
Changes eCRF. If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see Section 5.6.1 for 
reporting instructions).  The Adverse Event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and completing all 
data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an adverse event should be recorded as a separate event 
on the Adverse Event eCRF. 
 
5.5.5.5 Abnormal laboratory values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result must be 
reported as an adverse event if it meets any of the following criteria: 

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• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating whether the test result is above or below the normal range (e.g., "elevated potassium," 
as opposed to "abnormal potassium").  If the laboratory abnormality can be characterized by a 
precise clinical term per standard definitions, the clinical term should be recorded as the adverse 
event.  For example, an elevated serum potassium level of 7.0 mEq/L should be recorded as 
"hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (see Section 5.5.5.4 for details on recording 
persistent adverse events). 
 
5.5.5.6 Abnormal vital sign values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  

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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g. high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event 
eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (see Section 5.5.5.4 for details on recording 
persistent adverse events). 
 
5.5.5.7 Abnormal liver function tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated total 
bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by 
Hy's law).  Therefore, regardless of causality (including cholestasis, or other causes of 
hyperbilirubinemia) investigators must report as an adverse event the occurrence of either of the 
following: 
Treatment-emergent ALT or AST  3   ULN in combination with total bilirubin  2  ULN (of 
which  35% is direct bilirubin) 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the Adverse Event eCRF (see Section 5.5.5.2) and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event), as a serious 
adverse event. 
 
5.5.5.8 Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.5.1) that are attributed by the 
investigator solely to progression of NPC should be recorded as “disease progression” on the 
Adverse Event eCRF.  All other on-study deaths, regardless of relationship to study drug, must 
be recorded on the Adverse Event eCRF and immediately reported to the Sponsor except for 
those that occur due to PD after the AE reporting period, will be reported in the survival follow-
up page (see Section 5.6.1). 
Death should be considered an outcome and not a distinct event.  The event or condition that 
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the Adverse Event eCRF.  Generally, only one such event should be reported.  The term 
"sudden death" should be used only for the occurrence of an abrupt and unexpected death due 
to presumed cardiac causes in a patient with or without preexisting heart disease, within 1 hour 
after the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after 
the patient was last seen alive and stable.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, "unexplained death" should be recorded on the Adverse 
Event eCRF.  If the cause of death later becomes available (e.g., after autopsy), "unexplained 
death" should be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of NPC should be recorded only on 
the Survival eCRF.  
 
5.5.5.9 Preexisting medical conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  Such 
conditions should be recorded on the General Medical History and Baseline Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such events on 
the Adverse Event eCRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., "more frequent headaches"). 
 
5.5.5.10 Worsening of nasopharyngeal cancer  
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as adverse events. These data will be captured as efficacy 
assessment data only. In most cases, the expected pattern of progression will be based on 
RECIST v1.1 criteria. In rare cases, the determination of clinical progression will be on the basis 
of symptomatic deterioration. However, every effort should be made to document progression 
through use of objective criteria. If there is any uncertainty as to whether an event is caused by 
disease progression, it should be reported as an adverse event. 
 
5.5.5.11 Hospitalization or prolonged hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious adverse event 
in Section 5.4.2), except as outlined below.   
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
Hospitalization for respite care 

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• 
Planned hospitalization required by the protocol (e.g., for study drug administration or to 
perform an efficacy measurement for the study) 
• 
A hospitalization that was planned prior to the study or elective surgery not caused by an 
adverse event  
• 
Hospitalization caused solely by progression of the underlying cancer 
 
5.5.5.12 Adverse events associated with an overdose or error in drug 
administration 
Study drug overdose is the accidental or intentional use of the study drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study treatment itself is 
not an adverse event, unless it results in untoward medical effects.   
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration eCRF. 
All adverse events associated with an overdose or incorrect administration of study drug should 
be recorded in the Adverse Event eCRF.  If the associated adverse event fulfills serious criteria, 
the event should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.6.1). 
 
5.5.5.13 Patient-reported outcome data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety analyses 
will not be performed using PRO data. However, if any PRO responses suggestive of a possible 
adverse event are identified during site review of the PRO data, the investigator will determine 
whether the criteria for an adverse event have been met and, if so, will report the event on the 
Adverse Event eCRF. 
 
5.6 Immediate reporting requirements from investigator to sponsor 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial. The investigator must report such events to the 
Sponsor immediately; under no circumstances should reporting take place more than 24 hours 
after the investigator learns of the event. The following is a list of events that the investigator 
must report to the Sponsor within 24 hours after learning of the event, regardless of relationship 
to study drug: 
• 
Serious adverse events (see Section 5.6.1 for further details) 
• 
Pregnancies (see Section 5.6.2 for further details) 

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• 
Adverse events of special interest 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the information).  
New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
Investigators must also comply with local requirements for reporting serious adverse events to 
the local health authority and IRB/EC. 
 
5.6.1 Reporting requirements for serious adverse events  
5.6.1.1 Events that occur prior to study drug initiation 
After informed consent has been obtained but prior to initiation of study drug, only serious 
adverse events caused by a protocol-mandated intervention should be reported. The Serious 
Adverse Event Reporting Form provided to investigators should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the event), 
either by faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators. 
 
5.6.1.2 Events that occur after study drug initiation 
After initiation of study drug, serious adverse events will be reported until 60 days after the last 
dose of study drug. Investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours after learning of the event) on the Adverse Event eCRF and submit the 
report via the electronic data capture (EDC) system. A report will be generated and sent to Junshi 
Safety Risk Management designee. 
In the event that the EDC system is unavailable, the Serious Adverse Event Reporting Form 
provided to investigators should be completed and submitted to Junshi designee immediately 
(i.e., no more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form with use of the fax number or email address provided to investigators.  Once 
the EDC system is available, all information will need to be entered and submitted via the EDC 
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Instructions for reporting post-study adverse events are provided in Section 5.8. 
5.6.2 Reporting requirements for pregnancies 
5.6.2.1 Pregnancies in female patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 60 days after the last dose of 
study drug. A Pregnancy Report Form should be completed by the investigator and submitted to 
Junshi Safety Risk Management designee immediately (i.e., no more than 24 hours after learning 
of the pregnancy). Pregnancies should not be recorded on the Adverse Event eCRF. The 
investigator should discontinue study drug and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until 
the conclusion of the pregnancy. Any serious adverse events associated with the pregnancy (e.g., 
an event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF. In addition, 
the investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available. 
 
5.6.2.2 Pregnancies in female partners of male patients  
Male patients will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 60 days after the last 
dose of study drug.  A Pregnancy Report Form should be completed by the investigator and 
submitted to Junshi Safety Risk Management designee immediately (i.e., no more than 24 hours 
after learning of the pregnancy).  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study drug.  
The pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy 
Health Information to allow for follow-up on her pregnancy. Once the authorization has been 
signed, the investigator will update the Pregnancy Report Form with additional information on 
the course and outcome of the pregnancy.  An investigator who is contacted by the male patient 
or his pregnant partner may provide information on the risks of the pregnancy and the possible 
effects on the fetus to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
 
5.6.2.3 Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers abortions 
to be medically significant), recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.6.2).   
 

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5.6.2.4 Congenital anomalies/birth defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study drug or 
the female partner of a male patient exposed to study drug should be classified as a serious 
adverse event, recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.6.2). 
 
5.7 Follow-up of patients after adverse events 
5.7.1 Investigator follow-up 
The investigator should follow each adverse event until the event has resolved to baseline grade 
or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or trial-related procedures until a final outcome can be 
reported. 
During the study period, resolution of adverse events (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
 
5.7.2 Sponsor follow-up 
For serious adverse events, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details and 
outcome information (e.g., from hospital discharge summaries, consultant reports, autopsy 
reports) in order to perform an independent medical assessment of the reported case. 
 
5.8 Post-study adverse events 
The Sponsor should be notified if the investigator becomes aware of any serious adverse event 
that occurs after the end of the adverse event reporting period (defined as 60 days after the last 
dose of study drug), if the event is believed to be related to prior study drug treatment. All 
deaths, regardless of cause, should be reported through use of the Long-Term Survival Follow-
up eCRF.   
The investigator should report these events directly to Junshi or its designee, either by faxing or 
by scanning and emailing the Serious Adverse Event Reporting Form using the fax number or 
email address provided to investigators. 
 

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5.9 Expedited reporting to health authorities, investigators, institutional review boards, 
and ethics committees 
The Sponsor will promptly evaluate all serious adverse events against cumulative product 
experience to identify and expeditiously communicate the suspected adverse drug reaction that 
are both serious and unexpected, or possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on local regulations. 
To determine reporting requirements for single adverse event cases, the Sponsor will assess the 
expectedness of these events using the JS001 Investigator's Brochure as a reference. 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
An iDMC will monitor safety data during the study.  An aggregate report of any clinically 
relevant imbalances that do not favor the test product will be submitted to health authorities. 
 
6 Statistical Considerations and Analysis Plan 
This is a randomized, placebo-controlled, multi-center, double blinded, Phase III study to 
evaluate the efficacy and safety of Toripalimab Injection (JS001) in combination with 
gemcitabine/cisplatin compared with placebo in combination with gemcitabine/cisplatin as first-
line treatment in patients with histological/cytological confirmation of recurrent or metastatic 
NPC. 
Primary and secondary analyses (PFS, OS) will be performed on all randomized patients (i.e., 
ITT) irrespective of whether the assigned treatment was actually received.  ORR and DCR 
analyses will be performed on all randomized patients who have measurable disease at baseline.  
DOR analyses will be performed on the subset of patients who achieve an objective response. 
For all efficacy analyses, patients will be grouped according to the treatment assigned at 
randomization. 
The Per-Protocol Analysis Set (PPS) will include all ITT patients who do not have any major 
protocol violations, which have significant impact on the primary outcome measures, and have 
valid baseline and primary output measures. Patients will be analyzed according to the study arm 
to which they are randomized. Major protocol violations will be defined and inclusion of 
subjects in the PPS population will be finalized prior to study unblinding. The PPS population 
will be used for some secondary/exploratory analysis as well as sensitivity analysis of the 
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The safety population will include all randomized patients who received any amount of study 
drug. Patients who are randomized into the study but did not receive any amount of study drug 
will not be included in the safety population. 
 
6.1 Determination of Sample Size 
The sample size calculation is based on the primary endpoint PFS. Patients will be randomized in 
a 1:1 ratio. A total of 280 patients (140 per arm) are needed to observe 200 PFS events at 
approximately 25 months after the first patient is randomized in order to detect the PFS 
improvement of HR = 0.67 with 80% power at a 2-sided significance level of 0.05; The 
calculation of the sample size is based on the following assumptions: 
• 
PFS is exponentially distributed. 
• 
The median PFS is 7 months for the standard chemotherapy. 
• 
The interim and final analyses of PFS use the Lan DeMets alpha spending function to 
approximate the O’Brien Fleming boundary. 
• 
The recruitment of 280 patients will take place over 14 months. 
• 
The dropout rate is 5% over 12 months for PFS. 
 
6.2 Summaries of conduct of study 
The number of patients who enroll, discontinue, or complete the study will be summarized.  
Reasons for premature study withdrawal will be listed and summarized.  Enrollment and major 
protocol deviations will be listed and evaluated for their potential effects on the interpretation of 
study results. 
 
6.3 Summaries of treatment group comparability 
Demographic and baseline characteristic, such as age, sex, race/ethnicity, baseline disease 
characteristics, ECOG performance status, EBV virus copy number and PD-L1 expression, will 
be summarized by treatment arm. Baseline measurements are the last available data obtained 
prior to the first dose of study drug. 
Descriptive statistics (mean, median, SD, and range) will be presented for continuous data and 
frequencies and percentages will be presented for categorical data. 
 
6.4 Efficacy analyses 
6.4.1 Primary efficacy endpoint 

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The primary efficacy endpoint is PFS, defined as the time from randomization to the occurrence 
of disease progression, as determined by IRC from tumor assessments, per RECIST v1.1, or 
death from any cause, whichever occurs first.  Patients who have not experienced disease 
progression or death at the time of analysis will be censored at the time of the last tumor 
assessment. Patients with no post-baseline tumor assessment will be censored on the date of 
randomization. For patients who have two consecutive missing tumor assessments, PFS will be 
censored at the time of the last available tumor assessment before the missing assessments. Due 
to COVID-19 pandemic, for patients who have two consecutive missing tumor assessments due 
to COVID-19 pandemic’s impact, if a subsequent tumor assessment becomes available and does 
not show disease progression, the tumor assessment will be used in the PFS analysis and if the 
subsequent tumor assessment is disease progression, PFS will still be censored at the time of the 
last available tumor assessment before the missing assessments. 
The hypothesis test for PFS will be conducted at a two-sided alpha level of 0.05. The null and 
alternative hypotheses can be phrased in terms of the PFS survival functions SA(t) and SB(t) for 
Arm A and Arm B, respectively: 
H0: SA(t)  =  SB(t) versus H1: SA(t) ≠ SB(t) 
The two-sided log-rank test, stratified by ECOG performance status (0 vs. 1), and disease stage 
(recurrent vs. metastatic), as recorded in the IWRS, will be used as the primary analysis to 
compare PFS between the two treatment arms. The hazard ratio (HR) for disease progression or 
death will be estimated with the use of a stratified Cox proportional hazards model.  The 95% CI 
for the HR will be provided.  Results from an unstratified analysis will also be provided.  
The Kaplan-Meier methodology will be applied to estimate the median PFS for each treatment 
arm, and Kaplan-Meier curves will be developed.  The Brookmeyer-Crowley methodology will 
be used to construct the 95% CI for the median PFS for each treatment arm. 
 
6.4.2 Secondary efficacy endpoints 
6.4.2.1 Overall survival 
The OS is defined as the time from randomization to death from any cause. Data from patients 
who are alive at the time of the analysis will be censored as of the last date they are known to be 
alive.  The methods outlined for PFS will be used for the OS analysis. 
 
6.4.2.2 Objective response rate 
An objective response is defined as either a confirmed CR or a PR, as determined by the 
investigator and IRC using RECIST v1.1. Patients not meeting these criteria, including patients 
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ORR is defined as the proportion of patients who had an objective response. The analysis 
population for ORR will be all randomized patients with measurable disease at baseline.  An 
estimate of ORR and its 95% CI will be calculated using the Clopper-Pearson method for each 
treatment arm.  CIs for the difference in ORRs between the two treatment arms will be 
determined using the normal approximation to the binomial distribution. 
 
6.4.2.3 Disease control rate 
DCR is defined as the rate of patients with CR or PR as best response or stable disease 
maintained for 6 weeks, as determined by the investigator and IRC per RECIST v1.1. The 
methods outlined for ORR will be used for the DCR analysis. 
 
6.4.2.4 Duration of response 
DOR will be assessed in patients who have an objective response as determined by the 
investigator and IRC using RECIST v1.1.  DOR is defined as the time interval from the date of 
the first occurrence of a CR or PR (whichever status is recorded first) until the first date that 
progressive disease or death is documented, whichever occurs first.  Patients who have not 
progressed and who have not died at the time of analysis will be censored at the time of last 
tumor assessment date.  If no tumor assessments are performed after the date of the first 
occurrence of a CR or PR, DOR will be censored at the date of the first occurrence of a CR or 
PR plus 1 day.  The methods detailed for PFS will be used for the DOR analysis. 
6.4.2.5 Investigator-assessed PFS 
PFS assessed by investigators per RECIST v1.1 be analyzed in the same way as done for the 
IRC-assessed PFS. 
 
6.4.2.6 Survival rates of PFS and OS 
The OS and investigator- and IRC-assessed PFS rates at 1 and 2 years after randomization will 
be estimated with the use of the Kaplan Meier methodology for each treatment arm, along with 
95% CI’s that are calculated with use of the standard error derived from Greenwood’s formula.  
The 95% CI for the difference in the OS rate between the two treatment arms will be estimated 
with use of the normal approximation method. 
 
6.4.2.7 Progression-free survival, objective response rate, disease control rate and 
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Analyses using irRECIST for PFS, ORR, DCR and DOR as determined by the investigator and 
IRC will be conducted.  The applicable methods outlined for PFS and ORR will be used for these 
analyses. 
 
6.4.2.8 Patient-reported outcomes 
Summary statistics (mean, SD, median, and range) of absolute scores and mean changes from the 
baseline will be calculated for all disease and/or treatment related symptom items and subscales 
of the EORTC QLQ-C30 and QLQ-H&N35 at each assessment timepoint for each arm during 
the administration of the treatment and the survival follow up period. The mean (and 95% CI) 
and median of the absolute scores and the changes from the baseline will be reported for interval 
and continuous variables. Previously-published minimally-important differences will be used to 
identify meaningful change from the baseline within each treatment group on the disease and/or 
treatment related symptoms scales19). 
The EORTC QLQ-C30 and QLQ-H&N35 data will be scored according to the EORTC scoring 
manual.  In the event of incomplete data, if the scale has more than 50% of the constituent items 
completed, a pro-rated score will be computed that is consistent with the scoring manual and the 
validation papers of the measure.  For subscales with less than 50% of the items completed, the 
subscale will be considered missing.  PRO completion, compliance rates, and reasons for missing 
data will be summarized at each timepoint by treatment arm. 
 
6.4.3 Exploratory efficacy endpoints 
6.4.3.1 Subgroup analyses 
To assess the consistency of the study results in subgroups defined by demographics (e.g., age, 
sex, and race/ethnicity), baseline prognostic characteristics (e.g., ECOG performance status, 
disease stage, EBV virus copy number, and PD-1 expression status), the IRC-assessed PFS in 
these subgroups will be examined.  Summaries of PFS, including unstratified HRs estimated 
from Cox proportional hazards models and Kaplan-Meier estimates of median PFS, will be 
produced separately for each level of the categorical variables for the comparisons between 
treatment arms. 
 
6.5 Safety analyses 
Safety analyses will be performed on the safety population (see Section 6).  Summaries will be 
presented for the safety-evaluable population by treatment arm. 
Study drug exposure, including treatment duration, number of doses, and dose intensity, will be 
summarized for each treatment arm using descriptive statistics. 

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Verbatim description of adverse events will be mapped to MedDRA thesaurus terms and graded 
according to NCI CTCAE v5.0.  All adverse events occurring during or after the first study drug 
dose will be summarized by treatment arm and NCI CTCAE grade. In addition, serious adverse 
events, severe adverse events (Grade 3, 4, and 5), and adverse events leading to study drug 
discontinuation or interruption will be summarized accordingly. Multiple occurrences of the 
same event will be counted once at the maximum severity. The proportion of patients 
experiencing at least one adverse event will be reported by toxicity term and treatment arm. 
Deaths reported during the study treatment period and those reported during the follow-up period 
after treatment completion/discontinuation will be summarized by treatment arm. 
Laboratory data with values outside the normal ranges will be identified.  In addition, selected 
laboratory data will be summarized by treatment arm.  
Serum levels and incidence of ADA against JS001 will be summarized to explore the potential 
relationship of the immunogenicity response with pharmacokinetics, safety, and efficacy. 
 
6.6 Immunogenicity analyses  
The incidence and titers of Anti-JS001 antibodies will be summarized descriptively to explore 
the potential relationship of the immunogenicity response with pharmacokinetics, safety, and 
efficacy. 
 
6.7 Biomarker analyses  
Whole blood biomarker samples will be separated by density gradient centrifugation to acquire 
Peripheral Blood Mononuclear Cell (PBMC) and plasma. PBMC will be stored in liquid nitrogen 
and plasma will be stored at -80°C until further analysis.  
Plasma or serum samples will be analyzed for EBV DNA copy number, proinflammatory 
cytokines, immune-checkpoint related soluble proteins, etc.,  upon Toripalimab Injection (JS001)  
treatment to explore the prognosis and potential relationship with efficacy.  
Peripheral Blood Mononuclear Cell (PBMC) will be analyzed by flow cytometry for lymphocyte 
subgroup analysis, expression and modulation of PD-1 and other co-signaling receptors upon 
JS001 treatment to explore potential relationship with efficacy. 
Tumor biopsy samples prior to treatment and at the time of apparent disease progression will be 
collected and evaluated by immune-histochemistry (IHC) staining to explore PD-L1 expression 
and presence of tumor infiltration CD8+ lymphocyte (TIL). For the patients enrolled in the sites 
of Mainland China, the pathological classification will be uniformly and clearly classified 
according to the World Health Organization Classification in 2017. When available, whole exon 
sequencing will be performed on tumor tissues to evaluate tumor mutation burden (TMB). PD-

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L1 expression level and percentage, presence of CD8+ lymphocyte and TMB within tumor 
tissues will be analyzed for potential relationship with efficacy.  
 
6.8 Interim analysis 
An iDMC will be set up to evaluate safety data on an ongoing basis, as well as the efficacy data 
for the planned interim efficacy analysis.  All summaries/analyses by treatment arm for the 
iDMC’s review will be prepared by an independent party.  Members of the iDMC will be 
external to the Sponsor and will follow a charter that outlines their roles and responsibilities.  A 
detailed plan will be included in the iDMC Charter.  
One interim efficacy analysis of PFS is planned when approximately 130 PFS events in the ITT 
population have been observed.  This is expected to occur approximately 18 months after the 
first patient is randomized, while the exact timing of the interim analysis will depend on the 
actual occurrence of PFS events. 
The final analysis of PFS will be conducted when approximately 200 PFS events in the ITT 
population have been observed.  This is expected to occur approximately 25 months after the 
first patient is randomized, while the exact timing of the final analysis will depend on the actual 
occurrence of PFS events.  
To control the type I error for PFS analyses at a two-sided significance level of 0.05, the 
stopping boundaries for PFS interim and final analyses have been computed with use of the Lan-
DeMets approximation to the O’Brien-Fleming boundary20 as shown in Table 10. 
Table 10 
Timing and Stopping Boundary of PFS Analyses 
Type of Analysis  
Timing Since 
FSI (month) 
Planned 
Information 
Fraction (Event #) 
Stopping Boundary  
(Two-Sided p-
Value) 
PFS interim analysis 18 
65% (130) 
 0.011 
PFS final analysis 
25 
100% (200) 
0.047 
FSI = First subject in; PFS = progression-free survival; HR = hazard ratio. 
 
7 Data Collection and Management 
7.1 Data quality assurance 
A contract research organization (CRO) will be responsible for data management of this study, 
including quality checking of the data. Data entered manually will be collected via EDC through 
use of eCRFs. Sites will be responsible for data entry into the EDC system. In the event of 

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discrepant data, the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be performed 
on the data. Central laboratory data will be sent directly to the Sponsor or CRO, using the CRO's 
standard procedures to handle and process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including approval of 
the CRO’s data management plans and specifications.  Data will be periodically transferred 
electronically from the CRO to the Sponsor, and CRO’s standard procedures will be used to 
handle and process the electronic transfer of these data.   
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  System 
backups for data stored at the CRO and records retention for the study data will be consistent 
with the CRO’s standard procedures.  
 
7.2 Electronic case report forms  
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will receive 
training and have access to a manual for appropriate eCRF completion.  eCRFs will be submitted 
electronically to the Sponsor and should be handled in accordance with instructions from the 
Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be reviewed and 
electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a readable 
format on a compact disc that must be kept with the study records.  Acknowledgement of receipt 
of the compact disc is required. 
 
7.3 Source data documentation 
Study monitors will perform ongoing source data verification to confirm that critical protocol 
data (i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, and records kept at pharmacies, 
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Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Trial Monitoring Plan.  This includes any protocol data to be entered directly into 
the eCRFs (i.e., no prior written or electronic record of the data) and considered source data. 
Source documents that are required to verify the validity and completeness of data entered into 
the eCRFs must not be obliterated or destroyed and must be retained per the policy for retention 
of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the Sponsor 
direct access to applicable source documents and reports for trial-related monitoring, Sponsor 
audits, and IRB/EC review.  The study site must also allow inspection by applicable health 
authorities. 
 
7.4 Use of computerized systems 
When clinical observations are entered directly into a study site’s computerized medical record 
system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research.  An acceptable computerized data 
collection system allows preservation of the original entry of data.  If original data are modified, 
the system should maintain a viewable audit trail that shows the original data as well as the 
reason for the change, name of the person making the change, and date of the change. 
 
7.5 Retention of records 
Records and documents pertaining to the conduct of this study and the distribution of IMP and 
NIMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years after 
completion or discontinuation of the study or for the length of time required by relevant national 
or local health authorities, whichever is longer.  After that period of time, the documents may be 
destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written notification 
should be provided to the Sponsor prior to transferring any records to another party or moving 
them to another location. 
 
8 Ethical Considerations 
8.1 Compliance with laws and regulations 

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This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline (Clinical 
Safety Data Management:  Definitions and Standards for Expedited Reporting).  Studies 
conducted in the United States or under a U.S. Investigational New Drug (IND) application will 
comply with U.S. FDA regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U. 
Clinical Trial Directive (2001/20/EC). 
 
8.2 Informed consent 
The Sponsor’s sample Informed Consent Form will be provided to each site.  If applicable, it will 
be provided in a certified translation of the local language.  The Sponsor or its designee must 
review and approve any proposed deviations from the Sponsor's sample Informed Consent 
Forms or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission. The final IRB/EC approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the collection of 
optional samples and the disposition of remaining mandatory samples (plasma, serum, whole 
blood, and tissue) for optional exploratory research.  The investigator or authorized designee will 
explain to each patient the objectives, methods, and potential risks associated with each optional 
procedure.  Patients will be told that they are free to refuse to participate and may withdraw their 
consent and/or specimens at any time and for any reason during the storage period.  A separate, 
specific signature will be required to document a patient's agreement to allow the collection of 
optional samples for exploratory research and to inform subjects about the disposition of the 
remaining specimens.  Patients who decline to participate will not provide a separate signature.  
The Informed Consent Form will also contain the following additional signature pages: 
• 
A signature page for patients receiving Toripalimab Injection (JS001) /placebo who 
choose, if approved by the treating physician and sponsor medical monitor or designee, to 
continue treatment beyond initial radiographic disease progression and meet the criteria 
specified in Section 4.6.2. This separate consent is to be signed after initial radiographic 
disease progression has occurred and patients have discussed other available treatment 
options and the potential risks of continuing treatment.  
An optional Informed Consent Form will also be provided and contain a signature page for 
patients that consent to an optional biopsy at the time of radiographic disease progression.  See 
Section 4.5.7.2. 

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The Consent Forms must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the patient to participate.  
The final revised IRB/EC-approved Consent Forms must be provided to the Sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and IRB/EC 
policy) during their participation in the study. For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent process and 
that written informed consent was obtained using the updated/revised Consent Forms for 
continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated Consent Forms must remain in each patient’s 
study file or in the site file and must be available for verification by study monitors at any time. 
 
8.3 Institutional review board or ethics committee 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal Investigator 
and reviewed and approved by the IRB/EC before the study is initiated.  In addition, any patient 
recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB/EC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC.  Investigators are also responsible for promptly 
informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, investigators must 
comply with requirements of local regulations for reporting serious adverse events to the local 
health authority and IRB/EC. Investigators may receive written IND safety reports or other 
safety-related communications from the Sponsor.  Investigators are responsible for ensuring that 
such reports are reviewed and processed in accordance with health authority requirements and 
the policies and procedures established by their IRB/EC, and archived in the site’s study file.  
 
8.4 Confidentiality 

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The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. This means that patient names are 
not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the Informed Consent Form (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or required by 
law. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from exploratory 
biomarker specimens will generally not be provided to study investigators or patients unless 
required by law.  
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, Sponsor monitors, representatives, and collaborators, 
and the IRB/EC for each study site, as appropriate. 
 
8.5 Financial Disclosure 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate health authorities.  Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
 
9 Study Documentation, Monitoring, and Administration 
9.1 Study documentation 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented, including, but not limited to, the protocol, protocol amendments, 
Informed Consent Forms, and documentation of IRB/EC and governmental approval. In 
addition, at the end of the study, the investigator will receive the patient data, including an audit 
trail containing a complete record of all changes to data. 
 
9.2 Protocol deviations 

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The investigator should document and explain any protocol deviations.  The investigator should 
promptly report any deviations that might have an impact on patient safety and data integrity to 
the Sponsor and to the IRB/EC in accordance with established IRB/EC policies and procedures. 
 
9.3 Site inspections 
Site visits will be conducted by the Sponsor or an authorized representative for inspection of 
study data, subjects’ medical records, and eCRFs. The investigator will permit national and local 
health authorities; Sponsor monitors, representatives, and collaborators; and the IRBs/ECs to 
inspect facilities and records relevant to this study. 
 
9.4 Administrative structure 
This study will be sponsored and managed by Shanghai Junshi Biosciences Co., Ltd. 
Approximately 40 sites in China mainland, Taiwan, Singapore, will participate in the study and 
approximately 280 patients will be randomized.  
Randomization will occur through an IWRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests).  Accredited local laboratories 
will be used for routine monitoring; local laboratory ranges will be collected. 
 
9.5 Publication of data and protection of trade secrets 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing information on 
the trial to healthcare professionals and to the public, both at scientific congresses and in peer-
reviewed journals.  The Sponsor will comply with all requirements for publication of study 
results. 
The results of this study may be published or presented at scientific congresses.  For all clinical 
trials in patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to submit a journal manuscript reporting primary 
clinical trial results within 6 months after the availability of the respective Clinical Study Report.  
In addition, for all clinical trials in patients involving an IMP for which a marketing 
authorization application has been filed or approved in any country, the Sponsor aims to publish 
results from analyses of additional endpoints and exploratory data that are clinically meaningful 
and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation.  This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may not yet 
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In accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In this 
case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.  Any formal publication of the study in which 
contribution of Sponsor personnel exceeded that of conventional monitoring will be considered 
as a joint publication by the investigator and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use 
of data from this study will become and remain the exclusive and unburdened property of the 
Sponsor, except where agreed otherwise. 
 
9.6 Protocol amendments 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an immediate 
hazard to patients or changes that involve logistical or administrative aspects only (e.g., change 
in Medical Monitor or contact information). 
 
10 Independent data monitoring committee 
An independent data monitoring committee (iDMC) will be assembled to evaluate safety data for 
this study. The iDMC will consist of at least 2 clinicians and 1 biostatistician with expertise in 
oncology trials. The safety of the subjects will be determined by risk/benefit assessment at 
periodic data review meetings until the final PFS analysis. The iDMC will also review the 
efficacy data for the planned interim analysis. Following the data review, the iDMC will provide 
a recommendation as to whether the study may continue, whether amendment(s) to the protocol 
should be implemented, or whether the study should be stopped.  The final decision will rest with 
the Sponsor. A separate iDMC Charter document will specify the procedures governing the 
conduct of the iDMC. 
 
11 References 
1. Labrijn, AF, Buijsse AO, van den Bremer ET, et al. Therapeutic IgG4 antibodies engage in 
Fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol, 2009;27: 767-71. 

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2. Lazar-Molnar E, Gacser A, Freeman GJ, et al. The PD-1/PD-L costimulatory pathway 
critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl 
Acad Sci U S A, 2008;105:2658-63. 
3. Okazaki T, and Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int 
Immunol, 2007;19:813-24. 
4. JS001 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection). Investigator’s 
Brochure. TopAlliance Biosciences, Inc. most recent version. 
5. Chi ZH, Tang BX, Sheng XN, et al. Abstract 3067: A Phase I Study of JS001, A Humanized 
IgG4 mAb against Programmed Death-1(PD-1) in Patients with Advanced Solid Tumors. 
American Society of Clinical Oncology 2017. 
6. Fitzmaurice C, Dicker D, Pain A, et al. Global Burden of Disease Cancer Collaboration. The 
Global Burden of Cancer 2013. JAMA Oncol 2015;1:505-27. 
7. Jain A, Chia WK, Toh HC. Immunotherapy for nasopharyngeal cancer-a review. Chin Clin 
Oncol 2016;5(2):22. 
8. Chin YM, Mushiroda T, Takahashi A, et al. HLA-A SNPs and amino acid variants are 
associated with nasopharyngeal carcinoma in Malaysian Chinese. Int J Cancer 2015;136:678-
87. 
9. Tian W, Zhu FM, Wang WY, et al. Sequence-based typing of HLA-A gene in 930 patients 
with nasopharyngeal carcinoma in Hunan province, southern China. Tissue Antigens 
2015;86:15-20. 
10. Jin Y, Shi YX, Cai XY, et al. Comparison of five cisplatin based regimens frequently used as 
the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol 
2012;138:1717-25. 
11. Blanchard P, Lee A, Marguet S, et al. Chemotherapy and radiotherapy in nasopharyngeal 
carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol 2015;16:645-55. 
12. Zhang L, Huang Y, Hong SD, et al. Gemcitabine plus cisplatin versus fluorouracil plus 
cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, 
open-label, phase 3 study. The Lancet 2016;388(10054):1883–1892. 
13. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of 
aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 
2013;19:3462-73. 
14. Chiun Hsu, Lee SH, Ejadi S, et al. Antitumor activity and safety of pembrolizumab in 
patients with PD-L1 positive nasopharyngeal carcinoma: Interim results from a phase 1b 
study. Ann Oncol 2015;26:ix93-ix102. 

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15. Kong YC, and Flynn JC. Opportunistic Autoimmune Disorders Potentiated by 
Immune-Checkpoint Inhibitors Anti-CTLA-4 and Anti-PD-1. Front Immunol 2014;5:206. 
16. Abdel-Wahab N, Shah M, and Suarez-Almazor ME. Adverse Events Associated with 
Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case 
Reports. PLoS One 2016;11:e0160221. 
17. Linardou H and Gogas H. Toxicity management of immunotherapy for patients with 
metastatic melanoma. Ann Transl Med 2016;4:272. 
18. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, 
phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 
2016;17(11):1497-1508. 
19. Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:13944 
20. DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341-52. 
 

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12 Appendix 
12.1 Appendix 1 Schedule of Activities 
 
Screening a 
 
All treatment cycles 
 
Treatment 
Discontinuation 
c 
Survival 
Follow-Up d 
 
During chemotherapy 
Post chemotherapy 
Unplanned 
Visit b 
Day 
(Window) 
–28 to –1  
–7 
to –
1 
C1D1 
 
C1D8 
 
C2D1 
( 3) 
C2D8 
 
C3-
C6D1 
( 3) 
C3-
C6D8 
C7D1 
( 3) 
C8D1 to 
PD or 
intolerable 
toxicity 
( 3) 
NA 
 
 
Informed consent 
×e 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and baseline 
conditions 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Patient-reported outcomes f 
 
 
× 
 
× 
 
× 
 
× 
× 
 
 
 
Vital signsg 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
Weight 
 
× 
 
 
× 
 
× 
 
 
 
 
× 
 
ECOG 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
Height 
 
× 
 
 
 
 
 
 
 
 
 
 
 
ECGh 
× 
 
As clinically indicated 
 

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Screening a 
 
All treatment cycles 
 
Treatment 
Discontinuation 
c 
Survival 
Follow-Up d 
 
During chemotherapy 
Post chemotherapy 
Unplanned 
Visit b 
Day 
(Window) 
–28 to –1  
–7 
to –
1 
C1D1 
 
C1D8 
 
C2D1 
( 3) 
C2D8 
 
C3-
C6D1 
( 3) 
C3-
C6D8 
C7D1 
( 3) 
C8D1 to 
PD or 
intolerable 
toxicity 
( 3) 
NA 
 
 
Echocardiogramh 
× 
         As clinically indicated 
 
Complete physical 
examination i 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical 
examination j 
 
 
× 
 
× 
 
× 
 
× 
× 
 
× 
 
Hematology k 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
 
× 
 
Coagulation test (INR, PT, 
aPTT) 
 
× 
 
As clinically indicated 
 
Chemistry l 
 
× 
 
×m 
× 
×m 
× 
×m 
× 
× 
 
× 
 
Pregnancy test n 
 
× 
 
 
× 
 
× 
 
× 
× 
 
× 
 
TSH, free T3, free T4o 
× 
 
 
 
× 
 
× 
 
× 
× 
 
× 
 
Urinalysis p 
 
× 
 
 
× 
 
× 
 
× 
× 
 
× 
 
HIV, HBV, HCV serology q 
× 
 
 
 
 
 
 
 
 
 
 
 
 

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Screening a 
 
All treatment cycles 
 
Treatment 
Discontinuation 
c 
Survival 
Follow-Up d 
 
During chemotherapy 
Post chemotherapy 
Unplanned 
Visit b 
Day 
(Window) 
–28 to –1  
–7 
to –
1 
C1D1 
 
C1D8 
 
C2D1 
( 3) 
C2D8 
 
C3-
C6D1 
( 3) 
C3-
C6D8 
C7D1 
( 3) 
C8D1 to 
PD or 
intolerable 
toxicity 
( 3) 
NA 
 
 
EBV serology r 
 
 
× r 
 
 
 
× r 
 
×r 
× r 
 
 
 
Study drug administration 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
Tumor response assessment 
×s 
 
 
 
 
 
×t 
 
×t 
 
 
 
 
Serum sample for ADAs and 
trough concentration u 
 
 
× 
 
 
 
× 
 
× 
 
 
× 
 
 Blood sample for 
biomarkers v 
 
 
× 
 
  
 
× 
 
× 
 
 
 
 
Concomitant medications w 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
Adverse events x 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
ADA  anti-drug antibody; eCRF  electronic Case Report Form; NA  not applicable. 
Notes:  All assessments should be performed within 28 days of the scheduled visit, unless otherwise specified.  On treatment days, all assessments should be 
performed prior to dosing, unless otherwise specified.   
a. 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 may be used; such tests 
do not need to be repeated for screening.   
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c. 
Patients who complete the treatment period will return to the clinic for a treatment completion visit within 30 days after the last dose of study drugs. Patients 
who discontinue study drug prematurely will return to the clinic for a treatment discontinuation visit within 30  days after the last dose of study drug;  If the 
study drug infusion delayed and discontinued subsequently, and the interval between last dose of study treatment and decision of treatment discontinuation 
probably is near or longer than 30 days, the investigator should complete Treatment Discontinuation Visit as early as they can after patients formally 
withdrawal from study treatment. The visit at which response assessment shows progressive disease may be used as the treatment discontinuation visit. 
d. Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months (±7 days) after treatment discontinu ation until death, 
loss to follow-up, withdrawal of consent or study termination by the Sponsor. 
e. 
Informed consent must be documented before any study-specific screening procedure is performed. 
f. 
Questionnaires will be self-administered before the patient receives any information on disease status, prior to the performance of non-PRO assessments, and 
prior to the administration of study treatment. 
g. Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
h. A twelve-lead ECG and Echocardiogram is required at screening and as clinically indicated thereafter. 
i. 
Includes evaluation of the head, eyes, ears, nose, and throat, superficial lymph node, cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
j. 
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
k. Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells. Results for full blood count must be available before commencing an infusion (samples must have been obtained within 3 days 
prior to the infusion, except for C1D1). 
l. 
Chemistry panel (serum or plasma) includes glucose, BUN or urea, creatinine, sodium, potassium, magnesium, chloride, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin. Results for chemistry tests must be available before commencing an infusion (samples 
must have been obtained within 3 days prior to the infusion, except for C1D1). 
m. Only BUN or urea, creatinine, ALT and AST are needed to be performed on day 8 of gemcitabine. Results must be available before commencing an infusion 
(samples must have been obtained within 3days prior to the infusion, except for C1D1). 
n. All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at each cycle during treatment 
(samples must have been obtained within 3 days prior to the infusion, except for C1D1).  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test. 
o. Thyroid function testing (TSH, free T3, free T4) collected at screening, and each cycle thereafter (samples must have been obtained within 3 days prior to 
the infusion, except for C1D1). 

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p. Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs). Samples must have been 
obtained within 3 days prior to the infusion, except for C1D1.  
q. All patients will be tested for HCV and HIV prior to the inclusion into the study and HCV-positive and/or HIV-positive patients will be excluded from the 
clinical trial.  HBV DNA must be collected before Cycle 1, Day 1 in patients who have positive serology for hepatitis B surface antigen or negative serology 
for hepatitis B surface antigen and positive serology for anti-HBc. 
r. 
EBV serology samples will be collected before infusion of C1D1 and every two cycles prior to the infusion for 12 months and then every 3 cycles prior to 
the infusion until disease progression, loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first; See 
Appendix 2 for detailed schedule.  
s. 
Screening assessments must include CT scans (with oral/IV contrast unless contraindicated) or MRIs of the nasopharynx, neck, chest and abdomen. A CT 
(with contrast) or MRI scan of the head must be done at screening to evaluate CNS metastasis in all patients.  An MRI scan of the brain is required to 
confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan. 
t. 
Tumor assessment should be done to evaluate the target, non-target, and new lesions, it will include all known sites of disease documented at screening, 
which include but not limit to CT scans (with oral/IV contrast unless contraindicated) or MRIs of the nasopharynx, neck, chest and abdomen,  and the same 
radiographic procedure should be used throughout the study, bone scans should also be performed if clinically indicated.  Perform every 6 weeks (± 7 days; 
approximately every two cycles) for 12 months following Cycle 1, Day 1 and then every 9 weeks (± 7 days) thereafter, regardle ss of treatment delays, until 
disease progression, loss of clinical benefit, withdrawal of consent, initiation of new anti-cancer therapy, death, or study termination by the Sponsor, 
whichever occurs first.  CT scans may be repeated at any time if progressive disease is suspected. 
u. See Appendix 2 for detailed schedule. 
v. See Appendix 2 for detailed schedule. 
w. Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug to the treatment discontinuation visit. Subjects receiving anticonvulsants should undergo frequent 
assessments of their serum level to ensure that a therapeutic concentration is maintained. 
x. After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study drug, all adverse events will be reported until 60 days after the last dose of study drug. After this period, the 
Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment 
(see Section 5.6).The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by 
the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or trial-related procedures until a final outcome can be reported. 

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12.2 Appendix 2 Schedule of Biomarker and Anti-drug Antibody Samples 
Period 
Timepoint 
Visit 
Sample type 
Volume of 
Whole Blood 
Screening 
(Day 28 to 
Day –1) 
NA 
Screening  
Tumor tissue specimen 
(blocks or 8 or more FFPE 
slides preferred, if 
available). 
Fresh or archival tissue 
can be used. 
NA 
During the first 
year 
Pre-dose 
(same day as 
treatment 
administration) 
Day 1 of every 2 cycles from 
C1D1 
EBV serology 
3 mL 
Day 1 of every 2 cycles from 
C1D1 
Biomarkers 
10 mL 
Day 1 of every 4 cycles from 
C1D1 
JS001 ADA and trough 
concentration 
3 mL 
After the first 
year  
Pre-dose 
(same day as 
treatment 
administration) 
Day 1 of every 3 cycles 
EBV serology 
3 mL 
Day 1 of every 6 cycles 
Biomarkers 
10 mL 
Day 1 of every 8 cycles 
JS001 ADA and trough 
concentration 
3 mL 
At time of 
initial disease 
progression 
NA 
NA 
EBV serology 
3 mL 
Biomarkers 
10 mL 
Tumor tissue specimen，
biopsy (optional)* 
NA 
At time of 
JS001 
discontinuation  
NA 
NA 
JS001 ADA and trough 
concentration 
3 mL 
ADA= anti-drug antibody; NA= not applicable  
* preferably within 40 days of radiographic progression or prior to start of the next anti-cancer treatment, whichever 
is sooner. 
 
 

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12.3 Appendix 3 Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group Performance Status Criteria 
Score 
Description 
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 
 
 
 

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12.4 Appendix 4 The Response Evaluation in Solid Tumors (RECIST version 1.1) 
Guidelines 
 
The text below was obtained from the following reference: Eisenhauer EA, Therasse P, Bogaerts 
J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247. 
 
1 Inclusion Criteria  
Only subjects with measurable tumors at baseline can be enrolled into the trial protocol with 
objective tumor response rate as the primary endpoint.  
 
2 Definition 
Measurable Disease—At least 1 measurable lesion. Tumor lesions must be accurately 
measured in at least one dimension (longest diameter in the plane of measurement is to be 
recorded) with a minimum size of: 10 mm by CT scan (CT scan slice thickness no greater than 5 
mm); 10 mm caliper measurement by clinical exam (when superficial); 20 mm by chest X-ray (if 
clearly defined). Malignant 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). 
Non-measurable Disease—All other lesions, including small lesions (longest diameter > 10 mm 
or pathological lymph node short axis ≥ 10 to <15 mm) and really non-measurable lesions. 
Lesions that are deemed as really non-measurable include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly that is not measurable by reproducible 
imaging techniques. 
Exceptions of Measurable Disease: Including bone lesions, cystic lesions and lesions with prior 
local treatment. Bone scan, PET scan, or X-ray plain films cannot be used for measurement of 
bone lesions, but 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. If non-cystic lesions and cystic lesions coexist, non-cystic lesions are preferred for 
selection as target lesions. Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other locoregional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  

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All measurements should be recorded in metric notation, using rulers or calipers. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. 
 
3 Measurement Methods 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. 
CT and MRI are the best currently available and reproducible methods to measure target lesions. 
Conventional CT and MRI use a continuous ≤ 10 mm thick layer. Spiral CT uses 5 mm thick 
layer for continuous reconstruction algorithm. This standard is suitable for thoracic, abdominal 
and pelvic tumors, while head and neck tumors and extremity tumors usually require special 
schemes. 
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung. CT is preferred. 
Ultrasound (US) should not be used as a method of measurement of tumor lesion when the 
primary endpoint of the trial is objective response evaluation. The method is not readily accepted 
in clinical practice. This method can be used as an alternative method to clinically measure 
superficially palpable lymph nodes, subcutaneous lesions and thyroid nodules. US approach can 
also be used to confirm the complete disappearance of superficial lesions that are usually 
evaluated by clinical examination. 
Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, however, they must normalize for a subject to be considered in complete 
response if all tumor lesions disappear. Elevations of tumor markers must be accompanied by 
visible disease progression to meet the requirements of disease progression. 
In a few cases, cytology and histology can be used to differentiate between PR and CR (for 
example, residual lesions in tumor types such as germ cell tumors, where known residual benign 
tumors can remain). 
When effusions are known to be a potential adverse effect of treatment, the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
can be considered if the measurable tumor has met criteria for response or stable disease in order 
to differentiate between response (or stable disease) and progressive disease. 

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4 Tumor Response Evaluation  
4.1 “Target” and “Non-target” Lesions Recorded at Baseline  
- All measurable lesions, up to 2 lesions in each organ, the sum of up to 5 lesions, and 
representing all the organs involved as target lesions, are recorded and measured at baseline. 
- The selection of target lesions should be based on the size (lesions with a maximum diameter) 
and suitability, so that they can be (by imaging techniques or clinically) accurately and 
repeatedly measured. 
- Calculate the sum of the longest diameter (LD) of all target lesions, and report it as baseline 
sum LD. Use baseline sum LD as a reference value for description of objective tumor. 
- All other lesions (or sites of disease) should be used as non-target lesions and reported at 
baseline. These lesions are not required to be measured, but the presence or absence of each 
lesion during the entire follow-up period should be recorded. 
 
4.2 Criteria for Response 
Criteria for 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 lesions, taking 
as reference the baseline sum LD. 
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. 
 
Criteria for Evaluation of Non-target Lesions 

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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/SD: 
Persistence of ≥ 1 non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
Progressive 
Disease (PD): 
Appearance of ≥ 1 new lesions and/or unequivocal progression of existing 
non-target lesions.* 
* Although unequivocal progression of “non-target” lesions is an exception, the opinion of the treating doctor should 
be referred to, and the progression status later should be confirmed.  
 
4.3 Criteria for Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (the minimum measurements recorded from the start of the 
treatment should serve as reference values for PD). The subject’s best overall response will 
generally depend on the completion of two measurements and the confirmation criteria.  
When the treatment is required to be discontinued due to overall deterioration of the health 
status, and there is no objective evidence indicating disease progression, the subject should be 
reported as "symptomatic deterioration." Objective progression should be recorded as far as 
possible, even after cessation of the treatment. 
In some cases, it is difficult to distinguish residual lesion from normal tissue apart. When the 
evaluation of complete response depends on this decision, it is advised to study the residual 
lesion (fine needle extraction/biopsy) to confirm the complete response status.  
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 
NE 
PD 
Any 
Yes or No 
PD 

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Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
12.5 Appendix 5 Immuno-Related Response Evaluation in Solid Tumors (irRECIST) 
The text below was obtained from the following reference: Bohnsack O, Hoos A, and Ludajic K. 
Adaptation of the immune related response criteria: irRECIST. Annals of Oncology. 2014.25 
(suppl_4): iv361-iv372.  
RECIST 1.1 has its shortcomings for targeted immunotherapy in oncology. Using RECIST 1.1 in 
immunotherapy trials would lead to declaration of progressive disease (PD) too early, when the 
treatment effect is not yet fully evident. RECIST also neglects the importance of the ‘flare effect’ 
- pseudo-progression effect within the so-called flare time window. 
Immune related Response Criteria (irRC) based on WHO criteria were published with an aim to 
provide better assessment of the effect of immunotherapeutic agents. With this poster we 
introduce irRECIST based on RECIST 1.1, irRC and Nishino et al., 2013 findings. Our aim is to 
define criteria that better capture antitumor activity and reduce irRC criteria ambiguity. 
irRC and WHO criteria  
irRECIST Modifications and Clarifications 
Rationale for Modification 
At the baseline tumor 
assessment, the sum of the 
products of the two largest 
perpendicular diameters 
(SPD) of all index lesions 
(five lesions per organ, up 
to 10 visceral lesions and 
five cutaneous index 
lesions) is calculated. 
1.0. Baseline: Measurable Lesion 
Definitions and Target Lesion 
Selection 
Follow the definitions from RECIST 1.1. 
Measurable lesions must be accurately 
measured in at least one dimension with a 
minimum size of: 
• 10 mm in the longest diameter by CT or 
MRI scan (or no less than double the slice 
thickness) for non-nodal lesions and ≥ 15 mm 
in short axis for nodal lesions 
• 10 mm caliper measurement by clinical 
exam 
• 20 mm by chest X-ray 
Up to 5 target lesions may be 
selected at baseline. Lesions 
will be measured 
unidimensionally. The 
minimum target lesion size at 
baseline in irRECIST is aligned 
with RECIST 1.1, as outlined in 
Nishino et al., 2013. 
WHO 5.1.2 
Unmeasurable Disease 
1.1. Baseline: Non-measurable 
Lesion Definitions 
Although irRC does not 
specifically define non-target 
lesions, irRC is derived from 

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irRC and WHO criteria  
irRECIST Modifications and Clarifications 
Rationale for Modification 
There are many forms of 
unmeasurable disease, and 
only a few are mentioned 
as examples: 
1. Lymphangitic 
pulmonary metastases. 
2. Skin involvement in 
breast cancer. 
3. Abdominal masses that 
can be palpated but not 
measured. 
Follow the definitions from RECIST 1.1 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), ie. 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. 
WHO criteria and indicates 
accordance with the same for 
the purposes of definitions of 
non-target lesions. Further 
clarifications in alignment with 
RECIST 1.1 are provided. 
Not specified. 
1.2 Baseline: Target and Non-Target 
Lymph Node Lesion Definitions 
Follow the definitions from RECIST 1.1 
No change in definition of target 
and non-target lymph nodes 
from RECIST 1.1. 
Not specified. 
1.3 Baseline: Non-Target Lesion Selection 
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. 
In alignment with RECIST 1.1, 
all malignant lesions have to be 
selected at baseline. The excess 
of measurable lesions and all 
true non-measurable lesions will 
be selected as non-target lesions 
at baseline and followed at 
subsequent timepoints. 
Not specified. 
1.4 Baseline: Bone Lesions 
Follow the definitions from RECIST 1.1.  
Regardless of the imaging modality blastic 
bone lesions will not be selected as target 
lesions. Lytic or mixed lytic-blastic lesions 
with a measurable soft tissue component ≥ 
10 mm can be selected as target lesions. 
Bone lesions are to be handled 
the same as in RECIST 1.1. 
Not specified. 
1.5 Baseline: Brain Lesions  
Brain Lesions detected on brain scans can be 
considered as both target or non-target lesions. 
Brain lesions can be selected as 
target or non-target lesions at 
baseline, depending on the 

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irRC and WHO criteria  
irRECIST Modifications and Clarifications 
Rationale for Modification 
protocol definition, indication, 
and study design. 
Not specified. 
1.6 Baseline: Cystic and Necrotic Lesions as 
Target Lesions 
Lesions that are partially cystic or necrotic can 
be selected as target lesions. The longest 
diameter of such a lesion will be added to the 
Total Measured Tumor Burden (TMTB) of all 
target lesions at baseline. If other lesions with 
a non-liquid/non-necrotic component are 
present, those should be preferred. 
RECIST 1.1 does not integrate 
viability of tumor tissue into the 
assessment, and that is carried 
over into irRECIST. 
Not specified. 
1.7 Baseline: Lesions With Prior Local 
Treatment 
During target lesion selection the radiologist 
will consider information on the anatomical 
sites of previous intervention (e.g. previous 
irradiation, RF-ablation, TACE, surgery, etc.). 
Lesions undergoing prior intervention will not 
be selected as target lesions unless there has 
been a demonstration of progress in the lesion. 
In order to minimize site vs. 
central discrepancy information 
about prior intervention needs to 
be available to both the 
investigators and independent 
reviewers. 
Not specified. 
1.8 Baseline: No Disease at Baseline 
If a patient has no measurable and no non-
measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall 
tumor assessment for any available follow-up 
timepoints unless new measurable lesions are 
identified and contribute to the TMTB. 
irND is a valid assessment in 
studies with adjuvant setting 
where the protocol and study 
design allow to include subjects 
with no visible disease. This had 
not been addressed at all in any 
prior immune-response related 
criteria but needs to be included 
to also allow for these subjects 
to be assessed accurately. 
At each subsequent tumor 
assessment, the SPD of the 
index lesions and of new, 
measurable lesions 
(≥ 5×5  mm; up to 5 new 
lesions per organ: 5 new 
cutaneous lesions and 10 
visceral lesions) are added 
together to provide the total 
tumor burden.  
2.0 Follow-up: Recording of Target and 
New Measureable Lesion Measurements 
The longest diameters of non-nodal target and 
new non-nodal measurable lesions, and short 
axes of nodal target and new nodal 
measurable lesions will be recorded. Together 
they determine the Total Measured Tumor 
Burden (TMTB) at follow-up. 
In alignment with Nishino et al., 
2013, unidimensional 
measurements are used. 
Measurements of all measured 
lesions (baseline-selected target 
lesions and new measurable 
lesions) are combined into 
TMTB at follow-up. 
 
2.1 Follow-up: Definition of Measurable 
New Lesions 
Proposed selection of up to 5 
new measurable lesions of at 
least 10 mm each versus 10 new 

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irRC and WHO criteria  
irRECIST Modifications and Clarifications 
Rationale for Modification 
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 long diameter and 
minimum 15 mm in 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. 
measurable lesions as suggested 
in the irRC criteria is due to the 
following: 5 new measurable 
lesions add up at least 50 mm to 
the TMTB. Since PD is 
determined by at least a 20% 
increase in TMTB compared to 
nadir, this would mean that for 
irPD assessment the nadir 
TMTB had to be 25 cm, or 10 
cm for 2 lesions in one organ, 
which is a significant tumor 
burden already for any cancer 
subject. That is why measuring 
up to 5 new lesions in total is 
sufficient and will not obstruct 
an irPD assessment. Measuring 
more than 5 new lesions is not 
needed. 
Larger lesions must be preferred 
as new measurable over smaller 
lesions, because there will be a 
greater impact of the TMTB %-
increase by these larger lesions 
for irPD, to support a most 
conservative approach. 
Non-index lesions at 
follow-up time points 
contribute to defining irCR 
(complete disappearance 
required). 
2.2 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 
(irNN). Non-target lesions do not affect irPR 
and irSD assessments. Only a massive and 
unequivocal worsening of non-target lesions 
alone, even without progress in the TMTB is 
indicative of irPD. 
Non-target lesions have a 
subordinate function. In the 
event that non-target lesions 
massively progress one cannot 
ignore such worsening and in 
these rare cases irPD based only 
on non-target lesions will be a 
valid assessment option. 
New, non-measurable 
lesions at follow-up 
timepoints do not define 
progression, they only 
preclude irCR. 
2.3 Follow-up: New Non-Measurable 
Lesions Definition and Assessment 
All new lesions not selected as new 
measurable lesions are considered new non-
measurable lesions and are followed 
qualitatively. Only a massive and unequivocal 
progression of new non-measurable lesions 
When new non-measurable 
lesions substantially worsen in 
these rare cases irPD based only 
on new non-measurable lesions 
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irRC and WHO criteria  
irRECIST Modifications and Clarifications 
Rationale for Modification 
leads to an overall assessment of irPD for the 
time point. Persisting new non-measurable 
lesions prevent irCR. 
irRC Overall Tumor 
Assessments 
irCR, complete 
disappearance of all lesions 
(whether measurable or 
not, and no new lesions) 
• Confirmation by a repeat, 
consecutive assessment no 
less than 4 weeks from the 
date first documented  
irPR, decrease in tumor 
burden ≥ 50% relative to 
baseline 
• Confirmed by a 
consecutive assessment at 
least 4 weeks after first 
documentation 
irSD, not meeting criteria 
for irCR or irPR, in 
absence of irPD  
irPD, increase in tumor 
burden ≥ 25% relative to 
nadir (minimum recorded 
tumor burden) 
• Confirmation by a repeat, 
consecutive assessment no 
less than 4 weeks from the 
2.4 irRC Overall Tumor Assessments  
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 
mandatory.  
irPR, decrease of ≥ 30% in TMTB relative to 
baseline, non-target lesions are irNN, and no 
unequivocal progression of new non-
measurable lesions. 
irSD, failure to meet criteria for irCR or irPR 
in the absence of irPD. 
irNN, no target disease was identified at 
baseline and at follow-up the subject fails to 
meet criteria for irCR or irPD. 
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. 
irNE, used in exceptional cases where 
insufficient data exists. 
irND, in adjuvant setting when no disease is 
detected. 
The irRECIST overall tumor 
assessment is based on TMTB 
of measured target and new 
lesions, non-target lesion 
assessment and new non-
measurable lesions. 
 
The thresholds for irPR and 
irPD assessment are aligned 
with RECIST 1.1, and 
confirmation of response is not 
required. 
 
An irPD confirmation scan may 
be recommended for subjects 
with a minimal TMTB%-
increase over 20% and 
especially during the flare time-
window of the first 12 weeks of 
treatment, depending on the 
compound efficacy 
expectations, to account for 
expected delayed response. 
 
 
 

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12.6 Appendix 6 New York Heart Association Cardiac Function Classification 
New York Heart Association Function Classification 
Class 
Symptoms 
1 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. shortness 
of breath when walking, climbing stairs etc. 
2 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary 
activity. 
3 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. 
walking short distances (20–100 m). 
Comfortable only at rest. 
4 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
 
 
 

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12.7 Appendix 7 Body Surface Area Calculation Formula 
BSA (m2) = SQRT ( [Height(cm) × Weight(kg) ]/ 3600 ) 
Note: BSA=body surface area; SQRT =square root, H=height; W=weight. 
Resource: Mosteller RD, et al. N Engl J Med. 1987 Oct 22;317(17):1098 
 
 
 

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12.8 Appendix 8 Method for Calculation of Creatinine Clearance Rate 
For men, CrCL (mL/min) = [140- age (years)] × [weight (kg) 1]/(72) × [serum creatinine 
(mg/dL)] 
For women, CrCL (mL/min) = (0.85) × [140 - age (years)] × [weight (kg) 1]/(72) × [serum 
creatinine (mg/dL)] 
 
For SI unit: 
For men, CrCL (mL/min) = [140- age (years)] × [weight (kg) 1] × (1.23)/[serum creatinine 
(μmol/L)] 
For women CrCL (mL/min) = [140- age (years)] × [weight (kg) 1] × (1.05)/[serum creatinine 
(μmol/L)] 
 
1 If the subject is obese (30% over ideal body weight), use the ideal body weight to calculate 
CrCL 
Male: ideal body weight (kg) = height (cm) - 105 
Female: ideal body weight (kg) = height (cm) – 100 
 
 
 

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12.9 Appendix 9 EORTC QLQ-C30 (version 3) 

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12.10 Appendix 10 EORTC QLQ - H&N35 

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12.11 Appendix 11 Preexisting Autoimmune Diseases 
Patients should be carefully questioned regarding their history of acquired or congenital immune 
deficiencies or autoimmune disease.  Patients with any history of immune deficiencies or 
autoimmune disease listed in the table below are excluded from participating in the study.  
Possible exceptions to this exclusion could be subjects with a medical history of such entities as 
atopic disease or childhood arthralgias where the clinical suspicion of autoimmune disease is 
low.  Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible for this study.  In addition, transient autoimmune 
manifestations of an acute infectious disease that resolved upon treatment of the infectious agent 
are not excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty over autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
Acute disseminated 
encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody 
syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune 
hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic 
purpura 
Behcet’s disease 
Bullous pemphigold 
Chronic fatigue syndrome 
Chronic inflammatory 
demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease  
Dermatomyositis 
Diabetes mellitus type 1 
Dysautonomia 
Epidermolysis bullosa acquista 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture’s syndrome 
Graves’ disease 
Guillain-Barré syndrome  
Hashimoto’s disease 
IgA nephropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki’s disease 
Lambert-Eaton myasthenia 
syndrome 
Lupus erythematosus 
Lyme disease - chronic 
Meniere’s syndrome 
Mooren’s ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
 
Neuromyotonia 
Opsoclonus myoclonus 
syndrome 
Optic neuritis 
Ord’s thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodusa 
Polyarthritis 
Polyglandular autoimmune 
syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter’s syndrome 
Rheumatoid arthritis 
Sarcoidosis 
Scleroderma 
Sjögren’s syndrome 
Stiff-Person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vitiligo 
Vogt-Kovanagi-Harada disease 
Wegener’s granulomatosis 
 

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12.12 Appendix 12 Anaphylaxis Precautions 
Equipment Needed 
• 
Tourniquet 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance with standard 
practice 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
Procedures 
In the event of a suspected anaphylactic reaction during study drug infusion, the following 
procedures should be performed: 
1. Stop the study drug infusion. 
2. Apply a tourniquet proximal to the injection site to slow systemic absorption of study drug.  Do 
not obstruct arterial flow in the limb. 
3. Maintain an adequate airway. 
4. Administer antihistamines, epinephrine, or other medications as required by patient status and 
directed by the physician in charge.  
5. Continue to observe the patient and document observations 
 
 

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12.13 Appendix 13 Management of Immune-related Adverse Events 
From: 
Brahmer JR, et al. Management of immune-related adverse events in patients treated with 
immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice 
Guideline. J Clin Oncol. 2018 Jun 10;36(17):1714-1768. Link: 
http://ascopubs.org/doi/full/10.1200/JCO.2017.77.6385 
 
 
 
 
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS IN PATIENTS TREATED 
WITH IMMUNE CHECKPOINT INHIBITOR THERAPY: AMERICAN SOCIETY OF 
CLINICAL ONCOLOGY CLINICAL PRACTICE GUIDELINE 
 
1.0 SKIN TOXICITY 
1.1 Rash/Inflammatory Dermatitis Definition: Erythema multiforme minor (a targetoid 
reaction in the skin and mucous membranes usually triggered by infections, such as Herpes 
Simplex Viruses, but can be associated with an immune-related drug eruption and if progresses 
to EM major, it and can be a harbinger of SCAR, such as SJS), lichenoid (resembling the flat- 
topped, polygonal and sometimes scaly or hypertrophic lesions of lichen-planus), eczematous 
(Inflammatory dermatitis characterized by pruritic, erythematous, scaly or crusted papules or 
plaques on the skin, which is vulnerable to superinfection, psoriasiform (resembling the well-
demarcated, erythematous and scaly papules and plaques of psoriasis), morbilliform (a non-
pustular, non-bullous measles-like exanthematous rash of the skin often referred to as 
“maculopapular” and without systemic symptoms or lab abnormalities excluding occasional 
isolated peripheral eosinophilia, Palmoplantar erythrodysaesthesia (PPE) (hand-foot syndrome) 
(redness, numbness/burning/itching and superficial desquamation of the palms and soles), 
neutrophilic dermatoses (e.g. sweet’s syndrome) and others. 
Diagnostic Workup: 
• 
Pertinent history and physical exam 
• 
Rule out any other etiology of the skin problem, such as an 
infection, an effect of another drug or a skin condition linked to 
another systemic disease or unrelated primary skin disorder 
• 
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• 
Directed serologic studies if an autoimmune condition is suspected, 
such as lupus or dermatomyositis: a screening antinuclear antibody 
test, SS- A/Anti-Ro, SS-B/Anti-La if predominantly 
photodistributed/photosensitivity, anti-histone, ds-DNA and other 
relevant serologies. Consider expanding serologic studies or 
diagnostic work up if other autoimmune conditions are considered 
based on signs, symptoms. 
• 
Skin biopsy 
• 
Consider clinical monitoring with use of serial clinical photography 
• 
Review full list of patient medications to rule out other drug-induced cause for 
photosensitivity 
Grading 
Grading according to 
CTCAE criteria is a 
challenge for skin. 
Instead, severity may 
be based on BSA, 
tolerability, morbidity, 
and 
duration. 
  Management 
G1: Symptoms do not 
affect the quality of life 
or controlled with 
topical regimen and/or 
oral antipruritic 
• 
Continue immune checkpoint inhibitor (ICPi) 
• 
Treat with topical emollients and/or mild-moderate potency 
topical corticosteroids 
• 
Counsel patients to avoid skin irritants and sun exposure 
G2: Inflammatory 
reaction that affects 
quality of life and 
requires 
intervention based 
on diagnosis. 
• 
Consider holding ICPi and monitor weekly for 
improvement. If not resolved, interrupt treatment until 
skin AE has reverted to grade 1 
• 
Consider initiating prednisone (or equivalent) at dosing 1 
mg/kg tapering over at least 4 weeks 
• 
In addition, treat with topical emollients, oral antihistamines 
and medium-to-high potency topical corticosteroids 
G3: As grade 2 but with 
failure to respond to 
indicated interventions for 
• 
Hold ICPi therapy and consult with dermatology to determine 
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a grade 2 dermatitis. 
• 
Treat with topical emollients, oral antihistamines and high 
potency topical corticosteroids 
• 
Initiate oral prednisone or equivalent (0.5-1 mg/kg/day) 
tapering over at least 4 weeks 
G4: All severe rashes 
unmanageable with prior 
interventions and 
intolerable. 
• 
Immediate hold ICPi and consult dermatology to determine 
appropriateness of resuming ICPi therapy upon resolution of 
skin toxicity and once corticosteroids are reduced to 
prednisone (or equivalent) 10mg or less. 
• 
Systemic steroids: IV methylprednisolone (or equivalent) 
dosed at 1–2mg/kg with slow tapering when the toxicity 
resolves 
• 
Monitor closely for progression to Severe Cutaneous Adverse 
Reaction 
• 
Should admit patient immediately with direct oncology 
involvement and with an urgent consult by dermatology 
• 
Consider alternative antineoplastic therapy over resuming 
ICPi’s if the skin irAE does not resolve to grade 1 or less. 
• 
If ICPI’s are the patient’s only option, consider restarting 
once these side effects have resolved to a grade 1 level. 
1.2 Bullous Dermatoses 
Definition: including bullous pemphigoid or other autoimmune bullous dermatoses, bullous 
drug reaction 
Diagnostic Workup: 
• 
Physical exam 
• 
Rule out any other etiology of the skin problem, such as an 
infection, an effect of another drug or a skin condition linked to 
another systemic disease. 
• 
If needed, a biological checkup including a blood cell count, liver 
and kidney tests, consider serum antibody tests to rule out bullous 
pemphigoid or, under the guidance of dermatology, sending patient 
serum for indirect immunofluorescent testing to rule out other 
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• 
Referral to dermatology for blisters that are not explained by 
infectious or transient other causes (e.g. herpes simplex, herpes 
zoster, bullous impetigo, bullous insect bite, friction or pressure 
blister, etc.) 
• 
Consider skin biopsy (both H+E evaluation of lesional skin and direct 
immunofluorescence evaluation of peri-lesional skin), 
Grading 
Management 
G1: Asymptomatic, 
Blisters Covering < 
10% BSA and no 
associated erythema 
• 
If blisters are <10% BSA, are asymptomatic and non-
inflammatory (such as the case with friction blisters or 
pressure blisters), cessation of ICPi is not necessary and 
only observation/local wound care is warranted. 
• 
When symptomatic bullae or erosions, which are 
“deroofed” vesicles or bullae, are noted on the skin or 
mucosal surfaces, the cutaneous irAE is by definition 
considered at least grade 2 
• 
See grade 2 management recommendations. 
G2: Blistering that affects 
quality of life and require 
intervention based on 
diagnosis not meeting 
criteria for >grade 2. 
Blisters covering 10%-
30% BSA. 
• 
Hold ICPi therapy and consult with dermatology for work up 
and to determine appropriateness of resuming 
• 
Attention given to general local wound care, which includes 
plain petrolatum ointment and bandages or plain petrolatum 
ointment gauze and bandage over any open erosions, which 
are left over on the skin after the blister has “popped” or if the 
roof of the blister easily sloughs off. 
• 
Counsel patients to avoid skin irritants and overexposure to 
sun, wear protective clothing, use sunscreens 
• 
Workup for autoimmune bullous disease as above 
• 
Initiate class 1 high potency topical steroid, eg: clobetasol, 
betamethasone or equivalent and reassess every 3 days for 
progression or improvement. 
• 
Low threshold to initiate treatment with prednisone (or 
equivalent) at 0.5-1 mg/kg dosing and taper over at least 4 
weeks. 
• 
Monitor patients with grade 2 irAE’s closely for progression 
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membrane involvement. Consider following patients closely 
using serial photography. 
• 
Primer on monitoring for complicated cutaneous adverse 
drug reactions: 
o Review of Systems: Skin pain (“like a sunburn”), 
fevers, malaise, myalgias, arthralgias, abdominal 
pain, ocular discomfort or photophobia, sores or 
discomfort in the nares, sores or discomfort in the 
oropharynx, odynophagia, hoarseness, dysuria, sores 
or discomfort in the vaginal area for women or 
involving the meatus of the penis for men, sores in 
the perianal area or pain with bowel movements. 
o Physical Exam: Include vital signs and a full skin 
exam specifically evaluating all skin surfaces and 
mucous membranes (eyes, nares, oropharynx, 
genitals and perianal area). Assess for 
lymphadenopathy, facial or distal extremity swelling 
(may be signs of drug-induced hypersensitivity 
syndrome/DRESS). Assess for pustules or blisters or 
erosions in addition to areas of “dusky erythema” 
which may feel painful to palpation. To assess for a 
positive Nikolsky sign, place a gloved finger 
tangentially over erythematous skin apply friction 
parallel to the skin surface. Nikolsky sign is positive 
if this results in detached or sloughing epidermis 
demonstrating poor attachement of the epidermis to 
the dermis, which is the case in some autoimmune 
disorders (e.g. pemphigus) and SJS/TEN. 
G3: Skin sloughing 
covering >30% BSA with 
associated pain and 
limiting self care activity 
of daily living (ADL) 
• 
Hold ICPi therapy and consult with dermatology to determine 
appropriateness of resuming 
• 
Administer IV methylprednisolone (or equivalent) 1-2 mg/kg 
tapering over at least 4 weeks 
• 
If bullous pemphigoid is diagnosed, it may be possible to 
avoid longterm use of systemic steroids and treat with 
rituximab, as an alternative approach to treating the irAE. 
• 
Seek infectious disease consultation if patient might have 
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G4: Blisters 
covering >30% BSA with 
associated fluid or 
electrolyte abnormalities 
• 
Permanently discontinue ICPi 
• 
Admit patient immediately and place under supervision of a 
dermatologist 
• 
Administer IV methylprednisolone (or equivalent) 1–2mg/kg 
with tapering over at least 4 weeks when the toxicity resolves 
• 
If bullous pemphigoid is diagnosed, it may be possible to 
avoid long term use of systemic steroids and treat with 
rituximab, as an alternative approach to treating the irAE. 
• 
Seek infectious disease consultation if patient might have 
secondary cellulitis or if patient has other infection risk 
factors such as neutropenia etc. 
1.3 Severe Cutaneous Adverse Reactions (SCAR), including Stevens–Johnson syndrome 
(SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) 
and drug reaction with eosinophilia and systemic symptoms (DRESS)/Drug-induced 
Hypersensitivity Syndrome (DIHS) 
Definition: Severe changes in either structure or functions of skin, the appendages or the 
mucous membranes due to a drug 
Diagnostic Workup: 
• 
Total body skin exam with attention to examining ALL mucous membranes, as well as 
complete review of systems Rule out any other etiology of the skin problem, 
• 
such as an infection, an effect of another drug or a skin condition linked to another 
systemic disease. A biological checkup including a complete blood count (CBC) with 
differential test (DIFF), liver and kidney function tests, including urinalysis (UA) in 
addition to the blood work. If the patient is febrile, blood cultures should be considered, as 
well. 
• 
Skin biopsies to assess for full thickness epidermal necrosis, as is seen in SJS/TEN, as 
well as other possible etiologies like paraneoplastic pemphigus or other autoimmune 
blistering dermatoses or other drug reactions, such as acute generalized exanthematous 
pusulosis (AGEP) 
• 
Consider following patients closely using serial clinical photography 
If mucous membrane involvement or blistering is noted on the skin, consider early 
admission to a burn center for further monitoring and management. 
• 
Primer on monitoring for complicated cutaneous adverse drug reactions: 
o Review of Systems: Skin pain (“like a sunburn”), fevers, malaise, myalgias, 
arthralgias, abdominal pain, ocular discomfort or photophobia, sores or 
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hoarseness, dysuria, sores or discomfort in the vaginal area for women or 
involving the meatus of the penis for men, sores in the perianal area or pain with 
bowel movements. 
o Physical Exam: Include vital signs and a full skin exam specifically evaluating all 
skin surfaces and mucous membranes (eyes, nares, oropharynx, genitals and 
perianal area). Assess for lymphadenopathy, facial or distal extremity swelling 
(may be signs of drug-induced hypersensitivity syndrome/DRESS). Assess for 
pustules or blisters or erosions in addition to areas of “dusky erythema” which 
may feel painful to palpation. To assess for a positive Nikolsky sign, place a 
gloved finger tangentially over erythematous skin apply friction parallel to the 
skin surface. Nikolsky sign is positive if this results in detached or sloughing 
epidermis demonstrating poor attachment of the epidermis to the dermis, which is 
the case in some autoimmune disorders (e.g. pemphigus) and SJS/TEN. 
Grading 
Management 
All Grades 
In cases of suspected SJS or any mucous membranes involvement, 
discontinue ICPi treatment and monitor closely for improvement 
regardless of grade. 
G1: N/A 
• 
For the SCAR adverse reactions, there is not a grade 1 
category. If lower body surface area is involved with bullae 
or erosions, there should remain high concern that this 
reaction will progess to grade 3 or 4. 
G2: Morbilliform 
(“maculopapular”) 
exanthem covering 10-
30% BSA with systemic 
symptoms, 
lymphadenopathy or facial 
swelling 
• 
Hold ICPi and monitor patients closely every 3 days with 
grade 2 irAE’s for progression to involvement of greater body 
surface area and/or mucous membrane involvement. 
• 
Consider following patients closely using serial photography. 
• 
Initiate therapy with topical emollients, oral antihistamines 
and medium-to-high strength topical corticosteroids 
• 
Consider initiation of prednisone (or equivalent) 0.5-1 mg/kg 
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G3: Skin sloughing 
covering <10% BSA with 
mucosal involvement 
associated signs (e.g., 
erythema, purpura, 
epidermal detachment and 
mucous membrane 
detachment) 
• 
Hold ICPi therapy and consult with dermatology 
• 
Treat skin with topical emollients and other petrolatum 
emollients, oral antihistamines and high strength topical 
corticosteroids. Dimethicone may also be offered as an 
alternative to petrolatum 
• 
Administer IV methylprednisolone (or equivalent) 0.5 -1 
mg/kg and convert to oral corticosteroids on response, wean 
over at least 4 weeks 
• 
Admit to burn and/or consult wound services with attention to 
supportive care including fluid and electrolyte balance, 
minimizing insensible water losses and preventing infection. 
• 
Given the immune mechanism of action of these medicines, 
use of immune suppression is warranted and should be 
offered.  
• 
For mucous membrane involvement of SJS or toxic 
epidermal necrolysis (TEN), appropriate consulting services 
should be offered to guide management in preventing 
sequelae from scarring (e.g. ophthalmology, eyes nose and 
throat, urology, gynecology, etc. as appropriate) 
G4: Skin erythema and 
blistering/sloughing 
covering ≥10 to > 30% 
BSA with associated signs 
(e.g., erythema, purpura, 
epidermal detachment and 
mucous membrane 
detachment) and/or 
systemic symptoms and 
concerning associated 
blood work abnormalities 
(e.g. LFT elevations in the 
setting of DRESS/DIHS) 
• 
Permanently discontinue ICPi 
• 
Admit patient immediately to a burn unit or ICU with 
consulted dermatology and wound care services. Consider 
further consultations based on management of mucosal 
surfaces (e.g. ophthalmology, urology, gynecology, Ear, 
Nose and Throat Surgery, etc.) 
• 
Initiate IV methylprednisolone (or equivalent) 1-2 mg/kg, 
tapering when toxicity resolves to normal 
• 
IVIG or cyclosporine may also be considered in severe or 
steroid-unresponsive cases 
• 
Consider pain/palliative consultation and/or admission in 
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Additional Considerations: 
*The usual prohibition of corticosteroids for Stevens-Johnson Syndrome is not relevant here, as 
the underlying mechanism is a T-cell immuno- directed toxicity. Adequate suppression is 
necessary with corticosteroids or other agents and may be prolonged in cases of DRESS/Drug 
Hypersensitivity Syndrome. 
2.0 GASTOINTESTINAL TOXICITY 
2.1 Colitis 
Definition: A disorder characterized by inflammation of the colon. 
Diagnostic Workup: 
G2: 
• 
Work up of blood (CBC, CMP, TSH, ESR, CRP), stool (culture, C. diff, parasite, CMV or 
other viral etiology, O&P, should be performed 
• 
Consider testing for lactoferrin (for patient stratification to determine who needs more 
urgent endoscopy) and calprotectin (to follow up on disease activity) 
• 
Screening labs (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients 
to start infliximab should be routinely done in patients at high risk for those infections and 
appropriately selected patients based on Infectious disease expert’s evaluation 
• 
Imaging e.g. CT scan of abdomen and pelvis and GI endoscopy with biopsy should be 
considered as there is evidence showing the presence of ulceration in the colon can predict 
steroid refractory course, which may require early infliximab 
• 
Consider repeating endoscopy for patients who do not respond to immunosuppressive 
agents. Repeating endoscopy for disease monitoring can be considered when clinically 
indicated and when planning to resume therapy. 
G3-4: 
• 
All the work up listed for G2 (blood, stool, imaging and scope with biopsy) should be 
completed immediately 
• 
Consider repeating endoscopy for patients who do not respond to immunosuppressive 
agents. Repeating endoscopy for disease monitoring should only be considered when 
clinically indicated and when planning to resume ICPi. 
Grading 
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(Based on CTCAE for 
diarrhea, as most often 
used clinically) 
All Patients 
Counsel all patients to be aware of and inform their healthcare 
provider immediately if they experience: 
• 
abdominal pain, nausea, cramping, blood or mucus in stool or 
changes in bowel habits 
• 
fever, abdominal distention, obstipation, constipation 
• 
For Grade ≥2, consider permanently discontinuing CTLA-4 
agents and may restart PD-1, PD-L1 agents if patient can 
recover to Grade ≤1; concurrent immunosuppressant 
maintenance therapy should be considered only if clinically 
indicated in individual cases 
G1: Increase of <4 stools 
per day over baseline; 
mild increase in ostomy 
output compared to 
baseline 
• 
Continue ICPi. Alternatively, ICPi may be held temporarily 
and resumed if toxicity does not exceed grade 1 
• 
Monitor for dehydration and recommend dietary changes 
• 
Facilitate expedited phone contact with patient/caregiver 
• 
May obtain gastroenterology consult for prolonged G1 cases 
G2: Increase of 4 - 6 
stools per day over 
baseline; moderate 
increase in ostomy output 
compared to baseline 
• 
Should hold ICPi temporarily until patient’s symptoms 
recover to G1. Can consider permanently discontinuing 
CTLA-4 agents and may restart PD-1, PD-L1 agents if 
patient can recover to Grade ≤1. 
• 
Concurrent immunosuppressant maintenance therapy (<10 
mg prednisone equivalent dose) may be offered only if 
clinically indicated in individual cases. 
• 
May also include supportive care with medications such as 
Imodium if infection has been ruled out 
• 
Should consult with gastroenterology for G≥2 
• 
Administer corticosteroids, unless diarrhea is transient, 
starting with initial dose of 1 mg/kg/day prednisone or 
equivalent. 
• 
When symptoms improve to grade 1 or less, taper 
corticosteroids over at least 4-6 weeks before resuming 
treatment, although resuming treatment while on low dose 
corticosteroid may also be an option after an evaluation the 
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• 
EGD/colonoscopy, endoscopy evaluation should be highly 
recommended for cases grade ≥ 2 to stratify patients for early 
treatment of infliximab based on the endoscopic findings and 
to determine the safety of resuming PD-1, PD-L1 therapy. 
• 
Stool inflammatory markers can be considered (lactoferrin 
and calprotectin) in cases grade ≥ 2 to differentiate functional 
vs inflammatory diarrhea, and use calprotectin to monitor 
treatment response if provider prefers 
• 
Repeat colonoscopy is optional for cases grade ≥ 2 for 
disease activity monitoring to achieve complete remission, 
especially if there is a plan to resume ICPi 
G3: Increase of ≥7 stools 
per day over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self care 
ADL 
• 
Should consider permanently discontinuing CTLA-4 agents 
and may restart PD-1, PD-L1 agents if patient can recover to 
Grade ≤1. 
• 
Administer corticosteroids (initial dose of 1 to 2 mg/kg/day 
prednisone or equivalent) 
• 
Consider hospitalization or outpatient facility for patients 
with dehydration or electrolyte imbalance 
• 
If symptoms persist ≥3 to 5 days or recur after improvement 
consider administering intravenous steroid or non- 
corticosteroid (e.g., infliximab) 
• 
Consider colonoscopy in cases where patients have been on 
immunosuppression and may be at risk for opportunistic 
infections as an independent cause for diarrhea (i.e., CMV 
colitis) and for anti-TNF or steroid refractory 
G4: Life-threatening 
consequences; urgent 
intervention indicated 
• 
Permanently discontinue treatment 
• 
Should admit patient when clinically indicated. Patients 
managed as outpatients should be very closely monitored 
• 
Administer 1 to 2 mg/kg/day methylprednisolone or 
equivalent until symptoms improve to grade 1, and then start 
taper over 4-6 weeks. 
• 
Consider early infliximab 5-10mg/kg if symptoms refractory 
to steroid within 2-3 days 
• 
Consider lower GI endoscopy if symptoms are refractory 
despite treatment or there is concern of new infections 
Additional Considerations: 

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• 
The use of vedolizumab may be considered in patients refractory to infliximab and/or 
contraindicated to TNF-a blocker. The decision should be made on an individual basis 
from gastroenterology and oncology evaluation. This is based on case series showing 
promising results.1,2 
• 
Patients with hepatitis and irAE colitis are rare and management should include 
permanently discontinuing ICPi and offering other immunosuppressant agents that work 
systemically for both conditions. 
• 
Currently enteritis alone as the cause of diarrhea is uncommon, and requires small bowel 
biopsy as the evaluation tool. It may be managed similar as colitis including steroid and/or 
infliximab etc. 
2.2 Hepatitis 
Definition: A disorder characterized by a viral pathologic process involving the liver 
parenchyma 
Diagnostic Workup: 
• 
Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin prior to each 
infusion and/or weekly if Grade 1 LFT elevations. No treatment is recommended for 
Grade 1 LFT abnormality. 
For Grade ≥2: 
• 
Work up for other causes of elevated liver enzymes should be tested, viral hepatitis, 
alcohol history, iron study, thromboembolic event, liver ultrasound, cross- sectional 
imaging for potential liver metastasis from primary malignancy. If suspicion for 
primary autoimmune hepatitis is high, can consider ANA/ASMA/ANCA. If patients 
with elevated ALKP alone, GGT should be tested. For isolated elevation of 
transaminases, consider checking Creatine Kinase for other etiologies. 
Grading 
Management 
All Patients 
• 
Counsel all patients to be aware of and inform their 
healthcare provider immediately if they experience 
• 
Yellowing of skin or whites of the eyes 
• 
Severe nausea or vomiting 
• 
Pain on the right side of the abdomen 
• 
Drowsiness 
• 
Dark urine (tea colored) 
• 
Bleeding or bruising more easily than normal 
• 
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G1: Asymptomatic (AST 
or ALT >ULN to 3.0x 
ULN and/or total 
bilirubin >ULN to 1.5x 
ULN) 
• 
Continue ICPi with close monitoring; consider alternate 
etiologies 
• 
Monitor labs 1 to 2 times weekly 
• 
Manage with supportive care for symptom control 
G2: Asymptomatic (AST 
or ALT >3.0 to ≤5x ULN 
and/or total bilirubin >1.5 
to ≤3x ULN) 
• 
Hold ICPi temporarily and resume if recover to ≤ Grade 1 on 
prednisone ≤ 10mg/day 
• 
For grade 2 hepatic toxicity with symptoms, may administer 
steroid 0.5-1 mg/kg day prednisone or equivalent if the 
abnormal elevation persists with significant clinical 
symptoms in 3-5 days 
• 
Increase frequency of monitoring to every 3 days 
• 
Infliximab might not be the most appropriate treatment 
option in the situation of immune-mediated hepatitis given 
the potential risk of idiosyncratic liver failure (Note: no clear 
evidence showing the liver toxicity from infliximab from 
other studies) 
• 
In follow-up, may resume ICPi treatment follow by taper only 
when symptoms improve to grade 1 or less and steroid ≤ 
10mg/day. Taper over at least 1 month. 
Patients should be advised to stop unnecessary medications 
and any known hepatotoxic drugs 
G3: Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis; reactivation of 
chronic hepatitis (AST or 
ALT 5-20x ULN and/or 
total bilirubin 3-10 ULN) 
• 
Permanently discontinue ICPi 
• 
Immediately start steroid 1-2 mg/kg methylprednisolone or 
equivalents 
• 
If steroid refractory or no improvement after 3 days, consider 
mycophenolate mofetil or azathioprine (if using Azathioprine 
should test for thiopurine methyltransferase (TPMT) 
deficiency) 
• 
Labs at daily/qod; consider inpatient monitoring for patients 
with AST/ALT > 8 ULN and/or elevated TB 3 ULN 
• 
Increase frequency of monitoring to every 1 to 2 days 
• 
Infliximab might not be the most appropriate treatment option 
in the situation of immune-mediated hepatitis given the 
potential risk of liver failure (Note: no clear evidence 
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studies). Alternatives include non TNFα agents as systemic 
immunosuppressants 
• 
If no improvement is achieved with steroid or for patients on 
combination therapy with a novel agent, with standard 
chemotherapy or with targeted therapy refer to hepatologist 
for further pathologic evaluation of hepatitis 
• 
Steroid taper can be attempted around 4-6 weeks, re-escalate 
if needed, optimal duration unclear 
G4: Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
(AST or ALT >20x ULN 
and/or total bilirubin >10x 
ULN) 
• 
Permanently discontinue ICPi 
• 
Administer 2 mg/kg/day methylprednisolone equivalents 
• 
If steroid refractory or no improvement after 3 days, consider 
mycophenolate mofetil 
• 
Monitor labs daily; Consider inpatient monitoring 
• 
Avoid the use of infliximab in the situation of immune-
mediated hepatitis 
• 
Hepatology consult if no improvement was achieved with 
steroid 
• 
Steroid taper can be attempted around 4-6 weeks when 
symptoms improve to ≤G1, re-escalate if needed, optimal 
duration unclear 
• 
Consider transfer to tertiary care facility if necessary 
3.0 LUNG TOXICITY 
3.1 Pneumonitis 
Definition: Focal or diffuse inflammation of the lung parenchyma (typically identified on CT 
imaging). 
No symptomatic, pathologic or radiographic features are pathognomonic for pneumonitis 
  Diagnostic Workup 
• 
Should include the following: CXR, CT, pulse oximetry; 
• 
For G2 or higher, may include the following infectious workup: nasal swab, sputum culture 
and sensitivity, blood culture and sensitivity, urine culture and sensitivity 
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Additional Considerations: 
• 
GI and pneumocystis prophylaxis with PPI and Bactrim may be offered to patients on 
prolonged steroid use (>12 weeks), according to institutional guidelines3-6 
• 
Consider calcium and vitamin D supplementation with prolonged steroid use 
• 
The role of prophylactic fluconazole with prolonged steroid use (>12 weeks) remains 
unclear and physicians should proceed according to institutional guidelines7 
G1: Asymptomatic; 
confined to one lobe of the 
lung or less than 25% of 
lung parenchyma; clinical 
or diagnostic observations 
only 
• 
Hold ICPi with radiographic evidence of pneumonitis 
progression 
• 
May offer one repeat CT in 3-4 weeks. In patients who have 
had baseline testing, may offer a repeat spirometry/DLCO in 
3-4 weeks 
• 
May resume ICPi with radiographic evidence of improvement 
or resolution. If no improvement, should treat as G2 
• 
Monitor patients weekly with history and physical 
examination, pulse oximetry; may also offer CXR 
G2: Symptomatic; 
Involves more than one 
lobe of the lung or 25-
50% of lung parenchyma; 
medical intervention 
indicated; limiting 
instrumental ADL 
• 
Hold ICPi until resolution to grades ≤1 
• 
Prednisone 1-2 mg/kg/day and taper by 5-10 mg/week over 
4-6 weeks 
• 
Consider bronchoscopy with BAL 
• 
Consider empiric antibiotics 
• 
Monitor Q3 days with history and physical examination, pulse 
oximetry, consider CXR; No clinical improvement after 
• 
48-72 hours of prednisone, treat as grade 3. 
G3: Severe symptoms; 
Hospitalization required: 
Involves all lung lobes 
or > 50% of lung 
parenchyma; limiting self 
care ADL;   oxygen 
indicated. 
• 
Permanently discontinue ICPi 
• 
Empiric antibiotics; (methyl)prednisolone IV 1-2 mg/kg/day; 
No improvement after 48 hours, may add infliximab 5 mg/kg 
or mycophenolate mofetil IV 1 g BID or IVIG X 5 days or 
cyclophosphamide. Taper corticosteroids over 4-6 weeks 
• 
Pulmonary and infectious disease consults if necessary 
• 
Bronchoscopy with BAL +/- transbronchial biopsy 
• 
Patients should be hospitalized for further management 
G4: Life-threatening 
respiratory compromise; 
urgent intervention 
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• 
Bronchoscopy + Biopsy – if clinical picture is consistent with pneumonitis, no need for 
biopsy 
4.0 ENDOCRINE TOXICITY 
• 
Counsel patients to inform their healthcare provider immediately if they experience any 
changes in their health since their last visit, especially any of the following: 
• 
Headaches that will not go away or unusual headache patterns 
• 
Vision changes 
• 
Rapid heartbeat 
• 
Increased sweating 
• 
Extreme tiredness or weakness 
• 
Muscle aches 
• 
Weight gain or weight loss 
• 
Dizziness or fainting 
• 
Feeling more hungry or thirsty than usual 
• 
Hair loss 
• 
Changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness 
• 
Feeling cold 
• 
Constipation 
• 
Voice gets deeper 
• 
Urinating more often than usual 
• 
Nausea or vomiting 
• 
Abdominal pain 
4.1 THYROID 
4.1.1 Primary Hypothyroidism 
Definition: Elevated TSH, normal or low FT4 
Diagnostic Workup: 
TSH and FT4 every 4-6 weeks as part of routine clinical monitoring on therapy or for case 
detection in symptomatic patients 
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G1: TSH <10 
mIU/L and 
asymptomatic 
• 
Should continue ICPi with close follow-up and monitoring of TSH, 
fT4 
G2: Moderate 
symptoms, Able 
to Perform ADL. 
TSH 
persistently >10 
mIU/L 
• 
May hold ICPi until symptoms resolve to baseline 
• 
Consider endocrine consultation 
• 
Prescribe thyroid hormone supplementation in symptomatic patients 
with any degree of TSH elevation or in asymptomatic patients with 
TSH levels that persist over 10 mIU/L (measured 4 weeks apart). 
• 
Monitor TSH every 6-8 weeks while titrating hormone replacement 
to normal TSH. 
• 
FT4 can be used in the short term (2 weeks) to ensure adequacy of 
therapy in those with frank hypothyroidism where the FT4 was 
initially low. 
• 
Once adequately treated, should monitor thyroid function (at least 
TSH) every 6 weeks while on active ICPi therapy or as needed for 
symptoms to ensure appropriate replacement. Repeat testing annually 
or as indicated by symptoms 
• 
once stable 
G3-4: Severe 
symptoms, 
medically 
significant or life-
threatening 
consequences, 
Unable to Perform 
ADL 
• 
Hold ICPi until symptoms resolve to baseline with appropriate 
supplementation 
• 
Endocrine consultation 
• 
May admit for IV therapy if signs of myxedema (bradycardia, 
hypothermia). 
• 
Thyroid supplementation and reassessment as in G2 
Additional Considerations 
• 
For patients without risk factors, full replacement can be estimated with an ideal body 
weight based dose of approximately 1.6mcg/kg/day. 
• 
For elderly or fragile patients with multiple comorbidities, consider titrating up from low 
dose, starting at 25-50mcg. 
• 
Extreme elevations of TSH can be seen in the recovery phase of thyroiditis and can be 
watched in asymptomatic patients to determine whether there is recovery to normal 
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• 
Under guidance of endocrinology, consider tapering hormone replacement and retesting 
in patients with a history of thyroiditis (initial thyrotoxic phase). 
• 
Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy 
is initiated. 
4.1.2 Hyperthyroidism 
Definition: Suppressed TSH and high normal or elevated FT4 and/or T3. 
Diagnostic Workup: 
• 
Monitor TSH, free T4 every 4-6 weeks from the start of therapy or as needed for case 
detection in symptomatic patients. 
• 
Consider TSH receptor antibodies if there are clinical features and suspicion of Grave’s 
disease (e.g. ophthalmopathy). 
• 
Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch transition to 
hypothyroidism in patients with thyroiditis and hyperthyroidism. 
Grading 
Management 
G1: Asymptomatic or 
mild symptoms 
• 
Can continue ICPi with close follow-up and monitoring of 
TSH, fT4 every 2-3 weeks until it is clear whether there 
will be persistent hyperthyroidism (see below) or 
hypothyroidism (see 4.1.1). 
G2: Moderate symptoms, 
Able to Perform ADL 
• 
Consider holding ICPi until symptoms return to baseline 
• 
Consider endocrine consultation 
• 
Beta-blocker (e.g. atenolol or propranolol) for symptomatic 
relief. 
• 
Hydration and supportive care 
• 
Corticosteroids are not usually required to shorten duration. 
• 
For persistent hyperthyroidism (>6 weeks) or clinical 
suspicion, work up for Graves’ disease (TSI or TRAb) and 
consider thionamide (methimazole or PTU). 
• 
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G3-4: Severe 
symptoms, medically 
significant or life-
threatening 
consequences, Unable 
to Perform ADL 
• 
Hold ICPi until symptoms resolve to baseline with 
appropriate therapy 
• 
Endocrine consultation 
• 
Beta-blocker (e.g. atenolol or propranolol) for symptomatic 
relief. 
• 
For severe symptoms or concern for thyroid storm, 
hospitalize patient and initiate prednisone 1-
2mg/kg/day or equivalent tapered over 1-2 weeks. 
Consider also use of SSKI or thionamide (methimazole 
or PTU). 
Additional Considerations: 
• 
Thyroiditis is transient and resolves in a couple of weeks to primary hypothyroidism or 
normal. Hypothyroidism can be treated as above. 
• 
Graves’ disease is generally persistent and is due to increased thyroid hormone production 
that can be treated with anti-thyroid medical therapy. 
• 
Physical exam findings of ophthalmopathy or thyroid bruit are diagnostic of Graves and 
should prompt early Endocrine referral. 
4.2 Adrenal - Primary adrenal insufficiency (AI) 
Definition: Adrenal gland failure leading to low morning cortisol, high morning ACTH as well 
as hyponatremia and hyperkalemia with orthostasis and volume depletion due to loss of 
aldosterone. 
Diagnostic Workup for patients in whom adrenal insufficiency is suspected: 
• 
Evaluate ACTH (AM), cortisol level (AM) 
• 
Basic Metabolic Panel (Na, K, CO2, Glucose) 
• 
Consider ACTH stimulation test for indeterminate results 
• 
If primary adrenal insufficiency (high ACTH, low cortisol) is found biochemically: 
o Evaluate for precipitating cause of crisis such as infection 
o Adrenal CT for metastasis/hemorrhage 
Grading 
Management 
G1: Asymptomatic or 
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• 
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replacement hormone. 
• 
Endocrine consultation 
• 
Replacement therapy with prednisone (5-10mg daily) or 
hydrocortisone (10-20mg po qAM, 5-10mg po q2PM) 
• 
May require fludrocortisone (0.1mg/day) for 
mineralocorticoid replacement in primary adrenal 
insufficiency. 
• 
Titrate dose up or down as symptoms dictate 
G2: Moderate symptoms, 
Able to Perform ADL 
• 
Consider holding ICPi until patient is stabilized on 
replacement hormone. 
• 
Endocrine consultation 
• 
Initiate outpatient treatment at 2-3 times maintenance (e.g. if 
prednisone, 20 mg daily; if hydrocortisone 20-30 mg on the 
morning and 10-20 mg in the afternoon) to manage acute 
symptoms. 
• 
Taper stress dose corticosteroids down to maintenance doses 
over 5-10 days. 
• 
Maintenance therapy as in G1. 
G3-4: Severe symptoms, 
medically significant or 
life-threatening 
consequences, Unable to 
Perform ADL 
• 
Hold ICPi until patient is stabilized on replacement hormone. 
• 
Endocrine consultation 
• 
See in clinic or, after hours, make an ER referral for: 
o Normal saline (at least 2L) 
o IV Stress dose steroids on presentation: 
Hydrocortisone 100 mg or Dexamethasone 4 mg (if 
the diagnosis is not clear and stimulation testing will 
be needed) 
• 
Taper stress dose corticosteroids down to maintenance doses 
over 7-14 days after discharge 
• 
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Additional Considerations: 
• 
Primary and secondary adrenal insufficiency can be distinguished by the 
relationship between ACTH and cortisol. If the ACTH is low with low cortisol, 
then management is as per 4.3 
• 
Patients on corticosteroids for management of other conditions, will have low morning 
cortisol as a result of iatrogenic, secondary AI. ACTH will also be low in these 
patients. A diagnosis of AI is challenging to make in these situations (see below section 
on hypophysitis). 
• 
Emergent therapy for someone with suspected AI is best done with dexamethasone as a 
stimulation test can still be performed. If the diagnosis is already confirmed, can use 
hydrocortisone 100 mg. 
• 
All patients need education on stress dosing and a medical alert bracelet for adrenal 
insufficiency to trigger stress dose corticosteroids by EMS. 
• 
Endocrine consultation prior to surgery or any procedure for stress dose planning. 
4.3 Pituitary - Hypophysitis 
Definition: inflammation of the pituitary with varying impacts on hormone function. Most 
commonly presenting with central adrenal insufficiency. May also have central 
hypothyroidism, Diabetes insipidus and hypogonadism 
Diagnostic Workup: 
Diagnosis: Low ACTH with a low cortisol. Low or normal TSH with a low FT4. 
Hypernatremia and volume depletion with DI. Low testosterone or estradiol with low LH and 
FSH. 
Testing: 
• 
Evaluate ACTH, cortisol (AM), TSH, free T4, electrolytes. 
• 
Consider evaluating LH, FSH and testosterone levels in males or estrogen in 
premenopausal females with fatigue, loss of libido and mood changes 
• 
Consider MRI brain w/wo contrast with pituitary/sellar cuts in patients with multiple 
endocrine abnormalities +/- new severe headaches or complaints of vision changes 
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G1: Asymptomatic or 
mild symptoms 
• 
Considering holding ICPi until patient is stabilized on 
replacement hormones. 
• 
Hormonal supplementation as needed, using dosing as 
above for primary hypothyroidism and adrenal 
insufficiency (e.g. hydrocortisone 10-20 mg orally in the 
morning, 5-10 mg orally in early afternoon; levothyroxine 
by weight). 
• 
Testosterone or estrogen therapy as needed in those without 
contraindications. 
• 
Endocrine consultation 
• 
Always start corticosteroids several days before thyroid 
hormone to prevent precipitating adrenal crisis 
• 
Follow FT4 for thyroid hormone replacement titration (TSH 
is not accurate). 
G2: Moderate symptoms, 
Able to Perform ADL 
• 
Consider holding ICPi until patient is stabilized on 
replacement hormones. 
• 
Endocrine consultation 
• 
Hormonal supplementation as in G1 
G3-4: Severe symptoms, 
medically significant or 
life-threatening 
consequences, Unable to 
Perform ADL 
• 
Hold ICPi until patient is stabilized on replacement 
hormones. 
• 
Endocrine consultation 
• 
Hormonal supplementation as in G1 
• 
Consider initial pulse dose therapy with Prednisone 1-2mg/kg 
oral daily (or equivalent) tapered over at least 1-2 weeks 
Additional Considerations: 
• 
Please be aware of the need to START CORTICOSTEROIDS FIRST when planning 
hormone replacement therapy for multiple deficiencies. 
• 
All patients need instruction on doubling doses for illness (stress dosing) and a medical 
alert bracelet for adrenal insufficiency to trigger stress dose corticosteroids by EMS. 
• 
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• 
Workup cannot be done with a simple AM cortisol in a patient on corticosteroids for other 
conditions. 
• 
Laboratory confirmation of AI should not be attempted until treatment with 
corticosteroids for other disease is ready to be discontinued. 
• 
For long term exposure, consult endocrinology for recovery and weaning protocol using 
hydrocortisone 
4.4 Diabetes 
Definition: T2DM is a combination of insulin resistance and insufficiency that may require 
oral or insulin therapy. It may be new onset or exacerbated during therapy for non-
immunologic reasons such as steroid exposure. 
Autoimmune T1DM results from islet cell destruction and is often acute onset, with ketosis and 
an insulin requirement. 
Diagnostic Workup: 
• 
Monitor patients for hyperglycemia or other signs and symptoms of new or worsening 
DM, including measuring glucose at baseline and with each treatment cycle during 
induction X 12 weeks, then every 3-6 weeks thereafter. To guide the work up in new 
onset hyperglycemia, clinicians should consider a patient’s medical background, 
exposure history, and risk factors for each subtype of DM. 
• 
Laboratory evaluation in suspected T1DM should include testing for ketosis in urine and 
an assessment of the anion gap on a metabolic panel. Anti-GAD, anti-Islet Cell or anti-
Insulin antibodies are highly specific for autoimmune diabetes. Insulin and c-peptide 
levels can also assist in the diagnosis. 
Grading 
Management 
G1: Asymptomatic or 
mild symptoms; Fasting 
glucose value >ULN - 
160 mg/dL; Fasting 
glucose value >ULN - 8.9 
mmol/LNo evidence of 
ketosis or laboratory 
evidence of T1DM 
• 
Can continue ICPi with close clinical follow-up and 
laboratory evaluation 
• 
May initiate oral therapy for those with new onset T2DM. 
• 
Screen for T1DM if appropriate for example acute onset with 
prior normal values or clinical concern for ketosis 
G2: Moderate symptoms, 
Able to Perform Activities 
of Daily Living; Fasting 
glucose value 
>160 - 250 mg/dL; Fasting 
• 
May hold ICPi until glucose control is obtained. 
• 
Titrate oral therapy or add insulin for worsening control in 
T2DM. 
• 
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glucose value >8.9 - 13.9 
mmol/L. Ketosis or 
evidence of T1DM at any 
glucose level 
there is confusion about type) 
• 
Urgent Endocrine consultation for any patient with 
T1DM. In the absence of endocrinology, internal 
medicine may suffice 
• 
Consider admission for T1DM if early outpatient evaluation 
is not available or signs of ketoacidosis are present. 
G3-4: Severe 
symptoms, medically 
significant or life-
threatening 
consequences, Unable 
to Perform Activities of 
Daily Living; G3: >250 
- 500 mg/dL; >13.9 - 
27.8 mmol/L; G4: >500 
mg/dL; >27.8 mmol/L 
• 
Hold ICP i until glucose control is obtained on therapy with 
reduction of toxicity to grade 1 or less. 
• 
Urgent Endocrine consultation for all patients. 
• 
Initiate insulin therapy for all patients. 
• 
Admit for inpatient management: 
o Concerns for developing DKA 
o Symptomatic patients regardless of diabetes type 
o New onset T1DM unable to see Endocrinology. 
Additional Considerations: 
• 
Insulin therapy can be used as the default in any case with hyperglycemia. 
• 
Long acting therapy alone is not usually sufficient for T1DM, where half of daily 
requirements are usually given in divided doses as prandial coverage and half as long 
acting. 
• 
Insulin doses will be lower in T1DM because of preserved sensitivity (total daily 
requirement can be estimated at 0.3-0.4 units/kg/day). 
• 
In T2DM, sliding scale coverage with meals over a few days provides data to estimate a 
patient’s daily requirements and can be used to more rapidly titrate basal needs. 
5.0 MUSCULOSKELETAL TOXICITY 
5.1 Inflammatory Arthritis 
Definition: A disorder characterized by inflammation of the joints. 
Clinical Symptoms: Joint pain accompanied by joint swelling, inflammatory symptoms 
such as stiffness after inactivity or in the morning, lasting more than 30 mins-1 hour. 
Improvement of symptoms with NSAIDs or corticosteroids, but not with opioids or other 
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Diagnostic Workup: 
G1: 
• 
Complete rheumatologic history and examination of all peripheral joints for tenderness, 
swelling and range of motion. Examination of the spine 
• 
Consider plain X ray/imaging to exclude metastases and evaluate joint damage (erosions) 
if appropriate 
• 
Consider autoimmune blood panel including ANA, RF, and anti-CCP and anti-
inflammatory markers (ESR and CRP) if symptoms persist. If symptoms are suggestive 
of reactive arthritis or affect the spine consider HLA B27 testing 
G2: 
• 
Complete history and examination as above; laboratory tests as above 
• 
Consider US +/- MRI imaging of affected joints if clinically indicated (e.g. persistent 
arthritis unresponsive to treatment, suspicion for differential diagnoses such as 
metastatic lesions or septic arthritis) 
• 
Consider early referral to a rheumatologist, 
if there is joint swelling (synovitis) or if 
symptoms persist >4 weeks  
G3-4: 
• 
As for Grade 2 
• 
Seek rheumatologist advice and review 
Monitoring: 
• 
Patients with inflammatory arthritis should be monitored with serial rheumatologic 
examinations, including inflammatory markers, every 4-6 weeks after treatment is 
instituted 
Grading 
Management 
All Grades 
Clinicians should follow reports of new joint pain to determine 
if IA is present. Question whether symptom new since receiving 
ICPi. 
G1: Mild pain with 
inflammation, erythema, 
or joint swelling 
• 
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• 
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G2: Moderate pain 
associated with signs 
of inflammation, 
erythema, or joint 
swelling; limiting 
instrumental ADL 
• 
Hold ICPi and resume upon symptom control and on 
prednisone ≤ 10mg/day 
• 
Escalate analgesia and consider higher doses of NSAIDS as 
needed 
• 
If inadequately controlled, initiate prednisone or prednisolone 
10-20 mg/day or equivalent x 4-6 weeks 
• 
If improvement, slow taper according to response during the 
next 4-6 weeks. If no improvement after initial 4-6 weeks 
treat as G3. 
• 
If unable to lower corticosteroid dose to below 10mg/d 
after 3 months, consider disease-modifying antirrheumatic 
drug (DMARD) 
• 
Consider intra-articular steroid injections for large joints 
• 
Referral to rheumatology 
G3-4: Severe pain 
associated with signs of 
inflammation, 
erythema, or joint 
swelling; irreversible 
joint damage; disabling; 
limiting self care ADL 
• 
Hold ICPi temporarily and may resume in consultation with 
rheumatology, if recover to ≤G1 
• 
Initiate oral prednisone 0.5-1 mg/kg 
• 
If failure of improvement after 4 weeks or worsening in 
meantime – consideration of synthetic or biologic disease- 
modifying antirrheumatic drug (DMARD) 
o Synthetic: methotrexate, leflunomide; 
o Biologic: Consider anti-cytokine therapy such as 
TNFα or IL6 receptor inhibitors. Note: As caution, 
IL6 inhibition can cause intestinal perforation. 
While this is extremely rare, it should not be used in 
patients with colitis 
• 
Test for viral hepatitis B, C and latent/active TB test prior to 
DMARD treatment 
• 
Referral to rheumatology 
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• 
Corticosteroids can be used as part of initial therapy in IA, but due to likely prolonged 
treatment requirements, physicians should consider starting steroid-sparing agents earlier 
than one would with other irAEs. 
• 
Oligoarthritis can be treated early on with intra-articular steroids, consider early referral 
• 
Consider PCP prophylaxis for patients treated with high dose of corticosteroids for longer 
than 12 weeks, as per local guidelines 
5.2 Myositis 
Definition: A disorder characterized by muscle inflammation with weakness and elevated 
muscle enzymes (CK). Muscle pain can be present in severe cases. Can be life- threatening if 
respiratory muscles or myocardium are involved. 
Diagnostic Workup: 
• 
Complete rheumatological and neurological history regarding differential diagnosis and 
rheumatological and neurological examination including muscle strength, and 
examination of the skin for findings suggestive of dermatomyositis. Muscle weakness is 
more typical of myositis than pain. Consider pre-existing conditions that can cause 
similar symptoms; 
• 
Blood testing to evaluate muscle inflammation 
• 
Creatine kinase (CK), transaminases (AST, ALT), LDH and aldolase can also be elevated 
• 
Troponin to evaluate myocardial involvement, and other cardiac testing such as 
echocardiogram as needed 
• 
Inflammatory markers (ESR and CRP). 
• 
Consider electromyography (EMG), imaging (MRI) and/or biopsy on an individual 
basis when diagnosis is uncertain, and overlap with neurologic syndromes such as 
myasthenia gravis is suspected. 
• 
Consider paraneoplastic autoantibody testing for myositis and neurological conditions 
such as myasthenia gravis 
Monitoring: CK, ESR, CRP 
G1: Complete examination and laboratory work-up as above 
G2: Complete history and examination as above; 
autoimmune myositis blood panel; EMG, MRI imaging of 
affected joints Early referral to a rheumatologist or 
neurologist 
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Urgent referral to a rheumatologist or neurologist 
Grading 
Management 
G1: Mild weakness with 
or without pain 
• 
Continue ICPi 
• 
If CK is elevated and patient has muscle weakness may offer 
oral corticosteroids, and treat as grade 2 
• 
Offer analgesia with acetaminophen or NSAIDs if there are 
no contraindications 
G2: Moderate weakness 
with or without pain 
limiting age-appropriate 
instrumental ADL 
• 
Hold ICPi temporarily and may resume upon 
symptom control, if CK is normal and prednisone 
dose < 10mg; if worsens, treat as per G3 
• 
NSAIDs as needed 
• 
Referral to rheumatologist or neurologist 
• 
If CK is elevated (x3 or more), initiate prednisone or 
equivalent at 0.5-1 mg/kg 
• 
May require permanent discontinuation of ICPi in most cases 
with G2 symptoms and objective findings (elevated enzymes, 
abnormal EMG, abnormal muscle MRI or biopsy). 
G3-4: Severe weakness 
with or without pain; 
limiting self care ADL 
• 
Hold ICPi until grade ≤1 off immune suppression 
and permanently discontinue if any evidence of 
myocardial involvement 
• 
Consider hospitalization for severe weakness 
• 
Referral to rheumatologist or neurologist 
• 
Initiate prednisone 1 mg/kg or equivalent. Consider 1-
2mg/kg of methylprednisolone IV or higher dose bolus if 
severe compromise (weakness severely limiting mobility, 
cardiac, respiratory, dysphagia). 
• 
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• 
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• 
Consider other immunosuppressant therapy such as 
methotrexate, azathioprine, or mycophenolate mofetil if 
symptoms and CK levels do not improve or worsen after 4-6 
weeks. Rituximab is used in primary myositis but caution is 
advised given its long biological duration 
Additional Considerations: 
• 
Caution is advised with rechallenging 
5.3 Polymyalgia-like Syndrome 
Definition: Characterized by marked pain and stiffness in proximal upper and/or lower 
extremities, and no signs of true muscle inflammation such as CK elevation or EMG findings of 
myositis . No true muscle weakness, difficulty in active motion related to pain. 
Diagnostic Workup: 
G1: Complete rheumatological history regarding differential diagnosis and examination of all 
joints and skin 
Check for symptoms of temporal arteritis, such as headache or visual disturbances, refer 
to ophthalmologist if present, and consider temporal artery biopsy ANA, RF, anti-CCP 
CK to evaluate differential diagnosis of myositis Inflammatory markers (ESR, CRP) 
Monitoring: ESR, CRP 
G2: Complete history and examination as above; autoimmune tests as required for differential 
diagnosis; Early referral to a rheumatologist 
G3-4: As for Grade 2 
Seek rheumatologist advice and review 
Grading 
Management 
G1: Mild stiffness and 
pain 
• 
Continue ICPi 
• 
Initiate analgesia with acetaminophen and/or NSAIDs if there 
are no contraindications 
G2: Moderate stiffness 
and pain ; limiting age- 
appropriate instrumental 
ADL 
• 
Consider holding ICPi and resuming upon symptom control, 
prednisolone < 10mg; if worsens, treat as per G3 
• 
Initiate prednisone 20 mg/d or equivalent. If symptoms 
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• 
If no improvement or need for higher dosages after 4 weeks, 
escalate to G3 
• 
Consider referral to rheumatology 
G3-4: Severe stiffness 
and pain; limiting self 
care ADL 
• 
Hold ICPi and may resume, in consultation with 
rheumatology, if recover to ≤G1. However, note that cases 
of toxicity returning upon rechallenge have been reported. 
• 
Referral to rheumatology 
• 
Should initiate prednisone 20 mg/d or equivalent. If no 
improvement or need for higher dosages for prolonged time, 
may offer a steroid sparing agent such as methotrexate or 
IL6 inhibition with tocilizumab. Note: As caution, IL6 
inhibition can cause intestinal perforation. While this is 
extremely rare, it should not be used in patients with colitis 
or GI metastases 
• 
Consider admission for pain control 
 
6.0 RENAL TOXICITIES 
Nephritis and Renal Dysfunction – Diagnosis and Monitoring 
• 
For any suspected immune-mediated adverse reactions, exclude other causes. 
• 
Monitor patients for elevated serum creatinine prior to every dose. 
• 
Routine urinalysis is not necessary, other than to rule out UTIs etc. Nephrology may 
consider further. 
• 
If no potential alternative cause of AKI identified, then one should forego biopsy and 
proceed directly with immunosuppressive therapy. 
• 
Swift treatment of autoimmune component important 
6.1 Nephritis 
Definition: Inflammation of the kidney affecting the structure 
Grading 
Management 
G1: Creatinine level 
increase of >0.3 mg/dL; 
creatinine 1.5 - 2.0x above 
• 
Consider temporarily holding ICPi, pending consideration of 
potential alternative etiologies (recent IV contrast, 

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baseline 
medications, fluid status) and baseline renal function. A 
change that is still <1.5 ULN could be meaningful 
G2: Creatinine 2 - 3x 
above baseline 
• 
Hold ICPi temporarily 
• 
Consult nephrology 
• 
Evaluate for other causes (recent IV contrast, medications, 
fluid status etc.) If other etiologies ruled out, administer 0.5 to 
1 mg/kg/day prednisone equivalents 
• 
If worsening or no improvement: 1 to 2 mg/kg/day 
prednisone equivalents and permanently discontinue 
treatment 
• 
If improved to G1 or less taper steroids over 4-6 weeks. 
• 
If no recurrence of chronic renal insufficiency discuss 
resumption of ICPI with patient after taking into account the 
risks and benefits. 
G3: Creatinine >3 x 
baseline or >4.0 mg/dL; 
hospitalization indicated 
• 
Permanently discontinue ICPi 
• 
Consult nephrology 
• 
Evaluate for other causes (recent IV contrast, medications, 
fluid status etc.) 
• 
Administer corticosteroids (initial dose of 1 to 2 mg/kg/day 
prednisone or equivalent) 
G4: Life-threatening 
consequences; dialysis 
indicated 
Additional Considerations:  
Monitor creatinine weekly. 
Reflex kidney biopsy should be discouraged until steroid treatment has been attempted. 
6.2 Symptomatic Nephritis – Follow Up 
Grading 
Management 
G1 
If improved to baseline 
• 
Resume routine creatinine monitoring 
G2 
If improved to Grade 1: 
• 
Taper corticosteroids over at least 3 weeks before resuming 
treatment with routine creatinine monitoring 

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If elevations persist > 7 days or worsen and no other cause found, 
treat as Grade 3 
G3 
If improved to Grade 1: 
• 
Taper corticosteroids over at least 4 weeks 
If elevations persist > 3-5 days or worsen, consider additional 
immunosuppression (e.g. mycophenolate) 
G4 
If improved to Grade 1: 
• 
Taper corticosteroids over at least 4 weeks 
If elevations persist > 2-3 days or worsen, consider additional 
immunosuppression (e.g. mycophenolate). 
7.0 NERVOUS SYSTEM TOXICITY 
7.1 Myasthenia Gravis 
Definition: Fatigable or fluctuating muscle weakness, generally proximal>distal. 
Frequently has ocular and/or bulbar involvement (ptosis, extraocular movement 
abnormalities resulting in double vision, dysphagia, dysarthria, facial muscle weakness). 
May have neck and/or respiratory muscle weakness. Note, may occur with myositis and/or 
myocarditis. Respiratory symptoms may require evaluation to rule out pneumonitis, 
myocarditis. Miller Fisher variant of Guillain Barre syndrome (ophthalmoparesis) and the 
oculobulbar myositis (ptosis, ophthalmoparesis, dysphagia, neck and respiratory 
weakness) with ICPi may have overlapping symptoms. 
Diagnostic Workup: 
• 
Acetylcholine receptor (AChR) and anti-striated muscle antibodies in blood. If AChR 
antibodies are negative, consider muscle specific kinase (MuSK) and lipoprotein 
related 4 (LPR4) antibodies in blood. 
• 
Pulmonary function assessment with NIF (negative inspiratory force) and VC (vital 
capacity). 
• 
CPK, aldolase, ESR, CRP for possible concurrent myositis 
• 
Consider MRI brain and/or spine depending on symptoms to rule out CNS involvement 
by disease or alternate diagnosis 
• 
If respiratory insufficiency or elevated CPK, troponin T, perform cardiac exam, EKG and 
TTE for possible concomitant myocarditis 
• 
Neurological consultation 
• 
Electrodiagnositic studies including neuromuscular junction testing with repetitive 
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for myositis. 
Grading 
Management 
All Grades 
All grades warrant workup and intervention given potential for 
progressive MG to lead to respiratory compromise 
No G1 
G2: Some symptoms 
interfering with ADLs 
MGFA severity class I 
(ocular symptoms and 
findings only) and MGFA 
severity class II (mild 
generalized weakness). 
• 
Hold ICPi and may resume in G2 patients (MGFA 1 and 2) 
only if symptoms resolve8 
• 
Should consult neurology 
• 
Pyridostigmine starting at 30 mg PO TID and gradually 
increase to maximum of 120mg PO QID as tolerated and 
based on symptoms 
• 
Administer corticosteroids (prednisone 1-1.5mg/kg orally 
daily) if symptoms G2. Wean based on symptom 
improvement. 
G3-4: Limiting self-care 
and aids warranted, 
weakness limiting 
walking, ANY dysphagia, 
facial weakness, 
respiratory muscle 
weakness, or rapidly 
progressive symptoms. or 
MGFA Severity Class 
III-V moderate to severe 
generalized weakness to 
myasthenic crisis 
• 
Permanently discontinue ICPi 
• 
Admit patient, may need ICU-level monitoring. 
• 
Neurology consult 
• 
Continue steroids and initiate IVIG 2G/kg IV over 5 days 
(0.4G/kg/day) or plasmapheresis x 5 days. 
• 
Frequent pulmonary function assessment 
• 
Daily neurological review 

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Additional Considerations: 
• 
Avoid medications that can worsen myasthenia: beta-blockers, IV magnesium, 
fluoroquinolones, aminoglycosides and macrolides 
• 
Initially a 5 day course of plasmapheresis or a 2G/kg course of IVIG over 5 days 
• 
1-2 mg/kg methylprednisolone daily, wean based on symptom improvement 
• 
Pyridostigmine, wean based on improvement. 
• 
ICPi-associated MG may be monophasic and additional steroid sparing agents may not be 
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7.2 Guillain-Barre Syndrome 
Definition: Progressive most often symmetrical muscle weakness with absent or reduced deep 
tendon reflexes. Often starts with sensory symptoms/neuropathic pain localized to lower back 
and thighs. May involve extremities (typically ascending weakness but not always), facial, 
respiratory and bulbar & oculomotor nerves. May have dysregulation of autonomic nerves. 
Diagnostic Workup: 
• 
Neurologic consultation 
• 
MRI spine w/wo contrast (rule out compressive lesion and evaluate for nerve root 
enhancement/thickening) 
• 
Lumbar puncture: CSF typically has elevated protein and often elevated WBC as well 
even though this is not typically seen in classical Guillain-Barre, cytology (should be 
sent with any CSF sample from a patient with cancer). 
• 
Serum antibody tests for GBS variants (GQ1b for Miller Fisher variant a/w ataxia and 
ophthalmoplegia) 
• 
Electrodiagnostic studies to evaluate polyneuropathy 
• 
Pulmonary function testing (NIF/VC) 
• 
Frequent neurochecks 
Grading 
Management 
All grades warrant workup and intervention given potential for progressive GBS to lead to 
respiratory compromise. Note, there is no G1 toxicity. 
G1: Mild: None 
NA 
G2: Moderate: Some 
interference with ADLs, 
symptoms concerning to 
patient. 
• 
Discontinue ICPi 
• 
Admission to inpatient unit with capability of rapid transfer 
to ICU-level monitoring 
• 
Start IVIG (0.4G/kg/day for 5 days for a total dose of 
2G/kg) or plasmapheresis. Corticosteroids are usually 
not recommended for idiopathic GBS, however in ICPi-
related forms, a trial is reasonable (methylprednisolone 
2-4 mg/kg/day), followed by slow steroid taper. Pulse 
steroid dosing (methylprednisolone 1 gram daily for 5 
days)  may also be considered for G3-4 along with IVIG 
or plasmapheresis. 
• 
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• 
Monitor for concurrent autonomic dysfunction 
• 
Non opioid management of neuropathic pain 
       Treatment of constipation/ileus 
Additional Considerations: 
• 
Slow prednisone taper after steroid pulse plus IVIG or plasmapheresis 
• 
May require repeat IVIG courses 
• 
Caution with rechallenging for severe cases 
7.3 Peripheral Neuropathy 
Definition: Can present as asymmetric or symmetric sensory, motor, or sensory-motor deficit. 
Focal mononeuropathies including cranial neuropathies (e.g. facial neuropathies/Bell's palsy) 
may be present. Numbness and paresthesias may be painful or painless. Hypo- or areflexia. 
Sensory ataxia may be present. 
Diagnostic Workup: 
G1: 
• 
Screen for reversible neuropathy causes: diabetic screen, B12, folate, TSH, HIV, consider 
serum protein electrophoresis, and other vasculitic & autoimmune screen 
• 
Neurologic consultation 
• 
Consider MRI spine w/wo contrast 
G2: In addition to above: 
• 
MRI spine advised/ MRI brain if cranial nerve 
• 
Consider EMG/NCS 
• 
Consider Neurology consultation 
G3-4: go to Guillain-Barre Syndrome (GBS) algorithm 
Grading 
Management 
G1: Mild: No interference 
with function and 
symptoms not concerning 
to patient. Note: any 
cranial nerve problem 
should be managed as 
moderate 
• 
Low threshold to hold ICPi and monitor symptoms for a 
week. If to continue, monitor very closely for any 
symptom progression. 
G2: 
Moderate: 
Some 
interference with ADLs, 
symptoms concerning to 
• 
Hold ICPi and resume once return to G1 
• 
Initial observation OR initiate prednisone 0.5-1mg/kg (if 

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patient (i.e. Pain but no 
weakness 
or 
gait 
limitation). 
progressing from mild) 
• 
Neurontin, pregabalin, or duloxetine for pain 
G3-4: Severe: Limiting 
self-care and aids 
warranted, weakness 
limiting walking or 
respiratory problems (i.e. 
leg weakness, foot drop, 
rapidly ascending sensory 
changes). Severe may be 
GBS and should be 
managed as such. 
• 
Permanently discontinue ICPi 
• 
Admit patient 
• 
Neurologic consultation 
• 
Initiate IV methylprednisolone 2-4 mg/kg and proceed as 
per GBS management. 
G3-4: Severe: Limiting 
self-care and aids 
warranted, weakness 
limiting walking, ANY 
dysphagia, facial 
weakness, respiratory 
muscle weakness, or 
rapidly progressive 
symptoms. 
 
7.4 Autonomic neuropathy 
Definition: Nerves that control involuntary bodily functions are damaged. This may affect 
blood pressure, temperature control, digestion, bladder function and sexual function. A case 
of severe enteric neuropathy with ICPi has been reported. 
Can present with GI difficulties such as new severe constipation, nausea; urinary problems, 
sexual difficulties, sweating abnormalities, sluggish pupil reaction and orthostatic hypertension. 
Diagnostic Workup: 
An evaluation by neurologist or relevant specialist depending on organ system, with testing 
which may include: 
• 
Screen for other causes of autonomic dysfunction: diabetic screen, adrenal 
insufficiency, HIV, paraproteinemia, amyloidosis, botulism, consider chronic diseases 
such as Parkinson’s and other autoimmune screen 
• 
AM orthostatic vitals 
• 
Consider electrodiagnostic studies to evaluate for concurrent polyneuropathy 
• 
Consider paraneoplastic LEMS, ANNA-1 ab, ganglionic acetylcholine receptor ab testing 
Grading 
Management 

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G1: Mild: No 
interference with 
function and symptoms 
not concerning to 
patient. 
• 
Low threshold to hold ICPi and monitor symptoms for a 
week. If to continue, monitor very closely for any 
symptom progression. 
G2: Moderate: Some 
interference with ADLs, 
symptoms concerning to 
patient 
• 
Hold ICPi and resume once return to G1 
• 
Initial observation OR initiate prednisone 0.5-1mg/kg (if 
progressing from mild) 
• 
Neurological consultation 
G3-4: Severe: 
Limiting self-care 
and aids warranted 
• 
Permanently discontinue ICPi 
• 
Admit patient 
• 
Initiate methylprednisolone 1 gram daily x 3 days followed 
by oral steroid taper 
• 
Neurologic consultation 
7.5 Aseptic meningitis 
Definition: May present with headache, photophobia, neck stiffness, often afebrile but may be 
febrile. There may be nausea/vomiting 
Mental status should be normal (distinguishes from encephalitis) 
Diagnostic Workup: 
• 
MRI brain w/wo contrast + pituitary protocol 
• 
AM cortisol, ACTH to rule out adrenal insufficiency 
• 
Consider lumbar puncture: measure opening pressure, check cell count, protein 
glucose, gram stain, culture, PCR for HSV and other viral PCRs depending on 
suspicion, cytology 
• 
May see elevated WBC with normal glucose, normal culture and gram stain. May see 
reactive lymphocytes or histiocytes on cytology 
Grading 
Management 
G1: Mild: No interference 
with function and 
symptoms not concerning 
to patient. Note: any cranial 
nerve problem should be 
managed as moderate. 
• 
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and benefits 
• 
Consider empiric antiviral (IV acyclovir) and antibacterial 
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G2: Moderate: Some 
interference with ADLs, 
symptoms concerning to 
patient (i.e. Pain but 
no weakness or gait 
limitation). 
• 
Once bacterial and viral infection negative, may closely 
monitor off corticosteroids or consider oral prednisone 
0.5-1 mg/kg or IV methylprednisolone 1 mg/kg if 
moderate/severe symptoms. 
G3-4: Severe: 
Limiting self-care 
and aids warranted 
7.6 Encephalitis 
Definition: As for aseptic meningitis, need to exclude infectious causes, especially viral (i.e. 
HSV). 
Confusion, altered behavior, headaches, seizures, short term memory loss, depressed level of 
consciousness, focal weakness, speech abnormality 
Diagnostic Workup: 
• 
Neurologic Consultation 
• 
MRI brain w/wo contrast may reveal T2/FLAIR changes typical of what is seen in 
autoimmune encephalopathies or limbic encephalitis or may be normal 
• 
Lumbar puncture: check cell count, protein glucose, gram stain, culture, PCR for 
HSV and other viral PCRs depending on suspicion, cytology, oligoclonal bands, 
autoimmune encephalopathy and paraneoplastic panels. 
• 
May see elevated WBC with lymphocytic predominance and/or elevated protein 
• 
EEG to evaluate for subclinical seizures 
• 
Bloods: metabolic, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel 
including TPO and thyroglobulin 
• 
Rule out concurrent anemia/thrombocytopenia, which can present w severe headaches and 
confusion 
Grading 
Management 
G1: Mild: No interference 
with function and 
symptoms not concerning 
to patient. Note: any cranial 
nerve problem should be 
managed as moderate. 
• 
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and benefits 
• 
As above for aseptic meningitis suggest concurrent IV 
acyclovir until PCR results obtained and negative 
• 
Trial of methylprednisolone 1-2 mg/kg 
• 
If severe or progressing symptoms or oligoclonal bands 
G2: Moderate: Some 
interference with ADLs, 

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symptoms concerning to 
patient (i.e. Pain but no 
weakness or gait 
limitation). 
present, consider pulse corticosteroids methylprednisolone 
1G IV daily for 3-5 days plus IVIG 2 g/kg over 5 days. 
• 
If positive for autoimmune encephalopathy antibody and 
limited or no improvement, consider Rituximab or 
plasmapheresis in consultation with neurology 
G3-4: Severe: Limiting 
self-care and aids warranted 
7.7 Transverse Myelitis 
Definition: Acute or subacute weakness or sensory changes bilateral, often with increased deep 
tendon reflexes 
Diagnostic Workup: 
• 
Neurologic consultation 
• 
MRI spine (with thin axial cuts through the region of suspected abnormality) and MRI brain 
• 
Lumbar puncture: cell count, protein, glucose, oligoclonal bands, viral PCRs, cytology, 
onconeural antibodies 
• 
Bloods: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG 
• 
Evaluation for urinary retention, constipation 
Grading 
Management 
G1: Mild: No interference 
with function and 
symptoms not concerning 
to patient. Note: any 
cranial nerve problem 
should be managed as 
moderate 
• 
Permanently discontinue ICPi 
• 
Methylprednisolone 2 mg/kg 
• 
Strongly consider higher doses of 1g/day for 3-5 days 
• 
Strongly consider IVIG 
G2: Moderate: Some 
interference with ADLs, 
symptoms concerning to 
patient (i.e. Pain but no 
weakness or gait 
limitation). 
G3-4: Severe: Limiting 
self-care and aids warranted 
8.0 AUTOIMMUNE HEMATOLOGIC TOXICITY 
8.1 Hemolytic Anemia 
Definition: A condition in which red blood cells are destroyed and 
removed from the bloodstream before their normal lifespan is over. 
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fever, inability to do physical activity, and heart murmur. 
Diagnostic Workup: 
• 
History and physical examination (with special consideration of history of new drugs, 
insect, spider or snake bites) 
• 
Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on 
peripheral smear. LDH, haptoglobin, bilirubin, reticulocyte count, free hemoglobin 
• 
DIC panel which could include PT/INR, infectious causes 
• 
Autoimmune serology 
• 
PNH screening 
• 
Direct and indirect bilirubin, LDH, direct agglutinin test, and if no obvious cause, bone 
marrow analysis, cytogenetic analysis to evaluate MDS 
• 
Evaluation for viral/bacterial (mycoplasma etc. ) causes of hemolysis studies 
• 
Protein electrophoresis, cryoglobulin analysis 
• 
Workup for BM failure syndrome if refractory including B12, folate, copper, parvo virus, 
FE, thyroid, infectious 
• 
Glucose-6-phosphate dehydrogenase 
• 
Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, 
cephalosporins, penicillins, NSAIDS, Quinine/quinidine, fludarabine, ciprofloxacin, 
lorazepam, diclofenac etc) 
• 
Assessment of methemaglobinemia 
Grading 
Management 
G1: Hgb<LLN - 10.0 g/dL; 
<LLN - 6.2 mmol/L; <LLN 
- 100 g/L 
• 
Continue ICPi with close clinical follow-up and laboratory 
evaluation 
G2: Hgb <10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmol/L; <100 - 
80g/L 
• 
Hold ICPi and strongly consider permanent discontinuation 
• 
Administer 0.5 to 1 mg/kg/day prednisone equivalents 

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G3: Hgb <8.0 g/dL; <4.9 
mmol/L; <80 g/L; 
transfusion indicated 
• 
Permanently discontinue ICPi 
• 
Should use clinical judgement and consider admitting the 
patient 
• 
Hematology consult 
• 
Prednisone 1-2 mg/kg/day (oral or IV depending on 
symptoms/speed of development) 
• 
If worsening or no improvement, 1 to 2 mg/kg/day 
prednisone equivalents and permanently discontinue 
ICPi treatment 
• 
Consider RBC transfusion per existing guidelines. Do not 
transfuse more than the minimum number of red blood cell 
(RBC) units necessary to relieve symptoms of anemia or to 
return a patient to a safe hemoglobin range (7 to 8 g/dL in 
stable, non-cardiac in-patients) 
• 
Should offer patients supplementation with folic acid 1mg QD 
G4: Life-threatening 
consequences; urgent 
intervention indicated 
• 
Permanently discontinue ICPi 
• 
Admit patient 
• 
Hematology consult 
• 
IV prednisone corticosteroids 1-2 mg/kg/day 
• 
If no improvement on or if worsening on 
corticosteroids or severe symptoms on presentation, 
initiate other immunosuppressive drugs, such as 
rituximab, IVIG, CSA, infliximab, MMF and ATG 
• 
RBC transfusion per existing guidelines. Discuss with blood 
bank team prior to transfusions that a patient with possible 
ICPi SAE is in house. 
Additional Considerations: 
• 
Monitor hemoglobin levels on a weekly basis until the steroid tapering process is complete. 
Thereafter, less frequent testing is needed.9 
8.2 Acquired Thrombotic Thrombocytopenic Purpura 
Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, 
thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities such as 
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Diagnostic Workup: 
• 
If no improvement on or if worsening on corticosteroids or severe symptoms on 
presentation, initiate other immunosuppressive drugs, such as rituximab, IVIG, 
CSA, infliximab, MMF and ATG 
• 
History with specific questions related to drug exposure (e.g. chemotherapy, 
sirolimus, tacrolimus, Opana ER, antibiotics, quinine,) 
• 
Physical exam, peripheral smear 
• 
ADAMTS13 activity level and inhibitor titer 
• 
LDH, haptoglobin, reticulocyte count, bilirubin, urinalysis to rule out other causes 
• 
Prothrombin time, activated partial thromboplastin time, fibrinogen 
• 
Blood group and antibody screen, direct antiglobulin test, cytomegalovirus 
serology 
• 
Consider CT/MRI brain, echocardiogram, electrocardiogram Viral studies 
• 
Viral studies 
• 
Note: this disorder is usually associated with severe drop in platelets and 
hemolysis/anemia precipitously 
Grading 
Management 
All Grades 
• 
The first step in the management of TTP is a high 
index of suspicion for the diagnosis and timely 
recognition. Hematology consult should immediately 
be called, as delay in identification is associated with 
increased mortality/morbidity. 
• 
Initially, the patient should be stabilized and any critical organ 
dysfunction stabilized. 
G1: Evidence of RBC 
destruction 
(schistocytosis) without 
anemia, renal 
insufficiency or 
thrombocytopenia 
clinically 
• 
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and benefits, noting that there is 
currently no data to recommend restarting ICPi therapy 
• 
Hematology consult 
• 
Administer 0.5 to 1 mg/kg/day prednisone 
G2: Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequence with 
G2 anemia and 

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thrombocytopenia 
G3: Laboratory findings 
with clinical consequences 
(G3 thrombocytopenia, 
anemia, renal 
insufficiency >2) 
• 
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and benefits, noting that there is 
currently no data to recommend restarting ICPi therapy 
• 
Hematology consult 
• 
In conjunction with hematology Initiate plasma exchange 
(PEX) according to existing guidelines with further PEX 
dependent on clinical progress10-12 
• 
Administer methylprednisolone 1 g intravenously 
daily for 3 days, with the first dose typically 
administered immediately after the first PEX 
• 
May offer rituximab 
G4: 
Life-threatening 
consequences, (e.g., CNS 
hemorrhage 
or 
thrombosis/embolism or 
renal failure) 
8.3 Hemolytic uremic syndrome 
Definition: A disorder characterized by a form of thrombotic microangiopathy 
with renal failure, hemolytic anemia, and severe thrombocytopenia Signs and 
symptoms of HUS can include: 
•    Bloody diarrhea 
•    Decreased urination or blood in the urine 
•    Abdominal pain, vomiting and occasionally fever 
•    Pallor 
•    Small, unexplained bruises or bleeding from the nose and mouth 
•    Fatigue and irritability 
•    Confusion or seizures 
•    High blood pressure 
•    Swelling of the face, hands, feet or entire body 
Diagnostic Workup: 
•    History and PE (special consideration for new history of high risk drugs, HTN or cardiac 
causes) 
• 
CBC with indices 
• 
Blood smear morphology. Note that the presence of schistocytes on smear is critical for 
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• 
Serum creatinine 
• 
ADAMTS13 (to rule out TTP) 
• 
Homocystiene/MMA 
• 
Complement testing C3, C4, CH50 (complement inhibitory antibodies for suspected 
familial) 
• 
Evaluate reticulocyte count and MCV 
• 
Evaluation of infectious cause including screening for viral EBV, CMV, HHV6 
• 
Evaluation for nutritional causes of macrocytosis (B12 and folate) 
• 
Pancreatic enzymes 
• 
Evaluation for diarrheal causes, shiga toxin, Escherichia coli 0157, etc 
• 
Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia 
• 
Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, sirolimus etc) 
• 
Evaluation for concurrent confusion 
Grading 
Management 
G1-2: Evidence of RBC 
destruction (schistocytosis) 
without clinical 
consequences of anemia, 
thrombocytopenia grade II 
• 
Continue ICPi with close clinical follow-up and laboratory 
evaluation 
• 
Supportive care 
G3: Laboratory findings 
with clinical consequences 
(e.g., renal insufficiency, 
petechiae) 
• 
Permanently discontinue ICPi 
• 
Begin therapy with Eculizumab therapy 900mg weekly x 4 
doses, 1200mg week 5, then 1200mg every two weeks. 
• 
Red blood transfusion according to existing guidelines 
G4: Life-threatening 
consequences, (e.g., 
CNS 
thrombosis/embolism 
or renal failure) 
8.4 Aplastic Anemia 
Definition: Condition in which the body stops producing enough new blood cells. 
Diagnostic Workup: 
• 
History and physical examination (close attention to medications, exposure to radiation, 
toxins, recent viral infections) 
• 
CBC, smear, and reticulocyte count 
• 
Viral studies including CMV, HHV6, EBV, parvovirus 

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• 
Nutritional assessments including b12, folate, iron, copper, ceruloplasmin, vitamin D 
• 
Serum LDH, renal function 
• 
W/u for infectious causes. 
• 
Identify marrow hypo/aplasia 
• 
BM biopsy and BM aspirate analysis 
• 
Peripheral blood analysis including neutrophil count, proportion of GPI-negative cells by 
flow for PNH 
• 
Flow cytometry to evaluate loss of GPI-anchored proteins 
• 
Type and screen patient for transfusions and notify blood bank that all transfusions need to 
be irradiated and filtered 
Grading 
Management 
G1: nonsevere: >0.5 
polymorphonuclear cells 
(PMNs) × 10 9/L 
hypocellular marrow, with 
marrow cellularity<25%, 
Peripheral platelet 
count >20,000, reticulocyte 
count >20,000 
• 
Hold ICPi, provide growth factor support and close 
clinical follow-up and laboratory evaluation.  
• 
Supportive transfusions as per local guidelines 
G2: severe: 
Hypocellular marrow 
<25% and tow of the 
following ANC <500, 
peripheral platelet 
<20,000 and 
Reticulocyte <20,000 
• 
Hold ICPi and provide growth factor support and close 
clinical laboratory evaluations daily 
• 
Administer ATG + cyclosporine. HLA typing and evaluation 
for bone marrow transplantation if patient is candidate. All 
blood products should be irradiated and filtered. 
• 
Supportive care with GCSF may be added in addition 
G3-4: very severe:  
ANC<200, platelet count 
<20,000, reticulocyte count 
of <20,000, plus 
hypocellular marrow <25%. 
• 
Hold ICPi and monitor weekly for improvement. If not 
resolved, discontinue treatment until AE has reverted to grade 
1 
• 
Hematology consult, growth factor support 
• 
Horse ATG plus cyclosporine 
• 
If no response, repeat immunosuppression with Rabbit ATG 
plus cyclosporine, cyclophosphamide 
• 
For refractory patients consider eltrombopag plus supportive 
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8.5 Lymphopenia 
Definition: An abnormally low level of lymphocytes in peripheral blood (PB); for adults, 
counts of less than 1,500/mm3 
Diagnostic Workup: 
• 
History and physical exam (special attention for lymphocyte depleting therapy such as 
Fludarabine, ATG, steroids, cytotoxic chemotherapy, radiation exposure etc. well as 
history of autoimmune disease, family history of autoimmune disease) 
• 
Evaluation of nutritional state as cause 
• 
Spleen size 
• 
CBC with differential, peripheral smear and reticulocyte counts 
• 
CXR for evaluation of presence of thymoma 
• 
Bacterial cultures and evaluation for infection (fungal, viral, bacterial specifically 
CMV/HIV 
G1-2: 500-1000 PB 
lymphocyte count 
• 
Continue ICPi 
G3: 250-499 PB 
lymphocyte count 
• 
Continue ICPi, checking CBC weekly for monitoring, 
initiation of CMV screening 
 G4: <250 PB lymphocyte 
count 
• 
Consider holding ICPi 
• 
Initiate Mycobacterium avium complex prophylaxis 
and Pneumocystis jirovecii prophylaxis, CMV 
screening. HIV/hepatitis screening if not already 
done. 
• 
May consider EBV testing if evidence of 
lymphadenopathy/hepatitis, fevers, hemolysis occur c/w 
lymphoproliferative disease occurs 
8.6 Immune thrombocytopenia (ITP) 
Definition: an autoimmune disorder characterized by immunologic destruction of otherwise 
normal platelets 
Diagnostic Workup: 
• 
Initiate Mycobacterium avium complex prophylaxis and Pneumocystis jirovecii 
prophylaxis, CMV screening. HIV/Hepatitis screening if not already done. 
• 
History and physical examination (special attention for lymphocyte depleting 
therapy such as Fludarabine, ATG, steroids, cytotoxic therapy) 
• 
FH of autoimmunity or personal history of autoimmune disease 
• 
History of viral illness 

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• 
CBC 
• 
Peripheral blood smear, reticulocyte count 
• 
Bone marrow evaluation only if abnormalities in the above testing results and 
further investigation is necessary for a diagnosis 
• 
Patients with newly diagnosed ITP should undergo testing for HIV , HCV, HBV 
and H. pylori 
• 
Direct antigen test should be checked to rule out concurrent Evan’s syndrome 
• 
Nutritional evaluation 
• 
BM evaluation if other cell lines affected and concern for aplastic anemia 
Grading 
Management 
G1: Platelet count <100/μL • 
Continue ICPi with close clinical follow-up and laboratory 
evaluation 
G2: Platelet count <75/μL 
• 
Hold ICPi, but monitor for improvement. If not resolved, 
interrupt treatment until AE has reverted to Grade 1 
• 
Administer prednisone 1 mg/kg per day (dosage range, 0.5–2 
mg/kg per day) orally for 2-4 weeks after which time this 
medication should be tapered over 4-6 weeks to the lowest 
effective dose 
• 
IVIG may be used in conjunction with corticosteroids if a 
more rapid increase in platelet count is required. 
G3: Platelet count <50/μL 
• 
Hold ICPi, but monitor for improvement. If not resolved, 
interrupt treatment until AE has reverted to Grade 1 
• 
Hematology consult 
• 
Prednisone corticosteroids 1-2 mg/kg/day (oral or IV 
depending on symptoms) 
• 
If worsening or no improvement, 1 to 2 mg/kg/day prednisone 
equivalents and permanently discontinue treatment 
• 
IVIG be used with corticosteroids when a more rapid increase 
in platelet count is required 
• 
If IVIG is used, the dose should initially be 1 g/kg as a one-
time dose. This dosage may be repeated if necessary 
• 
If previous treatment with corticosteroids and/or, IVIG, 
has been unsuccessful, subsequent treatment may include 
G4: Platelet count <25/μL 

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rituximab, thrombopoietin receptor agonists, or more 
potent immunosuppression 
(From American Society of Hematology guideline on immune 
thrombocytopenia13 – consult for further details) 
8.7 Acquired Hemophilia 
Definition: disorder caused by the development of autoantibodies (inhibitors) directed against 
plasma coagulation factors, 
Diagnostic Workup: 
• 
If previous treatment with corticosteroids and/or, IVIG, has been unsuccessful, 
subsequent treatment may include rituximab, thrombopoietin receptor agonists, or more 
potent immunosuppression 
• 
Full blood count to assess platelet number, fibrinogen, PT, PTT, INR. The typical 
finding in patients with AHA is a prolonged aPTT with a normal prothrombin time 
(PT). 
• 
MRI, CT, and ultrasonography may be indicated to localize, quantify, and serially 
monitor the location and response of bleeding. 
• 
Medication review to assess for alternative causes 
• 
Determination of Bethesda unit level of inhibitor 
Grading 
Management 
G1: Mild: 5-40% of normal 
factor activity in blood; 
0.05-0.4 IU/ml of whole 
blood 
• 
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and benefits 
• 
Administer 0.5 to 1 mg/kg/day prednisone 
• 
Transfusion support as required 
• 
Treatment of bleeding disorders with hematology consult 
G2: Moderate: 1-5% of 
normal factor activity in 
blood; 0.01-0.05 IU/ml of 
whole blood 
• 
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and benefits 
• 
Hematology consult 
• 
Administration of factor replacement (choice based on BU of 
titer) 
• 
Administer 1 mg/kg/day prednisone ± rituximab (dose 
375mg/m2 weekly x 4 weeks) and/or cyclophosphamide 
(dose 1-2mg/kg/day). Choice of rituximab vs 
cyclophosphamide is patient specific and should be done 
with assistance of hematology consult. Prednisone, rituximab 

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and cyclophosphamide should be given for at least 5 weeks. 
• 
Factors should be provided to increase level during bleeding 
episodes, with choice of factor based on presence or absence 
of inhibitor 
G3-4: Severe: <1% of 
normal factor activity in 
blood; < 0.01 IU/ml of 
whole blood 
• 
Permanently discontinue ICPi 
• 
Admit patient 
• 
Hematology consult 
• 
Administration of factor replacement, choice based on BU 
level of inhibitor. 
• 
Bypassing agents may be used (Factor VII FEIBA). Caution 
should be taken in elderly and those with CAD 
• 
Prednisone corticosteroids 1-2 mg/kg/day (oral or IV 
depending on symptoms)± rituximab (dose 375mg/m2 weekly 
x 4 weeks) and/or cyclophosphamide (dose 1-2mg/kg/day). 
• 
Transfusion support as required for bleeding 
• 
If worsening or no improvement add, cyclosporine, or 
immunosuppression/immunoadsorption 
Additional Considerations: 
• 
AHA requires specialist clinical and laboratory expertise. Consult and/or transfer to a 
specialist center is often appropriate. If consultation with or transfer to a hemophilia center 
is not immediately possible, then investigation and treatment should be initiated while a 
liaison is being established.14 
9.0 CARDIOVASCULAR TOXICITY 
9.1 Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart 
failure and vasculitis 
Definition: 
Signs and symptoms may include: 
chest pain, arrhythmia, palpitations, peripheral edema, progressive or acute dyspnea, pleural 
effusion, fatigue 
Diagnostic Workup: 
At baseline: 
• 
Electrocardiogram 
• 
Consider Troponin, especially in patient treated with combination immune therapies 
Upon signs/symptoms (Consider cardiology consult) 

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• 
Electrocardiogram 
• 
Troponin 
• 
BNP 
• 
Echocardiogram 
• 
Chest X-ray 
Additional testing to be guided by cardiology and may include: 
• 
Stress test 
• 
Cardiac catherization 
Cardiac MRI 
Grading 
Management 
G1: Abnormal 
cardiac biomarker 
testing, including 
abnormal ECG 
All grades warrant workup and intervention given potential for 
cardiac compromise 
Please consider the following: 
• 
Hold ICPi and permanently discontinue after G1 
• 
High-dose corticosteroids (1-2 mg/kg of prednisone) initiated 
rapidly (oral or IV depending on symptoms). 
• 
Admit patient, cardiology consultation 
• 
Management of cardiac symptoms according to ACC/AHA 
guidelines and with guidance from cardiology 
• 
Immediate transfer to a coronary care unit should be 
considered for patients with elevated troponin or 
conduction abnormalities. 
• 
In patients without an immediate response to high-dose 
corticosteroids, consider early institution of cardiac transplant 
rejection doses of corticosteroids (methylprednisolone 1g 
every day) and the addition of either mycophenolate, 
infliximab, or anti-thymocyte globulin 
G2: Abnormal screening 
tests with mild symptoms 
G3: Moderately abnormal 
testing or symptoms with 
mild activity 
G4: Moderate to 
severe 
decompensation, 
intravenous 
medication or 
intervention required, 
life threatening 
conditions 
Qualifying Statement: Treatment recommendations are based on anecdotal evidence and 
the life-threatening nature of cardiovascular complications. Holding checkpoint inhibitor 
therapy is recommended for all grades of complications. The appropriateness of 
rechallenging remains unknown. Note that infliximab has been 
associated with heart failure and is contraindicated at high doses in patients with moderate-
severe heart failure. 15 

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9.2 Venous thromboembolism 
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated 
from a distal site via the blood stream. 
Clinical signs and symptoms are variable and may include pain, swelling, increased skin vein 
visibility, erythema, and cyanosis accompanied by unexplained fever for 
DVT and dyspnea, pleuritic pain, cough, wheezing or hemoptysis for PE 
Diagnostic Workup: 
Evaluation of signs and symptoms of PE or DVT may include: 
• 
Admit patient, cardiology consultation 
• 
Clinical prediction rule to stratify patients with suspected VTE 
• 
Venous US for suspected DVT 
• 
CTPA for suspected PE 
• 
Can also consider D-dimer for low risk patients based on risk stratification by clinical 
prediction rule for DVT/PE when CT or Doppler not available or appropriate 
• 
V/Q scan is also an option when CTPA is not appropriate 
• 
Consider other testing, including ECG, chest radiography, BNP and troponin levels, and 
ABG 
Grading 
Management 
G1: Venous thrombosis 
(e.g., superficial 
thrombosis) 
• 
Continue ICPi 
• 
Warm compress 
• 
Clinical surveillance 
G2: Venous thrombosis 
(e.g., uncomplicated deep 
vein thrombosis), medical 
intervention indicated 
• 
Continue ICPi 
• 
Management according to CHEST, ACC and/or AHA 
guidelines and consider consult from cardiology or other 
relevant specialties 
• 
LMWH is suggested over VKA, dabigatran, rivaroxaban 
apixaban, or edoxaban for initial and long-term treatment 
• 
IV heparin is an acceptable alternative for initial use and oral 
anticoagulants are acceptable for the long term 
G3: Thrombosis (e.g., 
uncomplicated 
pulmonary embolism 
[venous], non-embolic 
cardiac mural [arterial] 
thrombus), medical 
intervention indicated 
G4: Life-threatening 
(e.g., pulmonary 
embolism, 
cerebrovascular event, 
arterial insufficiency); 
• 
Permanently discontinue ICPi 
• 
Admit patient and management according to CHEST, ACC 
and/or AHA guidelines and with guidance from cardiology 
• 
Respiratory and hemodynamic support 

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hemodynamic or 
neurologic instability; 
urgent intervention 
indicated 
• 
LMWH is suggested over VKA, dabigatran, rivaroxaban, 
apixaban, or edoxaban for initial and long-term treatment 
• 
IV heparin is an acceptable alternative for initial use and oral 
anticoagulants are acceptable for the long term 
• 
Further clinical management as indicated based on symptoms 
Additional Considerations: 
•    While it may be impossible to determine the etiology of thromboembolic disease in patients 
with advanced cancer and the role, if any, that ICPi treatment plays, it is reasonable to 
remove the potential inciting agents given the severity and life-threatening potential of 
grade 4 complications. Clinicians are to use clinical judgement and take into account the 
risks and benefits when deciding whether to discontinue ICPi treatment. 
•    Anticoagulant therapy duration should continue for a minimum of 9-12 months to indefinitely
in the setting of active cancer unless patient is asymptomatic, doing well, or in remission.16,17
10.0 OCULAR TOXICITY 
Counsel all patients to inform their healthcare provider immediately if they experience any of 
the following ocular symptoms: 
• 
Blurred vision 
• 
Change in color vision 
• 
Photophobia 
• 
Distortion 
• 
Scotomas 
• 
Visual Field changes 
• 
Double vision 
• 
Tenderness 
• 
Pain with eye movement 
• 
Eyelid swelling 
• 
Proptosis 
Evaluation, under the guidance of ophthalmology: 
• 
Respiratory and hemodynamic support 
• 
Check vision in each eye separately 
• 
Color vision 
• 
Red reflex 

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• 
Pupil size, shape and reactivity 
• 
Fundoscopic examination 
• 
Inspection of anterior part of eye with penlight  
Prior Conditions 
• 
Inspection of anterior part of eye with penlight  
• 
Exclude patients with history of active uveitis 
• 
History of recurrent uveitis requiring systemic immunosuppression or continuous local 
therapy 
Additional Considerations: 
• 
Ocular irAEs are many times seen in the context of other organ irAEs 
• 
High level of clinical suspicion as symptoms may not always be associated with severity 
• 
Best to treat after ophthalmologist eye examination 
 
10.1 Uveitis/Iritis 
Definition: Inflammation of the middle layer of the eye 
Diagnostic Workup: As per 10.0 
Grading 
Management 
G1: Asymptomatic 
• 
Continue ICPi 
• 
Refer to ophthalmology within 1 week 
• 
Artificial Tears 
G2: Medical 
Intervention 
required, 
anterior 
uveitis 
• 
Hold ICPi temporarily until after ophthalmology consult 
• 
Urgent Ophthalmology referral 
• 
Topical corticosteroids, cycloplegic agents, systemic 
corticosteroids 
• 
May resume ICPi treatment once off systemic steroids 
which are purely indicated for ocular side effect or once 
corticosteroids for other concurrent systemic irAE are 
reduced to ≤10mg. Continued topical/ocular steroids are 
permitted when resuming therapy to manage and 
minimize local toxicity 
• 
Retreat after return to ≤ G1 
G3: Posterior or pan-uveitis • 
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• 
Urgent ophthalmology referral. 
• 
Systemic corticosteroids and intravitreal/periocular/topical 
corticosteroids 
G4: 20/200 or worse 
• 
Permanently discontinue ICPi 
• 
Emergent ophthalmology referral. 
• 
Systemic corticosteroids - IV prednisone 1-2mg/kg or 
methylprednisolone 0.8-1.6mg/kg and 
intravitreal/periocular/topical corticosteroids per ophthalmologist 
opinion 
Additional Considerations: Consider use of infliximab or other TNFa blockers in cases that 
are severe and refractory to standard treatment. 18,19 
10.2 Episcleritis 
Definition: Inflammatory condition affecting the episcleral tissue between the conjunctiva and 
the sclera that occurs in the absence of an infection 
Diagnostic Workup: As per 10.0 
Grading 
Management 
G1: Asymptomatic 
• 
Continue ICPi 
• 
Refer to ophthalmology within 1 week 
• 
Artificial Tears 
G2: vision 20/40 or better 
• 
Hold ICPi therapy temporarily until after ophthalmology 
consult 
• 
Urgent ophthalmology referral 
• 
Topical corticosteroids, cycloplegic agents, systemic 
corticosteroids 
G3: Symptomatic and 
vision worse than 2/40 
• 
Permanently discontinue ICPi 
• 
Urgent ophthalmology referral. 
• 
Systemic corticosteroids and topical corticosteroids with 
cycloplegic agents 
G4: 20/200 or worse 
• 
Permanently discontinue ICPi 
• 
Emergent ophthalmology referral. 
• 
Systemic corticosteroids and topical corticosteroids with 
cycloplegic agents 
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are severe and refractory to standard treatment. 18,19 
10.3 Blepharitis 
Definition: Inflammation of the eyelid that affects the eyelashes or tear production 
Diagnostic Workup: As per 10.0 
Grading 
Management 
No formal grading system 
• 
Warm compresses and lubrication drops 
• 
Continue therapy unless persistent and serious 
 
 
 

Shanghai Junshi Biosciences Co., Ltd. 
Model Informed Consent Form 
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CONFIDENTIAL 
 
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 MODEL INFORMED CONSENT FORM 
VERSION LOG 
Version 
Date 
Reason for Change 
1.0 
09 Mar 2018 
Not applicable 
2.0 
04 Apr 2018 
Update of the information about the optional 
exploratory biomarker assay 
3.0 
18 Sep 2018 
Update as per protocol V2.0 and IB V3.0 
4.0 
12Jun2019 
Update as per protocol V3.0 and IB V4.0 
5.0 
12Jun2020 
Update as per protocol V4.1 and IB V5.0 
6.0 
18Aug2020 
Update as per protocol V5.0 
 
This page should be deleted in all country/site-specific ICFs. 
 
 

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CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
 
Title of Study 
A PHASE III, RANDOMIZED, 
PLACEBO-CONTROLLED, 
MULTICENTER, DOUBLE-BLIND STUDY 
COMPARING TORIPALIMAB INJECTION 
(JS001) COMBINED WITH 
CHEMOTHERAPY VERSUS PLACEBO 
COMBINED WITH CHEMOTHERAPY 
FOR RECURRENT OR METASTATIC 
NASOPHARYNGEAL CANCER 
Protocol Number 
JS001-015-III-NPC 
Aligned with protocol version and 
date 
5.0/18Aug 2020 
Sponsor 
Shanghai Junshi Biosciences Co., Ltd. 
Investigator 
 
Patient 
 
Date of Document: 
18Aug2020 
 
1 WHY HAVE I BEEN GIVEN THIS FORM? 
You are being invited to take part in a clinical research study of an investigational drug, 
Toripalimab injection (JS001), to treat recurrent or metastatic nasopharyngeal cancer. 
Toripalimab injection was approved by Chinese National Medical Products 
Administration on 17 Dec 2018 for the treatment of non-resectable or metastatic 
melanoma that has failed systemic treatment. 
Before you decide if you want to take part in this study, it is important for you to 
understand  
 Why the study is being done,  
 How your information will be used,  
 What the study will involve, and  
 The possible benefits, risks and discomforts for you when you take part.  
Please take time to read the following information carefully. Some terms may be new to 
you. If there is anything you do not understand or if you would like more information, 
please ask the study doctor or study staff. You may also discuss the study with family 

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members, friends, and your own doctor if you wish. If you decide that you want to take 
part in this study, you will be asked to sign the consent statement at the end of this 
informed consent form (you will be given a copy of this to take home with you). You 
must not take part in any study procedures until you have read and signed this form.  
 
2 DO I HAVE TO TAKE PART? 
It is up to you to decide if you want to take part. You are free to choose not to take part. 
Even if you choose not to take part in this study, you will not be disadvantaged in any 
way, including all medical treatment and care you have the right to receive. If you choose 
to take part, you may change your mind and choose to leave the study at any time for any 
reason. You will not need to explain your reasons for leaving the study. If you leave the 
study, you will not bear any penalty or loss of benefits regarding your future care. 
The study doctor can withdraw you from the study at any time if he or she feels it is in 
your best interest or if you cannot comply with study requirements.  
Your participation in the study may also be stopped by the Sponsor or by the regulatory 
authorities at any time. Further, your participation may also be stopped by an independent 
ethics committee such as the Institutional Review Board (IRB) or Institutional Ethics 
Committee (IEC) at any time without your consent. These committees review study safety 
and ethics to make sure that patients’ rights are not violated. The reason(s) for stopping 
the study will be explained to you, and you will be given advice about continued care for 
your condition, if this is appropriate. In addition, the Sponsor has the right to stop the 
study for medical or business reasons. If this happens, all patients taking part in the study 
will be withdrawn. 
If you leave (or withdraw from) the study, you will be asked to go through study 
withdrawal procedures detailed in Section 6 and information about you will be handled as 
detailed in Section 14. 
 
3 WHO IS THE SPONSOR OF THIS STUDY? 
This clinical research study is being sponsored by Shanghai Junshi Biosciences Co., Ltd. 
(hereafter referred to as the Sponsor). 
 
4 WHAT IS THE STUDY ABOUT? 
Toripalimab injection (JS001, hereafter referred to as the Study Drug) is a monoclonal 
antibody acting on programmed cell death-1 (PD-1). Antibodies are a common type of 
proteins, through which the immune system finds and destroys bacteria, viruses and other 
foreign molecules. Antibodies can also be produced in the laboratory, and used for the 

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treatment of patients. Currently, several antibodies have been approved for the treatment 
of cancer and other diseases. 
PD-1 is a protein present on the surface of immune cells. After binding to its ligand, PD-1 
inhibits immune cells from killing cancer cells. The Study Drug acts on PD-1, thereby 
stopping it from inhibiting immune cells, so that immune cells can attack cancer cells. 
In an initial dose escalation Phase I study in patients with advanced solid tumors 
(melanoma, urothelial carcinoma, and renal cell carcinoma), the Study Drug showed a 
good safety profile, with no dose limiting toxicity (DLT) observed and no maximum 
tolerated dose (MTD) reached. Treatment-related side effects were similar to those from 
approved drugs of the same class. The most common treatment-related adverse events 
(AEs) were mild or moderate in intensity and the emergence of AEs was not dose related. 
The Study Drug has shown promising effect on certain kinds of tumors, especially in 
previously under-evaluated acral and mucosal melanomas. In addition, in an ongoing 
Phase Ib/II study, patients with advanced gastric adenocarcinoma, esophageal squamous 
cell carcinoma, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma 
who had failed at least one previous line standard anti-tumor treatment are being treated 
with the study drug on its own (monotherapy). Results so far from this study indicate that 
the monotherapy with study drug is effective against tumors and has manageable side 
effects (more than half of the AEs reported so far were mild or moderate in intensity). 
This study is to find out if the Study Drug combined with chemotherapy is more effective 
in the treatment of recurrent or metastatic nasopharyngeal cancer than placebo combined 
with chemotherapy. The study will recruit approximately 280 subjects at about 40 study 
centers in China mainland, Taiwan, and Singapore. Participants with nasopharyngeal 
cancer who qualify for the study and agree to take part will be allocated into one of the 
2 groups, either to receive the Study Drug plus gemcitabine and cisplatin, or placebo plus 
gemcitabine and cisplatin. The placebo is a medicine that looks like the Study Drug but 
does not contain the “active” ingredients.  
The group that you will be in is decided by chance, like tossing a coin or drawing names 
out of a hat. About 50% of patients will receive the Study Drug plus gemcitabine and 
cisplatin and about 50% will receive placebo plus gemcitabine and cisplatin. To make the 
comparison between Study Drug and placebo as fair as possible, this study is “double 
blinded.” This means that neither you nor the study doctor will know which kind of 
treatment you are receiving. The study doctor will be able to find out which treatment you 
are receiving if necessary, to treat any side effects that you may have.  
This study consists of 4 periods: a screening period, a during-chemotherapy period, a 
post-chemotherapy period, and a survival follow-up period. The screening period takes up 
to 28 days. The during-chemotherapy period starts from the first dosing day of the Study 
Drug, and will continue until progressive disease, excessive toxicity, noncompliance, 

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withdrawal of consent, or a maximum of 6 cycles (every 3 weeks is referred to as a 
“Cycle”), whichever occurs first. The post chemotherapy period follows the 
during-chemotherapy period, and will continue until excessive toxicity, progressive 
disease, withdrawal of consent or study doctor’s judgement, or a maximum of 2 years 
whichever comes first. 
At the end of the study and if you were randomized to the JS001 arm during the study, 
your study doctor and the Sponsor will evaluate if you are eligible to continue the 
treatment with the Study Drug（JS001） after completing the study based on certain 
conditions (your health conditions, the efficacy and safety of the Study Drug, etc). If you 
are eligible, the Sponsor will continue to provide the Study Drug （JS001）free of 
charge to you in accordance with local regulations. Patients who were randomized to the 
placebo arm are not permitted to cross over to receive Study Drug（JS001）. 
 
5 WHAT IS THE PURPOSE OF THE STUDY? 
The purpose of this study is to compare the effects, good or bad, of the Study Drug plus 
gemcitabine and cisplatin versus placebo plus gemcitabine and cisplatin on you and your 
disease, to find out which is better. In this study, you will get either Study Drug plus 
gemcitabine and cisplatin or placebo plus gemcitabine and cisplatin. 
You will also be asked if you are willing to take part in an optional biomarker research 
involving analysis of the optional tumor tissue samples collected when your cancer 
appeared to have worsened. This optional biomarker research is to evaluate certain 
biomarkers (some molecules and cells in your body) which could help doctors to better 
understand your disease and/or your response to the Study Drug. Such analysis may 
include analysis of the biological feature of your tumor tissue. You will be asked to sign a 
separate consent form if you agree to take part in the optional biomarker research. 
You will also be asked if you are willing to donate any remaining blood samples for the 
exploratory biomarker assay in case there are remaining blood samples from the 
mandatory analysis. You should read the following sections carefully to see how your 
remaining blood samples will be tested and state if you are willing to donate your 
remaining blood samples by checking the corresponding boxes on the signature page of 
this informed consent form (See Section 16). 
 
6 WHAT WILL HAPPEN TO ME DURING THE STUDY?  
No study-related procedures may be conducted before signing of this informed consent.  
Study Medication 
The Study Drug or placebo will be administered once every cycle (every 3 weeks) 
throughout the during-chemotherapy period and post-chemotherapy period. The Study 

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Drug will be administered in one of your veins (intravenously [IV]) in 100 mL  0.9% 
NaCl infusion bags at the dose of 240 mg on Day 1 of each cycle in the study center. 
Placebo will be given in the same way as the Study Drug in order to keep blind. The 
treatment (infusion) of the study drug or placebo will be administered about 60 minutes 
during the first 2 cycles. If no clinically significant infusion reaction is observed during or 
after the first 2 cycles, the Study Drug will be administered as a 30-minute IV infusion 
afterward. After each infusion, you will be monitored for a period of 60 minutes (only 
required in the first 2 cycles).  
Chemotherapy will be given only in the during-chemotherapy period (up to 6 cycles). 
Gemcitabine will be given IV over 30 minutes on Day 1 and Day 8 of each cycle, and 
cisplatin will be given IV over 4 hours on Day 1 of each cycle. 
Study Visits 
Screening Visit (From 1 Day up to 28 Days before Entering the During 
Chemotherapy Period) 
At screening visit, you will first sign the informed consent form. After that, the study 
personnel will perform the following examinations/procedures for you to see if you meet 
all eligibility criteria. 
 Ask your gender, age, race/ethnicity, and other basic information, and collect 
your medical history information, including your diseases, surgeries, cancer 
history, smoking history, childbearing history, drug/alcohol abuse, and 
treatment information. 
 You will be assessed for vital signs, including body temperature, pulse, blood 
pressure, and respiratory rate; you will also have a physical examination, 
including weight and height measurement. 
 The study doctor will assess your general well-being and ability to perform 
daily activities (performance status). 
 12-lead electrocardiogram (ECG): This is a painless, non-invasive test that 
shows how your heart works (takes a picture of the electrical activity of your 
heart). To have the ECG, you will lie on a bed/couch for several minutes with 
sensors called electrodes, which are sticky patches, taped to your arms, legs, 
and chest. 
 Echocardiogram: An echocardiogram is a type of ultrasound test that uses high 
pitched sound waves that are sent through a device called a transducer.  The 
device picks up echoes of the sound waves as they bounce off the different 
parts of your heart. These echoes are turned into moving pictures of your heart 
that can be seen on a video screen. It helps to evaluate the size, shape, and 
function of the heart. 

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 Blood samples will be taken for laboratory tests, including CBC, blood 
chemistry, thyroid function, and coagulation parameters. You will also have 
blood taken to test for hepatitis B virus (HBV), hepatitis C virus (HCV), and 
human immunodeficiency virus (HIV). HBV DNA and/or HCV RNA will be 
measured if your study doctor thinks it necessary, to find out the status of the 
hepatitis virus infection. If you are a woman who is able to become 
pregnant/have children, a blood sample will be collected for a pregnancy test. 
If you are pregnant, you cannot take part in this study. The volume of the 
blood samples is around 21-25 mL. 
 A urine sample of 10 mL will be collected during screening for urinary routine 
analysis. 
 You will be asked about any new disease or discomfort you have experienced, 
as well as any medications you have used. 
 Tumor assessment: You will have computed tomography (CT) scans (with 
oral/IV contrast unless contraindicated) or magnetic resonance imaging (MRI) 
of the nasopharynx, neck, chest, and abdomen. A CT scan is an X-ray that is 
transmitted onto a computer that gives your doctor clearer pictures of the 
inside of your body. A contrast medium is like a dye that will spread through 
your body and will help give clearer images. An MRI scan is an imaging 
procedure that uses radiowaves and a magnetic field to take pictures of the 
inside of your body. During the MRI scan, you may be asked to lie down on 
your back on a table and you will need to remain still until the pictures have 
been taken. A CT (with contrast) or an MRI scan of the brain is required to 
confirm or rule out the spread of cancer cell to the brain. Bone scans or other 
assessments to measure your disease should also be performed if your study 
doctor thinks them necessary. 
 Tumor tissue sampling: if you have had a tumor biopsy/tumor operation, the 
study doctor will request the original sample from the original biopsy from the 
hospital where the biopsy was taken. If there is no archived sample, you will 
be required to have a biopsy sample from tumor tissue collected by your study 
doctor before or within 4 weeks after entering the study. In addition, to take 
part in this study, you must allow the study center to obtain the original 
sample, and allow the study doctor to send samples to the laboratory for 
research test. The laboratory will test your tumor samples to determine 
whether there are some features of your tumors, help scientists better 
understand the nasopharyngeal cancer, and help scientists understand why the 
study drug is effective or ineffective to your specific cancer type.The 

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remaining tumor tissue samples will be returned to the study center if there are 
any remains after completing the required testing. 
If you have tests or examinations for ECG, echocardiogram, physical examination, 
thyroid function, HBV, HCV, HIV, EBV or tumor assessment performed before the 
Screening Visit but within 28 days prior to C1D1, you do not need to repeat them at the 
Screening Visit. 
After screening, if you qualify for the study, you will enter the during-chemotherapy 
period. Your study doctor will carefully arrange your hospitalization and follow-up 
schedule. The following processes need your cooperation. 
During-Chemotherapy Period (starting from the first dose of the Study Drug to a 
maximum of 6 cycles) 
You will return to the study center for visits on Day 1 and Day 8 of each cycle in this 
period. During the visits on Day 1 of each cycle, you need to have 
assessments/procedures as follows: 
 You will be asked to complete questionnaires about your life and health. The 
information collected from these questionnaires is valuable and important to 
us, and will allow analyses on your medical measurements and quality of life. 
 You will be assessed for vital signs, including body temperature, pulse, blood 
pressure, and respiratory rate. 
 The study doctor will assess your performance status. 
 You will have a limited physical examination, including body weight 
measurement (your weight will not be measured on C1D1). 
 12-lead ECG and echocardiogram will be performed if your study doctor 
thinks it necessary. 
 A urine sample of 10 mL will be collected for urinary routine analysis (not on 
C1D1). If you are a woman who is able to become pregnant/have children, a 
urine sample of 5 mL will also be collected for a pregnancy test (not on 
C1D1). Samples must be collected within 3 days prior to the treatment(except 
for C1D1). 
 Blood samples will be taken within 3 days (except for C1D1) prior to the 
treatment for laboratory tests, including CBC, blood chemistry, and thyroid 
function (not on C1D1). If your urine pregnancy test is positive, a blood 
sample will be collected for a further pregnancy test (not on C1D1). Blood 
coagulation test will be performed if your study doctor thinks it necessary (not 
on C1D1). The volume of the blood samples is around 12-16 mL at each visit. 

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 Blood samples of 3 mL will be taken for EBV test before the treatment on 
Day 1 of Cycle 1 (C1D1)  , Day 1 of Cycle 3 (C3D1) and Day 1 of Cycle 5 
(C5D1). 
 Blood samples will be taken for anti-drug antibodies (ADA) and JS001 
concentration assessment before the treatment on C1D1, Day 1 of 
Cycle 5(C5D1) . It helps to investigate if your body produces any response 
against the Study Drug. The volume of the blood samples is around 3 mL. 
 Blood samples of 10 mL will be taken for biomarker assessment before the 
treatment on C1D1, C3D1, and C5D1.  
 You will have CT scans (with oral/IV contrast unless contraindicated) or MRI 
every 6 weeks during-chemotherapy period, that would happen around on 
C3D1 and C5D1. You may have additional CT scans if you study doctor 
thinks it necessary. 
 You will be asked about any new disease or discomfort you have experienced, 
as well as any medications you have used since last visit. 
 The Study Drug or placebo will be given via IV infusion. Gemcitabine and 
cisplatin will be given via IV infusion on the same day.  
During the visits on Day 8 of each cycle in this period, you need to have 
assessments/procedures as follows: 
 The study doctor will assess your performance status. 
 You will be assessed for vital signs, including body temperature, pulse, blood 
pressure, and respiratory rate. 
 12-lead ECG and echocardiogram will be performed if your study doctor 
thinks it necessary. 
 Blood samples will be taken within 3 days before the treatment for laboratory 
tests including CBC and blood chemistry. Blood coagulation test will be 
performed if your study doctor thinks it necessary. The volume of the blood 
samples will be around 7-9 mL at each visit. 
 You will be asked about any new disease or discomfort you have experienced, 
as well as any medications you have used since last visit. 
 Gemcitabine will be given via IV infusion.  
 
Post-Chemotherapy Period (starting from Cycle 7 to a maximum of 2 years) 
At subsequent treatment cycles, you will return to the study center for visits on Day 1 of 
each cycle, and you need to have assessments/procedures as follows: 
 You will be asked to complete questionnaires about your life and health.  

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 You will be assessed for vital signs, including body temperature, pulse, blood 
pressure, and respiratory rate. 
 You will have a limited physical examination. 
 The study doctor will assess your performance status. 
 12-lead ECG and echocardiogram will be performed if your study doctor 
thinks it necessary. 
 A urine sample of 10 mL will be collected for urinary routine analysis. If you 
are a woman who is able to become pregnant/have children, a urine sample of 
5 mL will also be collected for a pregnancy test. Samples must be collected 
within 3 days prior to the treatment. 
 Blood samples will be taken within 3 days prior to the treatment for laboratory 
tests, including CBC, blood chemistry, and thyroid function. Blood 
coagulation test will be performed if your study doctor thinks it necessary. If 
your urine pregnancy test is positive, a blood sample will be collected for a 
further pregnancy test. The volume of the blood samples is around 12-16 mL 
at each visit. 
 Blood samples of 3 mL will be taken for EBV test before the treatment every 
2 cycles for 12 months following C1D1, and then every 3 cycles thereafter 
until initial disease progression. 
 Blood samples of 3 mL will be taken for ADA and JS001 concentration 
assessment before the treatment every 4 cycles for the first year following 
C1D1, and then every 8 cycles thereafter until discontinuation of study drug.  
 Blood samples of 10 mL will be taken for biomarker assessment before the 
treatment every 2 cycles for the first year following C1D1, and then every 
6 cycles thereafter until initial disease progression. 
 You will have CT scans (with oral/IV contrast unless contraindicated) or MRI 
every 6 weeks (approximately every 2 cycles) for 12 months following C1D1, 
and then every 9 weeks (approximately every 3 cycles) thereafter. You may 
have additional CT scans if your study doctor thinks it necessary. 
 You will be asked about any new disease or discomfort you have experienced, 
as well as any medications you have used since last visit. 
 The Study Drug or placebo will be given via IV infusion. 
Treatment Discontinuation/Completion Visit 
At 30 days after the last dose of the Study Drug, you will attend a treatment 
discontinuation/completion visit and have assessments/procedures including: 

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 You will be assessed for vital signs, including body temperature, pulse, blood 
pressure, and respiratory rate. 
 You will have a limited physical examination, including body weight 
measurement. 
 The study doctor will assess your performance status. 
 12-lead ECG and echocardiogram will be performed if your study doctor 
thinks it necessary. 
 A urine sample of 10 mL will be collected for urinary routine analysis. If you 
are a woman who is able to become pregnant/have children, a urine sample of 
5 mL will also be collected for a pregnancy test. 
 Blood samples will be taken for laboratory tests, including CBC, blood 
chemistry, and thyroid function. Blood coagulation test will be performed if 
your study doctor thinks it necessary. If your urine pregnancy test is positive, a 
blood sample will be collected for a further pregnancy test. The volume of the 
blood samples is around 12-16 mL. 
 Blood samples of 3 mL will be taken for EBV assessment at the time of initial 
disease progression.  
 Blood samples of 3 mL will be taken for ADA and JS001 concentration 
assessment at the time of study drug discontinuation. 
 Blood samples of 10 mL will be taken for biomarker assessment at the time of 
initial disease progression. 
 You will be asked about any new disease or discomfort you have experienced, 
as well as any medications you have used since last visit. 
Survival Follow-Up Period 
During this period, you will have a visit every 3 months after treatment discontinuation. 
Required follow-up information will be collected via telephone calls and/or study center 
visits. You will be asked about any new disease or discomfort you have experienced since 
your last call/visit.  
If you discontinued from the study treatment before disease progression and did not start 
any new anti-cancer therapy, you are advised to continue the CT scans or MRI for 
following the disease progression per the frequency (every 6 weeks for 1 year following 
C1D1, and then every 9 weeks thereafter) of the study.  
 

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Unplanned Visit 
If your study doctor believes that you should have extra visit(s) for your safety, e.g., if 
you have a new symptom or side effect, you may be asked to come for an extra visit. The 
procedures you may have include but not limited to: 
 You will be assessed for vital signs, including body temperature, pulse, blood 
pressure, and respiratory rate. 
 The study doctor will assess your performance status. 
 12-lead ECG and echocardiogram will be performed if your study doctor 
thinks it necessary. 
 You will be asked about any new disease or discomfort you have experienced, 
as well as any medications you have used since last visit. 
 You will have other assessments if your study doctor thinks them necessary. 
 
Initial Radiographic Disease Progression 
While receiving treatment in the study, your study doctor may find that your tumor has 
started to grow again. It has been shown in other similar investigational studies that in a 
small number of study participants, there is evidence that although the cancer has 
appeared to have worsened (that is, the tumors appear to have got bigger on the scan), the 
study drug is actually working. This is called “pseudo-progression”, which happens 
because immune cells activated by the study drug are starting to infiltrate the cancer and 
attack the cancer cells. This makes the tumor more swollen and so it appears larger on the 
scan. 
If the Sponsor medical monitor or designee and your study doctor evaluate that you will 
benefit from continuing the treatment and certain criteria are fully met, you will have the 
option to continue Study Drug (Toripalimab or placebo) treatment. In this case, you will 
continue to have all the same visits and assessments as detailed above. However, you 
must permanently discontinue Study Drug treatment when you experience second 
progression. 
Continuing study drug treatment after tumor progression is not a common standard 
procedure; you can also choose other alternative treatments, such as other approved drugs 
for the treatment of cancer or other clinical studies. You should discuss treatment options 
with your study doctor. If after discussion, you, your study doctor, and Sponsor medical 
monitor consider that continuing Study Drug treatment is the best choice, then you need 
to sign the signature page "Treatment Through Progression Consent Form", to show that 
you agree to continue Study Drug/placebo treatment and you are willing to undertake 
subsequent visits in accordance with the above procedure. 

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Optional Tumor Biopsy 
The optional tumor biopsy is performed for the optional biomarker research to find out 
why the tumor grows bigger (pseudo-progression, tumor immune infiltration, or true 
disease progression). The tumor sample will be collected within 40 days of radiographic 
progression or before start of the next anti-cancer treatment, whichever is sooner. If you 
are willing to have the optional tumor biopsy for the optional biomarker research, you 
need to sign a separate form "Biomarker Research Informed Consent Form". 
 
Optional Exploratory Biomarker Assay 
If there are remaining blood samples from the mandatory analysis, and you agree to 
donate these remaining blood samples for the exploratory biomarker assay, tests of 
biomarkers in your remaining blood samples (plasma, serum, and whole blood) will be 
done. The biomarkers to be tested may include but may not be limited to DNA, RNA, and 
other molecules. Cells in your body contain a type of molecule called deoxyribonucleic 
acid, or DNA for short. DNA is what your genes are made of. Genes are inherited and 
direct growth, development, and how the body functions. There are many differences, or 
variations, in DNA from one person to another. These variations may affect a person’s 
chance of suffering from a particular disease or the way a person responds to a particular 
drug. A gene is used to make RNA, which provides instructions for cell function and 
helps determine the characteristics of people. It is up to you whether to donate your 
remaining blood samples or not. You may refuse to donate the remaining blood samples at 
any time without penalty or loss of benefits to which you are otherwise entitled. You will 
receive the same treatment and care in the study whether or not you agree to donate the 
remaining blood samples for the exploratory biomarker assay. You should be aware that 
the Sponsor might not conduct all exploratory biomarker assays immediately and that 
your samples may be studied at any time before they are destroyed. If you are willing to 
donate your remaining blood samples, you should check the corresponding boxes on the 
signature page of this form at the time of informed consent. 
 
Blood Tests 
All your test results are private and will be made known only as required by law. 
Blood and urine samples will be taken for laboratory tests. Blood volumes for each test 
are listed in Table 1Table 1Table 1. The tests that will be done will include standard tests 
of your general health, tests of viral infections, tests of biomarkers, and a test of the drug 
antibody in your blood. If you are a woman who is able to become pregnant/have 
children, there will also be a blood pregnancy test at screening visit.  

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Table 1: Blood Volumes 
Assessment 
Visit 
 
Screening 
During 
Chemotherapy 
Period (Day 1 
of each cycle) 
During 
Chemotherapy 
Period (Day 8 
of each cycle) 
Post 
Chemotherapy 
Period (Day 1 
of each cycle) 
Treatment 
Discontinuatio
n/Completion 
Visit 
CBC 
2 mL 
2 mL, not on 
C1D1 
2 mL 
2 mL 
2 mL 
Blood 
chemistry 
3-5 mL 
3-5 mL, not on 
C1D1 
3-5 mL 
3-5 mL 
3-5 mL 
Thyroid 
function 
3-5 mL 
3-5 mL, not on 
C1D1 
NA 
3-5 mL 
3-5 mL 
Coagulation 
parameters 
2 mL 
2 mL, if 
needed, not on 
C1D1 
2 mL, if needed 
2 mL, if needed 
2 mL, if needed 
Testing for 
viral infections 
such as HBV, 
HCV and HIV 
3 mL 
NA 
NA 
NA 
NA 
Testing for 
EBV 
NA 
3 mL,C1D1, 
C3D1 and 
C5D1 only 
NA 
3 mLa 
3mld 
Testing for 
HBV DNA 
3 mL, if needed 
NA 
NA 
NA 
NA 
Testing for 
HCV RNA 
3 mL, if needed 
NA 
NA 
NA 
NA 
Blood 
pregnancy 
2 mL 
2 mL, if 
needed, not on 
C1D1 
NA 
2 mL, if needed 
2 mL, if needed 
Testing for 
ADA and 
JS001 
concentration 
NA 
3 mL, C1D1 
and C5D1 only 
NA 
3 mLb 
3 mLe 
Testing for 
biomarker 
assessment 
NA 
10 mL, C1D1, 
C3D1, and 
C5D1 only 
NA 
10 mLc 
10 mLd 
a: every 2 cycles for 12 months following C1D1, and then every 3 cycles thereafter 
b: every 4 cycles for the first year following C1D1, and then every 8 cycles thereafter 
c: every 2 cycles for the first year following C1D1, and then every 6 cycles thereafter 

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d:at the time of initial disease progression 
e:at the time of study drug discontinuation 
ADA=anti-drug antibodies; C=cycle; D=day; DNA=deoxyribonucleic acid; 
EBV=Epstein-Barr virus; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; NA=not applicable; RNA=ribonucleic acid 
 
Your blood samples and tumor tissue samples collected in the main study will be stored 
by the Sponsor with similar samples from other patients at secure central laboratories and 
at the Sponsor’s facilities, which have experience in storing and analysing such samples. 
These laboratories may be located outside of the countries in which the study is 
conducted.The remaining ADA、EBV and biomarker samples will be destroyed per the 
central labs’ SOP before study completion if there are any remains after completing the 
study required testing. 
7 WHAT WILL I HAVE TO DO DURING THE STUDY? 
If you decide to take part in this study, during the study period your responsibility is to 
closely cooperate with the study doctor's work, and strictly abide by the following: 
 You will be firstly asked to sign this consent form if you agree to take part in this 
study. If you take part in this study, you should follow the study procedures and go 
to all the study visits. You should report any changes to your well-being, including 
any side-effects, to the study doctor. 
 You will be expected to attend all visits listed in the study schedule and any others 
that may be deemed necessary. Please inform the study doctor if you will not be 
able to go to a visit. 
 You cannot take any other therapy intended for the treatment of cancer, no matter 
it is health authority approved or experimental. This includes but is not limited to 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy. 
 You should not be taking the following medications: 
 Traditional herbal medicines. 
 Denosumab; if you are receiving denosumab before entering the study, you 
must be willing and eligible to receive a bisphosphonate instead, while on 
study.  
 Any live, attenuated vaccine (e.g., FluMist®) within 4 weeks before 
randomization or at any time during the study. 

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 In case that CT scans with contrast are contraindicated for you, steroids 
will not be allowed before the scan. Instead, MRIs with a non-contrast CT 
scan will be performed.  
 Prophylactic granulocyte colony stimulating factor are not allowed before 
the first cycle. Thereafter, they must be administered according to your 
condition by your study doctor. 
Tell the study doctor before you start a new medication. 
 Highly effective birth control methods are required during the study and for at 
least 60 days following the last dose of the Study Drug. Birth control methods 
allowed in this study include double-barrier method and total abstinence. 
Double-barrier method, like condom with spermicidal jelly, foam, suppository, or 
film; or diaphragm with spermicide; or male condom and diaphragm, works by 
preventing the sperm from getting to and fertilizing the egg. Spermicide is 
medications placed in the vagina to kill sperm when they come in contact. 
Abstinence means abstaining from sexual intercourse/having sexual intercourse. 
You should discuss methods of effective birth control with your study doctor. 
 For women: women who may be able to have children must use a 
double-barrier method during the study and for at least 60 days following 
the last dose of the Study Drug. The same request is also applied to the 
female partners of male patients. 
 For men: male patients must use appropriate birth control methods (total 
abstinence or condom with spermicide) during the study and for at least 
60 days after the last dose of the Study Drug. 
 Strenuous exercise should be avoided up to 72 hours before planned study visits. 
 
8 WHAT ARE THE POSSIBLE RISKS? 
The risks of side effects, complications, and/or injuries are both predictable and 
unpredictable in all research studies. In rare cases, certain risks can lead to serious injury 
or even death. It is important to note that it is not possible to predict all the side effects 
that may occur when you are given the study drug. New side effects not described in this 
ICF may occur in this study. If you experience any discomfort or deterioration of health 
during the study period, please notify your study doctor immediately, who will make a 
medical judgment regarding your condition and give you appropriate management and 
treatment. 
 

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Treatment-related side effects have been observed in clinical trials with 
Toripalimab (JS001) monotherapy  
The side effects of the Study Drug on humans are not yet fully known. As of 16 Dec 
2019, the clinical database contained preliminary safety data from 985 patients who 
received JS001 across multiple tumor types.  
Adverse reactions observed in subjects who received JS001 monotherapy in clinical trials 
are presented as below: 
 Very common: may affect more than 1 in 10 people (≥10%) 
 Anemia(reduction of red blood cell number or hemoglobin level),  
 Rash,  
 Coughing,  
 Pruritus (itching), 
 Asthenia (weak), 
 Fever,  
 Decreased appetite,  
 Hypothyroidism (a decreased release of the thyroid hormone, which may 
result in tiredness, sluggishness, feeling cold or weight gain), 
 Musculoskeletal pain,  
 Leukopenia(white blood count decreased),  
 Hyperglycemia(high level of blood sugar),  
 ALT increased(elevation of liver enzyme),  
 AST increased(elevation of liver enzyme),  
 Thyroid stimulating hormone increased,  
 Proteinuria (presence of protein in the urine). 
 
Common: may affect up to 1 in 10 people (≥1% and <10%) 
 Platelet count decreased, 
 Headache,  
 Dizziness,  
 Hyperthyroidism(an increased release of thyroid hormone that may result 
in intolerance of heat, weight loss, weakness, palpitations, anxiety, heart 
rhythm abnormalities or heart failure),  
 Dyspnea (difficulty in breathing),  

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 Abdominal pain,  
 Vomiting,  
 Lung infection),  
 Hepatic function abnormalities, 
 Interstitial lung disease,  
 Skin depigmentation (absence or loss of pigmentation in the skin),  
 Upper respiratory tract infection, 
 Urinary tract infection,  
 Lymphocytopenia (lymphocyte count decreased),  
 Neutropenia (neutrophil count decreased),  
 Infusion-related reactions， 
 Hyponatremia(low blood sodium),  
 Hypokalemia(low blood potassium ),  
 Hypocalcemia (low blood calcium),  
 Insomnia(trouble falling and/or staying asleep)， 
 Peripheral neuropathy(damage to the nerves outside of the brain and spinal 
cord),  
 Blurred vision,  
 Tachycardia(abnormally fast heart rate),  
 Hypertension(high blood pressure),  
 Constipation(difficulty passing stools),  
 Nausea,    
 Diarrhoea(frequent loose, watery stools),  
 Stomatitis (inflammation of oral cavity),  
 Dermatitis (inflammation of skin),  
 Influenza-like illness,  
 Peripheral oedema(swelling of legs or hands),  
 Chest pain,  
 Alkaline phosphatase (ALP) increased(elevation of enzyme, related with 
liver and/or bone),  
 Blood bilirubin increased(abnormal testing related with liver function),  
 Blood creatinine increased(abnormal testing related with kidney function),  

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 Amylase increased(elevation of enzyme, related with pancreas),  
 Lipase increased(elevation of enzyme, related with pancreas),  
 Creatine phosphatase kinase (CPK) increased(elevation of enzyme, related 
with muscles). 
Uncommon: may affect up to 1 in 100 people (≥0.1% and <1%) 
 Pancreatitis (inflammation of the pancreas),   
 Diabetes mellitus(increase in blood sugar),  
 Adrenal insufficiency,  
 Hypersensitivity,  
 Thyroiditis(inflammation of the thyroid),  
 Hypophysitis(inflammation of pituitary gland), 
 Hypopituitarism(decreased function of pituitary),  
 Hepatitis(inflammation of the liver),  
 Liver injury,  
 Dysgeusia(dysfunction of the taste),  
 Uveitis(inflammation of the eyes),  
 Xerophthalmia(abnormal dryness of the eyes),  
 Pericardial effusion(accumulation of fluid around the heart),  
 Myocarditis (inflammation of the heart muscles )  
 Pleural effusion(accumulation of fluid inside the chest),  
 Pleurisy(inflammation of the pleural),  
 Gastritis(inflammation of the stomach),  
 Enteritis(Inflammation of the intestine),  
 Gastroenteritis (Inflammation of the stomach and intestine), 
 Myositis(inflammation of the muscles),  
 Arthritis(inflammation of the joints),  
 Renal injury,  
 Troponin increased(elevation of the blood protein related to heart 
muscles),  
 Cortisol decreased(decreased hormone, related with the function of the 
endocrine glands located on the top of kidney). 

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Immune-related Side Effects for the Study Drug 
Since JS001 is recombinant humanized monoclonal antibody, the use of such drugs may 
cause associated side effects including systemic anaphylaxis, infusion reactions, and 
immune-related side effects. Some immune-related side effects may also be delayed, in 
which discomfort or abnormalities in laboratory tests occur long after administration. 
Systemic allergic reactions: it may cause the following symptoms: swelling of the face, 
lips, and throat, dyspnea, and urticaria or urticaria-like rash. If you experience any of 
these symptoms above, you should notify your study doctor immediately. 
Infusion reactions: it may occur during or after infusion of the study drug. These reactions 
may include fever or chills, changes in blood pressure, or dyspnea (which may be a 
serious event).If you experience any of these symptoms above, please inform your study 
doctor immediately. 
The following immune-related side effects were observed, and the incidence data were 
obtained from a summary of safety information of 741 patients receiving the 
recommended therapeutic dose of JS001 in 9 single-arm studies: 
•Immune-related pneumonitis (non-infectious lung inflammation, 1.8%): symptoms 
include, but are not limited to, the onset of cough or worsening cough, shortness of breath, 
and possibly fever. If you experience any of the above symptoms, please inform your study 
doctor immediately. 
• Immune-related hepatitis (6.3%): liver function laboratory indicators, such as 
transaminase and bilirubin (the results of blood tests), are abnormal. The clinical 
manifestations of hepatitis may be yellowing of the skin or the whites of the eyes, fatigue, 
nausea and vomiting, right epigastric pain, itchy skin, and more bleeding and abrasions 
than normal. The study doctor will regularly assess your liver function laboratory 
indicators, and if your indicators are above certain criteria, your study doctor may need to 
stop the study drug. 
• Hypothyroidism (13.6%): symptoms occur when the thyroid produces fewer thyroid 
hormones than normal, resulting in excessively slow metabolism. Symptoms include, but 
are not limited to, fatigue, increased cold sensitivity, constipation, dry skin, unexplained 
weight gain, facial swelling, muscle weakness, decreased heart rate, hair loss, and 
impaired memory. The condition can be treated with replacement thyroid hormones. 
• Hyperthyroidism (4.7%): symptoms are due to excessive production of thyroid 
hormones by the thyroid gland. Symptoms include anxiety or nervousness, weight loss, 
increased and loose bowel movements, difficulty breathing, increased heat sensitivity, and 
possible heart palpitations. Depending on the severity of the symptoms, treatment may 
include monitoring the symptoms only, treating the symptoms and/or administering 
medication to block thyroid hormones. 

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• Immune-related diarrhea and colitis (0.9%): presenting with abdominal pain, diarrhea 
(loose bowels), possibly accompanied by fever. 
• Immune-related skin toxicity (8.1%): rash (3.5%), depigmentation of skin (3.1%), itchy 
skin (2.0%). 
• Immune-related pancreatitis (3.1%): persistent upper abdominal pain (sometimes 
worsened by diet), nausea, vomiting, and fatigue. You may have increases in laboratory 
tests  for lipase and amylase. If you experience any of the above symptoms, you should 
notify your study doctor immediately. 
• Immune-related hyperglycemia and diabetes (0.3%): increased blood glucose with 
weight loss, increased urination, increased thirst, and increased hunger. Immune-related 
diabetes requires insulin injections. If you experience any of the above symptoms, please 
inform your study doctor immediately. 
• Immune-related hypophysitis (0.2%): hypophysitis is a decrease in the amount of 
hormones secreted by the pituitary gland in the brain. Symptoms include headache, thirst, 
visual impairment or double vision, breast milk leakage or irregular menstruation in 
women. 
• Immune-related adrenocortical dysfunction (0.5%): may cause abdominal pain, 
vomiting, muscle weakness, fatigue, depression, hypotension, weight loss, kidney 
problems, and the changes in mood and personality. 
• Immune-related myocarditis (0.4%): symptoms may include chest pain, tachycardia or 
arrhythmia, shortness of breath, and swelling of the legs. If you develop these symptoms, 
please inform your study doctor immediately. 
• Immune-related myositis (0.1%): symptoms may include muscle weakness, pain, and 
swelling. If you develop these symptoms, please inform your study doctor immediately. 
 
Other Potential Immune-Related Adverse Reactions 
Some immune-related side effects have not been identified in JS001 clinical trials but 
were observed in other similar marketed medicines. If you develop below symptoms, 
inform your study doctor immediately. 
• Immune-related neurological side effects: Inflammation of the brain which may include 
headache, confusion, fever, memory problems or seizures. Rare symptoms of nervous 
system inflammation may include weakness in the legs, arms or face, numbness or 
tingling in the hands and feet. In very rare cases, inflammation of the nervous system can 
be severe, which may manifest as dysphagia, weakness and dyspnea in a short period of 
time.  
• Immune-related nephritis: Inflammation of the kidneys which may include abnormal 
kidney function tests, changes in the amount or color of your urine. 

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• Immune-related eye toxicity: Inflammation of the eyes which may include changes in 
eyesight, eye pain or redness. 
• Immune-related osteoarthritis: Symptoms which may include joint pain, joint swelling, 
joint effusion, and limited joint motion. 
If there are suspected immune-related adverse reactions, the investigators may order 
diagnostic tests to understand the immune response and confirm the diagnosis. If your 
symptoms are found to be due to immune related adverse reactions, the investigators will 
give you treatment, which may include oral or intravenous dose of corticosteroids or 
immunosuppressants according to the specific situation and severity. Even though 
thesymptoms have resolved, the dose of corticosteroids needs to be reduced slowly to 
maintain its therapeutic effect and avoid recurrence or worsening of the symptoms. 
 
Side Effects for Gemcitabine 
 Pulmonary toxicity (to be poisonous to the lung), 
 Myelosuppression including neutropenia, thrombocytopenia (low level of blood 
platelet), and anemia, 
 Haemolytic-uremic syndrome (an acute illness related to the renal function) and/or 
renal failure, 
 Serious hepatotoxicity (to be poisonous to the liver), including liver failure and 
death. 
For more details regarding the safety information of gemcitabine, see the appropriated 
Package Insert. 
Side Effects for Cisplatin 
 Myelosuppression, 
 Ototoxicity (to be poisonous to the ear), 
 Nephrotoxicity (to be poisonous to the kidney). 
For more details regarding the safety information of cisplatin, see the appropriated 
Package Insert. 
Other Risks and Possible Discomfort 
 Blood samples will be taken from a vein in your arm during the study. The taking 
of a blood sample may cause some discomfort and bruising, and there is a 
potential for infection. Other risks, although rare, include nerve damage, dizziness 
and fainting. 
 You will have ECG during the study. Small sticky pads will be stuck to your chest, 
arms, and legs, and a machine will measure the electrical activity of your heart. 

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We may need to clip small patches of your hair in these areas. These sticky pads 
may cause some local irritation and may be uncomfortable to remove. 
 Blood pressure and heart rate will be measured during the study. An inflatable cuff 
will be placed on your arm and a machine will measure your blood pressure and 
heart rate, after you have been sitting down for 10 minutes. You may experience 
mild discomfort in your arm while the cuff is inflated. 
 A MRI scan is painless and will not expose you to X-ray radiation. A CT scan is a 
type of X-ray. Before these scans, a contrast medium may be injected into one of 
your veins. A contrast medium is like a dye that will spread through your body and 
will help give clearer images. The injection of contrast medium may cause some 
discomfort and bruising. There is a risk of potentially serious allergic reactions in 
some people who receive contrast medium. Some people may feel frightened by 
the cramped space inside the machine or by the loud, repeated sounds the machine 
makes. The greatest risk of having an MRI is the chance of metal objects flying 
through the air toward the magnet and hitting you. To reduce this risk, all people 
getting the MRI scan will be asked to remove all metal from their clothing and all 
metal objects from their pockets. Please inform the study doctor if you have metal 
in your body from an operation, since you may not be able to have a MRI scan. 
Also, if you have a pacemaker you should not have a MRI scan. 
 You may have tumor sampling during the study in order to collect more 
information about your disease. During the sampling, you may experience minor 
local bleeding, pain at the needle site, redness at the needle site, swelling under 
the skin that contains blood (hematoma), and sleepiness if you choose to receive a 
"pain killer" and/or medicine to help you relax. Rare but serious reactions include 
infection; shortness of breath, slow heart rate, and low blood pressure if you 
choose to receive a "pain killer" and/or medicine to help you relax. 
 A heparin/saline lock may be placed in a vein for Study Drug administration 
during the site visits. The risks of a heparin/saline lock include pain, bruising, 
clotting, bleeding and possible infection at the site of the heparin/saline lock 
placement. Saline (salt water solution) or heparin may be used to flush the 
heparin/saline lock to prevent clots from forming in the catheter. 
Pregnancy and Breast-feeding 
If you are or become pregnant, or if your partner becomes pregnant, there may be 
unknown risks to the baby. If you are a woman who may be able to have children, you 
will be given a pregnancy test at screening, and if the result is positive, you will not be 
able to be in the study. If you are a sexually-active man or woman, you must use an 
accepted form of birth control throughout the study and for at least 60 days after the last 
dose of the Study Drug. Acceptable birth control methods include double barrier method 

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and total abstinence. The study doctor will discuss methods of effective birth control with 
you if needed. If you become pregnant or think you may be pregnant during the study or 
within 60 days after the last dose of the Study Drug, stop using the Study Drug and 
contact the study doctor’s office immediately. You may be asked to withdraw from the 
study. You must not be breast-feeding an infant during the study. If your partner becomes 
pregnant or thinks she may be pregnant during the study or within 60 days after the last 
dose of the Study Drug, contact the study doctor’s office immediately.  
The study doctor must follow up and keep a record of the course and the outcome of all 
pregnancies, even if you withdraw from the study or if the study has finished. If you or 
your partner becomes pregnant during the study, the study doctor or his/her staff will 
contact you/your partner and your/your partner’s doctor for information about the 
pregnancy until clear pregnancy outcome.  
 
9 WHAT ARE THE POSSIBLE BENEFITS? 
We hope that the Study Drug will help your condition. Also, you might benefit from the 
chemotherapy (gemcitabine and cisplatin) for your disease. However, you may not get 
any direct benefit from taking part in this study. You will be given close attention from the 
study staff during the time you are involved in the study. You may get information about 
your health from physical examinations and medical tests done in this study. 
This study will provide information about the safety and efficacy of the Study Drug, as 
well as the medical knowledge of your disease. 
If the results of this study are positive and, along with extra studies, lead to approval by 
the regulatory authorities of China for use in humans, there may be benefits for patients in 
the future. These benefits may include improvement for the future treatment of people 
with recurrent or metastatic nasopharyngeal cancer, and profound understanding of the 
disease.  
 
10 ARE THERE ALTERNATIVE TREATMENTS? 
You do not have to be in this study to get treatment for your nasopharyngeal cancer. Other 
treatments include chemotherapy, targeted therapy, or radiation therapy. Other 
experimental treatments may also be available. You can discuss your treatment options 
with your doctor. 
 

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11 WILL I INCUR ANY EXPENSES OR RECEIVE ANY 
PAYMENTS? 
There will be no cost to you or your insurance company for the study medication or the 
study-related procedures and examinations. 
You will not be paid for your participation in this study. You may have some expenses 
from being in the study, such as bus fare or parking fees when you visit the study center. 
You will be paid 100 CNY per visit for these expenses. 
The Sponsor is paying the study doctor and/or (name of Institution or site) for their work 
in this study. 
 
12 WHAT IF I AM INJURED DURING THE STUDY? 
If you experience any unexpected symptoms or injury, and if emergency medical 
treatment is required, please report it immediately to: 
_______________________________ (Site to insert contact name and number). 
If you have a physical injury or illness directly related to the study medication or study 
procedure which was properly performed in accordance with the protocol (referred to as a 
study-related injury), medical treatment will be provided to you. You will not be charged 
for this treatment. The Sponsor will cover the cost of reasonable and necessary medical 
treatment for a study-related injury and has insurance to cover the study-related injury 
Study-related injuries do not include injuries that result from your own fault or intention. 
Additionally, payment for such things as lost wages, expenses other than medical care, or 
pain and suffering is not available.  
 
13 WHAT WILL HAPPEN IF THERE IS ANY NEW INFORMATION? 
If any new information becomes available which may influence your decision to stay in 
the study, you will be told in a timely manner. 
 
14 WILL INFORMATION ABOUT ME BE KEPT CONFIDENTIAL? 
By signing this form you consent to the study doctor and his or her staff collecting and 
using your personal data for the study. This includes: your age, sex, your ethnic origin, 
and information on your physical or mental health or condition.  
The information shared with the Sponsor is protected by the use of a code, which is a 
number specifically assigned to you. The study doctor is in charge of the code needed to 
connect your data to you. 
All medical records and research materials that identify you by name will be held 
confidential (confidential data) as permitted by law. However the study doctor, the 

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Sponsor and its representatives, the study monitor (who checks how the study is going 
and makes sure that the information is being collected properly) and, under certain 
circumstances, the regulatory authorities and ethics committees will be able to inspect 
confidential data that identify you by name.  
All personal data from this study will be treated in accordance with national and local 
data protection laws. 
By signing this consent form, you grant permission for medical information about you 
obtained during this study (your study data) to be made available to authorized 
representatives of the regulatory authorities and other government agencies. You also 
grant permission for your study data to be made available to the Sponsor, the study 
monitor, other study personnel, and ethics committees. The Sponsor may transfer your 
study data to countries outside of <<country, and if applicable the European Union 
(EU)>> for the purposes described in this document. Please be aware that the laws in 
such countries may not provide the same level of data protection as in <<country>> and 
may not stop your study data from being shared with others. The study doctor, the 
regulatory authorities, and the Sponsor may keep the study data indefinitely. 
You have the right to request information about your study data held by the study doctor 
and the Sponsor. You also have the right to request that any inaccuracies in such data be 
corrected. If you wish to make a request, then please contact the study doctor, who can 
help you contact the Sponsor . 
Your consent for the use of your study data as described above does not have an 
expiration date. If you withdraw your consent for participating in this study, your study 
data that were collected before you withdrew your consent may still be used as described 
above. Once you have withdrawn your consent for participating in the study, no further 
data will be collected about you for the purposes of this study unless you agree otherwise, 
for example, you agree to have further tests and examinations. If you do agree to have 
further data collected after you have withdrawn your consent, these study data may also 
be used as described above. 
The results of this study may be published in a medical journal and shown at medical 
meetings. You will not be identified (by name or any other means, e.g., photo) in any of 
these publications. 
(For trials in China, include: A description of this clinical trial will be available on 
www.chinadrugtrials.org.cn. This Web site will not include information that can identify 
you. At most, the Web site will include a summary of the results. You can search this Web 
site at any time. 
For applicable clinical trials under a US Investigational New Drug (IND) application [or 
other FDA regulations] which are initiated on or after 07 March 2012, the following text 
is mandatory according to US CFR 50.25(c): “A description of this clinical trial will be 

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available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will 
not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. (delete as applicable for 
countries not under US IND or other FDA regulations).”  
For applicable clinical trials that are conducted in the EU and the European Economic 
Area (EEA) or Clinical trials conducted outside the EU / EEA that are part of an EU 
Paediatric Investigation Plan (PIP), include: “A description of this clinical trial will be 
available through the public website https://www.clinicaltrialsregister.eu. This website 
will include information on the trial and summary of the results, but will not include any 
information that can identify you. You can search this web site at any time.”) 
 
15 WHAT IF I HAVE QUESTIONS? 
If you have questions about the study, or have a problem related to the study, you may 
contact the study doctor or his/her staff at the telephone number below. 
 
Name:_______________________________Telephone: (_____)  ________________ 
 
If you are calling after hours or on a weekend, you may contact the individual below. 
 
Name:_______________________________Telephone: (_____)  ________________ 
 
If you have questions about your rights as a research participant, you should contact the 
individual below. 
(Note:  Insert name of IRB/IEC chairperson and/or name of IRB/IEC, address, and 
telephone number.) 
 
Name:_______________________________Telephone: (_____)  ________________ 
Address: ______________________________________________________________ 
 
16 CONSENT STATEMENT OF PATIENT 
I have received verbal information on the above study and have read the attached written 
information. I have been given the chance to discuss the study and ask questions. 
I voluntarily consent to participate in this study, including all assessments, lifestyle 
restrictions, birth control requirements, and taking of blood samples.  

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I consent to the remaining blood samples from the main study, which I will donate, being 
used as indicated in the text, and according to the options I have initialed/signed below: 
 
If my blood sample remains after mandatory analysis, I 
agree to donate the remaining blood samples from the main 
study to be used for exploratory biomarker assay related to 
my nasopharyngeal cancer and/or its treatment 
 
 
 
Yes 
No 
Initials of 
Patient 
 
 
I understand that I am free to withdraw at any time. I understand that if I choose to not 
participate or choose to withdraw, my current medical care will not be affected by this 
decision. 
I agree that my primary doctor may be told of my participation in this study.  
I agree that my primary doctor may be asked to give information about my medical 
history. 
I agree that my personal data, including data relating to my physical or mental health or 
condition, and ethnic origin, may be used as described in this consent form. 
I understand that I will get and may keep a copy of this signed and dated consent form. 
By signing and dating this consent form, I have not given up any of the legal rights that I 
would have if I were not a participant in a medical research study. 
 
 
 
 
AM/PM  
Signature of Patient 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of Patient 
 
 
 
 
AM/PM  
Signature of Witness 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of 
Witness 
 
 
 
AM/PM  
Signature of Legally 
Acceptable Representative 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of 
Legally Acceptable 
Representative 
The relationship between the Patient and the 
Legally Acceptable Representative: 
 
 
 

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17 STATEMENT OF PERSON CONDUCTING INFORMED 
CONSENT DISCUSSION 
I, the undersigned, certify that to the best of my knowledge, the patient signing this 
consent form had the study fully and carefully explained and clearly understands the 
nature, risks, and benefits of participation in this research study. 
 
 
 
 
AM/PM  
Signature of Investigator 
(or other Person Obtaining 
Consent) 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of Person 
Obtaining Consent 
 
 
 

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Only needs when treatment is continued after disease progress  
 
Treatment Through Progression Consent Form 
 
 I have read the information regarding “Initial Radiographic Disease Progression” 
of this Informed Consent Form. I have received answers to all of my questions 
about this study. 
 I agree to receive continued study treatment and follow-up on time in the study 
and to receive the appropriate examinations. I will comply with the requirements 
of the study, and fully cooperate with the study doctor, truthfully and objectively 
provide information about my health and related conditions before participating in 
the study, during the study, and in the follow-up period to study personnel. 
 I also understand that I can withdraw from the study at any time, which will not 
have any negative effects on my subsequent treatment. I understand that the 
Sponsor and my study doctor have the right to terminate the study at any time in 
my circumstances. 
 I freely agree to participate in this research study as described and understand that 
I am free to withdraw at any time during the research study without affecting my 
future health care.  
 I agree to inform my primary doctor that I have participated in the study.  
 I understand that I will receive a signed copy of this consent form. 
 I agree that my medical health data collected as part of this medical research study 
can be used and published. 
 After full consideration, I volunteer to participate in the clinical study and to 
maintain full cooperation with study doctor. 
 
 

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CONSENT STATEMENT OF PATIENT 
 
 
 
 
AM/PM  
Signature of Patient 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of Patient 
 
 
 
 
AM/PM  
Signature of Witness 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of 
Witness 
 
 
 
AM/PM  
Signature of Legally 
Acceptable Representative 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of 
Legally Acceptable 
Representative 
The relationship between the Patient and the 
Legally Acceptable Representative: 
 
 
 
 
STATEMENT OF PERSON CONDUCTING INFORMED CONSENT DISCUSSION 
 
I, the undersigned, certify that to the best of my knowledge, the patient signing this 
consent form had the study fully and carefully explained and clearly understands the 
nature, risks, and benefits of participation in this research study. 
 
 
 
 
AM/PM  
Signature of Investigator 
(or other Person Obtaining 
Consent) 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of Person 
Obtaining Consent 
 

Shanghai Junshi Biosciences Co., Ltd. 
 
JS001-015-III-NPC 
Statistical Analysis Plan 
 
TP-GDO-WW-016-06 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  28 Jun 17 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 1 of 62 
 
 PAREXEL International 
Shanghai Junshi Biosciences Co., Ltd. 
JS001-015-III-NPC 
A Phase III, Randomized, Placebo-Controlled, Multicenter, Double-Blind Study 
Comparing Toripalimab Injection (JS001) Combined with Chemotherapy versus Placebo 
Combined with Chemotherapy for Recurrent or Metastatic Nasopharyngeal Cancer 
Statistical Analysis Plan 
PAREXEL Project Number: 237456 
 
 

Shanghai Junshi Biosciences Co., Ltd. 
 
JS001-015-III-NPC 
Statistical Analysis Plan 
 
TP-GDO-WW-016-06 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  28 Jun 17 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 2 of 62 
 
SPONSOR SIGNATURE PAGE 
 
 
 
 
Approved by:  
_________________________ 
 
_______________ 
 
Xiongwen Tang 
 
 
 
Date 
 
Director, Biostatistics 
 
 
Shanghai Junshi Biosciences Co., Ltd. 
 
 
 
 
 
 
 

Shanghai Junshi Biosciences Co., Ltd. 
 
JS001-015-III-NPC 
Statistical Analysis Plan 
 
TP-GDO-WW-016-06 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  28 Jun 17 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 3 of 62 
 
PAREXEL SIGNATURE PAGE 
 
 
Signatures below confirm that the review process has been completed in accordance with 
SOP-GDO-WW-019. 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
 
 
Signatory 
Author  
Sean Chang 
Project Role: Biostatistics Lead  

Shanghai Junshi Biosciences Co., Ltd. 
 
JS001-015-III-NPC 
Statistical Analysis Plan 
 
TP-GDO-WW-016-06 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  28 Jun 17 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 4 of 62 
TABLE OF CONTENTS 
 
1 
INTRODUCTION ....................................................................................................... 8 
2 
STUDY OBJECTIVES ............................................................................................... 8 
3 
INVESTIGATIONAL PLAN ..................................................................................... 9 
3.1 Overall Study Design and Plan ............................................................................. 9 
3.2 Efficacy and Safety Endpoints............................................................................ 15 
3.2.1 Primary Efficacy Endpoint ....................................................................... 15 
3.2.2 Secondary Efficacy Endpoints .................................................................. 15 
3.2.3 Safety Endpoints ....................................................................................... 15 
4 
STATISTICAL METHODS ..................................................................................... 15 
4.1 Data Quality Assurance ...................................................................................... 15 
4.2 General Presentation Considerations .................................................................. 15 
4.3 Study Subjects .................................................................................................... 17 
4.3.1 Disposition of Patients .............................................................................. 17 
4.3.2 Protocol Deviations ................................................................................... 18 
4.4 Analysis Populations .......................................................................................... 18 
4.4.1 Enrolled Population .................................................................................. 18 
4.4.2 Intent-to-Treat (ITT) Population ............................................................... 18 
4.4.3 Per-Protocol Analysis Set (PPS) ............................................................... 18 
4.4.4 Safety Population ...................................................................................... 18 
4.5 Demographic and Other Baseline Characteristics .............................................. 19 
4.5.1 Nasopharyngeal Carcinoma Diagnosis ..................................................... 19 
4.5.2 Previous Systemic Therapy....................................................................... 20 
4.5.3 Previous Radiation Therapy ...................................................................... 20 
4.5.4 Concomitant Radiotherapy ....................................................................... 20 
4.5.5 Previous and Concomitant Medication ..................................................... 20 
4.5.6 Previous and Concomitant Surgery .......................................................... 21 
4.5.7 Concomitant Procedure ............................................................................. 21 
4.5.8 Post Anti-Cancer Therapy......................................................................... 21 
4.6 Extent of Exposure ............................................................................................. 22 
4.7 Efficacy Evaluation ............................................................................................ 23 
4.7.1 Analysis and Data Handling ..................................................................... 23 
4.7.1.1 Adjustments for Covariates ......................................................... 23 
4.7.1.2 Handling of Dropouts or Missing Data ....................................... 23 
4.7.1.3 Multiple Comparisons/Multiplicity ............................................. 23 
4.7.1.4 Examination of Subgroups .......................................................... 24 
4.7.2 Primary Efficacy Endpoint – IRC-Assessed PFS ..................................... 24 
4.7.3 Secondary Efficacy Variables ................................................................... 25 
4.7.3.1 Investigator-Assessed PFS .......................................................... 25 
4.7.3.2 Overall Survival (OS) .................................................................. 25 
4.7.3.3 Objective Response Rate (ORR) ................................................. 25 
4.7.3.4 Duration of Response (DoR) ....................................................... 26 
4.7.3.5 Disease Control Rate (DCR) ....................................................... 26 
4.7.3.6 PFS rate at 1 and 2 years ............................................................. 26 
4.7.3.7 OS rate at 1 and 2 years ............................................................... 26 

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4.7.3.8 Patient-Reported Outcomes (PRO) ............................................. 27 
4.8 Safety Evaluation ................................................................................................ 27 
4.8.1 Adverse Events ......................................................................................... 27 
4.8.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events. 29 
4.8.3 Vital Signs and Weight ............................................................................. 30 
4.8.4 Physical Examinations .............................................................................. 31 
4.8.5 Laboratory Evaluation .............................................................................. 31 
4.8.6 12-Lead Electrocardiogram (ECG) and Echocardiogram ......................... 32 
4.8.7 ECOG Performance Status ....................................................................... 32 
4.8.8 Pregnancy Test .......................................................................................... 33 
4.9 Other Evaluation ................................................................................................. 33 
4.9.1 Sensitivity Analyses for IRC-Assessed PFS ............................................. 33 
4.9.2 PFS, ORR, DoR, and DCR per Immune-Related RECIST ...................... 33 
4.9.3 Subgroup Analyses ................................................................................... 34 
4.9.4 Immunogenicity Analysis ......................................................................... 34 
4.9.5 Biomarker Analysis .................................................................................. 34 
4.9.6 Pharmacokinetic Analysis ......................................................................... 34 
4.10 
Interim Analysis ........................................................................................ 34 
4.10.1 
IRC-Assessed PFS ............................................................................ 34 
4.10.2 
OS ..................................................................................................... 35 
4.11 
Determination of Sample Size .................................................................. 35 
4.12 
Changes in the Conduct of the Study or Planned Analysis ...................... 36 
4.12.1 
Changes Made in SAP v2.0 .............................................................. 36 
4.12.2 
Changes Made in SAP v3.0 .............................................................. 43 
5 
REFERENCES .......................................................................................................... 49 
6 
APPENDIX ............................................................................................................... 50 
6.1 Appendix A: Patient-Reported Outcomes  Scoring Conversion Rule ................ 50 
6.2 Appendix B: Grading Criteria For Clinical Laboratory Tests ............................ 53 
6.3 Appendix C: Nasopharyngeal Carcinoma Diagnosis ......................................... 55 
6.4 Appendix D ......................................................................................................... 60 
 

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LIST OF ABBREVIATIONS 
 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CBC 
Complete blood cell 
CI 
Confidence interval 
CR 
Complete response 
CT 
Computed tomography 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ENR 
Enrolled Set 
HBV 
Hepatitis B virus 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus  
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
ICF 
Informed consent form 
iDMC 
Independent Date Monitoring Committee 
INR 
International normalized ratio 
IRC 
Independent Review Committee 
irRECIST 
Immune-related Response Evaluation Criteria In Solid 
Tumors 
ITT 
Intent-to-treat 
IWRS 
Interactive Web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 

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NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria 
for Adverse Events 
NPC 
Nasopharyngeal carcinoma 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Pharmacodynamic(s) 
PD-1 
Programmed cell death-1 
PD-L1 
Programmed cell death-ligand 1 
PFS 
Progression-free survival 
PK 
pharmacokinetics 
PPS 
Per-protocol analysis set 
PR 
Partial response 
PRO 
Patient-reported outcomes 
PT 
Prothrombin time 
Q3W 
Every 3 weeks 
QoL 
Quality of life 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
Sd 
Standard deviation 
SD 
Stable disease 
ULN 
Upper limit of normal 

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1 
INTRODUCTION 
This document presents the statistical analysis plan (SAP) for Junshi Protocol: A Phase III, 
Randomized, Placebo Controlled, Multicenter, Double-Blind Study Comparing 
Toripalimab Injection (JS001 or TAB001) Combined with Chemotherapy versus Placebo 
Combined with Chemotherapy for Recurrent or Metastatic Nasopharyngeal Cancer. This 
SAP contains definitions of analysis populations, derived variables, and statistical methods 
for the analysis of efficacy and safety parameters. 
 
This SAP is based upon the following study documents: 
• Study Protocol, Version 6.0 (Oct 14, 2020) 
• Electronic Case Report Form (eCRF), Version  9.0 (Sep 11, 2020) 
 
2 
STUDY OBJECTIVES 
Primary: 
• To evaluate the efficacy of Toripalimab Injection (JS001) plus chemotherapy 
compared with placebo plus chemotherapy, as measured by independent review 
committee (IRC) – assessed progression-free survival (PFS) according to RECIST 
v1.1 in patients with histological/cytological confirmation of recurrent or metastatic 
nasopharyngeal carcinoma (NPC). 
Secondary: 
• To evaluate the efficacy of Toripalimab Injection (JS001) plus chemotherapy 
compared with placebo plus chemotherapy, as measured by overall survival (OS).  
• To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus 
chemotherapy, as measured by investigator-assessed objective response rate (ORR), 
duration of response (DoR), disease control rate (DCR) according to RECIST v1.1. 
• To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus 
chemotherapy, as measured by investigator-assessed PFS according to RECIST 
v1.1. 
• To evaluate the IRC and investigator-assessed PFS rate at 1 and 2 years in each 
treatment arm. 
• To evaluate the OS rate at 1 and 2 years in each treatment arm. 
• To assess disease-related symptoms and HRQoL in patients treated with JS001 plus 
chemotherapy compared with placebo plus chemotherapy using the EORTC QLQ-
C30, EORTC QLQ-H&N35 and ECOG performance status assessments. 
• To evaluate the safety and tolerability of JS001 plus chemotherapy compared with 
placebo plus chemotherapy. 
• To evaluate the incidence and titers of anti-drug antibodies (ADA) against JS001 
and to explore the potential relationship of the immunogenicity response with 
pharmacodynamics, safety, and efficacy. 

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• To evaluate the efficacy of JS001 plus chemotherapy compared with placebo plus 
chemotherapy as measured by investigator and IRC-assessed PFS, ORR, DoR, and 
DCR according to irRECIST. 
Exploratory: 
• To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers 
(including but not limited to PBMC, PD-L1, PD-1, tumor mutation burden and 
others) in archival and/or fresh tumor tissue and blood and their association with 
disease status, mechanisms of resistance, and/or response to Toripalimab Injection 
(JS001). 
• To evaluate the utility of biopsy at the time of apparent disease progression to 
distinguish apparent increases in tumor volume related to the immunomodulatory 
activity of JS001 (i.e., pseudoprogression and tumor immune infiltration) from true 
disease progression. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a randomized, placebo-controlled, multi-center, double blinded, Phase III study to 
determine the efficacy and safety of Toripalimab Injection (JS001) in combination with 
gemcitabine/cisplatin compared with placebo in combination with gemcitabine/cisplatin as 
first-line treatment in patients with histological/cytological confirmation of recurrent or 
metastatic NPC.  
 
Approximately 280 patients who fulfill all of the inclusion criteria  and none of the 
exclusion criteria  will be randomized in a 1:1 ratio to one of the two treatment arms 
according to the following stratification factors:  
 
• ECOG performance status (0 versus 1) 
• Disease stage (recurrent versus metastatic) 
 
After stratification, patients will be randomly assigned by Interactive Web Response 
System (IWRS) to the combination of JS001 (Arm A) or placebo (Arm B) with gemcitabine 
and cisplatin given every 3 weeks (Q3W) in 3-week cycles. Day 1 (baseline) will be defined 
as the first day a patient receives study medication.  Patients will receive JS001 (Arm A) 
or placebo (Arm B) on Day 1 of each 3-week cycle. In Arms A & B, patients will receive 
gemcitabine on Days 1 & 8 and cisplatin on Day 1 of each cycle. The chemotherapy will 
continue until progressive disease, excessive toxicity, noncompliance, withdrawal of 
consent, or a maximum of 6 cycles, whichever occurs first in the ‘during chemotherapy’ 
phase. During the ‘post-chemotherapy’ phase, patients randomized to Arm A or Arm B 
will continue treatment with JS001 or placebo as maintenance therapy Q3W until excessive 
toxicity or progressive disease, withdrawal of consent or Investigator’s judgement or a 
maximum of 2 years. Patients may continue treatment with JS001 (Arm A) or placebo 
(Arm B) beyond radiographic progression by the Response Evaluation Criteria In Solid 

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Tumors (RECIST) version 1.1, provided they are experiencing clinical benefit, as assessed 
by the Investigator in the absence of unacceptable toxicity or symptomatic deterioration 
attributed to disease progression, as determined by the Investigator after an integrated 
assessment of radiographic data and clinical status. Patients will be permitted by sponsor 
medical monitor or designee and treating physician to continue JS001/placebo after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the criteria 
according to the protocol. 
 
Tumor evaluation scans will be performed at screening (as baseline) then every 6 weeks in 
the first 12 months then every 9 weeks thereafter until objective disease progression. The 
management of patients will be based solely upon the results of the tumor evaluation scans 
conducted by the Investigator. 
 
The IRC, consisting of independent experts, will review all radiologic scans according to 
RECIST 1.1 and irRECIST. 
 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 32 months. 
 
At the time of end of study, sponsor will continuously provide investigational product to 
patients who still are under treatment in accordance with local regulations. 
 
This is a double blinded and one interim efficacy analysis of PFS is planned and pre-
defined stopping boundary is set for two-sided p-value. The iDMC will provide the 
recommendation as to whether to unblind the study or not according to the data of interim 
analysis and the iDMC charter if the stopping boundary were met. If the Sponsor accepted 
the recommendation and unblind the study, JS001 will be provided to the patients who 
were randomized to arm A and still on JS001 treatment until the treatment discontinuation 
criteria are met according to protocol, the placebo treatment will be terminated for the 
patients who were randomized to arm B. After the study is unblinded, the tumor evaluation, 
survival follow-up, safety information, and so on information collection should be 
performed as required by the protocol. 
 
 

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Table 1. Schedule of Activities 
 
Screening a 
 
All treatment cycles 
 
Treatment 
Discontinua
tion c 
Survival Follow-
Up d 
 
During chemotherapy 
Post chemotherapy 
Unplanned 
Visit b 
Day 
(Window) 
–28 
to –1  
–7 to 
–1 
C1D1 
 
C1D8 
 
C2D1 
( 3) 
C2D8 
 
C3-C6D1 
( 3) 
C3-C6D8 
C7D1 
( 3) 
C8D1 to PD 
or intolerable 
toxicity 
( 3) 
NA 
 
 
Informed consent 
xe 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Patient-reported outcomes f 
 
 
x 
 
x 
 
x 
 
x 
x 
 
 
 
Vital signsg 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Weight 
 
x 
 
 
x 
 
x 
 
 
 
 
x 
 
ECOG 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Height 
 
x 
 
 
 
 
 
 
 
 
 
 
 
ECGh 
x 
 
As clinically indicated 
 
Echocardiogramh 
x 
         As clinically indicated 
 
Complete physical examination i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical examination j 
 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
 
Hematology k 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Coagulation test (INR, PT, aPTT) 
 
x 
 
As clinically indicated 
 

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Screening a 
All treatment cycles 
Treatment 
Discontinua
tion c 
Survival Follow-
Up d 
 
During chemotherapy 
Post chemotherapy 
Unplanned 
Visit b 
Day 
(Window) 
–28 
to –1  
–7 to 
–1 
C1D1 C1D8 
C2D1 
( 3) 
C2D8 C3-C6D1 
( 3) 
C3-C6D8 
C7D1 
( 3) 
C8D1 to PD 
or intolerable 
toxicity 
( 3) 
NA 
 
 
Chemistry l 
 
x 
 
xm 
x 
xm 
x 
xm 
x 
x 
 
x 
 
Pregnancy test n 
 
x 
 
 
x 
 
x 
 
x 
x 
 
x 
 
TSH, free T3, free T4o 
x 
 
 
 
x 
 
x 
 
x 
x 
 
x 
 
Urinalysis p 
 
x 
 
 
x 
 
x 
 
x 
x 
 
x 
 
HIV, HBV, HCV serology q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
EBV serology r 
 
 
x r 
 
 
 
x r 
 
x r 
xr 
 
 
 
Study drug administration 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Tumor response assessment 
xs 
 
 
 
 
 
xt 
 
xt 
 
 
 
 
Serum sample for ADAs u 
 
 
x 
 
 
 
x 
 
x 
 
 
x 
 
 Blood sample for biomarkers v 
 
 
x 
 
  
 
x 
 
x 
 
 
 
 
Concomitant medications w 
 
x  
x  
x 
x 
x 
x 
x 
x 
x 
x 
x  
 
Adverse events x 
x  
 
x  
x 
x 
x 
x 
x 
x 
x 
x 
x  
x  
 
ADA = anti-drug antibody; eCRF = electronic Case Report Form; NA = not applicable. 
Notes:  All assessments should be performed within 28 days of the scheduled visit, unless otherwise specified.  On treatment days, all assessments 
should be performed prior to dosing, unless otherwise specified.   
a 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 may be used; 
such tests do not need to be repeated for screening.   
b Visit not specified by the protocol.  Assessments should be performed as clinically indicated. 

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c Patients who complete the treatment period will return to the clinic for a treatment completion visit within  30 days after the last dose of study drugs. 
Patients who discontinue study drug prematurely will return to the clinic for a treatment discontinuation visit within 30  days after the last dose of study 
drug;  If the study drug infusion delayed and discontinued subsequently, and the interval between last dose of study treatment and decision of 
treatment discontinuation probably is near or longer than 30 days, the investigator should complete Treatment Discontinuation Visit as early as they 
can after patients formally withdrawal from study treatment. The visit at which response assessment shows progressive disease may be used as the 
treatment discontinuation visit. 
d Required follow-up information will be collected via telephone calls and/or clinic visits every 3 months (±7 days) after treatment discontinuation until 
death, loss to follow-up, withdrawal of consent or study termination by the Sponsor.  
e Informed consent must be documented before any study-specific screening procedure is performed. 
f Questionnaires will be self-administered before the patient receives any information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment. 
g Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF. 
h A twelve-lead ECG and Echocardiogram is required at screening and as clinically indicated thereafter. 
i Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  
At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
j Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells. Results for full blood count must be available before commencing an infusion (samples must have been obtained 
within 3 days prior to the infusion, except for C1D1). 
l Chemistry panel (serum or plasma) includes glucose, BUN or urea, creatinine, sodium, potassium, magnesium, chloride, calcium, phosphorus, total 
bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin. Results for chemistry tests must be available before commencing an 
infusion (samples must have been obtained within 3 days prior to the infusion, except for C1D1).  
m Only BUN or urea, creatinine, ALT and AST are needed to be performed on day 8 of gemcitabine. Results must be available before commencing an 
infusion (samples must have been obtained within 3 days prior to the infusion, except for C1D1). 
n All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at each cycle during 
treatment (samples must have been obtained within 3 days prior to the infusion, except for C1D1).  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
o Thyroid function testing (TSH, free T3, free T4) collected at screening, and each cycle thereafter (samples must have been obtained within 3days prior 
to the infusion, except for C1D1). 

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p Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs). Samples must have 
been obtained within 3 days prior to the infusion, except for C1D1.  
q All patients will be tested for HCV and HIV prior to the inclusion into the study and HCV-positive and/or HIV-positive patients will be excluded from the 
clinical trial.  HBV DNA must be collected before Cycle 1, Day 1 in patients who have positive serology for hepatitis B surface antigen or negative 
serology for hepatitis B surface antigen and positive serology for anti-HBc. 
r EBV serology samples will be collected before infusion of C1D1 and every two cycles prior to the infusion for 12 months and then every 3 cycles prior 
to the infusion until disease progression, loss of clinical benefit, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs 
first.  s 
Screening assessments must include CT scans (with oral/IV contrast unless contraindicated) or MRIs of the nasopharynx, neck, chest 
and abdomen. A CT (with contrast) or MRI scan of the head must be done at screening to evaluate CNS metastasis in all patients.  An MRI scan of 
the brain is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan. 
t Tumor assessment should be done to evaluate the target, non-target, and new lesions, it will include all known sites of disease documented at 
screening, which include but not limit to CT scans (with oral/IV contrast unless contraindicated) or MRIs of the nasopharynx, neck, chest and 
abdomen,  and the same radiographic procedure should be used throughout the study, bone scans should also be performed if clinically indicated.  
Perform every 6 weeks (± 7 days; approximately every two cycles) for 12 months following Cycle 1, Day 1 and then every 9 weeks (± 7 days) 
thereafter, regardless of treatment delays, until disease progression, loss of clinical benefit, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first.  CT scans may be repeated at any time if progressive disease is suspected. 
u See Protocol Appendix 2 for detailed schedule. 
v See Protocol Appendix 2 for detailed schedule. 
w Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by 
a patient from 7 days prior to initiation of study drug to the treatment discontinuation visit. 
x After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study drug, all adverse events will be reported until 60 days after the last dose of study drug. After this period, 
the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug 
treatment (see Section 5.6).The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is 
assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
 
 
 
 

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3.2 
Efficacy and Safety Endpoints 
3.2.1 Primary Efficacy Endpoint 
• IRC-assessed Progression-Free Survival (PFS) according to RECIST v1.1 
3.2.2 Secondary Efficacy Endpoints 
• OS 
• IRC-assessed ORR according to RECIST v1.1 
• IRC-assessed DoR according to RECIST v1.1 
• IRC-assessed DCR according to RECIST v1.1 
• Investigator-assessed ORR according to RECIST v1.1 
• Investigator-assessed DoR according to RECIST v1.1 
• Investigator-assessed DCR according to RECIST v1.1 
• Investigator-assessed PFS according to RECIST v1.1 
• IRC-assessed PFS rate at 1 and 2 years 
• Investigator-assessed PFS rate at 1 and 2 years 
• OS rate at 1 and 2 years 
• Patient-Reported Outcome (PRO) using EORTC QLQ-C30, EORTC QLQ-H&N35 
and ECOG performance status assessments 
• Anti-drug antibody 
• PFS, ORR, DoR, and DCR according to irRECIST 
3.2.3 Safety Endpoints 
The following safety variables will be monitored and reported in the eCRF according to 
the study schedule (Table 1 in Section 3.1): 
• The incidence of Adverse events (AEs)  
• The incidence of serious adverse events (SAEs) 
• Vital signs  
• Physical examinations 
• Laboratory variables 
• 12-Lead Electrocardiogram (ECG) and Electrocardiogram 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently 
checked for consistency, integrity and in accordance with standard PAREXEL procedures. 
 
4.2 
General Presentation Considerations 
‘End of Study’ is defined as the date of the last visit of the last patient, or the date of the 
last data point required for efficacy analyses or safety follow-up, whichever occurs later. 

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‘Treatment Day’ will be calculated relative to the first dose of study drug, i.e. Treatment 
Day = Assessment Date - The First Day a Patient Receives Study Medication + 1.  
 
Continuous data will be summarized in terms of the mean, standard deviation (Sd), median, 
minimum, maximum and number of observations, unless otherwise stated. Continuous data 
that are expected to be skewed will be presented in terms of the maximum, upper quartile, 
median, lower quartile, minimum and number of observations.  The minimum and 
maximum will be reported to the same number of decimal places as the raw data recorded 
in the database.  The mean, median, lower quartile and upper quartile will be reported to 
one more decimal place than the raw data recorded in the database.  The Sd will be reported 
to two more decimal places than the raw data recorded in the database.  In general, the 
maximum number of decimal places reported shall be four for any summary statistic. 
 
Categorical data will be summarized in terms of the number of patients providing data at 
the relevant time point (n), frequency counts and percentages.  Any planned collapsing of 
categories will be detailed in the SAP text and the data displays.   
 
Percentages will be presented to one decimal place. Percentages will not be presented for 
zero counts.  Percentages will be calculated using n as the denominator.  If sample sizes 
are small, the data displays will show the percentages, but any textual report will describe 
frequencies only.   
 
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
 
P-values greater than or equal to 0.0001, in general, will be presented to four decimal 
places.  P-values less than 0.0001 will be presented as “<0.0001”. 
 
Confidence interval (CI) will be presented to one more decimal place than the raw data. 
 
All report outputs will be produced using SAS® version 9.3 or a later version in a secure 
and validated environment.  All report outputs will be provided to the Sponsor in a single 
Microsoft Word document per each output.   
 
Baseline for Efficacy and Safety 
Baseline measurements are the last available data obtained prior to the first dose of study 
drug.  
 
Scheduled and Unscheduled Assessments 
Scheduled assessments taken outside of protocol allowable windows will be displayed 
according to the eCRF assessment recorded by the Investigator. The by-visit tables will 
only include the scheduled assessments, unless specifically stated otherwise. If more than 
one value is available for a given visit, the first valid observation will be used in summary 
tables, unless specifically stated otherwise, and all observations will be presented in listings. 
 
Unscheduled assessments will be included in listings, but not in summary tables. 

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Missing Data Conventions 
In general, missing data will not be imputed for both efficacy analysis and safety analysis, 
unless specifically stated otherwise.  
 
Detection of Outliers 
Any outliers that are detected during the review of the data before database lock will be 
investigated. If necessary, queries will be issued to the Investigator, to either correct or 
confirm the outlier. 
  
4.3 
Study Subjects 
4.3.1 Disposition of Patients 
A clear accounting of the disposition of all patients who enter the study will be provided, 
from screening to study completion. 
 
The following summaries will be provided: 
• A summary of the number and percentage of patients who were randomized, the 
number and percentage of patients who were excluded prior to randomization by 
major reason and overall, and the number of percentage of patients who were re-
screened, using the Enrolled Population. 
• A summary of the number and percentage of patients who were treated (with at 
least one dose of study drug) in each phase of the study (during-chemotherapy 
phase and post-chemotherapy phase) and the number and percentage of patients 
who were discontinued from treatment in each phase of the study (during-
chemotherapy phase and post-chemotherapy phase), and the number and 
percentage of major reason of patient discontinuation from treatment in each phase 
of the study (during-chemotherapy phase and post-chemotherapy phase), by 
treatment arm and overall, using the ITT population . 
• A summary of the number and percentage of patients completed the study and 
discontinued from the study, and the number and percentage of major reason of 
patient discontinuation from the study, by treatment arm and overall, using the ITT 
population. 
• A summary of follow-up time (months), which is defined as the time from 
randomization to a specified event (death, end of the study or the data cut-off for 
the analysis, whichever occurs first), by treatment arm and overall, using the ITT 
population. The study follow-up time (months) is calculated as 
 
(event date - randomization date + 1) / 30.4375 
 
A by-patient listing of disposition data will be provided, using the Enrolled Population. 
 

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4.3.2 Protocol Deviations 
Protocol Deviations will be classified as “major” or “minor”, and any action to be taken 
regarding the exclusion of patients or affected data from specific analyses will be defined 
in the project-specific Protocol Deviation Specification. 
 
Major protocol deviations are defined as those deviations from the protocol likely to have 
an impact on the patient’s rights, safety, well-being, and/or on the validity of the data for 
analysis. 
 
A summary of the number and percentage of patients with major protocol deviations by 
treatment arm and overall, and type of deviation will be provided, using the ITT population. 
 
A by-patient listing of protocol deviations will be provided using the ITT population. 
 
4.4 
Analysis Populations 
4.4.1 Enrolled Population 
Enrolled population is defined as all patients who provided informed consent from (ICF) 
for this study. 
 
4.4.2 Intent-to-Treat (ITT) Population 
 The intent-to-treat set (ITT) will include all patients randomized. Patients will be analyzed 
according to the study arm to which they are randomized. 
 
4.4.3 Per-Protocol Analysis Set (PPS) 
The Per-Protocol Analysis Set (PPS) will include all ITT patients who do not have any 
major protocol violations which may have potential impact on the key efficacy or safety 
endpoints.  Major protocol violations will be defined and inclusion of subjects in the PPS 
population will be finalized prior to study unbinding. Patients will be analyzed according 
to the study arm to which they are randomized.  The PPS population will be used for some 
secondary/exploratory analysis as well as sensitivity analysis of the primary efficacy 
endpoints. 
 
4.4.4 Safety Population 
The safety population will include all patients who receive any amount of JS001 or placebo.  
Patients who are randomized into the study but did not receive any amount of study drug 
will not be included in the safety population. 
 
A summary of the analysis populations and the set will be provided. 
 

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4.5 
Demographic and Other Baseline Characteristics 
Patient demographic and baseline characteristics will be summarized by treatment arm 
using the ITT population. 
 
Following summaries will be provided: 
• A summary of demographic data and baseline characteristics by treatment arm, 
including age, sex, ethnicity, race, baseline height (cm), baseline weight (kg), 
baseline ECOG performance status, baseline disease stage, smoking history, and 
alcohol use. 
• A summary of medical history by treatment arm, system organ class, and preferred 
term, coded by Medical Dictionary for Regulatory Activities (MedDRA) version 
23.0 
• A summary of nasopharyngeal carcinoma (NPC) diagnosis. 
 
Age will be calculated as the number of complete years between a patient's date of birth 
and the date of informed consent. Age (in years) will be calculated as: 
 
(Date of informed consent – date of birth + 1)/365.25 
 
If date of birth is a partial date missing month only, month will be assumed to be June. If 
date of birth is a partial date missing day only, day will be assumed to be 15th of the month. 
If date of birth is a partial date missing both month and day, it will be assumed to be Jun 
30 of the year. 
 
Following listings will be provided: 
• A by-patient listing of demographic and baseline characteristics 
• A by-patient listing of medical history will include reported term, coded term, onset 
date, ongoing (yes, no), and date of resolution 
• A by-patient listing of NPC diagnosis 
• A by-patient of tumor tissue 
 
4.5.1 Nasopharyngeal Carcinoma Diagnosis  
A summary of nasopharyngeal carcinoma (NPC) diagnosis will be provided using the ITT 
population, and a by-patient listing of NPC diagnosis will be provided as well. 
 
For the nasopharyngeal carcinoma diagnosis, the histology information recorded in the 
CRF of "Other" and "Unknown" is diverse therefore the data are manually reviewed and 
further categorized into "Nasopharyngeal carcinoma, unclassified", "Non-keratinizing 
squamous cell carcinoma, undifferentiated", "Non-keratinizing carcinoma, unclassified", 
or "Other (please see Section 6.2 Appendix C). 
 
 

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4.5.2 Previous Systemic Therapy 
A summary of previous systemic therapy categorized by anatomical therapeutic chemical 
(ATC) and preferred name using the ITT population will be provided.  
 
The systemic therapies will be coded using the WHODrug Dictionary. 
 
A by-patient listing of previous systemic therapy will be provided. 
 
4.5.3 Previous Radiation Therapy 
A summary of number and percentage of patients received previous radiation therapy, 
location, total dose (in centigrays), therapy category, mode of radiation therapy, and best 
response using the ITT population will be provided.  
 
A by-patient listing of previous radiation therapy will be provided. 
 
4.5.4 Concomitant Radiotherapy  
A summary of number and percentage of patients with concomitant radiotherapy during 
the study, location, total dose (in centigrays), therapy category, and intent of therapy, using 
the ITT population will be provided. 
 
A by-patient listing of concomitant therapy will be provided. 
 
4.5.5 Previous and Concomitant Medication 
Previous and concomitant medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) are those used by a 
patient from 7 days prior to initiation of study drug to the treatment discontinuation visit. 
All such medications should be reported to the investigator and recorded on the Previous 
and Concomitant Medications eCRF. 
 
The medications will be coded using the WHODrug Global Dictionary version Mar 2020 
B3. 
 
If medication start and/or stop dates are missing or partial, the dates will be compared as 
far as possible with the date of first dose of study medication.  Medications will be assumed 
to be Concomitant only, unless there is clear evidence (through comparison of partial dates) 
to suggest that the medication started prior to the first dose of study medication.  If there is 
clear evidence to suggest that the medication started prior to the first dose of study 
medication, the medication will be assumed to be both Prior and Concomitant, unless there 
is clear evidence to suggest that the medication stopped prior to the first dose of study 
medication.  If there is clear evidence to suggest that the medication stopped prior to the 
first dose of study medication, the medication will be assumed to be Prior only. 
 

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Following summaries will be provided using the ITT population: 
• A summary of concomitant medications categorized by anatomical therapeutic 
chemical (ATC) and preferred name  
• A summary of previous medications categorized by ATC drug class and PT 
 
A by-patient listing of previous and concomitant medications will be provided, including 
drug name, indication, dose, unit, frequency, route, start date, and stop date will be 
provided. 
 
4.5.6 Previous and Concomitant Surgery  
 
The surgeries will be coded using the MedDRA version 23.0.  Whether the surgery is 
considered as previous or concomitant, including the handling of missing or partial start 
date and stop date, will follow the same rule to the medication (see section 4.5.5).   
 
Following summaries will be provided using the ITT population: 
• A summary of concomitant surgeries categorized by system organ class and 
preferred term  
• A summary of previous surgeries categorized by system organ and preferred term 
 
A by-patient listing of previous and concomitant surgery, including surgery description, 
surgery date, indication, and cancer related flag (yes, no) will be provided. 
 
4.5.7 Concomitant Procedure  
The concomitant procedure will be coded using the MedDRA version 23.0.   
 
• A summary of concomitant procedure categorized by system organ class and 
preferred term will be provided 
 
A by-patient listing of concomitant procedure, including procedure description, start/end 
date, and indication will be provided. 
 
4.5.8 Post Anti-Cancer Therapy 
Post anti-cancer therapy will be coded using the WHODrug Global Dictionary version Mar 
2020 B3. 
 
• A summary of post anti-cancer therapy categorized by system organ class and 
preferred name will be provided using the ITT population . 
 
A by-patient listing of post anti-cancer therapy will be provided. 
 
 

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4.6 
Extent of Exposure 
The duration of exposure is defined as the duration from the first dosing date to the last 
dosing date of JS001/placebo and chemotherapy (gemcitabine or cisplatin)  at the end of 
treatment. Duration of exposure (in weeks) will be calculated as: 
 
(the last dosing date at the end of treatment – the first dosing date + 21) / 7 
 
The actual cumulative total dose of JS001 received (mg) is defined as the summation of all 
actual total dose administrated from the first dosing date to the last dosing date at the end 
of treatment.  For cisplatin and gemcitabine, the actual cumulative total dose received will 
be calculated cumulatively based on the data from CRF Drug Administration 
(Cisplatin/Gemcitabine): “Actual total dose administered”.   
 
Dose intensity will be calculated as: 
 
actual cumulative total dose received/ duration of exposure 
 
and relative dose intensity will be calculated as: 
 
(actual cumulative total dose received / planned cumulative total dose received)×100% 
 
where the planned cumulative total dose of JS001 received will be calculated according to 
the Q3W schedule (i.e. every 3 weeks) using the duration of exposure: 
 
 
Round down of [duration of exposure (in weeks) / 3] to integer * 240 mg 
 
For cisplatin and gemcitabine, the planned cumulative total dose received will be calculated 
cumulatively based on the data from CRF Drug Administration(Cisplatin/Gemcitabine): 
“Planned total dose administered”.   
 
 
A summary of the number of cycles received (number and proportion of patients), actual 
duration of treatment, actual cumulative total dose received per patient (mg), dose intensity, 
and relative dose intensity, weeks and number of cycles for chemotherapy will be provided 
by treatment arm, using the Safety Population.   
 
Following listings will be provided using the Safety Population: 
• A by-patient listing of administrations of study drug, including study drug 
administration (yes, no), reason for no administration, delayed administration (yes, 
no), reason for delay, start date and start time of administration, end date and end 
time of administration, actual total dose administrated, infusion temporarily 
interrupted/discontinued 
(interrupted, 
discontinued, 
no), 
reason 
for 
interrupted/discontinued.     
• A by-patient listing of administrations of chemotherapy (gemcitabine/cisplatin), 
including drug administration (yes, no), reason for no administration, delayed 

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administration (yes, no), reason for delay, start date and start time of administration, 
end date and end time of administration, dose level, planned and actual total dose 
administrated, dose change (no change, dose decreased), reason for dose change, 
infusion temporarily interrupted/discontinued (interrupted, discontinued, no), 
reason for interrupted/discontinued.     
 
4.7 
Efficacy Evaluation 
All efficacy summaries and analyses will be based upon the ITT population  unless 
otherwise indicated. A by-patient listing for survival outcomes, a by-patient for tumor 
response assessment, and a by-patient listing for tumor assessment results by visit will be 
provided. 
4.7.1 Analysis and Data Handling 
This study is designed to test for superiority. The null hypothesis for the treatment 
comparison will be that there is no difference between JS001 in combination with 
chemotherapy (Arm A) and placebo in combination with chemotherapy (Arm B) for the 
primary endpoint PFS. The alternative hypothesis will be that there is a difference. 
Symbolically, this is expressed as follows: 
 
𝐻0: 𝑆𝐴(𝑡) = 𝑆𝐵(𝑡) versus 𝐻1: 𝑆𝐴(𝑡) ≠𝑆𝐵(𝑡) 
 
where  𝑆𝐴(𝑡) and 𝑆𝐵(𝑡) are the survival distribution function of PFS for Arm A and Arm 
B, respectively. 
 
The study has crossed the O’Brien-Fleming boundary for the planned interim analysis of 
IRC-assessed PFS, with a data cutoff date of 30 May 2020, when 128 IRC-assessed PFS 
events had been observed in the ITT population.  The key secondary efficacy endpoints, 
including IRC-assessed objective response rate (ORR) and overall survival (OS), were to 
be tested hierarchically under a two-sided alpha level of 0.05. ORR was formally tested 
and reached its statistical significance at the interim analysis of PFS. OS will then be 
formally tested when 130 deaths are observed in the ITT population.  
 
 
4.7.1.1 Adjustments for Covariates 
The primary and secondary efficacy analyses of PFS and OS will be stratified by ECOG 
performance status (0 vs. 1), and disease stage (recurrent vs. metastatic). 
 
 
4.7.1.2 Handling of Dropouts or Missing Data 
In general, no imputation will be performed for missing data, unless specifically stated 
otherwise.  
 
4.7.1.3 Multiple Comparisons/Multiplicity 
No multiple comparisons will be performed in the study. 
 

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4.7.1.4 Examination of Subgroups 
The primary efficacy endpoint of investigator-assessed PFS according to RECIST v1.1 will 
be analyzed including but not limited to following subgroups: 
• Age: <=50 versus >50 
• Sex: Male versus Female 
• Baseline ECOG status per CRF: 0 versus 1 
• Baseline ECOG status per IWRS: 0 versus 1 
• Disease stage per CRF (recurrent versus metastatic) 
• Disease stage per IWRS (recurrent versus metastatic) 
• EBV copy number: <=500 versus >500; <=2000 versus >2000  
• Baseline PD-1 expression status: PD-1 will be categorized to <=1% vs. > 1%,  
<=5% vs. > 5%, and <=10% vs. > 10%.   
4.7.2 Primary Efficacy Endpoint – IRC-Assessed PFS 
PFS is defined as the time from randomization to the time of first documented disease 
progression, as determined by IRC assessments per RECIST v1.1, or death from any cause, 
whichever occurs first. Patients who have not experienced disease progression or death at 
the time of analysis will be censored at the time of the last tumor assessment.  Patients with 
no post-baseline tumor assessment and no death will be censored on the date of 
randomization. For patients who do not experience disease progression but have started 
any new anti-tumor therapy, PFS will be censored at the time of the last tumor assessment 
before the new therapy. For patients who have two or more consecutive missing tumor 
assessments, PFS will be censored at the time of the last available tumor assessment before 
the missing, or at the date of randomization if there was no post-baseline tumor assessment 
before the missing.  In the COVID-19 pandemic period, for patients who have two or more 
consecutive missing tumor assessments due to COVID-19, in the circumstance if 
subsequent tumor assessments become available and there is no immediate disease 
progression, the subsequent tumor assessments will be used in the PFS analysis; if the 
subsequent immediate tumor assessment is disease progression, PFS will still be censored 
at the last tumor assessment before the missing, or at the date of randomization if there is 
no post-baseline tumor assessment before the missing.   
 
PFS (month) will be calculated as: 
 
(event date or censoring date – randomization date + 1) / 30.4375. 
 
If the day of death is missing, it would be imputed with day 15.   
 
The two-sided log-rank test, stratified by ECOG performance status (0 vs. 1), and disease 
stage (recurrent vs. metastatic), as recorded in the IWRS, will be used as the primary 
analysis to compare PFS between the two treatment arms. 
 
The hazard ratio (HR) for disease progression or death will be estimated with the use of 
the stratified Cox proportional hazards model by including strata of ECOG performance 
status (0 vs. 1), and disease stage (recurrent vs. metastatic).  Efron’s method will be used 

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to handle ties. The 95% CI for the HR will be constructed. Results from an unstratified 
analysis will also be provided. 
 
The Kaplan-Meier methodology will be applied to estimate the median PFS for each 
treatment arm, and Kaplan-Meier curves will be developed. The Brookmeyer Crowley 
methodology[4] by using log-log transformation to survival function, will be used to 
construct the 95% CI for the median PFS for each treatment arm. 
 
Primary analysis will be performed using ITT population.  Sensitivity analysis will be 
performed using PPS as well.   
4.7.3 Secondary Efficacy Variables 
4.7.3.1 Investigator-Assessed PFS 
IRC-assessed PFS is defined as the time from randomization until the earliest occurrence 
of disease progression, as determined by the independent review committee, per RECIST 
v1.1, or death from any cause, whichever occurs first. 
 
The methods outlined for the investigator-assessed PFS will be used for the IRC-assessed 
PFS analysis. 
4.7.3.2 Overall Survival (OS) 
OS is defined as the time from randomization to death from any cause.  Data from patients 
who are alive at the time of the analysis will be censored as of the last date they are known 
to be alive.  OS (month) is calculated as: 
 
(death date or censoring date – date of randomization + 1) / 30.4375 
 
If the day of death is missing, it would be imputed with day 15.   
 
The methods outlined for PFS will be used for the OS analysis. 
 
A by-patient listing of survival follow-up status will be provided. 
 
4.7.3.3 Objective Response Rate (ORR) 
An objective response is defined as either a confirmed complete response (CR) or a partial 
response (PR), as determined by IRC and the investigator using RECIST v1.1.  Patients 
not meeting these criteria, including patients without any post baseline tumor assessment, 
will be considered non-responders. 
 
Any tumor assessment, either by the IRC or the investigator, after the first PD or the new 
anti-cancer therapy will not be used to determine the best overall response evaluation.   
 
ORR is defined as the proportion of patients who had an objective response. ORR and its 
95% CI will be calculated for each treatment arm, and its 95% CI will be constructed using 
the Clopper-Pearson method (Clopper and Pearson, 1934).  
 

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Treatment difference in ORR will be analyzed using the Cochran-Mantel-Heanszel test, 
stratified by ECOG performance status (0 vs. 1), and disease stage (recurrent vs. metastatic). 
The 95% CI for the difference in ORRs between the two treatment arms will be determined 
using the Mantel-Heanszel method. 
 
 
4.7.3.4 Duration of Response (DoR) 
DoR will be assessed in patients who have an objective response CR/PR as determined by 
IRC and the investigator using RECIST v1.1.   
 
DoR is defined as the time interval from the date of the first occurrence of a CR or PR 
(whichever status is recorded first) until the first date that progressive disease or death is 
documented, whichever occurs first.   
 
Patients who have not progressed and who have not died at the time of analysis will be 
censored at the time of last tumor assessment date.  If no tumor assessments are performed 
after the date of the first occurrence of a CR or PR, duration of response will be censored 
at the date of the first occurrence of a CR or PR.  The DoR (month) will be calculated as: 
 
(progression date or censoring date – first date of CR or PR + 1) / 30.4375 
 
The methods outlined for PFS will be used for the DoR analysis. 
 
4.7.3.5 Disease Control Rate (DCR) 
DCR is defined as the rate of patients with CR or PR as best response or stable disease (SD) 
maintained for 6 weeks (>= 6 weeks) as determined by IRC and the investigator according 
to RECIST v1.1.   
 
The methods outlined for ORR will be used for the DCR analysis. 
 
 
 
4.7.3.6 PFS rate at 1 and 2 years  
The PFS rate at 1 and 2 years after randomization will be estimated with the use of the 
Kaplan-Meier methodology for each treatment arm, along with 95% CI that are calculated 
with use of the standard error derived from Greenwood’s formula, where the PFS is the 
IRC and investigator-assessed PFS according to RECIST v1.1. The 95% CI for the 
difference in the PFS rate between the two treatment arms will be estimated with use of the 
normal approximation method. 
 
4.7.3.7 OS rate at 1 and 2 years  
 
The methods outlined for the PFS rate will be used for the OS rate analysis. 
 

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4.7.3.8 Patient-Reported Outcomes (PRO) 
The EORTC QLQ-C30 and QLQ-H&N35 data will be scored according to the EORTC 
scoring manual, the scoring can be seen in Section 6.1 6.1Appendix A.   
 
In the event of incomplete data, if the scale has more than 50% of the constituent items 
completed, a pro-rated score will be computed that is consistent with the scoring manual 
and the validation papers of the measure.  For subscales with less than 50% of the items 
completed, the subscale will be considered missing. 
 
Summary statistics (mean, Sd, median, and range) of absolute scores and mean changes 
from the baseline will be calculated for all disease and/or treatment related symptom items 
and subscales of the EORTC QLQ-C30 and QLQ-H&N35 at each assessment time point 
for each treatment arm during the administration of the treatment and the survival follow 
up period.   
 
The mean (and 95% CI) and median of the absolute scores and the changes from the 
baseline will be reported for interval and continuous variables.   
 
Previously-published minimally-important differences will be used to identify meaningful 
change from the baseline within each treatment arm on the disease and/or treatment related 
symptoms scales (Osoba et al., 1998). 
 
Questionnaire completion rate for EORTC-QLQ-C30 and QLQ-H&N35 is defined as the 
proportion of questionnaires actually received out of the expected number (i.e., number of 
patients during the administration of the treatment), which will be calculated and 
summarized for each assessment time point by treatment arm. 
 
Following listings will be provided: 
• A by-patient listing of EORTC-QLQ-C30 
• A by-patient listing of QLQ-H&N35 
 
4.8 
Safety Evaluation 
All safety summaries and analyses will be based upon the Safety Population  unless 
otherwise indicated. 
 
4.8.1 Adverse Events 
AEs will be coded using the MedDRA version 23.0.  
Treatment-emergent adverse events will be tabulated and are defined as those adverse 
events that either start or worsen in severity on or after the date/time of first dose of study 
treatment and on or before 60 days after the date/time of last dose of study treatment. 
Where dates are missing or partially missing, adverse events will be assumed to be 
treatment-emergent, unless there is clear evidence (through comparison of partial dates) to 

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suggest that the adverse event started prior to the first dose of study treatment or more than 
60 days after the last dose of study treatment. 
The incidence of some AEs, which should have been summarized under the same preferred 
term, could be underestimated because they were coded to different preferred terms due to 
different reported terms.  Aside from the MedDRA dictionary, additional aggregation rule 
are applied to the following AEs: Leukopenia, Neutropenia, Thrombocytopenia, 
Lymphopenia, Hypokalemia, Fatigue, Rash, Musculoskeletal pain, Cough, Diarrhea, 
Pneumonia, Neuropathy peripheral, Upper respiratory tract infection, Abdominal pain, 
Arrhythmia, Oedema, Proteinuria, Hypertension, Blood bilirubin increased, Insomnia 
(please see Section 6.4 Appendix D). 
 
Following summaries will be provided: 
• An overview of all TEAEs: the number and percentage of patients with any TEAEs, 
any >= grade 3 TEAE, any treatment-emergent immune-related adverse event 
(irAE), any treatment emergent adverse events of special interest (AESI), any >= 
grade 3 treatment-emergent AESI, any SAE, any TEAEs with relationship to study 
drug, any TEAEs with relationship to gemcitabine, any TEAEs with relationship to 
cisplatin, any TEAEs leading to drug withdrawn, any TEAEs leading to drug 
interruption, any TEAEs leading to dose reduced, and any TEAEs leading to death, 
by treatment arm 
• A summary of the number and percentage of patients reporting a TEAE and the 
number of TEAEs, by treatment arm, system organ class, and preferred term 
• A summary of the number and percentage of patients reporting a TEAE, by 
treatment arm, maximum severity (grade 1-2, grade 3, grade 4, grade 5, >= grade 
3), system organ class, and preferred term 
• A summary of the number and percentage of patients reporting a treatment-
emergent irAE and the number of irAEs, by treatment arm, system organ class, and 
preferred term 
• A summary of the number and percentage of patients reporting a treatment-
emergent irAE, by treatment arm, maximum severity (grade 1-2, grade 3, grade 4, 
grade 5, >= grade 3), system organ class, and preferred term 
• A summary of the number and percentage of patients reporting a study drug related 
TEAE and the number of study drug related TEAEs, by treatment arm, system 
organ class, and preferred term 
• A summary of the number and percentage of patients reporting a study drug related 
TEAE, by treatment arm, maximum severity (grade 1-2, grade 3, grade 4, grade 5, 
>= grade 3), system organ class, and preferred term 
• A summary of the number and percentage of patients reporting a gemcitabine 
related TEAE and the number of gemcitabine related TEAEs, by treatment arm, 
system organ class, and preferred term 
• A summary of the number and percentage of patients reporting a cisplatin related 
TEAE and the number of cisplatin related TEAEs, by treatment arm, system organ 
class, and preferred term 
 

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• A summary of the commonly occurring TEAEs, i.e., reported in at least 5% of 
patients in any treatment arm, by treatment arm, system organ class, and preferred 
term 
• A summary of the number and percentage of patients reporting a treatment 
emergent AESI and the number of AESI, by treatment arm, system organ class, and 
preferred term 
• A summary of the number and percentage of patients reporting a severe TEAE (AE 
with grade equal to or greater than 3) and the number of severe AEs, by treatment 
arm, system organ class, and preferred term 
• A summary of the number and percentage of patients reporting an TEAE leading 
to infusion reaction, by treatment arm, system organ class, and preferred term 
• A summary of the number and percentage of patients reporting the TEAE leading 
to death, by treatment arm, system organ class, and preferred term 
 
For the summarization of number of patients, a patient will be counted only once for each 
system organ class and each preferred term, even if the patient reported one or more event 
under each subcategory; for the summarization of number of events, the number of AEs 
will count all AEs of each patient under each system organ class and each preferred term.  
 
Unless specified otherwise, the table of a summary will be ordered in terms of decreasing 
number of patients for MedDRA system organ class and then preferred term within system 
organ class in the overall group. 
 
For each AE, severity will be graded based on the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, and the most extreme 
grade recorded in eCRF will be attributed and used in the by-severity summaries. If the 
severity is missing, it will not be imputed. Besides, if relationship to study drug or 
chemotherapy (gemcitabine, cisplatin) is missing, the relationship will be imputed as Yes. 
 
Following listings will be provided: 
• A by-patient listing of all AEs 
• A by-patient listing of all immune-related AEs  
 
By-patient listings will be presented by treatment arm and will include: center, patient 
identifier, age, sex, race, adverse event (system organ class, preferred term, and verbatim 
term), AE start date, AE stop date, severity, serious (yes, no), seriousness criteria, 
relationship (study drug, gemcitabine, cisplatin), causality, action taken, outcome, infusion 
reaction (yes, no) and timepoint of AE occurrence if yes (during  infusion, with 24 hours 
after end of infusion). 
 
4.8.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
An SAE is any AE that meets any of the following criteria: 
• Is fatal (i.e., the adverse event actually causes or leads to death). 

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• Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death). 
• Requires or prolongs inpatient hospitalization (see Section 5.3.5.11 of the protocol). 
• Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions). 
• Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug. 
• Is a significant medical event in the investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above). 
 
Other significant adverse events are those adverse events reported as leading to an 
intervention e.g. discontinuation of study treatment. 
 
Following summaries will be provided: 
• A summary of the number and percentage of deaths during the study treatment 
period, and the number and percentage of deaths during the follow-up period after 
treatment completion/discontinuation, by treatment arm 
• A summary of the number and percentage of patients reporting a SAE and the 
number of SAEs, by treatment arm, system organ class and preferred term 
 
4.8.3 Vital Signs and Weight 
Vital signs will include pulse rate (beats/minute), respiration rate (breaths/min), systolic 
and diastolic blood pressure (mmHg) while the patient is in a seated position, and 
temperature (˚C).  Vital sign will be measured and the relevant assessment will be 
performed at the period of pre-dose, JS001 infusion, and post-dose, respectively.     
 
Both raw values and changes from baseline will be summarized using descriptive statistics 
at each scheduled visit by treatment arm. Baseline is defined as the last evaluation prior to 
the first dose of study drug. 
 
Vital sign assessment will be summarized using frequencies and percentages.  
 
Following summaries will be provided: 
• A summary of the observed values and changes from baseline for each vital sign 
by each period (i.e. pre-dose, JS001 infusion, and post-dose) and by visit and 
treatment arm 
• A summary of vital sign assessment by each period (i.e. pre-dose, JS001 infusion, 
and post-dose) and by visit and treatment arm. 
 
• A summary of weight and change from baseline by visit and treatment arm. 
 
If vital sign data is missing, no imputation will be made. During the study, the measurement 
of vital signs may be repeated at the discretion of the Investigator for safety reasons. If 

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repeat measurements are taken at a particular time point, the last valid measurement will 
be used in the summaries. 
 
By-patient listings of vital signs and weight will be provided.  
 
4.8.4 Physical Examinations 
A complete physical examination, according to local practice, should be performed at the 
screening visit, which includes  
• head, eyes, ears, nose, and throat 
• cardiovascular 
• dermatological  
• musculoskeletal  
• respiratory  
• gastrointestinal  
• genitourinary 
• neurological systems 
• cranial nerve 
• Lymph node (head and neck) 
• Lymph node (other than head and neck) 
 
At subsequent visits, only limited, symptom-directed physical examinations will be 
performed.   
 
Following summaries will be provided: 
• A summary of the number and percentage of patients for the complete physical 
examination at the screening visit will be provided by category (normal, abnormal 
and clinically significant, abnormal but not clinically significant), body system, and 
treatment arm. 
• A summary of the number and percentage of patients for any abnormal findings in 
the subsequent visits will be provided by category (abnormal and clinically 
significant, abnormal but not clinically significant), visit, and treatment arm. 
 
By-patient listings of physical examination will be provided.  
 
4.8.5 Laboratory Evaluation 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count 
with differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and 
other cells], and platelet count) 
• Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate, calcium, phosphorus, total bilirubin, ALT, AST, 
alkaline phosphatase, LDH, total protein, and albumin) 

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• Coagulation (INR, PT, aPTT) 
• Serum pregnancy test should only be conducted at screening period for women of 
childbearing potential, including women who have had a tubal ligation; urine 
pregnancy tests will be performed at each cycle during treatment.  A serum 
pregnancy test must be performed if the urine pregnancy test is positive.  
 
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/or bilateral oophorectomy or not being postmenopausal (≥12 
months of amenorrhea).  
• Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood), dipstick 
permitted, and microscopic examination (RBCs, WBCs).  
• Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4) 
• HBV serology (HBsAg, HBsAb, HBcAb) 
• HBV DNA should be obtained prior to randomization if patient has positive 
serology for HBcAb or HBsAg. 
• HCV serology (HCV antibody) 
• HCV RNA if HCV antibody is positive. 
• HIV testing 
All patients will be tested for HIV prior to the inclusion into the study and HIV 
positive patients will be excluded from the clinical trial. 
 
The continuous test results for each test parameter and change from baseline by visit will 
be summarized using the descriptive statistics. The categorical test results for each test 
parameter will be summarized using frequencies and percentages. A shift table of the 
categorical test results at each visit compared to the categorical test results at baseline will 
be provided. 
 
The toxicity grade and abnormality worsened from the baseline will be summarized 
according to NCI-CTCAE version 5.0 (please see Section 6.2 Appendix B).   
 
A by-patient listing of all laboratory data will be provided by treatment arm. 
4.8.6 12-Lead Electrocardiogram (ECG) and Echocardiogram   
Frequency and percentage of patients who had abnormal (clinically significant or not 
clinically significant) ECG and echocardiogram overall assessment will be summarized by 
treatment arm.  When there are multiple ECGs taken at a visit, the worst ECG overall 
assessment will be used.  
 
By-patient listings of 12 ECG and echocardiogram, including the LVEF result (%), will be 
provided.  
  
4.8.7 ECOG Performance Status 
 
Following summaries will be provided: 

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• A summary of the number and percentage of patients for each ECOG performance 
status score by visit, and treatment arm. 
• A shift summary of baseline score by maximum post-baseline score by treatment 
arm 
 
A by-patient listing of ECOG performance status at each visit will be provided. 
 
4.8.8 Pregnancy Test 
A by-patient list of pregnancy test results will be provided only for female patients. 
 
4.9 
Other Evaluation 
4.9.1 Sensitivity Analyses for IRC-Assessed PFS 
The following analyses will be performed as the sensitivity analyses for the primary 
analysis of investigator-assessed PFS: 
• The unstratified analysis in which the log-rank test will be performed at two-sided 
alpha level of 0.05, the HR will be estimated using the proportional hazards model. 
Efron’s method will be used to handle ties. The 95% CI for the HR will be 
constructed. 
• The analysis using the methods outlined for the primary analysis in which the 
stratification factors are the actual variables recorded in CRF rather than the 
stratification factors recorded in the IWRS. 
• The analysis using the methods outlined for the primary analysis in which patients 
did not experience disease progression or death but started new anti-tumor therapy 
whose event date is defined as the start date of new treatment. 
• The analysis using the methods outlined for the primary analysis in which patients 
with disease progression or death being documented after missing two consecutive 
tumor assessments will be handled as event and will not be censored. 
• The analysis using the methods outlined for the primary analysis. Regardless 
patients with disease progression or death being documented after missing two 
consecutive tumor assessments due to COVID-19,  PFS will be censored at the last 
tumor assessment before the missing, or at the randomization date if there was no 
post-baseline tumor assessment before the missing. 
• The analysis using the methods outlined for the primary analysis in which the 
analysis population is the PPS.  
 
4.9.2 PFS, ORR, DoR, and DCR per Immune-Related RECIST  
Analyses using irRECIST for PFS, ORR, DoR and DCR as determined by the IRC and 
investigator will be conducted.  The applicable methods outlined for PFS and ORR will be 
used for these analyses. 
 
The ORR and its 95% CI will be calculated, and its 95% CI will be constructed using the 
Clopper-Pearson method (Clopper and Pearson, 1934). 
 

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All results of analysis will be summarized using the ITT population . 
4.9.3 Subgroup Analyses 
To assess the consistency of the study results, the IRC and investigator-assessed PFS will 
be analyzed according to the subgroups defined in Section 4.7.1.4. 
 
Summaries of PFS, including unstratified HRs estimated from Cox proportional hazards 
models and Kaplan-Meier estimates of median PFS, will be produced separately for each 
level of the categorical variables for the comparisons between treatment arms. 
 
Subgroup analyses will be performed using ITT population.  
 
4.9.4 Immunogenicity Analysis 
Anti-JS001 antibodies, immunoglobulins, and JS001 plasma level will be summarized with 
descriptive statistics by treatment arm using the Safety Population (Section 4.4.4). Ad hoc 
analyses may be pursued after data collection. 
4.9.5 Biomarker Analysis 
Biomarker data will be summarized with descriptive statistics by treatment arm using the 
Safety Population (Section4.4.4). Ad hoc analyses may be pursued after data collection. 
 
4.9.6 Pharmacokinetic Analysis 
Pharmacokinetic analyses will be limited to descriptive statistics conducted using the 
JS001 Treated Subjects.  Individual and average concentration-collect time curve will be 
plotted.   
 
 
4.10 Interim Analysis  
An iDMC will be set up to evaluate safety data on an ongoing basis, as well as the efficacy 
data from the planned interim efficacy analyses.  All summaries/analyses by treatment arm 
for the iDMC’s review will be prepared by an independent party.  Members of the iDMC 
will be external to the Sponsor and will follow a charter that outlines their roles and 
responsibilities.   
 
4.10.1 IRC-Assessed PFS 
One interim efficacy analysis of PFS was planned to be conducted when approximately 
130 PFS events in the ITT population had been observed.  This was expected to occur 
approximately 18 months after the first patient was randomized, although the exact timing 
of the interim analysis depended on the actual occurrence of PFS events.  
 
The final analysis of PFS was planned to be conducted when approximately 200 PFS events 
in the ITT population have been observed.  This was expected to occur approximately 25 

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months after the first patient was randomized, while the exact timing of the final analysis 
will depend on the actual occurrence of PFS events.   
 
To control the type I error for PFS analyses at a two-sided significance level of 0.05, the 
stopping boundaries for the PFS interim and final analyses were computed with use of the 
Lan-DeMets approximation to the O’Brien-Fleming boundary as shown in the following 
table:  
 
Timing and Stopping Boundary of PFS Analyses 
Type of Analysis   
Timing Since  
FSI (month) 
Planned 
Information  
Fraction (Event #) 
Stopping Boundary   
(Two-Sided p-
Value) 
PFS interim 
analysis 
18 
65% (130) 
0.011 
PFS final analysis 
25 
100% (200) 
0.047 
FSI = First subject in; PFS = progression-free survival; HR = hazard ratio. 
 
The planned interim analysis was performed with the data cutoff date of 30 May 2020, 
when 128 PFS events, as assessed by IRC per RECIST 1.1, had been observed in the ITT 
population. The PFS result generated at the interim analysis was highly statistically 
significant and was treated as definitive. The final PFS analysis will be conducted 18 
months after the last patient was randomized, when it is estimated that approximately 150 
IRC-assessed PFS events will be observed in the ITT population. The final PFS analysis 
will be performed for the descriptive purposes only. 
 
4.10.2 OS 
Two interim analyses of OS were planned at the interim and final analyses of PFS for the 
descriptive purpose only, where it was expected to observe approximately 49 and 74 deaths 
respectively.  The final analysis of OS will be performed when approximately 130 deaths 
have been observed in the ITT population. 
 
4.11 Determination of Sample Size 
The sample size calculation is based on the primary endpoint PFS. Patients will be 
randomized in a 1:1 ratio. A total of 280 patients (140 per arm) are needed to observe 200 
PFS events at approximately 25 months after the first patient is randomized in order to 
detect the PFS improvement of HR=0.67 with 80% power at a 2-sided significance level 
of 0.05; one interim analysis is planned when approximately 130 PFS events are observed.  
 
The calculation of the sample size is based on the following assumptions: 
• PFS is exponentially distributed 
• The median PFS is 7 months for the standard chemotherapy 
• The interim and final analyses of PFS use the Lan DeMets alpha spending function 
to approximate the O’Brien Fleming boundary 
• The recruitment of 280 patients will take place over 14 months, 

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• The dropout rate is 5% over 12 months for PFS. 
 
4.12 Changes in the Conduct of the Study or Planned Analysis 
4.12.1 Changes Made in SAP v2.0 
The following shows the changes made in the SAP v2.0 compared to the SAP v1.0.  
 
# 
SAP v1.0 
SAP v2.0 
#1 
Section 1 INTRODUCTION 
 
This SAP is based upon the following 
study documents: 
• Study Protocol, Version 5.0 
(Aug 18, 2020) 
 
 
Section 1 INTRODUCTION 
 
This SAP is based upon the following 
study documents: 
• Study Protocol, Version 6.0 
(12, 2020) 
 
#2 
Section 3.1 Overall Study Design and 
Plan 
…  
Crossover will not be permitted as part 
of this study.  Tumor evaluation scans 
will be performed at screening (as 
baseline) then every 6 weeks in the 
first 12 months then every 9 weeks 
thereafter until objective disease 
progression.  
… 
Section 3.1 Overall Study Design and 
Plan 
… 
Crossover will not be permitted as part 
of this study.  Tumor evaluation scans 
will be performed at screening (as 
baseline) then every 6 weeks in the 
first 12 months then every 9 weeks 
thereafter until objective disease 
progression. 
… 
#3 
Section 3.1 Overall Study Design and 
Plan 
 
Section 3.1 Overall Study Design and 
Plan 
<the following new paragraph is 
added> 
 
This is a double blinded and one 
interim efficacy analysis of PFS is 
planned and pre-defined stopping 
boundary is set for two-sided p-value. 
The iDMC will provide the 
recommendation as to whether to 
unblind the study or not according to 
the data of interim analysis and the 
iDMC charter if the stopping boundary 
were met. If the Sponsor accepted the 
recommendation and unblind the 
study, JS001 will be provided to the 
patients who were randomized to arm 

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# 
SAP v1.0 
SAP v2.0 
A and still on JS001 treatment until the 
treatment discontinuation criteria are 
met according to protocol, the placebo 
treatment will be terminated for the 
patients who were randomized to arm 
B. After the study is unblinded, the 
tumor evaluation, survival follow-up, 
safety information, and so on 
information collection should be 
performed as required by the protocol. 
 
#4 
4.3.1 Disposition of Patients 
4.3.1 Disposition of Patients 
<the following new table is added> 
• A summary of follow-up time 
(months), which is defined as 
the time from randomization to 
a specified event (death, end of 
the study or the data cut-off for 
the analysis, whichever occurs 
first), by treatment arm and 
overall, using the ITT 
population. The study follow-
up time (months) is calculated 
as 
 
(event date - randomization date + 
1) / 30.4375 
 
#5 
4.4.3 Per-Protocol Analysis Set (PPS) 
 
The Per-Protocol Analysis Set (PPS) 
will include all ITT patients who do 
not have any major protocol violations 
which have significant impact on the 
primary outcome measures and have 
valid baseline and primary outcome 
measures.  Major protocol violations 
will be defined and inclusion of 
subjects in the PPS population will be 
finalized prior to study unbinding. 
Patients will be analyzed according to 
the study arm to which they are 
randomized.  The PPS population will 
be used for some 
secondary/exploratory analysis as well 
4.4.3 Per-Protocol Analysis Set (PPS) 
 
The Per-Protocol Analysis Set (PPS) 
will include all ITT patients who do 
not have any major protocol violations 
which may have significant potential 
impact on the primary outcome 
measures and have valid baseline and 
primary outcome measures key 
efficacy or safety endpoints.  Major 
protocol violations will be defined and 
inclusion of subjects in the PPS 
population will be finalized prior to 
study unbinding. Patients will be 
analyzed according to the study arm to 
which they are randomized.  The PPS 
population will be used for some 

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# 
SAP v1.0 
SAP v2.0 
as sensitivity analysis of the primary 
efficacy endpoints. 
 
 
secondary/exploratory analysis as well 
as sensitivity analysis of the primary 
efficacy endpoints. 
 
 
#6  
4.5 Demographic and Other Baseline 
Characteristics 
… 
• A summary of medical history 
by treatment arm, system organ 
class, and preferred term, coded 
by Medical Dictionary for 
Regulatory Activities 
(MedDRA) version 20.0 or 
higher 
 
4.5 Demographic and Other Baseline 
Characteristics 
… 
• A summary of medical history 
by treatment arm, system organ 
class, and preferred term, coded 
by Medical Dictionary for 
Regulatory Activities 
(MedDRA) version 23.0 
 
#7 
4.5.2 Previous Systemic Therapy 
… 
The systemic therapies will be coded 
using the MedDRA with version 20.0 
or higher. 
4.5.2 Previous Systemic Therapy 
… 
The systemic therapies will be coded 
using the WHODrug Dictionary. 
 
#8 
4.5.5 Previous and Concomitant 
Medication 
… 
The medications will be coded using 
the World Health Organization-Drug 
Dictionary Enhanced (WHO-DDE) 
version March 2019 or later. 
4.5.5 Previous and Concomitant 
Medication 
… 
The medications will be coded using 
the WHODrug Global Dictionary 
Enhanced (WHO-DDE) version March 
2019 or later Mar 2020 B3. 
#9 
4.5.6 Previous and Concomitant 
Surgery  
… 
The surgeries will be coded using the 
Medical Dictionary for Regulatory 
Activities with version 20.0 or higher.   
4.5.6 Previous and Concomitant 
Surgery  
… 
The surgeries will be coded using the 
Medical Dictionary for Regulatory 
Activities with MedDRA version 23.0 
or higher. 
#10 
4.5.7 Concomitant Procedure  
 
The concomitant procedure will be 
coded using the Medical Dictionary for 
Regulatory Activities with version 
20.0 or higher.   
4.5.7 Concomitant Procedure  
 
The concomitant procedure will be 
coded using the Medical Dictionary for 
Regulatory Activities with MedDRA 
version 23.0 or higher.   
#11 
4.5.8 Post Anti-Cancer Therapy 
 
Post anti-cancer therapy will be coded 
using the World Health Organization-
4.5.8 Post Anti-Cancer Therapy 
 
Post anti-cancer therapy will be coded 
using the World Health Organization-

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# 
SAP v1.0 
SAP v2.0 
Drug Dictionary Enhanced (WHO-
DDE) version March 2019 or later. 
Drug WHODrug Global Dictionary 
Enhanced (WHO-DDE) version March 
2019 or later Mar 2020 B3. 
#12 
4.6 Extent of Exposure 
 
The duration of exposure is defined as 
the duration from the first dosing date 
to the last dosing date of 
JS001/placebo at the end of treatment. 
Duration of exposure (in days) will be 
calculated as: 
 
the last dosing date at the end of 
treatment – the first dosing date + 1 
4.6 
Extent of Exposure 
 
The duration of exposure is defined as 
the duration from the first dosing date 
to the last dosing date of 
JS001/placebo and chemotherapy 
(gemcitabine or cisplatin)  at the end of 
treatment. Duration of exposure (in 
weeks) will be calculated as: 
 
(the last dosing date at the end of 
treatment – the first dosing date + 21) / 
7 
#13 
4.6 Extent of Exposure 
… 
A summary of the number of cycles 
received (number and proportion of 
patients), actual duration of treatment, 
actual cumulative total dose received 
per patient (mg), dose intensity, and 
relative dose intensity and weeks of 
exposure for chemotherapy will be 
provided by treatment arm, using the 
Safety Population.   
4.6 
Extent of Exposure 
… 
A summary of the number of cycles 
received (number and proportion of 
patients), actual duration of treatment, 
actual cumulative total dose received 
per patient (mg), dose intensity, and 
relative dose intensity, weeks and 
number of cycles for chemotherapy 
will be provided by treatment arm, 
using the Safety Population.   
#14 
4.7.1.4 Examination of Subgroups 
 
The primary efficacy endpoint of 
investigator-assessed PFS according to 
RECIST v1.1 will be analyzed 
including but not limited to following 
subgroups: 
• Age: ≤50 vs >50 
• Sex: Male and Female 
• Race: Asian and Others  
• Baseline ECOG status: 0 and 1 
• Disease stage (recurrent versus 
metastatic) 
• EBV virus copy number 
• Baseline PD-1 expression status: PD-
1 will be categorized to <1% vs. >= 
1%,  <5% vs. >= 5%, and <10% vs. >= 
10%.   
4.7.1.4 Examination of Subgroups 
The primary efficacy endpoint of 
investigator-assessed PFS according to 
RECIST v1.1 will be analyzed 
including but not limited to following 
subgroups: 
• Age: <=50 versus >50 
• Sex: Male versus Female 
• Race: Asian and Others  
• Baseline ECOG status per CRF: 0 
versus 1 
• Baseline ECOG status per IWRS: 0 
versus 1 
• Disease stage per CRF (recurrent 
versus metastatic) 
• Disease stage per IWRS (recurrent 
versus metastatic) 

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TP-GDO-WW-016-06 
CONFIDENTIAL 
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# 
SAP v1.0 
SAP v2.0 
• EBV virus copy number: <=500 
versus >500; <=2000 versus >2000  
• Baseline PD-1 expression status: PD-
1 will be categorized to <=5% vs. > 
5%, and <=10% vs. > 10%.   
#15 
4.7.2 Primary Efficacy Endpoint – 
IRC-Assessed PFS 
 
… For patients who do not experience 
disease progression but have started 
any new anti-tumor therapy, PFS will 
be censored at the time of the last 
tumor assessment before the new 
therapy. For patients who have two 
consecutive missing tumor 
assessments, PFS will be censored at 
the time of the last available tumor 
assessment before the missing.  Due to 
COVID-19 pandemic, for patients who 
have two consecutive missing tumor 
assessments due to COVID-19, in the 
circumstance if subsequent tumor 
assessment becomes available and not 
disease progression, the tumor 
assessment will be used in the PFS 
analysis and if the subsequent tumor 
assessment is disease progression, PFS 
will still be censored at the time of the 
last available tumor assessment before 
the missing.   
 
 
 
4.7.2 Primary Efficacy Endpoint – 
IRC-Assessed PFS 
 
… For patients who do not experience 
disease progression but have started 
any new anti-tumor therapy, PFS will 
be censored at the time of the last 
tumor assessment before the new 
therapy. For patients who have two or 
more consecutive missing tumor 
assessments, PFS will be censored at 
the time of the last available tumor 
assessment before the missing.  Due to, 
or at the date of randomization if there 
was no post-baseline tumor assessment 
before the missing.  In the COVID-19 
pandemic period, for patients who 
have two or more consecutive missing 
tumor assessments due to COVID-19, 
in the circumstance if subsequent 
tumor assessments become available 
and there is no immediate disease 
progression, the subsequent tumor 
assessments will be used in the PFS 
analysis and; if the subsequent 
immediate tumor assessment is disease 
progression, PFS will still be censored 
at the last tumor assessment before the 
missing, or at the date of 
randomization if there is no post-
baseline tumor assessment before the 
missing.   
 
#16 
4.7.3.3 Objective Response Rate 
(ORR) 
… 
The 95% CI for the difference in 
ORRs between the two treatment arms 
will be determined using the normal 
4.7.3.3 Objective Response Rate 
(ORR) 
… 
The 95% CI for the difference in 
ORRs between the two treatment arms 
will be determined using the Mantel-
Heanszel method. 

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SAP v1.0 
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approximation to the binomial 
distribution. 
 
4.7.3.4 Duration of Response (DoR) 
… 
If no tumor assessments are performed 
after the date of the first occurrence of 
a CR or PR, duration of response will 
be censored at the date of the first 
occurrence of a CR or PR plus 1 day.   
4.7.3.4 Duration of Response (DoR) 
… 
If no tumor assessments are performed 
after the date of the first occurrence of 
a CR or PR, duration of response will 
be censored at the date of the first 
occurrence of a CR or PR plus 1 day.   
#17 
4.8.1 Adverse Events 
 
AEs will be coded using the Medical 
Dictionary for Regulatory Activities 
with version 20.0 or higher. 
4.8.1 Adverse Events 
 
AEs will be coded using the Medical 
Dictionary for Regulatory Activities 
with MedDRA version 23.0 or higher. 
#18 
4.8.1 Adverse Events 
… 
Following summaries will be provided: 
• An overview of all TEAEs: the 
number and percentage of patients 
with any TEAEs, TEAEs with 
relationship to study drug, any TEAEs 
with relationship to chemotherapy, any 
AEs leading to drug withdrawn, any 
TEAEs leading to drug interruption, 
any TEAEs leading to dose reduced, 
and any TEAEs leading to death, by 
treatment arm 
… 
 
4.8.1 Adverse Events 
… 
Following summaries will be provided: 
• An overview of all TEAEs: the 
number and percentage of patients 
with any TEAEs, any >= grade 3 
TEAE, any treatment-emergent 
immune-related adverse event (irAE), 
any treatment emergent adverse events 
of special interest (AESI), any >= 
grade 3 treatment-emergent AESI, any 
SAE, any TEAEs with relationship to 
study drug, any TEAEs with 
relationship to gemcitabine, any 
TEAEs with relationship to cisplatin, 
any TEAEs leading to drug withdrawn, 
any TEAEs leading to drug 
interruption, any TEAEs leading to 
dose reduced, and any TEAEs leading 
to death, by treatment arm 
… 
• A summary of the number and 
percentage of patients reporting a 
TEAE, by treatment arm, maximum 
severity (grade 1-2, grade 3, grade 4, 
grade 5, >= grade 3), system organ 
class, and preferred term 
… 
•A summary of the number and 
percentage of patients reporting 
treatment-emergent irAE, by treatment 

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SAP v1.0 
SAP v2.0 
arm, maximum severity (grade 1-2, 
grade 3, grade 4, grade 5, >= grade 3), 
system organ class, and preferred term 
… 
• A summary of the number and 
percentage of patients reporting a 
study drug related TEAEs, by 
treatment arm, maximum severity 
(grade 1-2, grade 3, grade 4, grade 5, 
>= grade 3), system organ class, and 
preferred term 
• A summary of the number and 
percentage of patients reporting a 
gemcitabine related TEAE and the 
number of gemcitabine related TEAEs, 
by treatment arm, system organ class, 
and preferred term 
• A summary of the number and 
percentage of patients reporting a 
cisplatin related TEAE and the number 
of cisplatin related TEAEs, by 
treatment arm, system organ class, and 
preferred term 
#19 
4.8.2 Deaths, Serious Adverse Events, 
and Other Significant Adverse Events 
… 
Following summaries will be provided: 
• An overview of all SAEs including 
all SAEs, any study drug related SAE, 
any SAEs with relationship to 
chemotherapy, any SAEs leading to 
drug withdrawn, any SAEs leading to 
drug interruption, any SAEs leading to 
dose reduced, and any SAEs leading to 
death, by treatment arm 
4.8.2 Deaths, Serious Adverse Events, 
and Other Significant Adverse Events 
… 
Following summaries will be provided: 
• An overview of all SAEs including 
all SAEs, any study drug related SAE, 
any SAEs with relationship to 
chemotherapy, any SAEs leading to 
drug withdrawn, any SAEs leading to 
drug interruption, any SAEs leading to 
dose reduced, and any SAEs leading to 
death, by treatment arm 
#20 
4.8.3 Vital Signs and Weight 
…  
If repeat measurements are taken at a 
particular time point, the first valid 
measurement will be used in the 
summaries. 
4.8.3 Vital Signs and Weight 
… 
If repeat measurements are taken at a 
particular time point, the last valid 
measurement will be used in the 
summaries. 
#21 
4.9.1 Sensitivity Analyses for IRC-
Assessed PFS 
… 
4.9.1 Sensitivity Analyses for IRC-
Assessed PFS 
… 

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SAP v1.0 
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• The analysis using the methods 
outlined for the primary analysis. 
Regardless patients with disease 
progression or death being documented 
after missing two consecutive tumor 
assessments due to COVID-19,  PFS 
will be censored at the last tumor 
assessment before the missing. 
• The analysis using the methods 
outlined for the primary analysis. 
Regardless patients with disease 
progression or death being documented 
after missing two consecutive tumor 
assessments due to COVID-19,  PFS 
will be censored at the last tumor 
assessment before the missing, or at 
the randomization date if there was no 
post-baseline tumor assessment before 
the missing. 
#22 
7 APPENDIX B 
GRADING CRITERIA FOR 
CLINICAL LABORATORY TESTS 
6.2 APPENDIX B 
GRADING CRITERIA FOR 
CLINICAL LABORATORY TESTS 
 
Global updates to CTCAE grading 
criteria  to 5.0 
 
4.12.2 Changes Made in SAP v3.0 
The following changes to the analyses specified in the protocol have been made in the SAP 
v3.0 
• Per FDA’s request received in April, 2020 during the IND application in the US, 
overall Type I error rate has been controlled for both the primary efficacy endpoint 
and the key secondary efficacy endpoints (IRC-assessed ORR and OS), instead of 
the primary efficacy endpoint only, as the interim analysis of primary efficacy 
endpoint IRC-assessed PFS has crossed the pre-specified O’Brien-Fleming 
boundary.  
• Final PFS analysis will be conducted when approximately 18 months after the last 
patient was randomized, instead of 200 PFS events have been observed. 
 
The following shows the changes made in the SAP v3.0 compared to the SAP v2.0.  
 
# 
SAP v2.0 
SAP v3.0 
#1 
Section 1 INTRODUCTION 
 
This SAP is based upon the following 
study documents: 
… 
• Electronic Case Report Form (eCRF), 
Version  7.0 (Jun 29, 2020) 
Section 1 INTRODUCTION 
 
This SAP is based upon the following 
study documents: 
… 
• Electronic Case Report Form (eCRF), 
Version  9.0 (Sep 11, 2020) 
#2 
4.5.1 Nasopharyngeal Carcinoma 
Diagnosis 
… 
 
4.5.1 Nasopharyngeal Carcinoma 
Diagnosis 
… 

Shanghai Junshi Biosciences Co., Ltd. 
 
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SAP v2.0 
SAP v3.0 
 
<the following new paragraph is 
added> 
 
For the nasopharyngeal carcinoma 
diagnosis, the histology information 
recorded in the CRF of "Other" and 
"Unknown" is diverse therefore the 
data are manually reviewed and further 
categorized into "Nasopharyngeal 
carcinoma, unclassified", "Non-
keratinizing squamous cell carcinoma, 
undifferentiated", "Non-keratinizing 
carcinoma, unclassified", or "Other 
(please see Section 6.3 Appendix C). 
#3 
4.6 Extent of Exposure 
… 
The actual cumulative total dose of 
received (mg) is defined as the 
summation of all actual total dose 
administrated from the first dosing 
date to the last dosing date at the end 
of treatment.   
… 
 
where the planned cumulative total 
dose of received will be calculated 
according to the Q3W schedule (i.e. 
every 3 weeks) using the duration of 
exposure: 
4.6 Extent of Exposure 
… 
The actual cumulative total dose of 
JS001 received (mg) is defined as the 
summation of all actual total dose 
administrated from the first dosing date 
to the last dosing date at the end of 
treatment.  For cisplatin and 
gemcitabine, the actual cumulative total 
dose received will be calculated 
cumulatively based on the data from 
CRF Drug Administration 
(Cisplatin/Gemcitabine): “Actual total 
dose administered”.   
 
… 
 
where the planned cumulative total 
dose of JS001 received will be 
calculated according to the Q3W 
schedule (i.e. every 3 weeks) using the 
duration of exposure: 
… 
 
For cisplatin and gemcitabine, the 
planned cumulative total dose received 
will be calculated cumulatively based 
on the data from CRF Drug 
Administration(Cisplatin/Gemcitabine): 
“Planned total dose administered”.   
#4 
4.7.1 Analysis and Data Handling 
4.7.1 Analysis and Data Handling 

Shanghai Junshi Biosciences Co., Ltd. 
 
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… 
… 
<the following new paragraph is 
added> 
 
The study has crossed the O’Brien-
Fleming boundary for the planned 
interim analysis of IRC-assessed PFS, 
with a data cutoff date of 30 May 2020, 
when 128 IRC-assessed PFS events had 
been observed in the ITT population.  
The key secondary efficacy endpoints, 
including IRC-assessed objective 
response rate (ORR) and overall 
survival (OS), were to be tested 
hierarchically under a two-sided alpha 
level of 0.05. ORR was formally tested 
and reached its statistical significance 
at the interim analysis of PFS. OS will 
then be formally tested when 130 
deaths are observed in the ITT 
population. 
 
#5 
4.7.2 Primary Efficacy Endpoint – 
IRC-Assessed PFS 
… 
4.7.2 Primary Efficacy Endpoint – 
IRC-Assessed PFS 
… 
<the following new paragraph is 
added> 
 
If the day of death is missing, it would 
be imputed with day 15.   
#6 
4.7.3.2 Overall Survival (OS) 
… 
4.7.3.2 Overall Survival (OS) 
… 
<the following new paragraph is 
added> 
 
If the day of death is missing, it would 
be imputed with day 15.   
#7 
4.7.3.3 Objective Response Rate 
(ORR) 
… 
4.7.3.3 Objective Response Rate 
(ORR) 
… 
<the following new paragraph is 
added> 
 
Any tumor assessment, either by the 
IRC or the investigator, after the first 

Shanghai Junshi Biosciences Co., Ltd. 
 
JS001-015-III-NPC 
Statistical Analysis Plan 
 
TP-GDO-WW-016-06 
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SAP v2.0 
SAP v3.0 
PD or the new anti-cancer therapy will 
not be used to determine the best 
overall response evaluation. 
#8 
4.8.1 Adverse Events 
… 
4.8.1 Adverse Events 
… 
<the following new paragraph is 
added> 
 
The incidence of some AEs, which 
should have been summarized under 
the same preferred term, could be 
underestimated because they were 
coded to different preferred terms due 
to different reported terms.  Aside from 
the MedDRA dictionary, additional 
aggregation rule are applied to the 
following AEs: Leukopenia, 
Neutropenia, Thrombocytopenia, 
Lymphopenia, Hypokalemia, Fatigue, 
Rash, Musculoskeletal pain, Cough, 
Diarrhea, Pneumonia, Neuropathy 
peripheral, Upper respiratory tract 
infection, Abdominal pain, Arrhythmia, 
Oedema, Proteinuria, Hypertension, 
Blood bilirubin increased, Insomnia 
(please see Section 6.4 Appendix D). 
#9 
4.8.5 Laboratory Evaluation 
… 
4.8.5 Laboratory Evaluation 
… 
<the following new paragraph is 
added> 
 
The toxicity grade and abnormality 
worsened from the baseline will be 
summarized according to NCI-CTCAE 
version 5.0 (please see Section 6.2 
Appendix B).   
 
#10 
4.9.2 PFS, ORR, DoR, and DCR per 
Immune-Related RECIST  
 
Analyses using irRECIST for PFS, 
ORR, DoR and DCR as determined by 
the IRC and investigator will be 
conducted for JS001 treated patients 
only.  The applicable methods 
4.9.2 PFS, ORR, DoR, and DCR per 
Immune-Related RECIST  
 
Analyses using irRECIST for PFS, 
ORR, DoR and DCR as determined by 
the IRC and investigator will be 
conducted JS001 treated patients only.  
The applicable methods outlined for 

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# 
SAP v2.0 
SAP v3.0 
outlined for PFS and ORR will be 
used for these analyses. 
PFS and ORR will be used for these 
analyses. 
#11 
 
<the following new section is added> 
 
4.9.6 Pharmacokinetic Analysis 
Pharmacokinetic analyses will be 
limited to descriptive statistics 
conducted using the Safety Population 
(Section 4.4.4).  Individual and average 
concentration-collect time curve will be 
plotted.   
#12 
4.10 Interim Analysis 
… 
 
 
One interim efficacy analysis of PFS 
is planned when approximately 130 
PFS events in the ITT population have 
been observed.  This is expected to 
occur approximately 18 months after 
the first patient is randomized, while 
the exact timing of the interim 
analysis will depend on the actual 
occurrence of PFS events.  
 
The final analysis of PFS will be 
conducted when approximately 200 
PFS events in the ITT population have 
been observed.  This is expected to 
occur approximately 25 months after 
the first patient is randomized, while 
the exact timing of the final analysis 
will depend on the actual occurrence 
of PFS events.   
 
To control the type I error for PFS 
analyses at a two-sided significance 
level of 0.05, the stopping boundaries 
for PFS interim and final analyses 
have been computed with use of the 
Lan-DeMets approximation to the 
O’Brien-Fleming boundary as shown 
in the following table: 
4.10 Interim Analysis 
… 
4.10.1 IRC-Assessed PFS 
 
One interim efficacy analysis of PFS 
was planned to be conducted when 
approximately 130 PFS events in the 
ITT population had been observed.  
This was expected to occur 
approximately 18 months after the first 
patient was randomized, although the 
exact timing of the interim analysis 
depended on the actual occurrence of 
PFS events.  
 
The final analysis of PFS was planned 
to be conducted when approximately 
200 PFS events in the ITT population 
have been observed.  This was 
expected to occur approximately 25 
months after the first patient was 
randomized, while the exact timing of 
the final analysis will depend on the 
actual occurrence of PFS events.   
 
To control the type I error for PFS 
analyses at a two-sided significance 
level of 0.05, the stopping boundaries 
for the PFS interim and final analyses 
were computed with use of the Lan-
DeMets approximation to the O’Brien-
Fleming boundary as shown in the 
following table: 
#13 
4.10 Interim Analysis 
4.10 Interim Analysis 

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# 
SAP v2.0 
SAP v3.0 
… 
 
 
 
… 
4.10.1 IRC-Assessed PFS 
 
<the following new paragraph is 
added> 
 
The planned interim analysis was 
performed with the data cutoff date of 
30 May 2020, when 128 PFS events, as 
assessed by IRC per RECIST 1.1, had 
been observed in the ITT population. 
The PFS result generated at the interim 
analysis was highly statistically 
significant and was treated as 
definitive. The final PFS analysis will 
be conducted 18 months after the last 
patient was randomized, when it is 
estimated that approximately 150 IRC-
assessed PFS events will be observed in 
the ITT population. The final PFS 
analysis will be performed for the 
descriptive purposes only. 
 
<the following new sections are added> 
 
4.10.2 OS 
Two interim analyses of OS were 
planned at the interim and final 
analyses of PFS for the descriptive 
purpose only, where it was expected to 
observe approximately 49 and 74 
deaths respectively.  The final analysis 
of OS will be performed when 
approximately 130 deaths have been 
observed in the ITT population. 
#14 
 
<the following new sections are added> 
 
6.3 Appendix C: Nasopharyngeal 
Carcinoma Diagnosis 
 
6.4 Appendix D 
 
 

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5 
REFERENCES 
[1] Fayers, P., Aaronson, N. K., Bjordal, K., Groenvold, M., Curran, D., & Bottomley, A. 
(2001). EORTC QLQ-C30 Scoring Manual (3rd edition). (3rd ed.) Brussels: European 
Organisation for Research and Treatment of Cancer. 
 
[2] Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality-of-life scores. J Clin Oncol 1998;16:139–44. 
 
[3] Cocks K, King MT, Velikova G, et al. Evidence-based guidelines for determination of 
sample size and interpretation of the European organisation for the research and treatment 
of cancer quality of life questionnaire core 30. J Clin Oncol 2011;29:89–96. 
 
[4] Brookmeyer R. and Crowley J. A confidence interval for the median survival time. 
Biometrics 1982; 38; 29-41. 
 
[5] Clopper C. and Pearson E. S. The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 1934; 26; 404-413. 
 
[6] Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health 
related quality-of-life scores. J Clin Oncol 1998;16:139-44 
 
[7] DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat 
Med 1994;13:1341-52. 
 
 

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6 
APPENDIX 
6.1 
Appendix A: Patient-Reported Outcomes  Scoring Conversion Rule 
 
The principle for scoring 
1. Estimate the average of the items that contribute to the scale; this is the raw score 
calculate by 
𝑅𝑎𝑤𝑆𝑐𝑜𝑟𝑒 =  𝑅𝑆= 𝐼1 + 𝐼2 + ⋯+ 𝐼𝑛
𝑛
 
where  𝐼1, 𝐼2, …, 𝐼𝑛 are items in the scale. 
2. Apply the linear transformation to 0-100 to obtain the score 𝑆, 
• Functional scales:  
𝑆= {1 −(𝑅𝑆−1)
𝑟𝑎𝑛𝑔𝑒} × 100 
• Symptom scales / items:  
𝑆= {
(𝑅𝑆−1)
𝑟𝑎𝑛𝑔𝑒} × 100 
• Global health status / QoL:  
𝑆= {
(𝑅𝑆−1)
𝑟𝑎𝑛𝑔𝑒} × 100 
where 𝑟𝑎𝑛𝑔𝑒 is the difference between the maximum possible value of 𝑅𝑆 and the 
minimum possible value. The QLQ-C30 has been designed so that all items in any 
scale take the same range of values. Therefore, the range of 𝑅𝑆 equals the range of 
the item values. Most items are scored 1 to 4, giving 𝑟𝑎𝑛𝑔𝑒= 3. The exceptions 
are the items contributing to the global health status / QoL, which are 7-point 
questions with 𝑟𝑎𝑛𝑔𝑒= 6. The QLQ-H&N35 has been designed so that all items 
in any scale take the same range of values as well, i.e., the range of 𝑅𝑆 equals the 
range of the item values. Most items are scored 1 to 4, giving 𝑟𝑎𝑛𝑔𝑒= 3. The 
exceptions are the items contributing to Pain killers, Nutritional supplements, 
Feeding tube, Weight loss, and Weight gain, which have 𝑟𝑎𝑛𝑔𝑒= 1. 
 
Table A1. Scoring the QLQ-C30 
 
Scale 
Number 
of items 
Item 
range 
Version 3.0 
Item numbers 
Function 
scales 
Global health status / QoL 
 
 
 
 
 
Global health status/QoL  
QL2 
2 
6 
29, 30 
 
 
 
 
 
 
 
Functional scales 
 
 
 
 
 
Physical functioning 
PF2 
5 
3 
1 to 5 
F 
Role functioning 
RF2 
2 
3 
6, 7 
F 
Emotional functioning 
EF 
4 
3 
21 to 24 
F 
Cognitive functioning 
CF 
2 
3 
20, 25 
F 

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Social functioning 
SF 
2 
3 
26, 27 
F 
 
 
 
 
 
 
Symptom scales / items 
 
 
 
 
 
Fatigue 
FA 
3 
3 
10, 12, 18 
 
Nausea and vomiting 
NV 
2 
3 
14, 15 
 
Pain 
PA 
2 
3 
9, 19 
 
Dyspnea 
DY 
1 
3 
8 
 
Insomnia 
SL 
1 
3 
11 
 
Appetite loss 
AP 
1 
3 
13 
 
Constipation 
CO 
1 
3 
16 
 
Diarrhea 
DI 
1 
3 
17 
 
Financial difficulties 
FI 
1 
3 
28 
 
 
Table A2. Scoring the QLQ-H&N35 
Scale name 
Scale 
Number 
of items 
Item 
range 
QLQ-H&N35 
Item numbers 
Symptom scales / items 
 
 
 
 
Pain 
HNPA 
4 
3 
1 – 4 
(CRF 31 – 34) 
Swallowing 
HNSW 
4 
3 
5 – 8 
(CRF 35 – 38) 
Senses problems 
HNSE 
2 
3 
13,14 
(CRF 43 – 44) 
Speech problems 
HNSP 
3 
3 
16,23,24 
(CRF 46, 53, 54) 
Trouble with social eating 
HNSO 
4 
3 
19 – 22 
(CRF 49 – 52) 
Trouble with social contact 
HNSC 
5 
3 
18,25 – 28 
(CRF 48, 55 – 
58) 
Less sexuality 
HNSX 
2 
3 
29,30 
(CRF 59, 60) 
Teeth 
HNTE 
1 
3 
9 
(CRF 39) 
Opening mouth 
HNOM 
1 
3 
10 
(CRF 40) 
Dry mouth 
HNDR 
1 
3 
11 
(CRF 41) 
Sticky saliva 
HNSS 
1 
3 
12 
(CRF 42) 
Coughing 
HNCO 
1 
3 
15 
(CRF 45) 
Felt ill 
HNFI 
1 
3 
17 
(CRF 47) 
Pain killers 
HNPK 
1 
1 
31 
(CRF 61) 

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Nutritional supplements 
HNNU 
1 
1 
32 
(CRF 62) 
Feeding tube 
HNFE 
1 
1 
33 
(CRF 63) 
Weight loss 
HNWL 
1 
1 
34 
(CRF 64) 
Weight gain 
HNWG 
1 
1 
35 
(CRF 65) 
 
 
 

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6.2 
Appendix B: Grading Criteria For Clinical Laboratory Tests 
 
Hematology 
Tests 
 
Criteria 
Test 
Direction 
1 
2 
3 
4 
Hemoglobin 
(g/L) 
Increase 
Increase in >0 - 
20 g/L above 
ULN  
Increase in >20 
- 40 g/dL 
above ULN  
Increase in >40 
g/L above 
ULN  
NA 
Hemoglobin 
(g/L) 
Decrease 
≥100 - <LLN 
≥80 - <100.0 
<80 
NA 
Neutrophils 
(109/L) 
Decrease 
≥1.5 - <LLN 
≥1.0 - <1.5 
≥0.5 - <1.0 
<0.5 
Platelets (109/L) 
Decrease 
≥75.0 - <LLN 
≥50.0 - <75.0 
≥25.0 - <50.0 
<25.0 
Total WBC count 
(109/L) 
Decrease 
≥3.0 - <LLN 
≥2.0 - <3.0 
≥1.0 - <2.0 
<1.0 
Lymphocytes 
(109/L) 
Increase 
NA 
>4 - ≤20 
>20 
NA 
Lymphocytes 
(109/L) 
Decrease 
≥0.8 - <LLN 
≥0.5 - <0.8 
≥0.2 - <0.5 
<0.2 
 
Chemistry Tests 
 
Criteria 
Test 
Direction 
1 
2 
3 
4 
ALT 
Increase 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 
- 3.0 x 
baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x 
ULN if 
baseline 
was normal; 
>3.0 - 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if 
baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN 
if baseline 
was 
normal; 
>20.0 x 
baseline if 
baseline was 
abnormal 
AST 
Increase 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 
- 3.0 x 
baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x 
ULN if 
baseline 
was normal; 
>3.0 - 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if 
baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN 
if baseline 
was 
normal; 
>20.0 x 
baseline if 
baseline was 
abnormal 
Albumin (g/L) 
Decrease 
≥30 - <LLN 
≥20 - <30 
<20 
 
Alkaline 
Phosphatase 
Increase 
>ULN - 2.5 x 
ULN if baseline 
was normal; 2.0 
- 2.5 x 
baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x 
ULN if 
baseline 
was normal; 
>2.5 - 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if 
baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN 
if baseline 
was 
normal; 
>20.0 x 
baseline if 
baseline was 
abnormal 
Bilirubin (total) 
Increase 
>ULN - 1.5 x 
ULN if baseline 
>1.5 - 3.0 x 
ULN if 
baseline 
>3.0 - 10.0 x 
ULN if 
baseline 
>10.0 x ULN 
if baseline 
was 

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was normal; > 
1.0 - 1.5 x 
baseline if 
baseline was 
abnormal 
was normal; 
>1.5 - 3.0 x 
baseline if 
baseline was 
abnormal 
was normal; 
>3.0 - 10.0 x 
baseline if 
baseline was 
abnormal 
normal; 
>10.0 x 
baseline if 
baseline was 
abnormal 
Calcium 
(mmol/L) 
Increase 
>ULN - ≤2.9 
>2.9 - ≤3.1 
>3.1 - ≤3.4 
>3.4 
Calcium 
(mmol/L) 
Decrease 
>=2.0 - <LLN 
 
>=1.75 - <2.0 
>=1.5 - <1.75 
<1.5 
Creatinine 
Increase 
>ULN - ≤1.5 
xULN 
>1.5 xULN - 
≤3.0 xULN 
>3.0 xULN - 
≤6.0 xULN 
>6.0 xULN 
Potassium 
(mmol/L) 
Increase 
>ULN - ≤5.5 
>5.5 - ≤6.0 
>6.0 - ≤7.0 
>7.0 
Potassium 
(mmol/L) 
Decrease 
≥3.0 - <LLN 
 
≥2.5 - <3.0 
<2.5 
Sodium 
(mmol/L) 
Increase 
>ULN - ≤150 
>150 - ≤155 
 
>155 - ≤160 
>160 
Sodium 
(mmol/L) 
Decrease 
≥130 - <LLN 
≥125 - <130 
≥120 - <125 
<120 
Glucose 
(mmol/L) 
Decrease 
≥ 3 - <LLN 
≥ 2.2 - <3 
≥ 1.7 - <2.2 
<1.7 
 
 
 

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6.3 
Appendix C: Nasopharyngeal Carcinoma Diagnosis 
The “Other” or “Unknown” histology type recorded in the CRF are re-mapped according 
to the following table: 
 
Histology 
type 
If other, please specify 
Histology type-New 
Other 
Metastatic nasopharyngeal carcinoma[center 
Histology report] 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated,non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Malignant tumor(center Histology 
report),undifferentiated Non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated,non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 

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Histology 
type 
If other, please specify 
Histology type-New 
Other 
undifferentiated Non-keratinizing 
carcinoma(local Histology report),  diagnos 
is uncler(center Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated Non-keratinizing 
carcinoma(local Histology report),No tumor 
is found(center Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated,non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated Non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated Non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
poorly differentiated carcinoma(local 
Histology report）,diagnos is uncler(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated Non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Malignant tumor[Center Histology 
report],undifferentiated,non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated Non-keratinizing 
carcinoma(local Histology report)(local 
Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
undifferentiated,non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Poorly differentiated squamous cell 
carcinoma(local Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Malignant tumor[Center Histology 
report],undifferentiated,non-keratinizing 
carcinoma(local Histology report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 

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Histology 
type 
If other, please specify 
Histology type-New 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma[center 
Histology report] 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma(center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharyngeal carcinoma(center Histology 
report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Non-keratinizing squamous cell carcinoma, 
undifferentiated(local report) 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Metastatic nasopharyngeal carcinoma 
(Central Pathology Report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Malignant tumor,important differential 
dignoses include nasopharyngeal carcinoma 
and neuroendocrine carcinoma.More IHC 
tests are essential for further diagnosis 
Nasopharyngeal 
carcinoma,unclassified 
Other 
metastatic lymphoepithelial carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastasis of nasopharyngeal carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Non-keratinzing squamous cell 
carcinoma,undifferentiated subtype 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Non-keratinizing squamous cell carcinoma, 
undifferentiated subtype 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Non-keratinizing squamous cell carcinoma, 
undifferentiated subtype 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Non-keratinizing squamous cell carcinoma, 
undifferentiated subtype 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Non-keratinizing squamous cell carcinoma, 
undifferentiated subtype 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Non-keratinizing squamous cell 
carcinoma,undifferentiated subtype is 
considered(center Histology report). 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Metastatic nasopharyngeal carcinoma (center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 

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Histology 
type 
If other, please specify 
Histology type-New 
Other 
squamous carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Non - keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Non-keratinizing carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Nasopharyngeal carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Lymphoepithelial carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic Lymphoepithelial carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
squamous cell carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma (center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma (center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Metastatic nasopharyngeal carcinoma (center 
Histology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Poorly differentiated squamous cell 
carcinoma（local pathological report） 
Nasopharyngeal 
carcinoma,unclassified 
Other 
nasopharynx（Non-keratinizing  cell 
carcinoma, undifferentiated） 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Unknown 
Non-keratinizing squamous cell 
carcinoma, undifferentiated 
Other 
Malignant tumor, metastatic poorly 
differentiated carcinoma（site pathological 
report） 
Nasopharyngeal 
carcinoma,unclassified 

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Histology 
type 
If other, please specify 
Histology type-New 
Other 
left parotid sarcoma, pleomorphic 
rhabdomyosarcoma（site pathological report
） 
Other 
Other 
Nasopharyngeal carcinoma (central 
pathology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Nasopharyngeal carcinoma (central 
pathology report) 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Lymphoepitheliomatous nasopharyngeal 
carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Nasopharyngeal carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Nasopharyngeal carcinoma with 
lymphoepithelioma-like carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
Other 
Nonkeratinising Nasopharyngeal Carcinoma 
Non-keratinizing 
carcinoma,unclassified 
Other 
Undifferentiated Carcinoma 
Nasopharyngeal 
carcinoma,unclassified 
 
 
 

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6.4 
Appendix D 
Previous AE PT 
Aggregated AE PT 
Aggregated AE SOC 
White blood cell count 
decreased 
Leukopenia 
Blood and lymphatic system 
disorders 
Leukopenia 
Leukopenia 
Blood and lymphatic system 
disorders 
Neutrophil count decreased Neutropenia 
Blood and lymphatic system 
disorders 
Febrile neutropenia 
Neutropenia 
Blood and lymphatic system 
disorders 
Granulocytopenia 
Neutropenia 
Blood and lymphatic system 
disorders 
Neutropenia 
Neutropenia 
Blood and lymphatic system 
disorders 
Platelet count decreased 
Thrombocytopenia 
Blood and lymphatic system 
disorders 
Thrombocytopenia 
Thrombocytopenia 
Blood and lymphatic system 
disorders 
Lymphocyte count 
decreased 
Lymphopenia 
Blood and lymphatic system 
disorders 
T-lymphocyte count 
decreased 
Lymphopenia 
Blood and lymphatic system 
disorders 
Lymphopenia 
Lymphopenia 
Blood and lymphatic system 
disorders 
Blood potassium decreased 
Hypokalaemia 
Metabolism and nutrition disorders 
Hypokalaemia 
Hypokalaemia 
Metabolism and nutrition disorders 
Malaise 
Fatigue 
General disorders and administration 
site conditions 
Asthenia 
Fatigue 
General disorders and administration 
site conditions 
Fatigue 
Fatigue 
General disorders and administration 
site conditions 
Catheter site rash 
Rash 
Skin and subcutaneous tissue 
disorders 
Rash maculo-papular 
Rash 
Skin and subcutaneous tissue 
disorders 
Erythema 
Rash 
Skin and subcutaneous tissue 
disorders 
Drug eruption 
Rash 
Skin and subcutaneous tissue 
disorders 
Papule 
Rash 
Skin and subcutaneous tissue 
disorders 
Rash pruritic 
Rash 
Skin and subcutaneous tissue 
disorders 
Rash 
Rash 
Skin and subcutaneous tissue 
disorders 
Back pain 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 

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Previous AE PT 
Aggregated AE PT 
Aggregated AE SOC 
Neck pain 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Pain in extremity 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Bone pain 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Pain in jaw 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Musculoskeletal chest pain 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Myalgia 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Musculoskeletal pain 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Chest pain 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Non-cardiac chest pain 
Musculoskeletal pain 
Musculoskeletal and connective 
tissue disorders 
Productive cough 
Cough 
Respiratory, thoracic and 
mediastinal disorders 
Cough 
Cough 
Respiratory, thoracic and 
mediastinal disorders 
Diarrhoea 
Diarrhoea 
Gastrointestinal disorders 
Gastroenteritis 
Diarrhoea 
Gastrointestinal disorders 
Pneumonia 
Pneumonia 
Infections and infestations 
Pneumonia aspiration 
Pneumonia 
Infections and infestations 
Hypoaesthesia 
Neuropathy peripheral 
Nervous system disorders 
Neuropathy peripheral 
Neuropathy peripheral 
Nervous system disorders 
Paraesthesia 
Neuropathy peripheral 
Nervous system disorders 
Peripheral sensory 
neuropathy 
Neuropathy peripheral 
Nervous system disorders 
Peroneal nerve palsy 
Neuropathy peripheral 
Nervous system disorders 
Rhinitis 
Upper respiratory tract 
infection 
Infections and infestations 
Sinusitis 
Upper respiratory tract 
infection 
Infections and infestations 
Acute sinusitis 
Upper respiratory tract 
infection 
Infections and infestations 
Upper respiratory tract 
infection 
Upper respiratory tract 
infection 
Infections and infestations 
Nasopharyngitis 
Upper respiratory tract 
infection 
Infections and infestations 
Bronchitis 
Upper respiratory tract 
infection 
Infections and infestations 
Laryngitis 
Upper respiratory tract 
infection 
Infections and infestations 

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Previous AE PT 
Aggregated AE PT 
Aggregated AE SOC 
Pharyngitis 
Upper respiratory tract 
infection 
Infections and infestations 
Respiratory tract infection 
Upper respiratory tract 
infection 
Infections and infestations 
Abdominal pain 
Abdominal pain 
Gastrointestinal disorders 
Abdominal discomfort 
Abdominal pain 
Gastrointestinal disorders 
Abdominal pain upper 
Abdominal pain 
Gastrointestinal disorders 
Abdominal pain lower 
Abdominal pain 
Gastrointestinal disorders 
Sinus arrhythmia 
Arrhythmia 
Cardiac disorders 
Sinus bradycardia 
Arrhythmia 
Cardiac disorders 
Tachycardia 
Arrhythmia 
Cardiac disorders 
Tachycardia paroxysmal 
Arrhythmia 
Cardiac disorders 
Peripheral swelling 
Oedema 
General disorders and administration 
site conditions 
Oedema 
Oedema 
General disorders and administration 
site conditions 
Oedema peripheral 
Oedema 
General disorders and administration 
site conditions 
Face oedema 
Oedema 
General disorders and administration 
site conditions 
Swelling face 
Oedema 
General disorders and administration 
site conditions 
Eyelid oedema 
Oedema 
General disorders and administration 
site conditions 
Periorbital oedema 
Oedema 
General disorders and administration 
site conditions 
Generalised oedema 
Oedema 
General disorders and administration 
site conditions 
Proteinuria 
Proteinuria 
Renal and urinary disorders 
Protein urine present 
Proteinuria 
Renal and urinary disorders 
Blood pressure systolic 
increased 
Hypertension 
Vascular disorders 
Blood pressure increased 
Hypertension 
Vascular disorders 
Hypertension 
Hypertension 
Vascular disorders 
Hypertensive crisis 
Hypertension 
Vascular disorders 
Blood bilirubin increased 
Blood bilirubin 
increased 
Investigations 
Blood bilirubin 
unconjugated increased 
Blood bilirubin 
increased 
Investigations 
Insomnia 
Insomnia 
Psychiatric disorders 
Initial insomnia 
Insomnia 
Psychiatric disorders