A Phase II Clinical Trial Evaluating the Efficacy and Safety of Sintilimab for Advanced Rare Cancers (SiARa Cancer Study) - Undifferentiated Pleomorphic Sarcoma (SiARa-UPS)
Phase: PHASE2
Conditions: Locally Advanced Undifferentiated Pleomorphic Sarcoma, Metastatic Undifferentiated Pleomorphic Sarcoma, Recurrent Undifferentiated Pleomorphic Sarcoma, Unresectable Undifferentiated Pleomorphic Sarcoma
Sponsor: M.D. Anderson Cancer Center

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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2020-1046 
Protocol Title 
A Phase II Clinical Trial Evaluating the Efficacy and Safety of 
Sintilimab for Advanced Rare Cancers (SiARa Cancer Study) – 
Undifferentiated Pleomorphic Sarcoma (SiARa-UPS) 
Protocol Phase 
II 
Protocol Version 
03 
Version Date 
03/02/2023 
 
Protocol PI 
Neeta Somaiah 
Department 
Sarcoma Medical Oncology 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
155055 
 
 
 
 
 
 

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Clinical Protocol 
Study Title: 
A Phase II Clinical Trial Evaluating the Efficacy and 
Safety of Sintilimab for Advanced Rare Cancers (SiARa 
Cancer Study) – Undifferentiated Pleomorphic Sarcoma 
(SiARa-UPS) 
Protocol Number: 
2020-1046 
Version and Date: 
Version 03, March 02, 2023 
Product Name: 
Sintilimab (Recombinant Fully Human Anti-PD-1 
Monoclonal Antibody Injection, R&D Code: IBI308) 
Study Phase: 
II 
Sponsor: 
MD Anderson Cancer Center  
 
 
 
Confidentiality Statement 
This document is the confidential information of MD Anderson. 
The content of this document shall not be disclosed to any person other than the investigators, research 
consultants or related personnel, and Institutional Review Board/Independent Ethics Committee. 
The information contained in this document must not be used for any purpose, except for the evaluation or 
conduction of this study, without the written consent of the sponsor. 
 
 

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Protocol Synopsis 
Protocol Number 
2020-1046 
Sponsor 
MD Anderson Cancer Center and Innovent Inc. 
Investigational Drug 
Sintilimab (R&D Code: IBI308) 
Active Ingredient 
Recombinant fully human anti-PD-1 monoclonal antibody 
Study Title
 
 
A Phase II Clinical Trial Evaluating the Efficacy and Safety of 
Sintilimab for Advanced Rare Cancers (SiARa Cancer Study) – 
Undifferentiated Pleomorphic Sarcoma (SiARa-UPS) 
Study Phase 
II 
Study Objectives 
Primary Objectives: 
 To evaluate the efficacy of sintilimab in subjects with UPS 
(ORR at 12W by RECIST 1.1)  
Secondary Objectives: 
 To evaluate the ORR (RECIST 1.1), disease control rate 
(DCR), progression-free survival (PFS), overall survival 
(OS), duration of response (DOR), and safety of sintilimab 
in subjects with UPS 
Exploratory Objectives: 
 To evaluate the correlation between biomarkers in tumor 
tissue and efficacy, including but not restricted to PD-L1 
expression level, presence of tertiary lymphoid structures 
(TLS), transcriptome sequencing, single-cell sequencing, 
and multicolor immunohistochemistry (IHC) analyses. 
 To evaluate the correlation between biomarkers in 
peripheral blood and efficacy, including but not restricted 
to soluble PD-L1, circulating tumor DNA (ctDNA), 
identification/quantification of immunologic changes and 
cytokine analyses 

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Study Design 
This is a Phase II clinical trial evaluating the efficacy and safety of 
sintilimab in subjects with UPS. 
A total of 25 subjects with UPS will be enrolled. Subjects will be 
treated with sintilimab (200 mg IV on Day 1 Q3W). The treatment 
will repeat every 3 weeks until progressive disease (PD), 
intolerable toxicity, initiation of new anti-tumor therapy, 
withdrawal of consent, lost to follow-up, death, completion of 
therapy, or any other investigator-determined reasons for treatment 
discontinuation (whichever occurs first). Treatment will continue 
for a maximum period of 24 months (starting from the first dose).  
During the trial, tumor imaging evaluation will be initially 
performed once Q6W (± 7 days) and will be based on RECIST 
1.1. After the completion or discontinuation of the study treatment, 
safety follow-up and survival follow-up will be performed. 
Inclusion Criteria 
1. Histopathologically confirmed unresectable, locally advanced, 
recurrent or metastatic UPS or high-grade myxofibrosarcoma. 
2. Refractory/ intolerant to at least one line of systemic 
chemotherapy. Patient ineligible for cytotoxic chemotherapy 
are eligibile.  
3. Aged ≥ 18. 
4. ECOG PS of 0 or 1. 
5. Subject must be unsuitable for definitive treatment, such as 
definitive chemoradiotherapy and/or surgery.  
6. Should be able to provide archival or fresh tissues for 
correlative analysis. 
7. Have at least one measurable lesion as per RECIST v1.1. 
8. Adequate organ and bone marrow functions, as defined below: 
1) Complete blood count: absolute neutrophil count (ANC) ≥ 1.0 
× 109/L, platelet (PLT) count ≥ 75 × 109/L, hemoglobin 
(HGB) ≥ 8.0 g/dL. Note: Subjects cannot receive blood 
transfusion, erythropoietin (EPO), or Granulocyte-colony 

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stimulating factor (GSF) within 7 days prior to the blood 
collection.  
2) Hepatic function: total bilirubin (TBIL) ≤ 1.5 × upper limit of 
normal (ULN), alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤ 2.5 × ULN in subjects without 
hepatic metastasis; TBIL ≤ 1.5 × ULN, ALT and AST ≤ 5 × 
ULN in subjects with hepatic metastasis.  
Exception: Patients with known Gilbert disease: serum 
bilirubin level ≤ 3 × ULN.  
3) Renal function: urine protein < 2+ from random sample or < 1 
g from 24-hour urine collection, and creatinine clearance rate 
(Ccr) ≥ 50 mL/min by Cockcroft-Gault formula: 
Female: 𝐶𝑐𝑟=
(140−𝑎𝑔𝑒)×weight(kg)×0.85
72×serum creatinine(mg/dL) 
Male: 𝐶𝑐𝑟=
(140−𝑎𝑔𝑒)×weight(kg)×1.00
72×serum creatinine(mg/dL) 
4) Adequate coagulation function, defined as international 
normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × 
ULN; if the subject is receiving anticoagulant therapy, the 
results of coagulation tests need to be within the acceptable 
range for anticoagulants. 
9. Expected survival ≥ 12 weeks. 
10. Subject (female subjects of childbearing age or male subjects 
whose partners are of childbearing age) must take effective 
contraceptive measures during the entire course of the trial 
and until 180 days after the last dose (see Section 4.3). 
11. Signed the informed consent form (ICF) and be able to 
comply with the scheduled follow-up visits and related 
procedures required in the protocol. 
Exclusion Criteria 
1. Received treatment with an anti-PD-1, anti-PD-L1, anti-PD-
L2, anti-CD137, or anti-CTLA-4 antibody, or any other 
antibody or drug that specifically targets T-cell co-stimulation 
or immune checkpoint pathways. 

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2. Enrolled in another interventional clinical study, unless only 
involved in an observational study (non-interventional) or in 
the follow-up phase of an interventional study. 
3. Received palliative therapy for a local lesion within 2 weeks 
prior to the first dose.  
4. Received systemic treatment with anti-cancer indications or 
immunomodulators (including thymosins, interferons, and 
interleukins) within 2 weeks prior to the first dose of study 
treatment. 
5. Received systemic immunosuppressants within 2 weeks, 
excluding local use of glucocorticoids administered by nasal, 
inhaled, or other routes, and systemic glucocorticoids at 
physiological doses (no more than 10 mg/day of prednisone or 
equivalents), or glucocorticoids to prevent allergies to contrast 
media. 
6. Received a live attenuated vaccine within 4 weeks prior to the 
first dose of study treatment or be scheduled to receive live 
attenuated vaccine during the study period. 
Note: Seasonal inactivated influenza virus vaccines within 4 
weeks prior to the first dose of study treatment are permitted, 
but attenuated influenza vaccines are not. 
7. Received major surgery (craniotomy, thoracotomy, or 
laparotomy) within 4 weeks prior to the first dose of study 
treatment or is scheduled to receive major surgery during the 
course of the trial. 
8. Any toxicity (excluding alopecia, events that are not clinically 
significant, or asymptomatic laboratory abnormalities) due to 
prior anti-tumor therapy that has not yet resolved to National 
Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v5.0 grade 0 or 1 prior to the first dose 
of study treatment. 
9. Known symptomatic central nervous system (CNS) metastasis 
or carcinomatous meningitis. Subjects with brain metastases 
who have received prior treatment can be enrolled if the 
disease is stable (no imaging evidence of PD for at least 4 

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weeks prior to the first dose of study treatment), there is no 
evidence of new brain metastases or progression of the 
existing metastatic lesion(s) upon repeated imaging, and 
corticosteroids have not been required for at least 14 days 
prior to the first dose of study treatment. Patients with 
carcinomatous meningitis are ineligible, regardless of whether 
the disease is clinically stable or not. 
10. Subjects with bone metastases at risk of paraplegia. 
11. Known active autoimmune disease requiring treatment or 
previous disease history within 2 years (subjects with vitiligo, 
psoriasis, alopecia, or Graves' disease not requiring systemic 
treatment, hypothyroidism only requiring thyroid replacement, 
or type I diabetes only requiring insulin can be enrolled). 
12. Known history of primary immunodeficiency diseases. 
13. Known active pulmonary tuberculosis. 
14. Known history of allogeneic organ transplantation or 
allogeneic hematopoietic stem cell transplantation. 
15. HIV-infected subjects (positive anti-HIV antibody). 
16. Active or poorly controlled serious infections. 
17. Symptomatic congestive heart failure (NYHA Class II–IV) or 
symptomatic or poorly controlled arrhythmia. 
18. Uncontrolled hypertension (systolic blood pressure ≥ 160 
mmHg or diastolic blood pressure ≥ 100 mmHg) despite 
standard treatment. 
19. Any arterial thromboembolic event within 6 months prior to 
enrollment, including myocardial infarction, unstable angina, 
cerebrovascular accident, or transient cerebral ischemic attack. 
20. Significant malnutrition, such as those requiring continuous 
parenteral nutrition ≥7 days; excluding those having received 
intravenous treatment for malnutrition for more than 4 weeks 
before the first dose of study treatment. 
21. History of clinically significant deep venous thrombosis, 
pulmonary embolism, or other serious thromboembolic events 
within 3 months prior to enrollment (implantable port or 

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catheter-related thrombosis or incidental PE detected on scan 
without symptoms or superficial venous thrombosis are not 
considered as "serious" thromboembolisms). 
22. Uncontrolled metabolic disorders, non-malignant organ or 
systemic diseases, or cancer-related secondary diseases that 
may lead to higher medical risks and/or survival evaluation 
uncertainties. 
23. Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis 
with Child-Pugh Class B or C. 
24. Bowel obstruction or history of the following diseases: 
inflammatory bowel disease, extensive bowel resection 
(partial colectomy or extensive small intestine resection 
accompanied with chronic diarrhea), Crohn's disease, or 
ulcerative colitis. 
25. Known acute or chronic active hepatitis B (positive HBsAg 
and HBV DNA viral load > 104 copies/mL or > 2000 IU/mL), 
or acute or chronic active hepatitis C (HCV RNA>103 
copies/mL), or simultaneously positive for HBsAg and HCV 
antibody. 
26. History of gastrointestinal (GI) perforation and/or fistula 
within 6 months prior to the enrollment, excluding 
gastrostomy or enterostomy. 
27. Interstitial lung disease requiring corticosteroids. 
28. History of other primary malignant tumors, excluding: 
 Malignant tumors that achieved a complete response (CR) 
at least 2 years prior to enrollment and expected to require 
no treatment during the trial. 
 Adequately treated nonmelanoma skin cancer or lentigo 
maligna with no sign of disease recurrence. 
 Adequately treated carcinoma in situ with no sign of 
disease recurrence. 
 Prostate cancer, CLL or other cancers where the indolent 
nature of tumor allows for and patient is under active 
surveillance. 

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29. Pregnant or breastfeeding female subjects. 
30. Acute or chronic diseases, psychiatric disorders, or laboratory 
abnormalities that may lead to the following consequences: 
increased investigational drug-related risks, interference with 
interpreration of trial results, or considered ineligible for 
participating in the trial by the investigators. 
Study Drugs, Strengths, 
and Administrations 
• 
Sintilimab 
- Administration: 200 mg IV D1 Q3W 
Evaluation Criteria 
 
 
Efficacy evaluation: 
 Primary endpoints: ORR at 12W as assessed by MD 
Anderson radiology review per RECIST v.1.1 
 Secondary endpoints: ORR (RECIST v.1.1), DCR, DOR, 
PFS, OS 
Safety evaluation: 
 The incidence and severity of treatment-emergent adverse 
events (TEAEs), treatment-related adverse events 
(TRAEs), serious adverse events (SAEs), AEs leading to 
discontinuation, AEs leading to death, and immune-related 
adverse events (irAEs). 
 Assessment of vital signs, physical examination, and 
laboratory tests results before, during, and after study 
treatment. 
Biomarker evaluation: 
 Correlation between biomarkers in the baseline tumor 
tissue and efficacy, including PD-L1 expression level, 
presence of tertiary lymphoid structures (TLS), 
transcriptome sequencing, single-cell sequencing, and IHC 
analyses 
 Correlation between biomarkers in peripheral blood and 
efficacy, including the soluble form of PD-L1, ctDNA, 
identification/quantification of immunologic changes and 
cytokine analyses 

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Statistical Analysis 
Method 
Efficacy endpoints: 
The ORR (12 weeks), best ORR and DCR and the corresponding 
95% CIs will be estimated. The DOR, PFS and OS will be 
analyzed using Kaplan-Meier Method. 
Safety data: 
The incidence and severity of AEs will be summarized, and 
laboratory abnormalities will be presented. 
Biomarkers: 
PD-L1 expression levels and distribution, presence of TLS and 
other potential biomarkers will be analyzed, and the potential 
correlation between these biomarkers and efficacy will be 
explored. 

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Table 1 Schedule of visits 
Phase 
Screening 
Treatment 
End-of-
Treatment 
Visit17 
Safety Follow-Up 
Survival 
Follow-Up20 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
From 
Cycle 7 
Onwards 
 
 
 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9–N 
Within ±7 
days after end 
of treatment 
30th 
day (± 
7 days) 
after 
the last 
dose18 
90th 
day 
(±7 
days) 
after 
the 
last 
dose19 
Every 60 
days (± 7 
days) 
Day 
-28 to -1 
1 
8 (± 3 
days) 
22 (± 
3 
days) 
43 (± 
3 
days) 
64 (± 
3 
days) 
85 (± 
3 
days) 
106 
(± 3 
days) 
Every 3 
weeks (± 
3 days) 
General Study Procedures 
Written ICF1 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History/Previous 
Medication2 
× 
 
 
 
 
 
 
 
 
 
 
 
 

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Vital Signs3 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
 
 
 
Weight/Height4 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
 
 
 
Physical Examination4 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
 
 
 
ECOG PS4 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
12-Lead ECG5 
× 
 
 
× 
× 
× 
× 
× 
× 
x 
× 
 
 
Laboratory Tests 
CBC/Blood 
Biochemistry/Routine 
Urinalysis6 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
Coagulation Function7 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test8 
× 
 
 
× 
 
× 
 
× 
×8 
× 
 
 
 
Thyroid Function9 
× 
 
 
× 
 
× 
 
× 
×9 
× 
 
 
 
HIV, HBV, and HCV10 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluation 
AE Evaluation11 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
Concomitant 
Medication 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 

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Survival Status 
 
 
Subsequent Anti-Tumor 
Therapy 
 
 
 
 
 
 
 
 
 
× 
× 
× 
× 
Efficacy Evaluation 
Tumor Imaging 
Evaluation12 
× 
 
 
 
x 
 
x 
 
× 
× 
 
 
 
Study Drug Infusion 
Sintilimab13 
 
× 
 
× 
× 
× 
× 
× 
× 
 
 
 
 
Quality of Life Evaluation14 
EQ 5D-5L + QLQ-C30 
 
× 
 
  
x 
 
x 
 
× 
× 
 
 
 
PRO-CTCAE™ 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
Biomarker Study 
Archival/Fresh Tumor 
Tissue Sample15 
× 
 
 
 
× 
 
 
 
 
x 
 
 
 
Blood16 
 
× 
× 
× 
× 
 
 
 
 
× 
 
 
 
PK/Antidrug antibodies (ADA) 
PK/ADA Sample21 
 
× 
× 
× 
 
× 
 
 
× 
 
 
 
 

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Note: 
1. The ICF should be signed by subjects prior to any procedures outlined in the protocol. 
2. Medical history includes all active diseases and diseases that are clinically significant as determined by the investigator, including surgery, and drug allergy. 
All autoimmune diseases should be documented, regardless of the date of onset. All medications (including replacement/supplement drugs) used within 3 
days prior to the first dose of study treatment, including any washout requirements specified in the protocol, should be documented. 
3. Vital signs: body temperature, pulse, respiratory rate, and blood pressure. 
4. Height will only be measured during screening. Weight, physical examination and PS need not be repeated if done previously within 7 days of C1D1. 
Comprehensive physical examination is needed at all day 1 visit for each cycle. Targeted physical examination can be performed for visit scheduled outside 
the protocol as clinically indicated.  
5. 12-lead ECG: within 7 days prior to the first dose during screening, within 3 days prior to administration of study treatment in each cycle (except Cycle 1), 
and during end-of-treatment visit. 
6. Complete blood count: red blood cell (RBC) count, HGB, white blood cell (WBC) count, PLT count, WBC differentials [lymphocyte (LYM) count and 
ANC]. Blood biochemistry: hepatic function [TBIL, ALT, AST, alkaline phosphatase (ALP), albumin (ALB), total protein (TP), and lactate dehydrogenase 
(LDH)], renal function [urea (UREA) and Cr], electrolytes (Na, K, Cl, Mg, Ca, and P), amylase, and blood glucose (BG). Routine urinalysis: pH (PH), urine 
white blood cell (UWBC), urine protein (UPRO), urine red blood cell (URBC), and urine glucose (UGLU), will be performed within 7 days prior to the first 
dose during screening, and during the end-of-treatment visit. Complete blood count and blood biochemistry are performed within 7 days prior to the first 
dose during screening, within 3 days prior to each dose, during the end-of-treatment visit, and during the first safety follow-up. Tests will be conducted in 
each local lab. 
7. Coagulation function tests: PT and INR. The test will be conducted within 7 days prior to the first dose. Tests will be conducted in each local lab. 
8. Women of childbearing potential will undergo a blood pregnancy test within 3 days prior to the first dose and during the end-of-treatment visit and a urine 
pregnancy test will be done prior to every other cycle from Cycle 2 onwards. If the urine pregnancy test is not conclusive, then a blood pregnancy test 
should be performed. The conclusion should be based on the blood pregnancy test. Tests will be conducted in each local lab. 
9. The tests will be conducted during screening, within 3 days prior to the administration of the study drug from Cycle 2 onwards, prior to every other cycle 
and during end-of-treatment visit. Thyroid function tests: thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free tetraiodothyronine 
(FT4). Tests will be conducted in each local lab. 

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10. Hepatitis B panel (HBsAg, HBsAB, HBcAB), HCV antibody, and HIV antibody will be tested during screening. If the result shows HBsAg positive, then 
HBV DNA test should be further conducted. If the result shows HCV antibody positive, then HCV RNA test should be further conducted. The results 
obtained within 28 days prior to start of therapy can be accepted. Prophylactic antiviral therapy is suggested to be performed according to the local 
treatment guidelines for HBV carriers. Tests will be conducted in each local lab. 
11. AE and laboratory safety evaluations will be performed according to NCI CTCAE v5.0. Refer to Section 8 for AE and SAE definitions, recording, 
determination of causal relationship, severity, reporting deadlines, and processing. C1D8 AE evaluation will be conducted via phone. 
12. Tumor evaluations will be performed based on RECIST v1.1 and the same imaging method (CT/MRI) should be used for the same subject during the trial. 
Baseline evaluation will be conducted within 28 days prior to enrollment. After the first dose of study treatment, tumor imaging evaluation will be 
performed once Q6W (± 7 days) and Q9W (± 7 days) starting from Cycle 7, until initiation of a new anti-tumor therapy, PD (assessed at 12W or after), 
withdrawal of informed consent, lost to follow up, completion of treatment, or death. If the subject has confirmed or suspected bone metastatic lesion 
presents at baseline, a PET scan with contrast can be used for imaging evaluation. For subjects who discontinue the treatment for reasons other than 
imaging-confirmed PD, if the subject’s last imaging evaluation is greater than 4 weeks prior to discontinuation, the imaging evaluation should be performed 
at the end-of-study treatment visit and be reperformed Q12W (± 7 days) thereafter until one of the followings occurs: start of new anti-tumor therapy, PD, 
withdrawal of informed consent, lost to follow-up or death. 
13. Sintilimab: 200 mg, IV Q3W, for up to 24 months (starting from the first dose), or until PD, death, intolerable toxicity, withdrawal of informed consent, 
completion of treatment, or any other investigator-determined reason for treatment discontinuation.  Treatment can be delayed for up to 1 week if the 
administration day is on a holiday. The study treatment can be administered 3 days before or 3 days after the scheduled day of administration. 
14. Quality of life evaluation: on the day of the first dose, during each imaging evaluation, including EQ 5D-5L, EORTC QLQ-C30. PRO-CTCAE™ will be 
administered day 1 of every cycle, and during the first safety follow up.  
15. Subjects are required to provide at least 20 slices of archived or fresh tumor tissue samples during screening for biomarkers. If not available, a fresh biopsy 
will be performed. Optional biopsy at C3D1 +/-7 days, and when PD is confirmed. 
16. 60 mL whole blood samples are required to be provided by subjects for biomarker testing at the following time points: prior to the first dose, C1D8, C2D1, 
C3D1, when first PD is seen, and EOT/when PD is confirmed. 
17. The end-of-treatment visit should be conducted within ±7 days after the end of treatment is confirmed. 
18. Safety follow-up at 30th day (± 7 days) after the last dose or before initiation of a new anti-tumor therapy. If the safety follow-up is performed within 7 days 
of the end-of-treatment visit, then the safety follow-up may be replaced by the end-of-treatment visit and does not need to be repeated. However, all 
procedures for the safety follow-up should be completed. 

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19. Safety follow-up at 90th day (±7 days) after the last dose. All AEs including SAEs and irAEs will be collected within 90 days (±7 days) after the last dose if 
new anti-tumor therapy has not been initiated. Only irAEs and sintilimab- or procedure-related SAE will be collected if a new anti-tumor therapy has been 
initiated. 
20. Survival follow-up: once every 60 days (± 7 days) after the safety follow-up till death or for a duration of 3 years after last patient enrolled. Telephone visits 
are allowed. 
21. PK/ADA sample (5 ml each) will be collected at the following time points: within 1h before, any point within 2-24h after, any point within 120-264h after 
Sintilimab infusion in Cycle 1, within 1h before sintilimab infusion in Cycle 2/4, and then within 1h before sintilimab infusion with every 4 cycles 
thereafter starting cycle 7 (e.g. Cycle 7, 11, 15 etc.). 

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Table of Contents 
Title Page ........................................................................................................................................ 1 
Protocol Synopsis............................................................................................................................ 3 
Table of Contents .......................................................................................................................... 17 
List of Tables ................................................................................................................................ 22 
List of Figures ............................................................................................................................... 22 
List of Abbreviations .................................................................................................................... 23 
1 Background ................................................................................................................................ 28 
1.1 Disease Background ............................................................................................... 28 
1.1.1 Scope of Problem ................................................................................................ 28 
1.1.2 Rationale for use of Immunotherapy in UPS ...................................................... 28 
1.2 Investigational Drug (Sintilimab) ........................................................................... 29 
1.2.1 Mechanism of action ........................................................................................... 29 
1.2.2 Clinical study results of sintilimab ...................................................................... 30 
1.3 Risk/Benefit Assessment ........................................................................................ 31 
1.3.1 Potential risks ...................................................................................................... 31 
1.3.2 Potential benefits ................................................................................................. 31 
2 Study Objectives ........................................................................................................................ 32 
2.1 Primary Objectives ................................................................................................. 32 
2.2 Secondary Objectives ............................................................................................. 32 
2.3 Exploratory Objectives: .......................................................................................... 32 
3 Study Design .............................................................................................................................. 32 
3.1 Overall Design ........................................................................................................ 32 
3.2 Definition of Study Completion ............................................................................. 33 
3.3 Criteria for Study Discontinuation ......................................................................... 33 

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4 Study Population ...................................................................................................................... 334 
4.1 Inclusion Criteria .................................................................................................... 34 
  4.2 Exclusion Criteria ............................................................................................................... 35 
  4.3 Restrictions During the Study ............................................................................................. 38 
4.4 Criteria for Discontinuation/Withdrawal ................................................................ 39 
4.4.1 Treatment discontinuation ................................................................................... 39 
4.4.2 Subject withdrawal .............................................................................................. 40 
4.4.3 Lost to follow-up ................................................................................................. 40 
5 Study Drugs and Other Treatments............................................................................................ 41 
5.1 Treatment Regimens of Study Drugs ..................................................................... 41 
5.1.1 Sintilimab ............................................................................................................ 41 
5.2 Dose Adjustments ................................................................................................... 43 
5.2.1 General principles ................................................................................................ 43 
5.2.2 Sintilimab dose adjustments ................................................................................ 43 
5.2.3 Management of sintilimab-related infusion reactions ......................................... 56 
5.3 Principles for Managing Immune Checkpoint Inhibitor Toxicities ........................ 58 
5.4 Concomitant Treatments ......................................................................................... 58 
5.4.1 Prohibited treatments ........................................................................................... 58 
5.4.2 Permitted treatments ............................................................................................ 59 
5.4.3 Drug-drug interactions ........................................................................................ 60 
5.5 Drug Management .................................................................................................. 60 
5.5.1 Return and destruction ......................................................................................... 60 
5.6 Study Drug Records ............................................................................................... 60 
6 Study Procedure ......................................................................................................................... 61 
6.1 Enrollment .............................................................................................................. 61 

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6.1.1 Enrollment ........................................................................................................... 61 
6.1.2 Enrollment error handling ................................................................................... 61 
6.2 Study Plan and Schedule ........................................................................................ 61 
6.2.1 Screening ............................................................................................................. 61 
    6.2.1.1 Medical history ......................................................................................... 62 
    6.2.1.2 Prior medications ...................................................................................... 62 
    6.2.1.3 Concomitant medications ......................................................................... 63 
6.2.2 Baseline (prior to Day 1 of Cycle 1) ................................................................... 63 
6.2.3 Tumor imaging evaluation (if applicable) Tumor biopsy (if applicable) Treatment 
visits  ............................................................................................................................ 63 
6.2.4 End-of-treatment visits ........................................................................................ 64 
6.2.5 Safety follow-up .................................................................................................. 64 
6.2.6 Survival follow-up ............................................................................................... 65 
6.2.7 Unscheduled visits ............................................................................................... 66 
7 Study Evaluation ........................................................................................................................ 66 
7.1 Efficacy Evaluation ................................................................................................ 66 
7.1.1 Tumor imaging and disease evaluations .............................................................. 66 
7.1.2 Tumor imaging during the study ......................................................................... 66 
7.2 Safety Evaluation ................................................................................................... 68 
7.2.1 Physical Examination .......................................................................................... 68 
    7.2.1.1 Comprehensive physical examination ...................................................... 68 
    7.2.1.2 Targeted physical examination ................................................................. 68 
    7.2.1.3 ECOG PS .................................................................................................. 68 
    7.2.1.4 Vital signs ................................................................................................. 69 
    7.2.1.5 12-lead ECG ............................................................................................. 69 
7.2.2 Routine laboratory safety evaluations ................................................................. 69 

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    7.2.2.1 Laboratory safety evaluation .................................................................... 69 
    7.2.2.2 Pregnancy test ........................................................................................... 69 
7.3 Biomarker Analysis ................................................................................................ 70 
7.3.1 Tissue biomarkers ................................................................................................ 70 
7.3.2 Serum biomarkers ................................................................................................ 71 
7.4 Pharmacokinetics (PK) ................................................................................................... 71 
8 Safety Reports and AE Management ......................................................................................... 71 
8.1 Definition of AEs .................................................................................................... 71 
8.2 Evaluating Adverse Events ..................................................................................... 72 
8.3 AE Documentation ................................................................................................. 76 
8.3.1 Collection and time of AEs ................................................................................. 76 
8.3.2 Follow-up of AEs ................................................................................................ 77 
8.3.3 Contents of AE documentation ............................................................................ 77 
8.4 Serious Adverse Events  ........................................................................................ 80 
8.4.1 Serious Adverse Event (SAE) Reporting Requirements for M D Anderson 
Sponsor Single Site IND Protocols .............................................................................. 80 
8.4.2 Serious Adverse Event (SAE) Reporting to the Supporting Company ............... 81 
8.4.3 Pregnancy ............................................................................................................ 82 
8.5 Abnormal Hepatic Function ................................................................................... 83 
8.6 Management of Drug-Related Toxicities ............................................................... 83 
8.6.1 irAEs .................................................................................................................... 83 
9 Statistics ..................................................................................................................................... 83 
9.1 Statistical Analysis Plan ......................................................................................... 83 
9.2 Statistical Analysis Population ............................................................................... 83 
9.3 Statistical Analysis Methods  ................................................................................ 85 
9.3.1 General statistical analysis .................................................................................. 85 

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    9.3.1.1 Analysis of primary efficacy endpoints .................................................... 85 
    9.3.1.2 Design and sample size/power ................................................................. 85 
    9.3.1.3 Stopping Rule Monitoring ........................................................................ 85 
9.3.2 Safety analysis ..................................................................................................... 86 
    9.3.2.1 Drug exposure .......................................................................................... 87 
    9.3.2.2 AEs ........................................................................................................... 87 
    9.3.2.3 Laboratory tests ........................................................................................ 87 
    9.3.2.4 ECG .......................................................................................................... 88 
    9.3.2.5 Vital signs, physical examination, and other safety-related examinations 88 
9.3.3 Compliance .......................................................................................................... 88 
9.3.4 Baseline characteristics and concomitant medications ....................................... 88 
9.3.5 Data lists of eligible subjects ............................................................................... 88 
9.3.6 Exploratory analysis ............................................................................................ 88 
10 Quality Assurance and Quality Control ................................................................................... 89 
10.1 Clinical Monitoring .............................................................................................. 89 
11 Data Management and Record Keeping .................................................................................. 89 
12 Ethics........................................................................................................................................ 91 
12.1 Implementation of Ethics ..................................................................................... 91 
12.2 Informed Consent ................................................................................................. 91 
12.3 Protection of Subjects' Data ................................................................................. 92 
12.4 Protocol Violation ................................................................................................. 92 
13 Publishing of Study Data ......................................................................................................... 92 
14 References ................................................................................................................................ 93 
15 Appendix .................................................................................................................................. 95 
Appendix 1: Signature Page for Investigator  ............................................................. 95 

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Appendix 2: ECOG PS ................................................................................................. 96 
Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) .............. 97 
Appendix 4: Schedule of Biomarker Samples ............................................................113 
Appendix 5: EQ 5D-5L Paper Interviewer Administration V1.0 ................................114 
Appendix 6: EQ 5D-5L Self-Complete V1.1 ..............................................................117 
Appendix 7: EORTC QLQ-C30 ................................................................................. 120 
Appendix 8: PRO-CTCAE ™ .................................................................................... 122 
List of Tables 
Table 1 Schedule of visits ..............................................................................................................11 
Table 2 Effective methods of contraception ................................................................................. 39 
Table 3 Dosage and administration ............................................................................................... 41 
Table 4 Sintilimab dose adjustments ............................................................................................. 43 
Table 5 Guidelines for the management of sintilimab-related infusion reactions ........................ 56 
Table 6 Routine laboratory safety evaluation ............................................................................... 69 
Table 7 Detailed rules of AE evaluation ....................................................................................... 73 
Table 8 Liver injuries required to be reported as SAEs ................................................................ 83 
Table 9 Time point response: subjects with target (with or without non-target) disease. ........... 107 
Table 10 Time point response: subjects with non-target disease only. ....................................... 108 
Table 11 Best overall response when confirmation of CR and PR required. .............................. 109 
 
List of Figures 
Figure 1 Schematic of study design and administration ............................................................... 33 

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List of Abbreviations 
Abbreviations 
Full Name 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALB 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATG 
Antithymocyte globulin 
AUC 
Area under the curve 
β-hCG 
β-human chorionic gonadotropin 
Ccr 
Endogenous creatinine clearance rate 
CK 
Creatine Kinase 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA4 
Cytotoxic T-lymphocyte-associated protein 4 

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Abbreviations 
Full Name 
Cr 
Creatinine 
DCR 
Disease control rate 
DoR 
Duration of response 
DMARD 
Disease-modifying antirheumatic drug 
EC 
Ethics committee 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC QLQ-
C30 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire-Core 30 
FAS 
Full analysis set 
FBG 
Fasting blood glucose 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
γ-GT 
γ-glutamyltransferase 
HBcAb 
Hepatitis B core antibody 
HBeAb 
Hepatitis B e antibody 
HBeAg 
Hepatitis B e antigen 
HBsAb 
Hepatitis B surface antibody 

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Abbreviations 
Full Name 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HGB 
Hemoglobin 
HR 
Hazard ratio 
ICF 
Informed consent form 
ICPi 
Immune Checkpoint inhibitor 
iDMC 
Independent Data Monitoring Committee 
Ig 
Immunoglobulin 
INR 
International normalized ratio 
irAE 
Immunity-related adverse event 
ITT 
Intention to treat 
IV 
Intravenous 
IRR 
Independent radiology review 
LCSS 
The Lung Cancer Symptom Scale 
MRI 
Magnetic resonance imaging 
NAb 
Neutralizing antibody 
NGS 
Next-generation sequencing 
NSAIDS 
Nonsteroidal anti-inflammatory drugs 

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Abbreviations 
Full Name 
NSCLC 
Non-small-cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PEX 
Physical Examimation 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PLT 
Platelet count 
PPS 
Per-protocol set 
PR 
Partial response 
PT 
Prothrombin time 
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 

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Abbreviations 
Full Name 
SD 
Stable disease 
SS 
Safety set 
TCR 
T-cell receptor 
TBIL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
TP 
Total protein 
TPS 
Tumor Proportion Score 
TSH 
Thyroid stimulating hormone 
TTR 
Time to response 
ULN 
Upper limit of normal 
UGLU 
Urine glucose 
UPRO 
Urine protein 
URBC 
Urine red blood cell 
UREA 
Urea 
UWBC 
Urine white blood cell 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell count 
 
 

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1 Background 
1.1 Disease Background 
1.1.1 Scope of Problem 
Malignant Fibrous Histiocytoma/ Undifferentiated Pleomorphic Sarcoma (MFH/UPS) represents 
a group of soft tissue sarcoma (STSs) considered to be of probable fibrohistiocytic or fibroblastic 
lineage. UPSs account for 10% of adult STSs and represent one of the most common STSs of 
older adults, with most occurring in patients between the ages of 50 and 70 years [1]. Pediatric 
UPSs are rare. The etiology is unknown, although some of these tumors occur in a previously 
irradiated field. The most frequent location are the limbs followed by the trunk. As for other 
STSs, surgery performed by an experienced surgeon plus radiotherapy remain the cornerstone of 
treatment of nonmetastatic tumors. With the majority of these tumors being high grade, 
perioperative chemotherapy is an option, but recurrence/metastasis is common. In the metastatic 
setting, doxorubicin as a single agent is considered the standard first choice (ORR<20%), but is 
also used in combination with ifosfamide (ORR 26%), which assumes that the findings with 
these treatments in other STSs also are applicable to UPS [2]. In fact, despite being one the most 
common STS subtypes, few data are available in this specific subtype. Other drugs such as 
gemcitabine and docetaxel, and pazopanib also have shown activity in the advanced setting. 
Median survival in advanced STS ranges from 12-20 months on average [3,4]. Patients with 
advanced UPS have the worst outcome compared with other histologic STS subtypes [5]. 
Metastatic/recurrent high-grade myxofibrosarcoma has a similar behaviour to UPS. Some 
pathologists might call high grade myxofibrosarcoma with pleomorphic cells as UPS. No 
standard of care or FDA approved agents specific to this subtype exist. There is an urgent 
unmet and critical need to develop novel agents for this orphan disease.  
1.1.2 Rationale for use of Immunotherapy in UPS 
Compared to “immunogenic” tumors such as melanoma characterized by high mutation rates, 
STS are considered to be immunologically “quiet.” [6] Among STS subtypes, however, some 
histologies such as undifferentiated pleomorphic sarcoma (UPS) are characterized by complex 
genomic features, and a baseline immune infiltrate, which may provide immunologic mutated 
protein targets, and may respond to immune checkpoint inhibition [7]. T-cell infiltration and PD-
L1 expression were found to be higher in sarcomas with complex genomics and particularly in 
UPS than in other STSs. Indeed, this was described in the recently reported open-label phase II 

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SARC028 trial (NCT02301039) of anti-PD-1 monotherapy in patients with advanced bone and 
soft tissue sarcomas [8]. In the SARC028 study, pembrolizumab demonstrated promising activity 
in UPS with a 40% overall response rate in the first 10 patients, with median PFS of 7 months 
(95% CI: 1.9-15.9). This study was expanded to include a total of 40 UPS patients, and though 
the ORR reported was lower at 23% with a median PFS of 3 months, among the included 
subtypes, UPS was still the subtype with the higest activity [9]. Activity of checkpoint inhibitors 
in this subtype was also seen in the Sarcoma Alliance study with nivolumab plus ipilimumab 
with ORR of 18% (2/11) [10]. In these studies high-grade myxofibrosarcoma patients were also 
included.  
Based on this information, we propose a phase II clinical trial evaluating the efficacy and safety 
of sintilimab in subjects with UPS/ high-grade myxofibrosarcoma to explore activity of 
Sintilimab in UPS. 
Study Hypothesis: Sintilimab, fully humanized anti-PD1 antibody, can result in durable tumor 
responses in advanced refractory UPS.        
1.2 Investigational Drug (Sintilimab) 
1.2.1 Mechanism of action  
Immune checkpoints are a type of immune inhibitory molecule, whose physiological function is 
to regulate the intensity and extent of the immune response and to avoid damage and destruction 
of normal tissues. Cancer cells often manipulate these immune checkpoints to escape immune 
surveillance. The efficacy of drugs designed to block the actions of immune checkpoints such as, 
CTLA-4 and PD-1/PD-L1, has been validated clinically. 
PD-1, the receptor primarily expressed on activated T-cells, has two ligands, PD-L1 and PD-L2. 
PD-L1 is the main ligand that is expressed on activated T-cells, antigen-presenting cells, and 
tumor cells [11]. The binding of PD-1 with PD-L1 plays an important role in regulating T cell 
activation and maintaining peripheral immune tolerance. When T cells do not express PD-1, they 
interact with antigen-presenting cells to enable the activation and proliferation of T cells as well 
as the secretion of activated cytokines, which can kill tumor cells. Activated T cells begin to 
express PD-1. After PD-1 binds to the ligand PD-L1 expressed on the surface of antigen-
presenting cells or tumor cells, the inhibitory signal transmitted by PD-1 inhibits the proliferation 
of T cells and the secretion of activated cytokines, thus weakening the function of T cells. Most 
tumor cells evade the attack from immune cells through this mechanism. The activity of T cells 

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and their ability to kill cancer cells can be restored by blocking the PD-1/PD-L1 interaction with 
drugs [12].  
Sintilimab is a recombinant fully human IgG4 anti-PD-1 monoclonal antibody (R&D code: 
IBI308). Multiple preclinical in vitro and in vivo studies have demonstrated the ability of 
sintilimab to block the PD-1 pathway. The anti-tumor activity of murine analogs of sintilimab 
has also been demonstrated in various murine tumor models. 
1.2.2 Clinical study results of sintilimab 
A Phase 1a dose-escalation trial was initiated in Sep. 2016 to evaluate 4 dose levels (1 mg/kg, 3 
mg/kg, 200 mg, and 10 mg/kg) of sintilimab. The Phase 1a trial has enrolled 9 subjects (3 for 
each arm) in 3 treatment arms (1 mg/kg, 3 mg/kg, and 200 mg), and evaluated the dose-limiting 
toxicities specified in the protocol for each arm. No dose-limiting toxicities were observed.  
The preliminary pharmacokinetic (PK) results of sintilimab in subjects with multiple tumors 
demonstrated a typical IgG4 PK with a slow elimination (t1/2 ≈ 17.3 d). The elimination half-life 
is similar to the physiological half-life of IgG4. 
The pharmacodynamic (PD) results showed that: a dose of sintilimab at 1 mg/kg rapidly (24 h) 
saturated peripheral PD-1 (95.8 ± 2.3%) and maintained the receptor occupancy with decreasing 
concentrations throughout the study. The minimum concentration at steady state was 13 μg/mL 
and peripheral PD-1 receptor occupancy was maintained.  
Following completion of the dose escalation trial, clinical studies of sintilimab for the treatment 
of lymphomas and solid tumors were subsequently conducted. A total of 595 Chinese subjects 
and 36 US subjects received ≥ 1 dose of sintilimab, of which 534 Chinese subjects and 36 US 
subjects received sintilimab monotherapy, and 61 Chinese subjects received sintilimab in 
combination with chemotherapy. Over 93% of the subjects completed at least 2 cycles of 
treatment, 83.5% completed at least 3 cycles of treatment, 73.6% completed at least 4 cycles of 
treatment, and 65.9% completed at least 5 cycles of treatment. The median treatment duration for 
subjects that received 200mg Q3W was 24.29 weeks (range: 9.57~57.86 weeks). 
Overall, a total of 77.3% of Chinese subjects (460/595) experienced a sintilimab-related adverse 
events (TRAE), the three most common (≥10%) TRAE including fever (15.0%), hypothyroidism 
(14.1%), and increased AST (13.6%). A total of 18.7% (111/595) of subjects had TRAE ≥ grade 
3, among which the most common (incidence ≥ 1%) were decreased platelet count (1.2%), 
decreased neutrophil count (1.0%), and decreased lymphocyte count (1.0%). A total of 55.6% of 

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US subjects (20/36) experienced sintilimab-related adverse events (TRAE), the most common (≥ 
10%) included fatigue (16.7%), nausea (13.9%), and diarrhea (13.9%).  
A total of 29.4% of Chinese subjects (175/595 subjects) experienced treatment-emergent SAEs 
during the study. The most common treatment-emergent SAEs included lung infection (4.0%), 
pneumonia (2.5%), and pulmonitis (2.5%). A total of 36.1% of US subjects (13/36 subjects) 
experienced treatment-emergent SAEs during the study. The most common treatment-emergent 
SAEs included urinary tract infection (8.3%), pleural effusion (5.6%), and hypotension (5.6%). 
The overall safety profile of sintilimab is comparable with current globally marketed PD-1/PD-
L1 products.  
In US, one Phase 1b study (IND #136159) is ongoing that enrolls patients with solid tumors, and 
a Phase 3 trial in patients with first line esophageal squamous cell carcinoma (IND #145675) has 
also been initiated. 
1.3 Risk/Benefit Assessment 
1.3.1 Potential risks 
Considering the mechanism of action and the clinical safety information available for IBI308, the 
additional adverse events (AEs) in the sintilimab arm that occur during this clinical trial are 
expected to be the immune-mediated inflammatory response resulting from the activation of 
immune system, e.g. pneumonitis, colitis, hepatitis, renal insufficiency, and endocrine events. 
According to the available clinical data, anti-PD-1 monoclonal antibodies are well-tolerable 
despite a high incidence of adverse reactions. Treatment discontinuation due to adverse reactions 
only occurs in a small number of subjects, and most events resolve after appropriate 
interventions. As early symptoms of immune-related adverse events (irAEs) vary, the 
investigators should pay extra attention to early signs and symptoms of irAEs during the trial, 
make decisions promptly, adjust the dose according to Section 5.2 in the protocol, and provide 
effective treatment measures to reduce the subject’s risk.  
1.3.2 Potential benefits 
Pharmacological and safety data from multiple clinical trials showed that sintilimab has clear 
pharmacological activity and good tolerability in subjects with advanced cancers. Similar drugs 
have shown significant anti-tumor activity in subjects with advanced UPS, supporting the 
conduct of clinical trials in subjects with advanced UPS. 
 

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2 Study Objectives 
2.1 Primary Objectives 
 To evaluate the efficacy of sintilimab in subjects with UPS (ORR at 12W by RECIST 
1.1) 
2.2 Secondary Objectives 
 To evaluate the ORR (RECIST 1.1) and DCR, PFS, OS, safety and DOR of sintilimab in 
subjects with UPS 
2.3 Exploratory Objectives: 
 To evaluate the correlation between biomarkers in tumor tissue and efficacy, including 
but not restricted to PD-L1 expression level, tertiary lymphoid structures (TLS) 
transcriptome sequencing, single-cell sequencing, and multicolor immunohistochemistry 
(IHC) analyses 
 To evaluate the correlation between biomarkers in peripheral blood and efficacy, 
including but not restricted to soluble PD-L1, circulating tumor DNA (ctDNA), 
identification/quantification of immunologic changes, and cytokine analyses. 
 
3 Study Design 
3.1 Overall Design 
This is a Phase 2 clinical trial evaluating the efficacy and safety of sintilimab in subjects with 
UPS. Subjects with unresectable, locally advanced, recurrent or metastatic UPS will be enrolled. 
A total of 25 evaluable subjects will be enrolled and treated. Subjects will be treated with 
sintilimab (200 mg IV on Day 1 Q3W). The treatment will be repeated every 3 weeks until 
progressive disease (PD), intolerable toxicity, initiation of new anti-tumor therapy, withdrawal of 
informed consent, lost to follow-up, completion of therapy, death, or any other investigator-
determined reasons for treatment discontinuation (whichever occurs first). Treatment will be 
infused for a maximum period of up to 24 months (starting from the first dose). During the trial, 
tumor imaging evaluation will be initially performed once Q6W (± 7 days) and Q9W (± 7 days) 
starting from Cycle 7, and will be based on RECIST 1.1, until PD (assessed at 12W or after), 
initiation of new anti-tumor therapy, withdrawal of informed consent, lost to follow-up, death, or 
completion of the study (whichever comes first). After the completion or discontinuation of the 

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study treatment, safety follow-up (30 days ± 7 days and 90 days ± 7 days after the last dose) and 
survival follow-up (every 60 days ± 7 days) will be performed. The primary endpoints of the trial 
will be confirmed ORR per RECIST v.1.1. 
Figure 1 Schematic of SiARa-UPS study design and administration  
 
 
 
3.2 Definition of Study Completion 
The subject is considered to have completed the study if the survival follow-up is completed or 
the subject withdraws consent. 
The trial is completed if the last subject has completed the survival follow-up, been treated for 24 
months, or the sponsor decides to discontinue the trial early and/or the agreement between 
sponsor and health authority. 
3.3 Criteria for Study Discontinuation 
This study may be interrupted temporarily or discontinued prematurely if there are sufficient 
reasons to do so. The party who discontinues or interrupts the study should provide written 
notification to the subjects, investigators, funding agencies, and regulatory authorities, with 
documented reasons for interruption or discontinuation. If the study is discontinued prematurely 
or interrupted, the principal investigator should notify the subjects, Ethics Committee (EC), and 
sponsor immediately, and provide the reasons for discontinuation or interruption. Where 
applicable, the investigators should contact the subjects and inform them of the changes in the 

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visit schedule. 
Reasons for study discontinuation or interruption include but are not limited to: 
 Unexpected, significant, or unacceptable risks to the subjects are identified; 
 The study is discontinued or interrupted based on overwhelming lack of efficacy at the 
time of the interim analysis; 
 The subjects are unable to meet protocol requirements for compliance; 
 The data is incomplete and/or insufficient for evaluation; 
 The primary endpoint has been met. 
The study may be resumed only if the safety, protocol compliance, and data quality issues have 
been addressed, and the requirements of the sponsor, EC, and US Food and Drug Administration 
are met. 
 
4 Study Population 
4.1 Inclusion Criteria 
1. Histopathologically confirmed unresectable, locally advanced, recurrent or metastatic UPS or 
high-grade myxofibrosarcoma. 
2. Refractory or intolerant to at least one line of systemic chemotherapy. Patient ineligible for 
cytotoxic chemotherapy are eligibile.  
3. Aged ≥ 18. 
4. ECOG PS of 0 or 1. 
5. Subject must be unsuitable for definitive treatment, such as definitive chemoradiotherapy 
and/or surgery.  
6. Could provide archival or fresh tissues for correlative analysis. 
7. Have at least one measurable lesion as per RECIST v1.1. 
8. Adequate organs and bone marrow functions, as defined below: 

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1) Complete blood count: absolute neutrophil count (ANC) ≥ 1.0 × 109/L, platelet (PLT) 
count ≥ 75 × 109/L, hemoglobin (HGB) ≥ 8.0 g/dL. Note: Subjects cannot receive blood 
transfusion, erythropoietin (EPO), or Granulocyte-colony stimulating factor (GSF) within 
7 days prior to the blood collection.  
2) Hepatic function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN in subjects 
without hepatic metastasis; TBIL ≤ 1.5 × ULN, ALT and AST ≤ 5 × ULN in subjects with 
hepatic metastasis. Exception: Patients with known Gilbert disease: serum bilirubin level 
≤ 3 × ULN.  
3) Renal function: urine protein < 2+ from random sample or < 1 g from 24-hour urine 
collection, and creatinine clearance rate (Ccr) ≥ 60 mL/min by Cockcroft-Gault formula: 
Female: 𝐶𝑐𝑟=
(140−𝑎𝑔𝑒)×weight(kg)×0.85
72×serum creatinine(mg/dL) 
Male: 𝐶𝑐𝑟=
(140−𝑎𝑔𝑒)×weight(kg)×1.00
72×serum creatinine(mg/dL) 
4) Adequate coagulation function, defined as international normalized ratio (INR) ≤ 1.5 or 
prothrombin time (PT) ≤ 1.5 × ULN; if the subject is receiving anticoagulant therapy, the 
results of coagulation tests need to be within the acceptable range for anticoagulants. 
9. Expected survival ≥ 12 weeks. 
10. Subject (female subjects of childbearing age or male subjects whose partners are of 
childbearing age) must take effective contraceptive measures during the entire course of the 
trial and until 180 days after the last dose (see Section 4.3). 
11. Signed the informed consent form (ICF) and be able to comply with the scheduled follow-up 
visits and related procedures required in the protocol. 
4.2 Exclusion Criteria 
1. Received treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug that specifically targets T-cell co-stimulation or 
immune checkpoint pathways. 
2. Enrolled in another interventional clinical study, unless only involved in an observational 
study (non-interventional) or in the follow-up phase of an interventional study. 
3. Received palliative therapy for local lesion within 2 weeks prior to the first dose.  

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4. Received systemic treatment with anti-cancer indications or immunomodulators (including 
thymosins, interferons, and interleukins) within 2 weeks prior to the first dose of study 
treatment. 
5. Received systemic immunosuppressants within 2 weeks prior to first dose, excluding local 
use of glucocorticoids administered by nasal, inhaled, or other routes, and systemic 
glucocorticoids at physiological doses (no more than 10 mg/day of prednisone or 
equivalents), or glucocorticoids to prevent allergies to contrast media. 
6. Received a live attenuated vaccine within 4 weeks prior to the first dose of study treatment or 
be scheduled to receive live attenuated vaccine during the study period.  
Note: Seasonal inactivated influenza virus vaccines within 4 weeks prior to the first dose of 
study treatment are permitted, but attenuated influenza vaccines are not. 
7. Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to 
the first dose of study treatment or is scheduled to receive major surgery during the course of 
the trial. 
8. Any toxicity (excluding alopecia, events that are not clinically significant, or asymptomatic 
laboratory abnormalities) due to prior anti-tumor therapy that has not yet resolved to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 
grade 0 or 1 prior to the first dose of study treatment. 
9. Known symptomatic central nervous system (CNS) metastasis or carcinomatous meningitis. 
Subjects with brain metastases who have received prior treatment can be enrolled if the 
disease is stable (no imaging evidence of PD for at least 4 weeks prior to the first dose of 
study treatment), there is no evidence of new brain metastases or progression of the existing 
metastatic lesion(s) upon repeated imaging, and corticosteroids have not been required for at 
least 14 days prior to the first dose of study treatment. Patients with carcinomatous 
meningitis are ineligible, regardless of whether the disease is clinically stable or not. 
10. Subjects with bone metastases at risk of paraplegia. 
11. Known active autoimmune disease requiring treatment or previous disease history within 2 
years (subjects with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic 
treatment, hypothyroidism only requiring thyroid replacement, or type I diabetes only 
requiring insulin can be enrolled). 
12. Known history of primary immunodeficiency diseases. 
13. Known active pulmonary tuberculosis. 
14. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell 
transplantation. 

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15. HIV-infected subjects (positive anti-HIV antibody). 
16. Active or poorly controlled serious infections. 
17. Symptomatic congestive heart failure (NYHA Class II–IV) or symptomatic or poorly 
controlled arrhythmia. 
18. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure 
≥ 100 mmHg) despite of standard treatment. 
19. Any arterial thromboembolic event within 6 months prior to enrollment, including 
myocardial infarction, unstable angina, cerebrovascular accident, or transient cerebral 
ischemic attack. 
20. Significant malnutrition, such as those requiring continuous parenteral nutrition ≥7 days; 
excluding those having received intravenous treatment for malnutrition for more than 4 
weeks before the first dose of study treatment. 
21. History of clinically significant deep venous thrombosis, pulmonary embolism, or other 
serious thromboembolic events within 3 months prior to enrollment (implantable port or 
catheter-related thrombosis or incidental PE detected on scan without symptoms or 
superficial venous thrombosis are not considered as "serious" thromboembolisms). 
22. Uncontrolled metabolic disorders, non-malignant organ or systemic diseases, or cancer-
related secondary diseases that may lead to higher medical risks and/or survival evaluation 
uncertainties. 
23. Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh Class B or C. 
24. Bowel obstruction or history of the following diseases: inflammatory bowel disease, 
extensive bowel resection (partial colectomy or extensive small intestine resection 
accompanied with chronic diarrhea), Crohn's disease, or ulcerative colitis. 
25. Known acute or chronic active hepatitis B (positive HBsAg and HBV DNA viral load ≥ 104 
copies/mL or > 2000 IU/mL), or acute or chronic active hepatitis C (HCV RNA>103 
copies/mL), or simultaneously positive for HBsAg and HCV antibody. 
26. History of gastrointestinal (GI) perforation and/or fistula within 6 months prior to the 
enrollment, excluding gastrostomy or enterostomy. 
27. Interstitial lung disease requiring corticosteroids. 
28. History of other primary malignant tumors, excluding: 
 Malignant tumors that achieved a complete response (CR) at least 2 years prior to 
enrollment and expected to require no treatment during the trial. 

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 Adequately treated nonmelanoma skin cancer or lentigo maligna with no sign of disease 
recurrence. 
 Adequately treated carcinoma in situ with no sign of disease recurrence. 
 Prostate, CLL or other cancers where the indolent nature of tumor allows for and patient 
is cancer under active surveillance. 
29. Pregnant or breastfeeding female subjects. 
30. Acute or chronic diseases, psychiatric disorders, or laboratory abnormalities that may lead to 
the following consequences: increased investigational drug-related risks, interference with 
interpretation of trial results or considered ineligible for participating in the trial by the 
investigators. 
4.3 Restrictions During the Study 
For women of childbearing potential who are sexually active with male partners who have not 
undergone sterilization, and men who have not undergone sterilization and are sexually active 
with women of childbearing potential, the subjects and their partners must use one of the 
acceptable methods of contraception listed in Table 2 during the entire course of the trial and 
until 180 days after the last dose of study treatment. Periodic abstinence, a calendar-based 
method, and withdrawal are not acceptable forms of contraception. Women of childbearing 
potential are defined as females who have experienced menarche, have not undergone surgical 
sterilization (bilateral tubal ligation, bilateral salpingectomy, or panhysterectomy), and are not 
postmenopausal. 
Menopause is defined as 12 months of amenorrhea of a woman without any other medical 
reasons. Age requirements are as follows: 
 Females ≥ 50 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy; 
 Females < 50 years old who have at least 12 months of amenorrhea after stopping 
hormone replacement therapy, who have undergone radiation-induced ovariectomy or 
chemotherapy-induced amenorrhea, AND whose luteining hormone and follicle 
stimulating hormone levels are within the postmenopausal range are considered 
menopausal. 
 

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Table 2 Effective methods of contraception  
Single method (must use one) 
Double barrier (must use two) 
Intrauterine device 
Condom 
Contraceptive implant 
Diaphragm/cervical cap with spermicide 
 
Hormonal contraceptives including: Oral contraceptive, 
contraceptive patch, contraceptive ring 
4.4 Criteria for Discontinuation/Withdrawal 
4.4.1 Treatment discontinuation 
Treatment discontinuation is not the same as withdrawal from the study. Since data on some 
clinical events after treatment discontinuation may be important to the study, these data must be 
collected until the subject's last scheduled visit, even if the treatment has already been 
discontinued. 
A subject must discontinue the treatment in the case of any of the following, but can continue to 
be monitored during the study: 
 Disease progression as per RECIST v1.1 at 12 W or after 
 Treatment discontinuation required by the subject or his/her legal representative; 
 Occurrence of an AE that requires discontinuation due to protocol-specified reasons 
(refer to Section 5.2); 
 Onset of another malignant tumor that requires active treatment; 
 Onset of a concurrent disease that interferes further treatment; 
 Positive serum pregnancy test results; 
 Poor compliance of the subject; 
 Inappropriate to continue participating in the study when continued participation would 
result in unacceptable risk to the subject, as determined by the investigator and/or 
sponsor; 
 Completion of 24-month of treatment with the study drugs. 

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All the visits and procedures presented in the study schedule (Table 1) should be completed for 
subjects who discontinued treatment but continue to be followed. 
4.4.2 Subject withdrawal 
A subject has the right to withdraw from the study at any time for any reasons. A subject must 
withdraw from the study if the subject or his/her legal representative withdraws informed 
consent. 
A subject can withdraw from the study for the following: 
 Screen failures; 
 A subject or his/her legal representative withdraws informed consent; 
 Death; 
 Lost to follow-up; 
 Study completion. 
A subject who withdraws from the study will no longer receive the treatment and protocol-
specified follow-up visits. However, the investigator should make every effort to persuade him / 
her to complete all the examinations specified for the end-of-treatment visit. 
The reasons for withdrawal should be documented in the electronic case report forms (database). 
A subject who has signed the ICF and received any study interventions cannot be replaced after 
withdrawal or treatment discontinuation. 
4.4.3 Lost to follow-up 
A subject is considered lost to follow-up when he/she fails to return to the study site for 2 
consecutive scheduled visits and the site personnel are unable to contact the subject. 
The following actions must be taken if a subject does not return to the study site for a scheduled 
visit: 
 The study site should try to contact the subject, reschedule the missed visits, reiterate the 
importance of complying with the schedule of visits, and confirm whether he/she is 
willing and/or should continue to participate in the study. 
 Before a subject is considered lost to follow-up, the investigator or designee should make 
every effort to recontact the subject (at least 2 phone calls should be made; if the subject 

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is still out of contact, a letter should be mailed to the subject's last known address). These 
attempts to contact the subject should be documented in the subject's medical records or 
study documents. 
The subject is considered lost to follow-up and determined to have withdrawn from the study if 
the subject is still unable to be contacted. 
 
5 Study Drugs and Other Treatments 
The study drug is sintilimab. The first dose of study treatment would be designated Day 1 of 
Cycle 1. For the rest of the treatment cycles, the study treatment can be administered 3 days 
before or 3 days after the scheduled day of administration. Treatment can be delayed for up to 1 
week if the administration day is on a holiday or if the subject is otherwise unavailable.  
Table 3 Dosage and administration 
Study 
Drug 
Dose 
Frequency 
Route 
Treatment Cycle 
Sintilimab 
200 mg 
Q3W 
IV infusion 
on Day 1, every 21 days 
The study drugs in Table 3 is provided by the drug/supporting company. The administering 
institution (MD Anderson Cancer Center) is responsible for recording the batch numbers, 
manufacturers, and expiration dates. 
5.1 Treatment Regimens of Study Drugs 
5.1.1 Sintilimab 
The main active ingredient of sintilimab is the recombinant fully human anti-PD-1 monoclonal 
antibody at a concentration of 10 mg/mL. This product is a clear, colorless or light yellow liquid 
free of foreign matter. The excipients include 30.06 mg/L mannitol, 3.73 mg/L histidine, 5.88 
mg/L dihydrate sodium citrate, 2.92 mg/L sodium chloride, 0.0075 mg/L disodium edetate 
(ethylenediaminetetraacetic acid disodium salt), and 0.2 mg/mL polysorbate 80, with a pH of 6.0. 
The smallest packaging unit is one box, with each box containing 2 vials of sintilimab (IBI308) 
injection. The package contains the drug name, dosage form, strength, drug code, batch number, 
expiration date, storage conditions, and sponsor's information, etc. The label on the vial contains 
the same information as the outer package except for dosage form, precautions, and dosage and 

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administration. The package and vial should both be labeled "for clinical study use only". 
Sintilimab should be stored at 2–8℃ away from light. The shelf life is 24 months. If quality 
issues such as turbidity and precipitation are observed in the vial, seal the vial immediately and 
notify the sponsor. 
The preparation and administration of sintilimab is as follows: 
1. Calculate the required dose of sintilimab (200 mg IV Q3W). 
2. Calculate the volume of 0.9% (weight/volume) sodium chloride solution needed to dilute 
the sintilimab. The final concentration should be between 1.5 and 2 mg/mL. Then, 
calculate the redundant volume in the 0.9% (weight/volume) sodium chloride solution 
containing IV infusion bag, draw and discard the redundant volume. 
3. Warm the vial of sintilimab injection to room temperature (25℃) and draw the required 
dose of sintilimab (step 1) completely and transfer it into the IV infusion bag in step 2 at 
one time. Record the time when the preparation process starts.  
4. Gently invert the IV bag to mix the solution, ensuring the uniformity of the contents. Do 
not shake vigorously so as to avoid bubbles. If a large amount of bubbles appear, allow 
the IV bag to stand until the bubbles disappear. 
5. Administer with a 0.2 μm in-line filter (infusion time is 30–60 min). Document the start 
and stop time of infusion.  
Note: Before preparation, make sure that the sintilimab injection is clear without any quality 
issues such as turbidity or precipitation. To avoid medication errors and to ensure sterility, make 
sure that the required dose of sintilimab is drawn and transferred into the IV infusion bag at one 
time. Do not draw and transfer several times. Make sure that the time from sintilimab drawing to 
the end of infusion is no more than 6 h. The prepared solution can be stored for 24 h at 2-8℃ 
protected from light, and can be stored up to 6 h at 20 -25℃ under indoor lighting (including the 
duration of dosing). Avoid mixing with other drugs. Do not administer as an IV push. 
5.2 Dose Adjustments 
5.2.1 General principles 
 The subject's hematologic, hepatic, and renal function must meet the requirements for 
study drug administration prior to Day 1 of each cycle. All the toxicities related to the 

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study drug must resolve to NCI CTCAE v5.0 grade 0 – 1 or baseline levels, excluding the 
following cases: 
▪ Alopecia 
▪ Grade 2 fatigue 
▪ Hemoglobin (HGB) ≥ 8.0 g/dL 
▪ Grade 2 neurotoxicities* 
▪ Grade 2 weight loss 
 All the dose adjustments should be documented, including the reasons and actions taken. 
 The investigator should discuss with the sponsor to determine administration for any 
further concerns. 
* refer to section 5.2.2 for more details 
5.2.2 Sintilimab dose adjustments 
Dose adjustments for sintilimab are not permitted during the entire course of the study. Attached 
below is the reference table for sintilimab dose adjustments (only for sintilimab-related AEs 
determined by the investigator). If the administration delay occurs in a 3-week treatment cycle 
for sintilimab, all the subsequent administration should be delayed to ensure a dosing interval of 
21 ± 3 days. 
Sintilimab administration under special circumstances: 
 An administration delay is not required for grade 3 lymphopenia. 
 An administration delay is not required for any drug-related Grade 3 amylase or lipase 
abnormalities if it is not related to symptoms or clinical manifestations of pancreatitis. 
 Administration can be continued for grade 3–4 drug-related endocrine AEs, such as 
adrenocortical insufficiency, hypophysitis, hyperthyroidism, hypothyroidism, and type I 
diabetes, that are adequately controlled with physiologic hormone replacement therapy 
(corticosteroids or thyroid hormone). 
Table 4 Sintilimab dose adjustments 

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Drug-Related 
Toxicities 
Severity 
Management 
1. Skin Toxicities 
Rash/Inflammatory 
Dermatitis 
Grade 1 
Continue, Consider topical emollients and/or mild-moderate potency 
topical corticosteroids 
Grade 2 
Consider interruption, treat with topical emollients, oral 
antihistamines, and medium- to high-potency topical corticosteroids, 
Consider initiating prednisone 1 mg/kg, tapering over > 4 weeks 
Grade 3 
Interrupt and consult a dermatologist to decide whether and when to 
resume the treatment, treat with topical emollients, oral antihistamines, 
and high-potency topical corticosteroids, Initiate (methyl)prednisolone 
or equivalent 1-2 mg/kg/d, tapering over > 4 weeks 
Grade 4 
Interrupt and consult a dermatologist to decide whether and when to 
resume the treatment after resolving and prednisone requirement ≤ 10 
mg/day, Initiate (methyl)prednisolone or equivalent 1-2 mg/kg with 
slow tapering when toxicity resolves, initiate topical therapies 
recommended by a dermatologist 
Bullous Dermatosis 
Grade 1 
Interrupt and consult a dermatologist to decide whether and when to 
resume the treatment 
Grade 2–3 
Interrupt and consult a dermatologist to decide whether and when to 
resume the treatment. For Grade 2 toxicity, Initiate class 1 high-
potency topical corticosteroid (eg, clobetasol, betamethasone or 
equivalent) and reassess every 3 days for progression or improvement 
and Low threshold to initiate treatment with prednisone (or equivalent) 
at 0.5-1 mg/kg dosing and taper over at least 4 weeks; For Grade 3 
toxicity, Administer IV (methyl) prednisolone (or equivalent) 1-2 
mg/kg, tapering over at least 4 weeks. If bullous pemphigoid is 
diagnosed, it may be possible to avoid long-term use of systemic 
corticosteroids and treat with rituximab, as an alternative approach to 
treating the irAE.  
Grade 4 
Permanently discontinue. Administer IV (methyl) prednisolone (or 
equivalent) 1-2 mg/kg with tapering over at least 4 weeks when the 

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toxicity resolves. If bullous pemphigoid is diagnosed, it may be 
possible to avoid long-term use of systemic corticosteroids and treat 
with rituximab as an alternative approach to treating the irAE 
Serious Skin Adverse 
Reactions: SJS, TEN, 
AGEP, and DRESS 
Grade 1 (not 
applicable) 
/ 
Grade 2 
Interrupt and consult a dermatologist to decide whether and when to 
resume the treatment. 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 tapered 
over at least 4 weeks  
Grade 3 
Interrupt and consult a dermatologist to decide whether and when to 
resume the treatment. 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 (methyl)prednisolone (or equivalent) 0.5-1 
mg/kg and convert to oral corticosteroids on response, wean over at 
least 4 weeks 
Grade 4 
Permanently discontinue. Initiate IV (methyl)prednisolone (or 
equivalent) 1-2 mg/kg, tapering when toxicity resolves to normal IVIG 
or cyclosporine may also be considered in severe or corticosteroid 
unresponsive cases 
2. GI Toxicities 
Colitis 
Grade 1 
Continue, or interrupt until resolve to grade 0–1 
Grade 2 
Interrupt until resolve to grade 1. Administer corticosteroids, unless 
diarrhea is transient, starting with initial dose of 1 mg/kg/day 
prednisone or equivalent when symptoms improve to G1 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 of the risks and benefits 

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Drug-Related 
Toxicities 
Severity 
Management 
Grade 3 
Interrupt until resolve to grade 1. Administer corticosteroids (initial 
dose of 1-2 mg/kg/d prednisone or equivalent). If symptoms persist ≥ 
3-5 days or recur after improvement, consider administering IV 
corticosteroid or non-corticosteroid (eg, infliximab). 
Grade 4 
Permanently discontinue. Administer 1-2 mg/kg/d methylprednisolone 
or equivalent until symptoms improve to G1, and then start taper over 
4-6 weeks. Consider early infliximab 5-10 mg/kg if symptoms 
refractory to corticosteroid within 2-3 days 
Hepatitis 
Grade 1 
Continue and monitor 
Grade 2 
Interrupt, resume after resolving to grade 0–1 and prednisone 
requirement ≤ 10 mg/day. For grade 2 hepatic toxicity with symptoms, 
may administer corticosteroid 0.5-1 mg/kg/d prednisone 
or equivalent if the abnormal elevation persists with significant clinical 
symptoms in 3-5 days. 
In follow-up, may resume ICPi treatment followed by taper only when 
symptoms improve to G1 or less and corticosteroid ≤ 10 mg/d; taper 
over at least 1 month 
Grade 3–4 
Permanently discontinue. Immediately start corticosteroid 1-2 mg/kg 
methylprednisolone or equivalent. Corticosteroid taper can be 
attempted around 4-6 weeks; re-escalate if needed; 
If corticosteroid refractory or no improvement after 3 days, consider 
mycophenolate mofetil or azathioprine (if using azathioprine should 
test for thiopurine methyltransferase deficiency). 
 
3. Pulmonary Toxicities 
Pneumonitis 
Grade 1 
Interrupt if exacerbation confirmed by imaging 
Grade 2 
Interrupt until resolve to grade 0–1 Prednisone 1-2 mg/kg/d and taper 
by 5-10 mg/wk over 4-6 weeks.  

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Drug-Related 
Toxicities 
Severity 
Management 
Grade 3–4 
Permanently discontinue. Empirical antibiotics; (methyl)prednisolone 
IV 1-2 mg/kg/d; no improvement after 48 hours, may add infliximab 5 
mg/kg or mycophenolate mofetil IV 1 g twice a day or IVIG for 5 days 
or cyclophosphamide; taper corticosteroids over 4-6 weeks 
4. Endocrine Toxicities 
Primary 
Hypothyroidism 
Grade 1 
Continue and monitor closely 
Grade 2 
Continue and monitor closely 
Grade 3–4 
Continue, consult an endocrinologist, and symptom management 
Hyperthyroidism 
Grade 1 
Continue and monitor closely 
Grade 2 
Continue and monitor closely 
Grade 3–4 
Continue, consult an endocrinologist, and symptom management 
Primary 
Adrenocortical 
Insufficiency 
Grade 1–2 
Continue and monitor closely.  
For Grade 1, replacement therapy with prednisone (5-10 mg daily) or 
hydrocortisone (10-20 mg orally every morning, 5-10 mg orally in 
early afternoon). May require fludrocortisone (0.1 mg/d) 
formineralocorticoid replacement in primary adrenal insufficiency. 
For Grade 2, initiate outpatient treatment at two to three times 
maintenance. (if prednisone, 20 mg daily; if hydrocortisone, 20-30 mg 
in 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. 
Grade 3–4 
Continue, consult an endocrinologist, and symptom management. 
emergency department referral for normal saline (at least 2 L) and IV 
stress-dose corticosteroids on presentation (hydrocortisone 100 mg or 

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Management 
dexamethasone 4 mg. 
Taper stress-dose corticosteroids down to maintenance doses over 7-14 
days after discharge. 
Maintenance therapy as in G1 
Hypophysitis 
Grade 1–2 
Continue, monitor closely, and hormonal supplementation 
Grade 3–4 
Continue, consult an endocrinologist, hormonal supplementation and 
initial pulse dose therapy with prednisone 1-2 mg/kg oral daily (or 
equivalent) tapered over at least 1-2 weeks 
Diabetes 
Grade 1 
Continue and monitor closely 
Grade 2 
Continue and monitor closely 
Grade 3–4 
Continue and consult an endocrinologist to determine whether to 
resume the treatment 
5. Musculoskeletal Toxicities 
Inflammatory Arthritis 
Grade 1 
Continue 
Grade 2 
Interrupt until the symptoms are controlled and prednisone 
requirement is ≤ 10 mg/day. 
If inadequately controlled by NSAIDS, initiate prednisone or 
prednisolone 10-20 mg/d or equivalent for 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 10 mg/d after 3 months, 
consider DMARD 
Consider intra-articular corticosteroid injections for large joints 
Grade 3–4 
Interrupt consult a rheumatologist to decide whether to resume the 
treatment after resolving to grade 0–1. Initiate oral prednisone 0.5-1 

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mg/kg 
If failure of improvement after 4 weeks or worsening in meantime, 
consider synthetic or biologic DMARD 
Synthetic: methotrexate, leflunomide 
Biologic: consider anticytokine therapy such as TNF-α or IL-6 
receptor inhibitors. (Note: As caution, IL-6 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 
Myositis 
Grade 1 
Continue 
Grade 2 
Interrupt until the symptoms are controlled and CK is normal. If CK is 
elevated three times or more, initiate prednisone or equivalent at 
0.5-1 mg/kg. 
Grade 3–4 
Interrupt until resolve to grade 0–1 without immunosuppression; 
permanently discontinue if there are signs of myocardial involvement. 
Initiate prednisone 1 mg/kg or equivalent. Consider 1-2 mg/kg of 
methylprednisolone IV or higher-dose bolus if severe compromise 
(weakness severely limiting mobility, cardiac, respiratory, dysphagia) 
Consider plasmapheresis 
Consider IVIG therapy 
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; 
Polymyalgia 
Rheumatica-Like 
Grade 1 
Continue 
Grade 2 
Consider interruption until symptoms are controlled. prednisolone 

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Syndrome 
< 10 mg; 
Grade 3–4 
Interrupt, consult a rheumatologist to decide whether to resume the 
treatment after resolving to grade 0–1. Initiate prednisone 20 mg/d or 
equivalent. If no improvement or need for higher dosages for 
prolonged time, may offer a corticosteroid-sparing agent, such as 
methotrexate or IL-6 inhibition with tocilizumab 
6. Nephrotoxicities 
Nephritis 
Grade 1 
Consider interruption, make judgment based on other possible causes 
and the baseline renal function 
Grade 2 
Interrupt administer 0.5-1mg/kg/d prednisone equivalents.  
If worsening or no improvement: 1 to 2 mg/kg/d prednisone 
equivalents and permanently discontinue treatment. If improved to G1 
or less, taper corticosteroids over 4-6 weeks 
Grade 3 
Permanently discontinue. Initiate 1 to 2 mg/kg/d prednisone 
equivalents 
Grade 4 
Permanently discontinue, Consult a nephrologist. Administer 
corticosteroids (initial dose of 1-2mg/kg/d prednisone or equivalent) 
Symptomatic 
Nephritis: Follow-Up 
Grade 1 
Resume routine creatinine monitoring if resolve to baseline values 
Grade 2 
If resolve to grade 1, taper glucocorticoid dose for at least 3 weeks; If 
elevations persist. 7 days or worsen and no other cause found, treat as 
G3 
Grade 3–4 
If resolve to grade 1, taper glucocorticoid dose for at least 4 weeks. If 
elevations persist >3-5 days or worsen, consider additional 
immunosuppression (eg, mycophenolate) 
7. Neurotoxicities 
Myasthenia Gravis 
Grade 1 (not 
applicable) 
/ 

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Severity 
Management 
Grade 2 
Interrupt until resolve. Administer corticosteroids (prednisone, 1-1.5 
mg/kg orally daily) if symptoms G2; wean based on symptom 
improvement 
Grade 3–4 
Permanently discontinue. Continue corticosteroids and initiate IVIG 2 
g/kg IV over 5 days (0.4 g/kg/d) or plasmapheresis for 5 days 
Guillain-Barré 
Syndrome 
Grade 1 (not 
applicable) 
/ 
Grade 2–4 
Permanently discontinue. Start IVIG (0.4 g/kg/d for 5 days for a total 
dose of 2 g/kg) or plasmapheresis.  
Or methylprednisolone 2-4 mg/kg/d, followed by slow corticosteroid 
taper. Or pulse corticosteroid dosing (methylprednisolone 1 g/d for 5 
days) for G3-4 along with IVIG or plasmapheresis 
Peripheral 
Neurotoxicity 
Grade 1 
Lower the criteria for interruption and monitor the symptoms for 1 
week; closely monitor the symptoms if continue the treatment 
Grade 2 
Interrupt until resolve to grade 0–1. Initial observation OR initiate 
prednisone 0.5-1 mg/kg (if progressing from mild). 
Grade 3–4 
Permanently discontinue. Initiate IV methylprednisolone 2-4 mg/kg 
and proceed as per Guillain-Barre' syndrome management. 
Autonomic 
Neuropathy 
Grade 1 
Lower the criteria for interruption and monitor the symptoms for 1 
week; closely monitor the symptoms if continue the treatment 
Grade 2 
Interrupt until resolve to grade 0–1. Initial observation OR initiate 
prednisone 0.5-1 mg/kg (if progressing from mild). 
Grade 3–4 
Permanently discontinue. Initiate methylprednisolone 1 g daily for 3 
days followed by oral corticosteroid taper. 
Aseptic Meningitis 
Grade 1–4 
Permanently discontinue. Once bacterial and viral infection are 
negative, may closely monitor off corticosteroids or consider oral 
prednisone 0.5-1 mg/kg or IV methylprednisolone 1mg/kg if 

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Toxicities 
Severity 
Management 
moderate/severe symptoms 
Encephalitis 
Grade 1–4 
Permanently discontinue. Once bacterial and viral infection are 
negative, trial of methylprednisolone 1-2 mg/kg. 
If severe or progressing symptoms or oligoclonal bands present, 
consider pulse corticosteroids methylprednisolone 1 g 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 
Transverse 
Myelitis 
Grade 1–4 
Permanently discontinue. Methylprednisolone 2 mg/kg 
Strongly consider higher doses of 1 g/d for 3-5 days 
Strongly consider IVIG 
8. Hematotoxicities 
Autoimmune 
Hemolytic Anemia 
Grade 1 
Continue and monitor closely 
Grade 2 
Interrupt and consider permanently discontinuing. Administer 0.5-1 
mg/kg/d prednisone equivalents 
Grade 3–4 
Permanently discontinue, IV prednisone corticosteroids 1-2 mg/kg/d 
If no improvement or if worsening while on corticosteroids or severe 
symptoms on presentation, initiate other immunosuppressive drugs, 
such as rituximab, IVIG, cyclosporin A, and mycophenolate mofetil 
Acquired Thrombotic 
Thrombocytopenic 
Purpura 
Grade 1–4 
Interrupt. Administer 0.5-1 mg/kg/d prednisone for Grade 1-2. For 
Grade 3-4, administer methylprednisolone 1 g IV daily for 3 days, with 
the first dose typically administered immediately after the first PEX  
Hemolytic Uremic 
Syndrome 
Grade 1–2 
Continue and monitor closely 
Grade 3–4 
Permanently discontinue. Begin therapy with eculizumab therapy 900 
mg weekly for four doses, 1,200 mg week 5, the 1,200 mg every 2 
weeks 

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Drug-Related 
Toxicities 
Severity 
Management 
Aplastic Anemia 
Grade 1–2 
Interrupt treat with growth factors and monitor closely. For Grade 2, 
administer ATG + cyclosporine  
Grade 3–4 
Interrupt treat with growth factors, horse ATG plus cyclosporine and 
monitor daily. 
If no response, repeat immunosuppression with rabbit ATG plus 
cyclosporine, cyclophosphamide  
Lymphopenia 
Grade 1 
Continue 
Grade 2–3 
Continue and monitor the complete blood  
count and CMV weekly 
Grade 4 
Interrupt 
Immune 
Thrombocytopenia 
Grade 1 
Continue and monitor closely 
Grade 2–4 
Interrupt resume the treatment after resolving to grade 1. For Grade 2, 
administer prednisone 1 mg/kg/d (dosage range, 0.5-2 mg/kg/d) orally 
for 2-4 weeks after which time this medication should be tapered over 
4-6 weeks to the lowest effective dose.  
For Grade 3-4, Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms). If worsening or no improvement, 1-2 mg/kg/d prednisone 
equivalents and permanently discontinue treatment IVIG 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 unsuccessful, 
subsequent treatment may include rituximab, thrombopoietin receptor 
agonists, or more-potent immunosuppression 
Acquired Hemophilia 
Grade 1–2 
Interrupt, For Grade 1, administer 0.5-1 mg/kg/d prednisone; For 
Grade 2, administer 1 mg/kg/d prednisone 6 rituximab (dose, 375 
mg/m2 weekly for 4 weeks) and/or cyclophosphamide (dose, 1-2 
mg/kg/d); choice of rituximab v cyclophosphamide is patient specific 

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Drug-Related 
Toxicities 
Severity 
Management 
and should be done with assistance of hematology consult; prednisone, 
rituximab, and cyclophosphamide should be given for at least 5 weeks 
Grade 3–4 
Permanently discontinue. Prednisone 1-2 mg/kg/d (oral or IV 
depending on symptoms) 6 rituximab (dose, 375 mg/m2 weekly for 4 
weeks) and/or (dose, 1-2 mg/kg/d). If worsening or no improvement 
add cyclosporine or immunosuppression/immunoadsorption 
9. Cardiovascular 
Toxicities 
 
_ 
Myocarditis, 
Pericarditis, 
Arrhythmia, 
Ventricular 
Insufficiency with 
Heart Failure and 
Vasculitis 
Grade 1 
Interrupt 
Grade 2–4 
Permanently discontinue. High-dose corticosteroids (1-2 mg/kg of 
prednisone) initiated rapidly (oral or IV depending on symptoms). In 
patients without an immediate response to high-dose corticosteroids, 
consider early institution of cardiac transplant rejection doses of 
corticosteroids (methylprednisolone 1 g every day) and the addition of 
either mycophenolate, infliximab, or antithymocyte globulin.  
Venous 
Thromboembolism 
Grade 1–3 
Continue 
Grade 4 
Permanently discontinue 
10. Ocular Toxicities 
Uveitis/Iritis 
Grade 1 
Continue 
Grade 2 
Interrupt until after consulting an ophthalmologist. Topical 
corticosteroids, cycloplegic agents, systemic corticosteroids 
May resume ICPi treatment once off systemic corticosteroids, which 
are purely indicated for ocular adverse effects or once corticosteroids 
for other concurrent systemic irAEs are reduced to ≤ 10 mg; continued 
topical/ocular corticosteroids are permitted when resuming therapy to 
manage and minimize local toxicity. Re-treat after return to G1 or less  
Grade 3–4 
Permanently discontinue. Emergent ophthalmology referral. Systemic 

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Drug-Related 
Toxicities 
Severity 
Management 
corticosteroids (IV prednisone 1-2 mg/kg or methylprednisolone 0.8-
1.6 
mg/kg) and intravitreal/periocular/topical corticosteroids per 
ophthalmologist opinion. 
Episcleritis 
Grade 1 
Continue 
Grade 2 
Interrupt and consult an ophthalmologist. Topical corticosteroids, 
cycloplegic agents, systemic corticosteroids 
Grade 3–4 
Permanently discontinue. Urgent ophthalmology referral. 
Systemic corticosteroids and topical corticosteroids with cycloplegic 
agents 
Blepharitis 
No grades 
available 
Continue, unless the symptoms are persistent and serious 
SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; AGEP: acute generalized exanthematous 
pustulosis; DRESS: drug rash with eosinophilia and systemic symptoms; NSAIDs: Non-Steroidal Anti-
Inflammatory Drug; DMARD: Disease-modifying antirheumatic drug; IVIG: Intravenous Immunoglobulin; CK: 
Creatine Kinase; PEX: Physical Examination; ATG: Antithymocyte Globulin; ICPi: Immune Checkpoint inhibitor.  
 
 
Sintilimab treatment is allowed to be held for up to 12 weeks. If the symptoms do not resolve 
and treatment cannot be resumed within 12 weeks, the subject must permanently discontinue 
sintilimab treatment and enter the follow-up phase of the study except for the following two 
cases: 
 Sintilimab hold > 12 weeks due to glucocorticoid taper while treating immune-related 
adverse events (irAEs): Consult the sponsor's medical monitor prior to resuming 
sintilimab. Tumor imaging evaluation for efficacy shall not be affected by treatment 
interruption and will be performed as scheduled. 

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 Sintilimab hold > 12 weeks due to AEs unrelated to sintilimab: Consult the sponsor's 
medical monitor prior to resuming sintilimab. Tumor imaging evaluation for efficacy 
shall not be affected by treatment interruption and will be performed as scheduled. 
5.2.3 Management of sintilimab-related infusion reactions 
Sintilimab may cause severe or life-threatening infusion reactions, including severe 
hypersensitivity reactions or allergic reactions. Signs and symptoms usually occur during or after 
drug infusion and usually resolve within 24 h after the infusion completion. Refer to Table  for 
the guidelines for management of sintilimab-related infusion reactions. 
Table 5 Guidelines for the management of sintilimab-related infusion reactions 
NCI CTCAE Grades 
Treatments 
Premedications for 
Subsequent Infusions 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Monitor the subject, including vital signs, 
closely until the subject is stable as 
determined by the investigator. 
Not applicable. 
Grade 2 
Treatment or infusion 
interruption required, but 
responds promptly to timely 
symptomatic treatment (e.g. 
antihistamines, nonsteroidal anti-
inflammatory drugs [NSAIDS], 
anesthetics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 h 
Stop the infusion and monitor 
symptoms. 
Other appropriate treatments include but 
are not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Consider bronchodilators 
Consider corticosteroids 
 
Monitor the subject, including vital signs, 
closely until the subject is stable as 
determined by the investigator. 
 
If symptoms resolve within 1 h after 
interrupting the infusion, then the infusion 
will be resumed at 50% of the original 
infusion rate (e.g. from 100 mL/h to 50 
mL/h).  
 
Premedications should be 
given for subsequent infusions.  
 
The following premedications 
are recommended within 1.5 h 
(± 30 min) prior to sintilimab 
infusion: 
 
Diphenhydramine 50 mg PO 
(or equivalent antihistamines) 
 
Acetaminophen 500–1000 mg 
PO (or equivalent antipyretics) 
 
If grade 2 toxicities occur 
despite of adequate 
premedications, the study 
drugs should be permanently 
discontinued. 

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NCI CTCAE Grades 
Treatments 
Premedications for 
Subsequent Infusions 
If symptoms recur with resumption of the 
infusion, discontinue further treatment at 
that visit. Monitor the subject closely until 
the subject is stable. 
 
If symptoms resolve in > 1 h, discontinue 
the treatment at that visit.  
Grade 3 or 4 
Grade 3 
Prolonged (i.e. not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g. renal 
impairment, pulmonary 
infiltration) 
Grade 4 
Life threatening; pressors or 
ventilatory support indicated 
Discontinue the infusion. 
Other appropriate treatments include but 
are not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Oxygen 
Bronchodilators 
Pressors 
Corticosteroids 
 
Monitor the subject, including the vital 
signs, closely until the subject is stable as 
determined by the investigator. 
 
Hospitalization may be indicated. 
**Epinephrine should be used immediately 
for allergic reactions. 
 
Not applicable. 
 
The study drugs should be 
permanently discontinued. 
Appropriate first-aid equipment should be provided in the ward and physicians should be available at all times 
during the administration. 
For more information, refer to CTCAE v5.0 (http://ctep.cancer.gov). 
5.3 Principles for Managing Immune Checkpoint Inhibitor Toxicities 
The mechanism of sintilimab is to stimulate T-cell activation and proliferation, which may lead 
to autoimmune disease involving multiple systems. Autoimmune AEs such as immune-related 
pneumonitis, diarrhea/enterocolitis, renal insufficiency, rash, hepatitis, endocrine disorders, and 

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peripheral or central neuritis have been observed with checkpoint inhibitors including 
ipilimumab, nivolumab, pembrolizumab, and atezolizumab. If subjects experienced the irAEs 
described above, the signs and symptoms should be monitored, relevant examinations should be 
performed, and the cause should be identified. If an alternative cause is not found (such as PD, 
concomitant medications, or infections) and glucocorticoids and/or other immunosuppressants 
are required, then any AE described above is considered related to sintilimab-induced immune 
hyperfunction, which should be diagnosed as an irAE. Endocrine events such as 
hyperthyroidism/hypothyroidism, hypophysitis, type I diabetes, and adrenal insufficiency may 
not require immunosuppressants, but are still considered as immune-related events. 
See Table 4 Sintilimab dose adjustments, Table  and the latest NCCN guidelines for 
management of immune-related toxicity in cancer immunotherapy for dose adjustments and 
management of toxicity. 
5.4 Concomitant Treatments 
All concomitant medications will be recorded in the EMR only. 
5.4.1 Prohibited treatments 
The following treatments are prohibited throughout the trial: 
 Any systemic chemotherapy or biotherapy (except for cytokine drugs to treat 
chemotherapy-induced AEs), as well as herbal and proprietary Chinese medicines, with 
anti-tumor effects other than sintilimab. 
 Immunomodulators, including but not limited to non-specific immunomodulators (such 
as thymosin, interferon, interleukin, immunoglobulin, and gamma globulin) as well as 
herbal and proprietary Chinese medicines with immunomodulating effects; 
 Radiotherapy to control tumors (palliative radiotherapy is allowed if not directed towards 
the target lesion, such as radiotherapy for relieving pain from bone metastasis and 
symptoms of brain metastasis); 
 Inoculation with live vaccine within 30 days prior to the first dose of study treatment and 
throughout the trial. Live vaccines include but are not limited to measles, mumps, rubella, 
chicken pox, yellow fever, rabies, Bacillus Calmette Guerin, and typhoid (oral) vaccines; 
Seasonal inactivated influenza virus vaccines are permitted, but live attenuated influenza 
vaccines are not; 

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 Corticosteroids. Inhaled steroids for subjects with asthma or chronic obstructive 
pulmonary disease (COPD) are permitted; temporary use of corticosteroids for dyspnea 
are permitted; corticosteroids are permitted for the treatment of immune-related AEs; 
corticosteroids of physiologic dose are permitted after consulting the PI. 
Note: Prophylactic corticosteroids as pretreatment of allergic reactions (e.g. premedication prior 
to IV contrast agent or chemotherapy) are permitted. 
Based on the assessment of the investigator, subjects requiring any one of the treatment methods 
above must be excluded from the trial. Subjects may receive other medications that the 
investigator considers medically necessary. 
It is very important for the investigator to review every drug (prescription and non-prescription) 
used by the subject prior to the trial and during each visit.  
 During each visit, subjects must be asked about any new medications received.  
 To minimize the risk of drug-drug interactions, the concomitant medications should be 
limited to those that are really necessary. 
 Drugs with hepatotoxicity (i.e. those with warnings in the prescribing information) 
should be avoided if possible during the treatment. The investigators are encouraged to 
review every potential hepatotoxic drug via www.livertox.nih.gov. 
 Prohibited drugs listed in the exclusion criteria are not permitted. 
5.4.2 Permitted treatments 
 Medications that meet the protocol requirements, as determined by the investigator (e.g. 
concomitant medication used for disease-related symptoms and treatment-related AEs); 
 Subjects with underlying diseases such as hypertension and diabetes requiring chronic 
medications can continue these treatments; 
 Local surgery or radiotherapy used for isolated lesions (excluding target lesions); 
 Supportive care for relieving tumor-related symptoms, such as bisphosphonate treatment 
for bone metastases; 
 Use of corticosteroids by topical administration, such as dermal, ocular, nasal, and 
inhaled; 

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 Prophylactic antiviral therapy is permitted for hepatitis B carriers. Refer to treatment 
guidelines for dosage and administration. 
5.4.3 Drug-drug interactions 
 Sintilimab: No interaction information is currently available. 
5.5 Drug Management 
Sintilimab should be refrigerated at 2–8℃ in a dry place and away from light. Do not freeze. 
Cold-chain should be maintained during transport, and the study drug should be maintained and 
dispensed by a designee. 
The study drugs should be stored in a refrigerator only accessible to the authorized personnel. 
After receiving the study drugs, the investigator should ensure that the temperature during the 
transport is maintained within the specified range, sign for receipt upon verification, and store 
the study drugs at the specified temperature. If abnormalities of the storage temperature during 
either the transport or storage at the study site arise, the study drugs should be moved to an 
environment in the specified temperature as soon as possible and should not be administered. 
Notify the sponsor in a timely manner and follow the advice of the sponsor. 
All the study drugs provided by the sponsor should only be used for this clinical trial. Any 
purposes other than those specified in the protocol are not permitted. The investigator must agree 
not to provide the study drugs to any patients not in the trial. 
5.5.1 Return and destruction 
Upon the completion or discontinuation of the study, all unused or expired study drugs will be 
destroyed locally in accordance with all applicable institutional standard operating procedures, 
local and federal laws.  
5.6 Study Drug Records 
The designee of the study site(s) should keep accurate and complete records for receiving, 
dispensing, using, storing, returning, and destroying study drugs in accordance with the relevant 
regulations and guidelines and the operational requirements of this study. 
 

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6 Study Procedure 
6.1 Enrollment  
6.1.1 Enrollment  
All protocol participants will be registered in Clinical Oncology Research System 
(OnCore/CORe) websit. The investigator will enroll subjects using the following steps: 
1. Obtain the ICF signed by the subjects prior to any study-related procedures; 
2. Confirmation of the subjects' eligibility by the principal investigator or trained designee 
after reviewing the inclusion/exclusion criteria; 
Subjects who do not meet the criteria (screen failures) may be re-screened. If re-screening is 
considered, the investigator must contact the study PI. Each subject can be re-screened once. The 
subject must sign the ICF again and be assigned a new identification number when re-screening. 
6.1.2 Enrollment error handling 
The inclusion/exclusion criteria must be followed strictly. If an ineligible subject is enrolled, the 
sponsor's medical monitor and investigator must discuss whether the subject is allowed to 
continue the study and whether the subject can be treated with the study drugs. If it is determined 
by the investigator that allowing the subject to continue the study is medically appropriate and 
this is agreed to by the sponsor's medical monitor, then the subject will continue the study and 
receive the study drugs. On the other hand, if the investigator/IND does not agree, the subject 
should not continue the study (regardless of receiving the study drugs or not).  
6.2 Study Plan and Schedule 
6.2.1 Screening 
The following procedures must be completed during the screening (Day -28 to -1) to ensure 
subject eligibility: 
 Signing the ICF 
 Confirming the inclusion/exclusion criteria 
 Recording the demographics, medical history, and prior medications 
 Recording the vital signs, height, and weight 
 Physical examination 

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 ECOG PS 
 12-lead ECG (within 7 days prior to the first dose) 
 Complete blood count/blood biochemistry/routine urinalysis (within 7 days prior to the 
first dose) 
 Coagulation function (within 7 days prior to the first dose) 
 Pregnancy test (where applicable within 3 days prior to the first dose) 
 Thyroid function (results obtained within 28 days prior to first dose) 
 HIV antibody, hepatitis B panel (test HBV DNA for subjects with positive HBsAg), and 
HCV antibody (test HCV RNA for subjects with positive HCV antibodies). Results 
obtained within 28 days prior to first dose are also accepted. 
 AE evaluation 
 Concomitant medications 
 Tumor imaging evaluation 
 Archival or fresh tumor tissue 
Refer to Sections 7.1 and 7.2 for details regarding tumor evaluation and safety evaluation. 
6.2.1.1 Medical history 
A medical history should be obtained by the investigator or qualified designee. It includes all 
active diseases and diseases diagnosed that are clinically significant, as determined by the 
investigator, including but not limited to history of cigarette use, alcohol use, surgery, and drug 
allergy. All autoimmune diseases should be documented, regardless of the date of onset. 
6.2.1.2 Prior medications 
All medications (including over-the-counter supplements) used within 30 days prior to the first 
dose of study treatment, including any washout requirements specified in the protocol, will be 
reviewed by the investigator or qualified designee and should be documented. 
6.2.1.3 Concomitant medications 
The investigator or qualified designee will document all the medications used throughout the 
trial (from the signing of the ICF to the safety follow-up). Concomitant medications related to 
SAEs and irAEs should be documented. 

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6.2.2 Baseline (prior to Day 1 of Cycle 1) 
 Recording the vital signs 
 Weight (no need to repeat if done previously within 7 days prior to the first dose) 
 ECOG PS (no need to repeat if done previously within 7 days prior to the first dose) 
 12-lead ECG 
 AE evaluation 
 Concomitant medicationsThyroid function 
 Complete blood count/blood biochemistry 
 Coagulaion function 
 Blood pregnant test 
 HBV DNA and/or HCV RNA (if applicable) 
6.2.3 Tumor imaging evaluation (if applicable), Tumor biopsy (if applicable), Treatment 
visits 
 Recording the vital signs  
 Weight  
 Physical examination 
 ECOG PS 
 12-lead ECG 
 Complete blood count/blood biochemistry 
 Urine or Blood pregnant test (if applicable, every other cycle from Cycle 2 onwards)) 
 Thyroid function (every other cycle from Cycle 2 onwards) 
 AE evaluation 
 Concomitant medications 
 EQ 5D-5L (if applicable) 
 EORTC QLQ-C30 (if applicable) 
 PRO-CTCAE (if applicable) Tumor imaging evaluation (if applicable) 

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 Fresh tumor tissue (C3D1) (optional if clinically feasible) 
 Administration of study drugs (tumor imaging evaluation should be performed prior to 
administration) 
 Blood sampling for biomarkers and PK sampling (if applicable) 
 Survival status    
Refer to Table 1 for the study schedule during the treatment. 
Refer to Sections 7.1, 7.2, 7.3 and 7.4 for details regarding tumor imaging evaluation, safety 
evaluation, biomarker sampling, and PK sampling, respectively. 
6.2.4 End-of-treatment visits 
The following should be completed within ± 7 days after confirming the end of treatment: 
 Recording the vital signs 
 Physical examination 
 Weight 
 ECOG PS 
 12-lead ECG 
 Complete blood count/blood biochemistry/routine urinalysis 
 Thyroid function 
 Pregnancy test (if applicable) 
 Blood sampling for biomarkers (if applicable) 
 Tumor imaging evaluation (if applicable) 
 AE evaluation 
 Concomitant medications 
 Survival status 
 Subsequent anti-tumor therapy 
 EQ 5D-5L 
 EORTC QLQ-C30 

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 PRO-CTCAE 
6.2.5 Safety follow-up 
The safety follow-up will be performed at the 30th day (± 7 days) and 90th day (± 7 days) after 
the last dose and will include the following procedures: 
 ECOG PS 
 12-lead ECG (for the 30-day safety follow-up only) 
 Complete blood count/blood biochemistry (for the 30-day safety follow-up only) 
 AE evaluation 
 Concomitant medications (for the 30-day safety follow-up only) 
 Document subsequent anti-tumor therapy 
 PRO-CTCAE (for the 30-day safety follow-up only)  
 Survival status 
If the safety follow-up is less than 7 days after the end-of-treatment visit, then the safety follow-
up may be replaced by the end-of-treatment visit and does not need to be repeated.  
If the subject initiates a new anti-tumor therapy within 30 days after the last dose, then the safety 
follow-up must be performed before initiation of the new therapy. 
6.2.6 Survival follow-up 
After completing the safety follow-ups, the subject should be contacted (telephone visits are 
allowed) once every 60 days (± 7 days) to obtain the survival information, any subsequent 
systemic anti-tumor therapy, and PD information. Long-term follow-up should be continued until 
death or 3 years after last patient enrolled. 
Subsequent anti-tumor therapy 
The investigator or qualified designee will collect all the information about new anti-tumor 
therapies initiated after the last dose of the study drugs and the corresponding efficacy. If the 
subject initiates a new anti-tumor therapy within 30 days after the last dose, then the safety 
follow-up must be performed before initiation of the new therapy.  
The subject should be followed for survival after initiation of a new anti-tumor therapy. Refer to 
Section 6.2.6 – Survival follow-up for details regarding survival follow-up. 

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6.2.7 Unscheduled visits 
Unscheduled visits may be performed if requested by the subject or investigator. The investigator 
will carry out relevant examinations based on the subject's status, which includes but is not 
limited to the vital signs, targeted physical examination, ECOG PS, complete blood count/blood 
biochemistry/routine urinalysis, and tumor imaging evaluation.  
 
7 Study Evaluation 
7.1 Efficacy Evaluation 
Tumor evaluations will be performed based on RECIST v1.1. Refer to Appendix 3 for the 
evaluation methods. 
All the decisions made during the study will be based on the imaging evaluations by the 
independent and investigator radiology review, subject’s clinical status, and relevant examination 
results. 
7.1.1 Tumor imaging and disease evaluations 
Tumor imaging examinations usually include contrast-enhanced CT or MRI of the chest, 
abdomen, and pelvis. Contrast-enhanced MRI should also be performed on the brain at baseline 
for subjects with signs and symptoms of CNS metastasis. The imaging method should be 
consistent for a given subject during the trial. 
During the screening, the investigator of the study site will confirm the presence of measurable 
lesions based on RECIST v1.1 to determine the eligibility of the subject. According to RECIST 
v1.1, a maximum of 5 lesions in total and 2 lesions per organ will be recorded. 
7.1.2 Tumor imaging during the study 
The imaging method used for the evaluation of tumor burden during each visit should be the 
same as the one used at baseline. Other affected sites should be examined based on the signs and 
symptoms of each subject. Baseline evaluation will be conducted within 28 days prior to the first 
dose of the study treatment, which means the investigator can evaluate the imaging results within 
28 days prior to the enrollment. 
After the first dose of study treatment, tumor imaging evaluation will initially be performed once 
Q6W (± 7 days) and Q9W (± 7 days) starting from Cycle 7, until initiation of a new anti-tumor 

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therapy, PD (at 12W or after), withdrawal of informed consent, lost to follow-up, death, or 
completion of the study (whichever comes first). 
Patients who have radiographic PD will be allowed to continue therapy if clinically stable till 
next scheduled scans. If PD is confirmed on the next scan, patient will discontinue therapy. For 
certain cases which PD cannot be determined, especially on those with equivocal non-target 
lesions enlargement or equivocal new lesions, the treatment may be continued until signs of 
clinical instability develop or when PD is confirmed by the investigator in the next scheduled 
scan. Once PD is confirmed, the disease progression date will be recorded as the date when the 
suspected PD was initially observed. Definition of clinical stability is as follows: 
 Absence of clinically significant signs and symptoms suggesting PD (including 
worsening laboratory values); 
 No reduction in ECOG PS score; 
 No rapid PD; 
 Absence of rapid progression of disease or progressive tumor at critical anatomical sites 
(e.g. spinal cord compression) that requires urgent medical interventions. 
Tumor evaluations should be performed as scheduled and should not be delayed due to 
treatment delays, holidays, or any other reasons. 
Further tumor evaluations are not required for subjects who discontinue the treatment due to 
radiographic PD. 
For subjects who discontinue the treatment for reasons other than radiographic PD, tumor 
evaluation should be performed Q12W (± 7 days) until one of the followings occurs: start of new 
anti-tumor therapy, PD, withdrawal of informed consent, or death. A scan at the end of the 
treatment is not mandatory if it were less than 4 weeks after the last tumor evaluation. 
If the subject has confirmed or suspected bone metastatic lesion(s) present at baseline, a contrast 
enhanced PET/CT can be used for efficacy assessment. 
7.2 Safety Evaluation 
The investigator or qualified designee should evaluate each subject, as specified in the schematic 
of the study design, to identify the potential new or worsening AEs. Safety evaluations can be 
performed more frequently if clinically indicated. AEs are graded and documented according to 

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NCI CTCAE v5.0 during the study and follow-up. Toxicities will be characterized by severity 
grade, attribution/causality, and actions taken with the study treatment. 
All AEs with unknown causes after exposure to the study treatment must be evaluated to 
determine whether the event is potentially immune-related. 
Refer to Sections 8.2 and 8.3 for details regarding AE evaluation and documentation. 
Refer to the schedule of visits in Table 1 for the timing of the evaluations. Refer to Appendix 2 
for ECOG PS criteria. 
7.2.1 Physical Examination 
7.2.1.1 Comprehensive physical examination 
A comprehensive physical examination will be performed by the investigator or designee during 
the screening. All the clinically significant abnormalities should be documented in the disease 
history. After the first dose of study treatment, any new clinically significant abnormalities 
should be documented as AEs. 
7.2.1.2 Targeted physical examination 
In cycles where a comprehensive physical examination is not required by the study protocol, 
targeted physical examination should be performed by the investigator or qualified designee if 
clinically indicated. The examination should be scheduled prior to administration on Day 1 of 
each treatment cycle. All of the clinically significant abnormalities should be documented as 
AEs. 
7.2.1.3 ECOG PS 
The investigator or qualified designee will evaluate PS during screening, prior to administration 
on Day 1 of each treatment cycle, during the end-of-treatment visit, and during safety follow-up 
in accordance with the instructions in the Schedule of Visits. 
7.2.1.4 Vital signs 
Vital signs will be examined in accordance with the schedule of visits in Table 1, including 
temperature, pulse, respiratory rate, and blood pressure.The time and date of measurement 
should be documented in the appropriate section of the database. Temperature, pulse, respiratory 
rate, and blood pressure should be measured prior to the administration of study drugs. 

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7.2.1.5 12-lead ECG 
A resting 12-lead ECG will be performed at the local laboratory in accordance with the schedule 
of visits in Table 1.  
The subject must be resting in a supine position for at least 5 min prior to 12-Lead ECG. All the 
12-lead ECG results should be recorded in the supine position. Further ECGs (or other related 
tests) should be performed if clinically indicated, such as a cardiac AE. The investigator should 
review the ECG on the day it is performed. The evaluation method should be consistent 
throughout the trial. 
The investigator should evaluate all the ECGs as either normal, clinically significant 
abnormalities, or clinically insignificant abnormalities. If it is a clinically significant 
abnormality(s), the investigator should document an AE in the database. 
7.2.2 Routine laboratory safety evaluations 
See below for the specific laboratory procedures/evaluations. Refer to the Procedure Manual for 
the total amount of blood/tissues extracted/collected throughout the trial (from pre-trial to post-
trial visits), including the amount of each subject's blood/tissues extracted/collected for each 
specimen type during each visit. Refer to the section on laboratory evaluations in the Schedule of 
Visits. 
7.2.2.1 Laboratory safety evaluation (complete blood count, routine urinalysis, and blood 
biochemistry) 
Refer to Table  for laboratory tests including complete blood count, routine urinalysis, and 
blood biochemistry. 
Table 6 Routine laboratory safety evaluation 
Complete blood count 
RBC, HGB, WBC, PLT, LYM, and ANC 
Blood Biochemistry 
TBIL, ALT, AST, ALP, ALB, TP, LDH, UREA, Cr, Na, K, Cl, Mg, Ca, P, amylase, and 
BG 
Routine Urinalysis 
PH, UWBC, UPRO, URBC, and UGLU 
Thyroid Function 
FT3, FT4, and TSH 
Coagulation Function 
PT and INR 
Viral Serological Test 
HBsAg, HBsAb, HBcAb, HCV antibody, HCV RNA, and HIV antibody 

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ALB = albumin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; Cr = serum creatinine; BG = blood glucose; FT3 = free triiodothyronine; FT4 = 
free thyroxine; HBcAb = hepatitis B core antibody; HBeAb = hepatitis B e antibody; HBeAg = hepatitis B e 
antigen; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HGB = hemoglobin; HIV = human immunodeficiency virus; INR = international 
normalized ratio; LDH = lactate dehydrogenase; LYM = lymphocyte count; PH = pH; PLT = platelet; PT = partial 
thromboplastin time; TBIL = total bilirubin; TP = total protein; TSH = thyroid stimulating hormone; RBC = red 
blood cell; UGLU = urine glucose; UPRO = urine protein; URBC = urine red blood cell; UREA = urea; UWBC = 
urine white blood cell; WBC = white blood cell. 
7.2.2.2 Pregnancy test 
Serum β-human chorionic gonadotropin (β-hCG) pregnancy tests should be performed in women 
of childbearing potential (refer to Section 4.3 for definition) within 3 days prior to the first dose 
of study treatment and at the end-of-treatment visit. At every other cycle starting cycle 2) a urine 
pregnancy test should be performed ONLY in women of childbearing potential. If the result of 
urine β-hCG is positive or inconclusive, then serum β-hCG pregnancy test should be performed. 
Result of the serum pregnancy test is determinative. If the serum β-hCG result is positive, the 
subject is not eligible and must be excluded from the study.  
7.3 Biomarker Analysis  
7.3.1 Tissue biomarkers 
All the eligible subjects must provide tumor tissues during screening, and optional biopsy at 
C3D1 +/-7 days, EOT/when PD is confirmed (Table 1). Acceptable tumor tissues include 
archival specimens or at least 20 unstained, 4–5 μm sections from a fresh specimen (tissue 
should have a surface area of 25 mm2 containing greater than 20% of tumor cells) for evaluating 
PD-L1 expression, transcriptome sequencing, single-cell sequencing, and multicolor IHC. 
7.3.2 Serum biomarkers 
Subjects need to provide a 60 mL of whole blood sample for serum biomarker detection prior to 
the first dose, C1D8, C2D1, C3D1, first PD is seen, and when PD is confirmed (See Table 1 and 
Appendix 4). 
7.4 Pharmacokinetics (PK) 
PK samples will be collected at the following time points: within 1 h before, any point within 2-
24 h after, any point within 120-264 h after sintilimab infusion in Cycle 1, within 1 h before 

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sintilimab infusion in Cycle 2/4, and then within 1h before sintilimab infusion with every 4 
cycles thereafter starting cycle 7 (e.g. Cycle 7, 11, 15 etc.).  
For PK analysis, 5 mL of whole blood will be collected using vacutainers with clot activator. 
Serum is then separated and frozen in aliquots. Refer to the Laboratory Manual provided by the 
supporting company’s designated central laboratory for sampling methods, sample storage, 
transportation, and analysis. 
 
8 Safety Reports and AE Management 
8.1 Definition of AEs 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient regardless of 
its causal relationship to study treatment. An AE can be any unfavorable and unintended sign 
(including any clinically significant abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study treatment, whether or not it is considered to be 
study drug(s) related. Included in this definition are any newly occurring events and any previous 
condition that has increased in severity or frequency since the administration of study treatment.  
AEs include but are not limited to the followings: 
 Deterioration of pre-existing (prior to enrollment) medical conditions/diseases (including 
symptoms, signs, and laboratory abnormalities); 
 Any new adverse medical conditions (including symptoms, signs, and newly diagnosed 
diseases); 
 Clinically significant laboratory abnormalities, changes in the vital signs, ECG 
abnormalities, and findings on physical examination.  
 
All AEs that are observed by the Investigator, staff or mentioned by the subject either 
spontaneously or upon questioning will be recorded in Prometheus. 
8.2 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events and determine the 
attribution/relationship with study therapy. Any adverse event should be evaluated according to 
the NCI Common Terminology for Adverse Events (CTCAE), version 5.0. All adverse events  

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must also be evaluated for severity and seriousness. 
The severity of the adverse events (AEs) will be graded according to the U.S. Department of 
Health and Human Services, National Institutes of Health, National Cancer Institute, Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.0. 
 
 
 

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Table 7 Detailed rules of AE evaluation 
Severity based 
on CTCAE 
V.5.0 
Grade 
Events not 
included in the 
NCI CTCAE 
will be scored 
as follows: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; medical intervention not 
indicated 
Grade 2 
Moderate; minimal, local or non-invasive intervention required; limiting age-appropriate instrumental activities 
of daily living 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization 
indicated; disabling; limiting self-care activities of daily life, but not bedridden 
 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
 
Grade 5 
AE-related deaths 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of investigational product that: 
 
† Results in death (excluding those death due to PD);  
 
† Is life threatening; or, places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: 
This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); 
 
† Results in a persistent or significant disability/incapacity; (substantial disruption of one’s ability to conduct normal life functions); or 
 
† Results in or prolongs an existing inpatient hospitalization; (hospitalization is defined as an inpatient admission, regardless of length of 
stay) (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a serious adverse event. A 
pre-existing condition is a clinical condition that is diagnosed prior to the use of a Innovent product and is documented in the patient’s 
medical history.); or 
 
† Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a 
serious adverse event when,based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 

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Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action Taken  
Did the adverse event cause the investigational product to be discontinued? 
Relationship 
to Sponsor’s 
Product 
Did the Sponsor’s product cause the adverse event?  
The investigator (or physician designee) is responsible for verifying and providing source documentation for all adverse events; assigning 
the attribution and assessing the severity of the AE, the causal relationship between any events and the clinical study procedure, activities or 
drug. Additionally, the Investigator is responsible for providing appropriate treatment for the event and for adequately following the event 
until resolution for all adverse events for subjects enrolled.  
The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test 
drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between the investigational product and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely the investigational product 
caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the investigational product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen? 
Time course 
Did the AE follow in a reasonable temporal sequence from administration of the investigational product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)? 
Possible causes 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other 
host or environmental factors? 
Dechallenge  
Was the investigational product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the investigational product; or (3) the trial is a single-dose drug trial); or (4) 
investigational product(s) is/are only used one time.) 

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Rechallenge 
Tests 
Was the subject re-exposed to the investigational product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) investigational product(s) is/are used only one time). 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the investigational 
product or drug class pharmacology or toxicology? 
The assessment of attribution/relationship will be reported in the database as assessed by an investigator who is a qualified physician according to his/her best 
clinical judgment, including consideration of the above elements. 
 
Attribution/Causality 
Attribution is the determination of whether an adverse event is related to a medical treatment or procedure. 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of an 
investigational product relationship). 
• Definite - the adverse event is clearly related to the investigational agent(s). 
• Probable - the adverse event is likely related to the investigational agent(s). 
• Possible - the adverse event may be related to the investigational agent(s). 
• Unlikely - The adverse event is doubtfully related to the investigational agent(s).  
• Unrelated- The adverse event is clearly NOT related to the investigational agent(s). 

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8.3 AE Documentation 
The investigator should document AEs and SAEs from the time of signing of informed consent 
form until 90 days after the last study drug administration if new anti-tumor therapy has not been 
initiated, using medical terms and concepts. Avoid colloquialisms and abbreviations. All the AEs 
(including SAEs) will be recorded in the Prometheus database. 
8.3.1 Collection and time of AEs 
The investigator should use non-leading questions when asking the subjects about AEs. 
AEs will be recorded in Prometheus, following the NCI recommended Adverse Event Recording 
Guidelines for Phase II studies: 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
  
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
Phase I 
Phase II   
Phase I 
Phase II   
Phase I 
Phase II  
Phase I 
Phase II   

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Phase III 
Phase III 
Phase III  
Phase III 
 
All AEs including SAEs and irAEs will be collected within 90 days after the last dose if new 
anti-tumor therapy has not been initiated. Only irAEs and study treatment- or procedure-related 
SAE will be collected if a new anti-tumor therapy has been initiated. 
After 90 days since the last dose, investigator should report sintilimab-related or procedure-
related SAEs. 
8.3.2 Follow-up of AEs 
The AEs should be followed until the events return to the baseline values or grade 0–1, or until 
the investigator believes that no further follow-up is required for reasonable reasons (if the event 
cannot resolve or has already been improved). If the event cannot resolve, a reasonable 
explanation should be documented in the database. The outcome and date of an AE/SAE should 
be documented in the medical record and recorded in the eCRF, regardless of whether the event 
is related to the study drugs. 
8.3.3 Contents of AE documentation 
The investigator must document all the AEs, including the diagnosis (document signs and 
symptoms including the laboratory abnormalities if there is no diagnosis),  date of occurrence 
(if applicable), CTCAE grade and changes in severity, whether it is an SAE, irAE or not, 
measures taken for the study drugs, treatment for the AE and outcome of the event, and 
relationship between the event and study drugs. 
Descriptions of the AE are as follows: 
Diagnosis, signs, and symptoms 
Document the definite diagnosis, if there is one, rather than just listing the independent signs and 
symptoms (e.g. hepatic failure rather than jaundice, elevated transaminase, and asterixis). Signs 
and symptoms should be reported as separate AEs/SAEs if they cannot be attributed to the 
diagnosis. If it is determined that the signs and symptoms are caused by the diagnosis, then only 
the diagnosis should be reported, which has the signs and symptoms included in. The record of 
signs and symptoms should then be deleted. A follow-up SAE report should be submitted. 
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Generally, for AEs secondary to other events (such as result of another event or clinical 
sequelae), the primary event should be documented. However, clinically significant secondary 
events should be recorded as independent AEs in the database if they occur at different time from 
the primary event. If the relationship between events is unclear, document them as separate 
events in the database. 
Ongoing or recurrent AEs 
An ongoing AE refers to an event that does not resolve and is ongoing between two assessment 
time points. These AEs should only be documented once in the database.  
Recurrent AEs refer to AEs that have resolved between the two time points of assessment but 
subsequently occur again. These events should be independently documented in the database. 
Laboratory abnormalities 
Any abnormal laboratory finding that is clinically significant (that requires 
treatment/intervention) should be reported as an AE. The investigator is responsible for 
reviewing all the laboratory abnormalities and determine whether the findings should be reported 
as AEs. 
Death 
All deaths (including those that occur before Day 90) that happen during the entire course of the 
study, and after the last dose should be documented in the patient’s medical record, captured in 
the database and reported as an SAE to the sponsor and supporting company, in a timely manner, 
according to the specific SAE reporting guidelines, regardless of the causality with the study 
drugs. 
If the cause of death is known, record the cause of death as an AE and the outcome of the event 
as a death and submit an SAE report; if the cause of death is unclear, the AE should be recorded 
as Death of Unknown Cause in the AE form, and submit the SAE report as Death of Unknown 
Cause. The exact cause of the death should be further investigated and, when feasible, updated in 
the eCRF and SAE report. 
If the cause of death is confirmed to be PD then the event may not be documented or reported as 
an SAE, but the event should be documented in the database and reported to the sponsor and 
supporting company in a timely manner, according to the specific SAE reporting guidelines. 
If the subject initiates a new anti-tumor therapy within the 90 days after the last dose, the death 

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after the initiation of new therapy should not be reported as an SAE, unless the death is believed 
to be related to study drugs or study procedures. 
Pre-existing medical conditions 
Symptoms/signs presenting during the screening period will be recorded and reported as AEs 
only if their severity or frequency becomes aggravated (except for worsening of the studied 
disease). The relative change should be documented, such as increased frequency of headaches. 
Hospitalization, prolonged hospitalization, or surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE, except for the following situations: 
 Hospitalization or prolonged hospitalization as required by study protocol (such as for 
dose administration or efficacy evaluation). 
 Hospitalization due to a pre-existing medical condition that remains stable, e.g. elective 
surgery/therapy scheduled prior to the study. 
However, elective surgery/therapy required because of the exacerbated condition during the 
study (e.g. surgery/therapy required earlier than scheduled) should be considered as an AE. 
Progressive disease 
A PD is defined as the worsening of subject condition caused by the primary tumor that the study 
drug is targeting, the appearance of new lesions, or the progression of the primary lesion. PD will 
not be reported as an AE. Any life-threatening events, hospitalization or prolonged 
hospitalization, permanent or significant disability/incapacity, congenital anomaly/birth defects, 
or other important medical events caused by PD will not be reported as an SAE. 
Overdose 
An overdose is the administration of a drug at more than 20% of the dose specified in the study 
protocol. All the occurrences of overdose must be documented in the database. Any adverse 
events resulting from the overdose should be recorded. If the adverse events met the serious 
criteria, it should be reported as a SAE.  
New anti-tumor therapy 
All irAEs and study treatment- or procedure-related SAEs occurred within 90 days after the last 
dose are required to be documented and reported if a new anti-tumor therapy has been initiated. 

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8.4 Serious Adverse Events 
8.4.1 Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsor 
Single Site IND Protocols 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
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be reported to the IRB of record in accordance with its policies and procedures. 
the timeframes and procedures outlined in “The University of Texas M. D. Anderson Cancer 
Center Institutional Review Board Policy on Reporting Adverse Events for Drugs and Devices”. 
Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 90 days after the last dose of drug, unless the participant withdraws consent.  
Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND Office 
within 5 working days of knowledge of the event regardless of the attribution. 
Death or life-threatening events that are unexpected, possibly, probably or definitely related to 
drug must be reported (initial or follow up) to the IND Office within 24 hours of knowledge of 
the event  
Additionally, any serious adverse events that occur after the 90 day time period that are related to 
the study treatment must be reported to the IND Office. This may include the development of a 
secondary malignancy. 
The electronic SAE application (eSAE) will be utilized for safety reporting to the IND Office 
and MD Anderson IRB.  
All events reported to the supporting company must also be reported to the IND Office. 
Reporting to FDA: Serious adverse events will be forwarded to FDA by the IND Sponsor 
according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
8.4.2 Serious Adverse Event (SAE) Reporting to the Supporting Company 
All the SAEs that occur from the signing of ICF through Day 90 (inclusive) after the last dose 
must be reported within 24 hours. The investigator must fill out the SAE Report Form provided 

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by Innovent or MDACC e-SAE form, regardless of whether it is the initial report or a follow-up 
report. Besides, the investigator must report the SAE to the supporting company 
(drugsafety@innoventbio.com) by the time within 24 hours after noticing the event. In 
accordance with the laws and regulations of corresponding regions and countries, the 
investigator should also report the SAE to the regulatory authorities and EC/IRB. 
For SAEs occurring beyond the above period, those considered related to sintilimab should also 
be reported. 
The investigator must submit the completed MDACC e-SAE report form to the supporting 
company, within 24 h after noticing the event. The investigator should urgently collect all 
missing information and provide a complete SAE report. 
For an SAE, the investigator should also provide the date when the AE meets the criteria for an 
SAE, the date when the investigator is informed of the SAE, the reason that it is considered an 
SAE, date of hospitalization, date of hospital discharge, possible cause of death, date of death, 
whether an autopsy has been performed, causality assessment (the drug being investigator or 
other drugs included in the regimen), and other possible causes of the SAE.  
 
8.4.3 Pregnancy 
The risk of embryotoxicity exists for similar drugs. All the subjects with childbearing potential 
must take effective contraceptive measures. 
During the study, if a female subject exposed to the study drugs becomes pregnant, she must be 
excluded from the study. The investigator must report the sponsor and the supporting company, 
within 24 h of noticing the event and submit the Innovent Clinical Study Pregnancy 
Report/Follow-Up Form. 
During the study, if a female partner of a male subject who exposed to the study drugs becomes 
pregnant, the subject will continue with the study. The investigator must report the sponsor and 
the supporting company, within 24 h of noticing the event and submit the Innovent Clinical 
Study Pregnancy Report/Follow-Up Form. 
The investigator must continuously monitor and visit on the outcome of the pregnancy until the 
8th week after the subject gives birth. The outcome should be reported to the sponsor. 
If the outcome of the pregnancy is stillbirth, spontaneous abortion, fetal malformation (any 

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congenital anomaly/birth defect), or medical abortion, it should be considered as an SAE and the 
event is required to be reported to the sponsor and the supporting company, in accordance with 
SAE procedures and time limits. 
If the subject also experienced an SAE during the pregnancy, the event should be reported 
according to SAE procedures. 
8.5 Abnormal Hepatic Function 
Drug-induced liver injury is considered if abnormal AST and/or ALT levels are accompanied 
with abnormal elevation of TBIL, and the following conditions are met without other possible 
causes. Such cases should always be considered as important medical events. 
Table 8 Liver injuries required to be reported as SAEs 
Baseline 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT and TBIL) 
Treatment Period 
ALT or AST ≥ 3 × ULN  
with TBIL ≥ 2 × ULN 
and ALP ≤ 2 × ULN 
and no hemolysis 
ALT or AST ≥ 8 × ULN 
and the increased value of TBIL ≥ 1× ULN 
or TBIL ≥ 3× ULN 
Once being notified with the abnormalities, the subject must return to the study site promptly 
(ideally within 48 h) and receive an assessment. The assessment must include the laboratory 
tests, detailed medical history, and physical assessment. The possibility of hepatic tumor 
(primary or secondary) should be considered. 
Other than repeated AST and ALT tests, albumin, creatine kinase, TBIL, direct and indirect 
bilirubin, γ-GT, PT/INR, and ALP should also be tested. Detailed medical history includes 
history of alcohol, acetaminophen, soft drugs, various supplements, traditional Chinese 
medicine, chemical drug exposure, family diseases, occupational exposure, sexual behavior, 
travel, contact with subjects with jaundice, surgery, blood transfusion, hepatic diseases or 
allergies, cardiac diseases, and immune diseases. Further tests may include the detection of acute 
hepatitis A, B, C and E, hepatic imaging (such as biliary tract), autoantibodies, and 
echocardiography. If a retest showed consistency with the criteria outlined in Table 8 and there is 
no other possible cause, the possibility of drug-induced liver injury should be considered before 
all the results of etiological tests are accessible. This potential drug-induced liver injury should 

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be reported as SAEs. Additional dosing with the study drugs should follow the Dose 
Modification Criteria included in Section 5.2.2. 
8.6 Management of Drug-Related Toxicities 
8.6.1 irAEs 
Since the mechanism of sintilimab involves T-cell activation and proliferation, irAEs are likely to 
be observed during this study. Signs and symptoms of irAEs should be monitored. If there are no 
alternative causes (e.g. infections), signs and symptoms of the subjects during the study may be 
related to the immune system. 
Refer to Section 5.2 for dose adjustments of sintilimab and principles of AE management. Refer 
to the latest version of NCCN guideline for Management of Immunotherapy-Related Toxicities 
for a detailed guide on irAE management. 
We will continue to collect irAEs until 90th day after the last dose. An irAE should be followed 
up until it resolves to Grade 0-1 or baseline level, or investigators decide not to follow up 
anymore with acceptable reasons (e.g. cannot fully recover or getting better). 
 
9 Statistics 
9.1 Statistical Analysis Plan 
This is a Phase II, open label, single arm study, evaluating the efficacy and safety of 
sintilimab in subjects with UPS. Up to 25 subjects with UPS will be enrolled.  
9.2 Statistical Analysis Population 
Intention-to-treat set (ITT): all enrolled subjects who are treated. 
Evaluable set (EP): all enrolled subjects who have measurable lesions at baseline and have at 
least one restaging evaluation. This analysis set is used for ORR analysis. 
Safety analysis set (SS): all subjects who received at least one dose of study treatment. The SS is 
used for all the safety evaluations.  
Per-protocol set (PPS): A subset of ITT, refers to subjects who do not have major protocol 
violations that affect the efficacy evaluation. The PPS is used for the sensitivity analyses of 
primary efficacy endpoints and key secondary efficacy endpoints. 
9.3 Statistical Analysis Methods 

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9.3.1 General statistical analysis 
Continuous variable data will be summarized using mean, standard deviation, median, 
maximum, and minimum. Attribute data will be described using frequency and percentage. 
Student t-test/Wilcoxon test and ANOVA/Kruskal-Wallis test will be used to compare continuous 
variables between different patient groups. The chi-square test or the Fisher’s exact test will be 
applied to assess the association between two categorical variables. 
9.3.1.1 Analysis of primary efficacy endpoints 
The primary efficacy endpoints is confirmed ORR at 12W, defined as the proportion of subjects 
with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial 
response (PR), based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 
v.1.1) in the evaluable population. 
9.3.1.2 Design and sample size/power 
The primary efficacy endpoint will be confirmed ORR at 12W. A patient will be considered as a 
responder to the treatment if he/she has achieved confirmed complete response (CR) or partial 
response (PR) determined by RECIST 1.1. 
A Simon’s two-stage Minimax design will be used to monitor the efficacy of sintilimab. The null 
hypothesis involves an ORR of 10% that will be tested against an ORR of 30%, i.e. a 20% 
improvement. In the first stage, 15 patients will be treated. If there is ≤ 1 patient who achieves 
objective response in these 15 patients, the study will be terminated. If the study moves forward 
to second stage, an additional 10 patients will be treated leading to a total of 25 patients. Six or 
more responders out of the 25 treated patients will be considered clinically relevant to justify 
further investigation. The power of this design is 80% under the 1-sided type I error rate of 5%. 
The early stopping probability is 55% if the ORR is 10% and the average sample size would be 
19.5. Assuming a 5% dropout rate, we will need to enroll up to a total of 27 patients. 
Analysis of key and other secondary efficacy endpoints 
The key secondary efficacy endpoints are ORR (RECIST 1.1), DCR, DOR, PFS and OS in the 
evaluable and ITT populations. 
The ORR, DCR and corresponding exact 95% CIs of the sintilimab arm will be estimated using 
binomial distribution.  
PFS is the time from first dose to first date of Investigator-determined progression (by imaging), 

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or to death due to any cause. OS is the time from first dose to death due to any cause. Subjects 
who neither progress nor die will be censored at the date of their last tumor imaging evaluation. 
Subjects who do not have any tumor imaging evaluation after baseline will be censored on the 
date of first dose. The mPFS amd mOS and corresponding 95% CI will be estimated via the 
Kaplan-Meier method, and survival curves will be plotted [13]. Log-rank test will be performed 
to test the difference in survival between groups [14]. Regression analyses of survival data based 
on the Cox proportional hazards model [15] will be conducted on PFS or OS. The proportional 
hazards assumption will be evaluated graphically and analytically, and regression diagnostics 
(e.g., martingale and Shoenfeld residuals) will be examined to ensure that the models are 
appropriate. For repeated measures, linear mixed model will be used for continuous outcomes 
and GEE model will be fit for binary outcomes [16]. Appropriate methods will be applied to 
analyze correlative data. Other statistical analyses may be performed as appropriate. 
DOR: subjects who have achieved CR or PR: from first date of Investigator-determined response 
to Investigator-determined PD or death; subjects who neither progress nor die: be censored at the 
date of their last tumor imaging evaluation. The mDoR will be estimated via the Kaplan-Meier 
method and survival plots will be presented. 
9.3.1.3 Stopping Rule Monitoring 
The Investigator is responsible for completing efficacy/safety summary reports and submitting 
them to the IND Office Medical Affairs and Safety Group, for review. These should be submitted 
after the first 15 evaluable subjects, complete 6 cycles of study treatment, and again after the 
total of 25 evaluable subjects, complete 6 cycles of therapy. 
 
9.3.2 Safety analysis 
The safety analysis will use the SS. Safety parameters include AEs, laboratory tests, vital signs, 
ECG, immunogenicity, etc.  
9.3.2.1 Drug exposure 
The amount of drug exposure and duration of treatment (number of treatment cycles) will be 
summarized. 
9.3.2.2 AEs 
The incidence (frequency) of AEs, TEAEs, TRAEs, irAEs, SAEs, resulting in treatment 

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discontinuation, and AEs resulting in death will be summarized. The severity distribution of 
TEAEs, TRAEs, and irAEs will be summarized using NCI CTCAE v5.0 presented via SOC/PT. 
Subjects who discontinue the treatment due to AEs, develop SAE, or die will be listed (include at 
least the followings: start and end dates of the AEs, severity grades, relationship with study 
drugs, measures taken, and outcomes). 
9.3.2.3 Laboratory tests 
Abnormalities in hematology and biochemistry will be assessed through laboratory parameters. 
Each laboratory test result will be graded according to NCI CTCAE v5.0. The number of 
subjects with laboratory abnormalities at baseline will be presented by severity grade. Laboratory 
parameters measured on the day of first dose of study treatment (Day 1 of Cycle 1) will be 
considered as baseline measurements. The treatment phase for all laboratory parameters begins 
on Day 1 of study treatment. 
The frequency of laboratory abnormalities of each subject during the treatment phase will be 
summarized by severity grade. The worst grade (most severe) for each subject will be used if the 
same laboratory parameter was found to be abnormal repeatedly. All the laboratory parameters 
will be summarized by the worst NCI grade. 
Cross-classification tables describing changes in frequency of any given laboratory parameter 
before and after treatment based on NCI grades will be provided. 
Lists of subjects with laboratory abnormalities ≥ grade 3 will be provided. 
For any given laboratory parameter, a subject is considered evaluable if at least one measurement 
is available. 
Routine urinalysis: A cross-classification table is used to describe changes between normalities 
and abnormalities before and after the treatment. 
9.3.2.4 ECG 
Descriptive statistics are used for ECG and changes from baseline. 
9.3.2.5 Vital signs, physical examinations, and other safety-related examinations 
Descriptive statistics of vital signs and relative changes from baseline will be shown. 
Abnormal changes from baseline in physical examination will be listed. 

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9.3.3 Compliance 
The frequency and proportion of subjects who violate the treatment regimen will be presented. 
The proportion of subjects administered study drugs of doses between 80–110% of the dose 
specified in the protocol, who complete the study in accordance with study protocol, and who 
complete different number of treatment cycles will also be summarized. 
9.3.4 Baseline characteristics and concomitant medications 
Subjects' demographics (sex, race, ethnicity and age), tumor diagnosis information (pathological 
diagnosis, tumor staging, prior treatment), baseline tumor evaluation (target lesion, number of 
non-target lesions, sites, total diameter, etc), and other baseline information [height and weight 
(BMI, BSA), vital signs, laboratory tests, past/concomitant medications] will be analyzed using 
descriptive statistics. 
9.3.5 Data lists of eligible subjects 
In addition to subjects' data lists, tumor evaluations (date of evaluation, lesion status, and 
evaluation results) and efficacy endpoints of subjects who have achieved CR and PR will be 
listed separately. 
Data including the PFS and OS of all the subjects at the end of the study (date of progression, 
date of death, PFS, and OS) will be also be presented. 
9.3.6 Exploratory analysis 
Evaluate the correlation between biomarkers in tumor tissue and efficacy, including PD-L1 
expression level, transcriptome sequencing, single-cell sequencing, and multicolor IHC analyses; 
Evaluate the correlation between biomarkers in peripheral blood and efficacy, including soluble 
PD-L1, ctDNA, and cytokines analyses. 
10 Quality Assurance and Quality Control 
In accordance with the Good Clinical Practice (GCP), the sponsor is responsible for the 
implementation and maintenance of quality assurance and quality control systems as per 
appropriate standard operating procedures, to ensure the study is implemented and the authentic 
data is collected, documented, and reported in accordance with the requirements of the protocol, 
GCP, and applicable regulations. 

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10.1 Clinical Monitoring 
The MD Anderson IND will conduct clinical monitoring of this study. The monitor should 
perform the monitoring in accordance with the standard operating procedures, and has the same 
rights and responsibilities as the sponsor's medical monitor. The monitor must maintain regular 
communication with the investigator, authorized research personnel, and sponsor. 
During the course of the study, the monitor is responsible for the monitoring of whether the 
written ICF from all subjects have been obtained and whether the data records are correct and 
complete. The monitor should compare the data recorded in the databases with the raw data, and 
inform the investigator of any errors or omissions. Besides, the monitor should also control the 
compliance of the protocol and study procedures for each study site, arrange for the supply of 
study drugs, and ensure that the drugs are kept under proper conditions. 
The monitoring visits should be conducted in accordance with relevant laws and regulations. 
From the time the subjects are enrolled, each center shall receive regular visits for the purpose of 
monitoring. After each visit to the investigator, the monitor should submit a written report to the 
sponsor. 
The study will be monitored by the MD Anderson External Data and Safety Monitoring Board 
(EDSMB). 
11 Data Management and Record Keeping 
This study will use an electronic data collection (EDC) system, and the research data will be 
recorded in the Prometheus database by the investigators or its authorized personnel. Before the 
initialization of the study site or data entry, the investigators and authorized personnel should be 
properly trained, and appropriate security measures should be applied for the computer and other 
equipment.  
Data entry into the database should be completed as soon as possible during or after visiting. The 
database should be updated at any time to ensure that they reflect the latest conditions of the 
subjects. To avoid variations in outcome evaluations by different evaluators, it is recommended 
that the baseline and all subsequent efficacy and safety evaluations of a given subject should be 
performed by the same individual. The investigators are required to review the data to ensure the 
accuracy and correctness of all the data entered into the database. If no evaluations are conducted 
during the study, or some information obtained are not evaluable, not applicable, or unknown, 
the investigators should record the above information in the database. The investigator should 

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sign the verified data electronically. 
The CRA will review the database, then evaluate the completeness and consistency by 
comparing them with the source document especially the key data. Data entry, corrections, and 
modifications should be performed by the investigator or designee. The data in the database is 
submitted to the data server and any modifications in the data should be recorded in the audit 
trail, including reasons, operator names, time, and dates of modifications. The roles and 
permission levels of the personnel responsible for data entry in the study site will be determined 
in advance. The CRA or data management personnel may raise an inquiry in the EDC for 
suspicious data. The study site personnel are responsible for dealing with such inquiry. The EDC 
system will record the audit trail of the inquiry, including the investigator name, time, and date. 
Unless otherwise stated, the database should only be used as forms to collect data instead of 
source. The source documents are records that used by the investigators or hospital, including all 
those related to the subjects, which are able to demonstrate the presence, inclusion/exclusion 
criteria, and participation of subjects (laboratory records, ECGs, pharmaceutical records, and 
subject folders etc.). Permanent copies of study visit records will be considered as source 
documents which is used to record the data of enrolled subjects. Data in the database should be 
retrieved from the source documents and consistent with source data. 
The investigator is responsible for the maintenance of all source documents and should offer the 
documents to the CRA for review during each visit. In addition, the investigator must submit a 
complete eCRF for each enrolled subject, regardless of the duration of participation. The 
protocol number and subject numbers of all supporting documents (such as laboratory records or 
hospital records) submitted with the database should be carefully verified. All the personal 
identities (including the subjects' names) should be deleted or made illegible to protect the 
privacy of the subjects. The investigator verifies that the record has been reviewed and ensures 
the accuracy of the recorded data by using an electronic signature. The electronic signature 
should be completed using the investigator's user ID and password. The system will 
automatically attach the date and time for signing to the signature. The investigator cannot share 
his/her user ID and password with others. If the data in the database are required to be changed, 
the change should be performed according to the procedure outlined by the EDC system. All the 
changes and corresponding reasons should be recorded in the audit trail. 
AEs and concomitant diseases/history should be coded. The dictionary used for coding will be 
described in the CSR. 

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Records from the clinical trial (such as protocol and protocol revision, completed database, and 
signed ICFs) should be kept and managed in accordance with the GCP. The study sites should 
keep these documents for 5 years after the end of the study. 
The study documents should be properly kept for future reviews or data tracking. Security and 
environmental risks should be considered for keeping documents. 
No study documents can be destroyed without the written consent from the sponsor and 
investigator. The investigator/study site may transfer the study documents to other parties or 
another location that comply with the record-keeping requirements only after notifying the 
sponsor and obtaining the written consent. 
12 Ethics 
12.1 Implementation of Ethics 
The investigator is required to follow the procedures specified in this protocol and cannot change 
the procedures without the permission from the sponsor. Any protocol violations must be 
reported to the IRB, sponsor, or regulatory authorities. 
12.2 Informed Consent 
Before the start of any study process, the ICF is introduced to explain the risks and benefits of 
this study to potential participants, and the language in the ICF should be straightforward. The 
ICF statement should clarify that this ICF signing is voluntary, and the risks and benefits of 
participating in this study should be clearly outlined. The subject can withdraw from the study at 
any time. Subjects can only be enrolled if he/she fully understands the study in detail, has 
received satisfactory answers to his/her inquiries, and has sufficient time for consideration. 
Written consent must be obtained from the subject. All signed ICFs must be kept in the 
investigator's files or in the subject's folder. 
The investigator is responsible for the interpretation of the ICF of the subject, obtaining informed 
and dated ICF from the subject prior to the start of the study. After signing, the investigator 
should send the subject a copy of the signed ICF. The investigator is required to document the 
process of ICF in the source study document. Subject recruitment, enrollment, and informed 
consent procedures will comply with Clinical Research SOP 04_Informed Consent Process. 
12.3 Protection of Subjects' Data 
An ICF should include (or in some cases, use separate files together) information about data and 

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privacy protection. 
Take precautions to ensure the confidentiality of the documents so as to prevent the disclosure of 
information that can determine the identity of the subject. However, under special circumstances, 
some personnel may be permitted to see the genetic data and personal identification number of a 
subject. For example, in the event of a medical emergency, the sponsor, designated physician, or 
investigator will have an access to the subject identification code and the subject's genetic data. 
In addition, relevant regulatory authorities may require access to relevant documents. 
12.4 Protocol Violation 
Protocol violation refers to any non-compliance with the study protocol, the International 
Conference on Harmonization Good Clinical Practice (ICH GCP), or operating manual. Non-
compliance may come from the subjects, investigators, or study site personnel. Violations should 
be corrected promptly. 
13 Publishing of Study Data 
All the data generated in this study is the confidential information owned by the sponsor. The 
sponsor has the right to publish the study results. Information about the publishing policies 
between the sponsor and investigator will be described in the clinical trial agreement. 
All the information about this trial (not limited to the protocol and Investigators Brochure) must 
be kept strictly confidential. The investigator should realize that the scientific or medical 
information derived from this trial may be of commercial value to the sponsor. The investigator 
should keep the information and data related to this study confidential. The sponsor must be 
consulted in advance and written consent must be obtained prior to publishing of any study-
related information or conclusions. In order to protect the rights and interests, the sponsor may 
request the investigator not to publish the information from this trial before the investigational 
product is approved for marketing. 
The sponsor has the right to announce or publish information or data related to the trial or to 
report it to the drug administration. The sponsor must obtain the consent of the investigator if the 
name of the investigator would be included in the content of the announcement, publication, or 
advertisements. 
 

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14 References 
1. Fletcher CDM, Mertens F. World Health Organization Classification of Tumors: Pathology 
and Genetics of Tumors of Soft Tissue and Bone.  IARC Press, 2002. 
2. Judson I, Verweij J, Gelderblom H et al. Doxorubicin alone versus intensified doxorubicin 
plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a 
randomised controlled phase 3 trial. Lancet Onco 2014:15:415-23 DOI: 
https://doi.org/10.1016/S1470-2045(14)70063-4 
3. Maki RG, Wathen JK, Patel SR, et al. Randomized Phase II Study of Gemcitabine and 
Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: 
Results of Sarcoma Alliance for Research Through Collaboration Study 002 J Clin Oncol, 2007 
Jul 1;25(19):2755-63. doi: 10.1200/JCO.2006.10.4117. 
4. Graaf WTA, Blay JY, Sant P Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma 
(PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet, 2012 May 
19;379(9829):1879-86. doi: 10.1016/S0140-6736(12)60651-5. 
5. Smith HG, Memos N, Thomas JM, et al. Patterns of disease relapse in primary extremity soft-
tissue sarcoma. Br J Surg. 2016;103(11):1487–1496. doi:10.1002/bjs.10227.  
6. Keung EZ, Tsai JW, Ali AM, et al. Analysis of the immune infiltrate in undifferentiated 
pleomorphic sarcoma of the extremity and trunk in response to radiotherapy: Rationale for 
combination neoadjuvant immune checkpoint inhibition and radiotherapy. Oncoimmunology. 
2018 ;7(2):e1385689. DOI: 10.1080/2162402x.2017.1385689. 
7. Cancer Genome Atlas Research Network. Electronic address: 
elizabeth.demicco@sinaihealthsystem.ca, Cancer genome atlas research network. 
Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell. 
2017;171(4):950–65. 
8. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and 
bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. 
Lancet Oncol. 2017;18:1493–501. 
9. Burgess MA, Bolejack V, Andrew B et al. Multicenter phase II study of pembrolizumab (P) in 
advanced soft tissue (STS) and bone sarcomas (BS): Final results of SARC028 and biomarker 
analyses. J Clin Oncol. 2017;35(suppl; abstr 11008).  

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10. D'Angelo SP, Mahoney MR, Tine BA et al. Nivolumab with or without ipilimumab treatment 
for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 
2 trials. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance 
A091401): two open-label, non-comparative, randomised, phase 2 trials.   Lancet 
Oncol.2018;19:416-426  https://doi.org/10.1016/S1470-2045(18)30006-8 
11. Zou W, Chen L: Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
Immunol 8:467-77, 2008 
12. Chen L, Han X: Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. 
Journal of Clinical Investigation 125:3384-3391, 2015 
13. Kaplan EL, Meier P: Nonparametric Estimation from Incomplete Observations. Journal of 
the American Statistical Association 53:457-481, 1958 
14. Mantel N: Evaluation of survival data and two new rank order statistics arising in its 
consideration. Cancer Chemother Rep 50:163-70, 1966 
15. Cox DR. Regression Models and Life-Tables. Journal of the Royal Statistical Society. Series 
B (Methodological) 1972;34(2):187-220 
16. Jiang WX. Bayesian variable selection for high dimensional generalized linear models: 
Convergence rates of the fitted densities Ann. Statist. 2007;35(4):1487-1511. 
 
 

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15 Appendix 
Appendix 1: Signature Page for Investigator 
Protocol Title: A MultiCenter, Double-Blind, Randomized Phase 3 Clinical Trial Evaluating the 
Efficacy and Safety of Sintilimab vs. Placebo, in Combination with Paclitaxel and Cisplatin 
(TP), for First-Line Treatment of Unresectable, Locally Advanced, Recurrent, or Metastatic 
Esophageal Squamous Cell Carcinoma (ORIENT-15) 
Protocol Number: CIBI308A301 
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd.. I have read and 
fully understood this protocol, and agree to conduct this study in accordance with the 
requirements found in this protocol and the Good Clinical Practice, and in compliance with 
relevant laws and regulations and the Declaration of Helsinki. Also, I promise not to reveal any 
confidential information to a third-party without the written consent from Innovent Biologics 
(Suzhou) Co., Ltd.. 
Instructions for investigators: please sign and date this page, print the name of the 
investigator, position, and study site, and return the signed form to Innovent Biologics 
(Suzhou) Co., Ltd.. 
 
I have read the entire content of this study protocol and will perform the study as required: 
Signature of Investigator:       ____________ Date:  ________ 
Name (Print):         ___________________________________ 
Title of Investigator:         _____________________________ 
Study Site/Address:       ________________________________ 
 
___________________________________________________ 
 
___________________________________________________ 

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Appendix 2: ECOG PS 
Score 
Performance Status 
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 
nature or office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Death 
 
References 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
 
 
 
 

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Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
The following is an excerpt from the RECIST v1.1. 
 
1. Measurability of Tumor at Baseline 
1.1 Definitions 
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1 Measurable 
Tumour 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 by conventional instruments in clinical exam (lesions which cannot be accurately 
measured by calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
 Malignant lymph nodule: pathologically enlarged and measurable, single lymph nodule 
must be ≥ 15mm in short axis by CT scan (CT scan slice thickness no greater than 5 mm). 
At baseline and during follow-up, only the short axis will be measured and followed. 
1.1.2 Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodule with ≥ 10 mm to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses that cannot be diagnosed and followed by reproducible imaging techniques, and cystic 
lesions. 
1.1.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 

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 Bone scan, PET scan or plain films are not considered adequate to measure bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone 
lesions; 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts; 
 Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same subject, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
1.2 Specifications by methods of measurements 
1.2.1. Measurements of lesions 
All measurements should be recorded in the Quantitative Imaging Analysis Core (QIAC) in 
metric notation when clinically assessed. All baseline measurements of tumor lesions should be 
performed as close as possible to the treatment start and must be within 28 days (4 weeks) before 
the beginning of the treatment. 
1.2.2 Method of assessment 
The same method of assessment and the same technique should be used to characterize each 

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identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion being followed cannot be 
imaged but is assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter (e.g. skin nodules). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. When lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be undertaken since it is 
more objective and may also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. Lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is ≤ 5 mm. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). 
Ultrasound: Ultrasound should not be used as a method of measurement to assess lesion size. 
Ultrasound examinations cannot be reproduced for review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm CR when biopsies are obtained or to determine 
relapse in trials where recurrence following CR or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a subject to 
be considered in complete response. Because tumor markers are disease-specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 

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recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease in order to differentiate between response (or SD) and PD. 
 
2. Tumor Response Evaluation 
2.1 Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only subjects with 
measurable disease at baseline should be included in protocols where objective tumor response is 
the primary endpoint. Measurable disease is defined by the presence of at least one measurable 
lesion. In studies where the primary endpoint is tumor progression (either time to progression or 
proportion with progression at a fixed date), the protocol must specify if entry is restricted to 
those with measurable disease or whether subjects having non-measurable disease only are also 
eligible. 
2.2 Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where subjects have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. On occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be measured 

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reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may 
be axial, saggital or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. Nodes with short axis ≥ 10 mm but < 15 mm should not be considered target 
lesions. Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference for baseline level of disease. 
All other lesions including pathological lymph nodes should be identified as non-target lesions 
and should also be recorded at baseline. These lesions should be followed as "present", "absent", 
or in rare cases "unequivocal progression". Multiple target lesions involving the same target 
organ may be recorded as a single item (e.g. "multiple enlarged pelvic lymph nodes" or "multiple 
liver metastases"). 
2.3 Response Criteria 
2.3.1 Evaluation of target lesions 
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 diameters. 
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 

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addition, 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). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
2.3.2 Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the "sum" of lesions may not be zero even if complete response 
criteria are met, since a normal lymph node is defined as having a short axis of < 10 mm 
Electronic CRFs or other data collection methods may therefore be designed to have target nodal 
lesions recorded in a separate section where, in order to qualify for CR, each node must achieve 
a short axis < 10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to 
be included in the sum of target lesions. 
Target lesions that become too small to measure: While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being "too small to 
measure". When this occurs it is important that a value be recorded on the case report form. If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned. (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error. To reiterate, however, if the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions "fragment", the longest 

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diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter should be the 
maximal longest diameter for the coalesced lesion. 
2.3.3 Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response of non-
target lesions. While some non-target lesions may actually be measurable, they need not be 
measured and instead should be assessed only qualitatively at the time points specified in the 
protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PD: Unequivocal progression of existing non-target lesions. Note: the appearance of one or more 
new lesions is also considered progression. 
2.3.4 Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the subject also has measurable disease. In this setting, to achieve "unequivocal 
progression" on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
"increase" in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the subject only has non-measurable disease: This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing subjects 

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for unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumor burden representing an 
additional 73% increase in "volume" (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from "trace" to "large", an 
increase in lymphangitic disease from "localized" to "widespread", or may be described in 
protocols as "sufficient to require a change in therapy". Examples include an increase in a pleural 
effusion from "trace" to "large", an increase in lymphangitic disease from "localized" to 
"widespread", or may be described in protocols as "sufficient to require a change in therapy". If 
"unequivocal progression" is seen, the subject should be considered to have had overall PD at 
that point. While it would be ideal to have objective criteria to apply to non-measurable disease, 
the increase must be substantial. 
2.3.5 New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal. For example, progression should not be attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than 
tumor (for example, some "new" bone lesions may be simply healing or flare of pre-existing 
lesions) This is particularly important when the subject’s baseline lesions show partial or 
complete response. For example, necrosis of a liver lesion may be reported on a CT scan report 
as a "new" cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate PD. An example of this is the subject who 
has visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals 
metastases. The subject’s brain metastases are considered to be evidence of PD even if he/she did 
not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 

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progression (particularly possible "new" disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
2.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The subject’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, it depends on the nature of the study, protocol requirements, and results. 
Specifically, in non-randomized trials where response is the primary endpoint, confirmation of 
PR or CR is needed to deem either one the "best overall response". 
2.4.1 Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 9 
provides a summary of the overall response status calculation at each time point for subjects who 
have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only,  
 

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Table 10 is to be used. 
 
2.4.2 Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a subject had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved 
PD status, regardless of the contribution of the missing lesion. 
2.4.3 Best overall response: all time points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in trials where confirmation of complete or partial response is not 
required: Best response in these trials is defined as the best response across all time points (for 
example, a subject who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it must 
also meet the protocol specified minimum time from baseline. If the minimum time is not met 
when SD is otherwise the best time point response, the subject’s best response depends on the 
subsequent assessments. For example, a subject who has SD at first assessment, PD at second 
and does not meet minimum duration for SD, will have a best response of PD. The same subject 
lost to follow-up after the first SD assessment would be considered inevaluable. 
Best response determination in trials where confirmation of CR or PR is required: CR or PR may 
be claimed only if the criteria for each are met at a subsequent time point as specified in the 
protocol (generally 4 weeks later). In this circumstance, the best overall response can be 
interpreted as in Table 11. 
2.4.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to "normal" 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 

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based on increase in size of the nodes. As noted earlier, this means that subjects with CR may not 
have a total sum of "zero" on the database. 
In trials where confirmation of response is required, repeated "NE" time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as "symptomatic deterioration". 
Every effort should be made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a descriptor of an objective response: it is a reason 
for stopping study therapy. The objective response status of such subjects is to be determined by 
evaluation of target and non-target disease as shown in Table 9 and  
Table 10. 
Conditions that define "early progression, early death and inevaluability" are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, a biopsy of the 
residual lesion is recommended before assigning a status of complete response. FDG-PET may 
be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease specific 
medical literature for the indication. However, it must be acknowledged that FDG-PET and 
biopsy may lead to false positive CR due to limitations of both approaches 
(resolution/sensitivity). 
Table 9 Time point response: subjects with target (with or without non-target) disease. 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 

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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
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 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete 
response 
PR = partial response 
SD = stable disease 
PD = progressive disease NE = 
inevaluable 
 
 
Table 10 Time point response: subjects with non-target disease only. 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Note: "Non-CR/non-PD" is preferred over "stable disease" for non-target disease. Since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign Non-CR/non-PD when no lesions can be measured is 

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not advised.  
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or necrosis in 
existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment, 
progression is confirmed, the date of progression should be the earlier date when progression was suspected.  
 
Table 11 Best overall response when confirmation of CR and PR required. 
Overall response 
first time point 
Overall response 
subsequent time point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 

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meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD is met. However, sometimes "CR" may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR 
at the first time point. Under these circumstances, the original CR should be changed to PR and the best response is 
PR. 
2.5 Frequency of Tumor Re-Evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to 
the type and schedule of treatment. However, in the context of Phase 2 studies where the 
beneficial effect of therapy is not known, follow-up every 6–8 weeks (timed to coincide with the 
end of a cycle) is reasonable. The protocol should specify which organ sites are to be evaluated 
at baseline (usually those most likely to be involved with metastatic disease for the tumor type 
under study) and how often evaluations are repeated. Normally, all target and non-target sites are 
evaluated at each assessment. In selected circumstances certain non-target organs may be 
evaluated less frequently. For example, bone scans may need to be repeated only when complete 
response is identified in target disease or when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on whether the 
trial has as a goal the response rate or the time to an event (progression/death). If "time to an 
event" (e.g. time to progression, disease-free survival, progression-free survival) is the main 
endpoint of the study, then routine scheduled re-evaluation of protocol specified sites of disease 
is warranted. In randomized comparative trials in particular, the scheduled assessments should be 
performed as identified on a calendar schedule (for example: every 6–8 weeks on treatment or 
every 3–4 months after treatment) and should not be affected by delays in therapy, drug holidays 
or any other events that might lead to imbalance in a treatment arm in the timing of disease 
assessment. 
2.6 Confirmatory Measurement/Duration of Response 
2.6.1 Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e. in 
randomized trials (Phase 2 or 3) or studies where stable disease or progression are the primary 

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endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in studies 
which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
2.6.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). The 
duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
2.6.3 Duration of SD 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical 
relevance of the duration of SD varies in different studies and diseases. If the proportion of 
subjects achieving stable disease for a minimum period of time is an endpoint of importance in a 
particular trial, the protocol should specify the minimal time interval required between two 
measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account many 
parameters including disease types and stages, treatment periodicity and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made 
2.7 PFS/TTP 
2.7.1. Phase 2 trials 
This guideline is focused primarily on the use of objective response endpoints for Phase 2 trials. 
In some circumstances, "response rate" may not be the optimal method to assess the potential 

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anticancer activity of new agents/regimens. In such cases PFS/PPF at landmark time points, 
might be considered appropriate alternatives to provide an initial signal of biologic effect of new 
agents. It is clear, however, that in an uncontrolled trial, these measures are subject to criticism 
since an apparently promising observation may be related to biological factors such as subject 
selection and not the impact of the intervention. Thus, Phase 2 screening trials utilizing these 
endpoints are best designed with a randomized control. Exceptions may exist where the behavior 
patterns of certain cancers are so consistent (and usually consistently poor), that a non-
randomized trial is justifiable. However, in these cases it will be essential to document with care 
the basis for estimating the expected PFS or proportion progression-free in the absence of a 
treatment effect. 
 

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Appendix 4: Schedule of Biomarker Samples 
Visit 
Sample Type t 
Timepoin 
Cycle 1 Day 1 
(C1D1) 
Biomarker (blood) Baseline (Prior to infusion, within previous 7 days) 
C1D8, C2D1, and 
C3D1 
Biomarker (blood) Prior to infusion (within 1 previous day) 
First Progression, 
and when PD is 
confirmed /EOT  
Biomarker (blood) 
For first progression, prior to the next infusion 
For EOT/confirmed progression ( 40 days after progression is 
radiographically determined) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 5: EQ 5D-5L Paper Interviewer Administration V1.0 
 

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Appendix 6: EQ 5D-5L Self-Complete V1.1 
 
 

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Appendix 7: EORTC QLQ-C30 
 
 

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Protocol Number 2020-1046  
Date 03/02/2023  
Version 03  
 
 
The PRO-CTCAE™ items and information herein were developed by the Division of Cancer Control and Population Sciences in the 
NATIONAL CANCER INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO- 
CTCAE™ is subject to NCI’s Terms of Use. 
Page 122 of 126 
 
Appendix 8 PRO-CTCAE ™ 
NCI PRO-CTCAE ™ ITEMS 
Item Library Version 1.0 
English 
Form Created on 28 October 2020 
As individuals go through treatment for their cancer they sometimes experience different 
symptoms and side effects. For each question, please select the one response that best 
describes your experiences over the past 7 days… 
 
1a.  In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
1b.  In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
2a.  In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
2b.  In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or daily activities? 
Ο Not at all 
ΟA little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
3a.  In the last 7 days, how OFTEN did you have NAUSEA? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
3b.  In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 

Protocol Number 2020-1046  
Date 03/02/2023  
Version 03  
 
 
The PRO-CTCAE™ items and information herein were developed by the Division of Cancer Control and Population Sciences in the 
NATIONAL CANCER INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO- 
CTCAE™ is subject to NCI’s Terms of Use. 
Page 123 of 126 
4a.  In the last 7 days, how OFTEN did you have VOMITING? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
4b.  In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
5a.  In the last 7 days, what was the SEVERITY of your CONSTIPATION at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
 
6a.  In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS (DIARRHEA/DIARRHOEA)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
 
7a.  In the last 7 days, what was the SEVERITY of your SHORTNESS OF BREATH at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
7b.  In the last 7 days, how much did your SHORTNESS OF BREATH INTERFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
8a.  In the last 7 days, what was the SEVERITY of your COUGH at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
8b.  In the last 7 days, how much did COUGH INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 

Protocol Number 2020-1046  
Date 03/02/2023  
Version 03  
 
 
The PRO-CTCAE™ items and information herein were developed by the Division of Cancer Control and Population Sciences in the 
NATIONAL CANCER INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO- 
CTCAE™ is subject to NCI’s Terms of Use. 
Page 124 of 126 
9a.  In the last 7 days, how OFTEN did you have ARM OR LEG SWELLING? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
9b.  In the last 7 days, what was the SEVERITY of your ARM OR LEG SWELLING at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
9c.  In the last 7 days, how much did ARM OR LEG SWELLING INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
10a.  In the last 7 days, did you have any RASH? 
Ο Yes 
Ο No 
 
11a.  In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING IN YOUR HANDS OR FEET 
at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
11b.  In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS OR FEET INTERFERE with 
your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
12a.  In the last 7 days, how OFTEN did you have PAIN? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
12b.  In the last 7 days, what was the SEVERITY of your PAIN at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
12c.  In the last 7 days, how much did PAIN INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 

Protocol Number 2020-1046  
Date 03/02/2023  
Version 03  
 
 
The PRO-CTCAE™ items and information herein were developed by the Division of Cancer Control and Population Sciences in the 
NATIONAL CANCER INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO- 
CTCAE™ is subject to NCI’s Terms of Use. 
Page 125 of 126 
13a.  In the last 7 days, how OFTEN did you have ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
13b.  In the last 7 days, what was the SEVERITY of your ACHING JOINTS (SUCH AS ELBOWS, KNEES, 
SHOULDERS) at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
13c.  In the last 7 days, how much did ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS) INTERFERE 
with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
14a.  In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF ENERGY at its 
WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
14b.  In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY INTERFERE with your 
usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 
15a.  In the last 7 days, how OFTEN did you feel ANXIETY? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost 
constantly 
15b.  In the last 7 days, what was the SEVERITY of your ANXIETY at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
15c.  In the last 7 days, how much did ANXIETY INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
 

Protocol Number 2020-1046  
Date 03/02/2023  
Version 03  
 
 
The PRO-CTCAE™ items and information herein were developed by the Division of Cancer Control and Population Sciences in the 
NATIONAL CANCER INSTITUTE at the NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO- 
CTCAE™ is subject to NCI’s Terms of Use. 
Page 126 of 126 
OTHER SYMPTOMS 
Do you have any other symptoms that you wish to report? 
Ο Yes 
Ο No 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe