A Phase 2 Clinical Trial Evaluating the Efficacy and Safety of Sintilimab for Advanced Rare Cancers (SiARa Cancer Study) - Cancer of Unknown Primary (SiARa-CUP)
Phase: PHASE2
Conditions: Cancer of Unknown Primary Site
Sponsor: M.D. Anderson Cancer Center

Investigational Drug: Sintilimab 
MD Anderson Cancer Center & Innovent Biologics 
Protocol # 2020-0902 
23rd March 2021 Version 2.0 
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MD Anderson IND Sponsor Cover Sheet
Protocol ID 
2020-0902 
Protocol Title 
A Phase 2 Clinical Trial Evaluating the Efficacy and Safety 
of Sintilimab for Advanced Rare Cancers (SiARa Cancer 
Study) – Cancer of Unknown Primary (SiARa-CUP) 
Protocol Version 
02 
Version Date 
March 23, 2021 
Protocol PI 
Kanwal Raghav, MD 
Department 
Gastrointestinal Medical Oncology 
IND Sponsor 
The UT MD Anderson Cancer Center (MD Anderson) 
IND # 
155013 
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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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Clinical Protocol 
Study Title: 
A Phase 2 Clinical Trial Evaluating the Efficacy and Safety 
of Sintilimab for Advanced Rare Cancers (SiARa Cancer 
Study) – Cancer of Unknown Primary (SiARa-CUP) 
Protocol Number: 
2020-0902 
Product Name: 
Sintilimab (Recombinant Fully Human Anti-PD-1 
Monoclonal Antibody Injection, R&D Code: IBI308) 
Study Phase: 
2 
Sponsor(s): 
UT MD Anderson Cancer Center and Innovent Inc.  
Medical Monitor: 
UT M.D. Anderson IND Office 
Principal Investigator: Kanwal Raghav, MD 
1515 Holcombe Blvd, Unit 426, Houston, TX 77030 
Telephone: 713-792-2828; Fax: 713-745-1163 
E-mail: kpraghav@mdanderson.org  
 
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Protocol Synopsis 
Protocol Number 
2020-0902 
Investigational Drug 
Sintilimab (R&D Code: IBI308) 
Active Ingredient 
Recombinant fully human anti-PD-1 monoclonal antibody 
Study 
Title 
 
A Phase 2 Clinical Trial Evaluating the Efficacy and Safety of 
Sintilimab for Advanced Rare Cancers (SiARa Cancer Study) – 
Cancer of Unknown Primary (SiARa-CUP) 
Study Phase 
2 
Study Objectives 
Primary Objectives: 
 To evaluate the safety and efficacy of sintilimab in subjects 
with CUP 
Secondary Objectives: 
 To evaluate the overall objective response rate (ORR) 
(investigator assessed), disease control rate (DCR), 
duration of response (DOR), progression-free survival 
(PFS), overall survival (OS) and Quality of Life (QOL) on 
sintilimab in subjects with CUP 
Exploratory Objectives: 
 To evaluate the correlation between biomarkers in tumor 
tissue and efficacy, including but not restricted to PD-L1 
expression level, transcriptome sequencing, single-cell 
sequencing, and multicolor immunohistochemistry (IHC) 
analyses; 
 To evaluate the correlation between biomarkers in 
peripheral blood and drug efficacy, including but not 
restricted to soluble PD-L1, circulating tumor DNA 
(ctDNA), and cytokine analyses. 
Study Design 
This is a Phase 2 clinical trial evaluating the efficacy and safety of 
sintilimab in subjects with CUP. 
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Up to 45 subjects with CUP will be enrolled. Subjects will be 
treated with sintilimab at 200 mg via intravenous (IV) 
administration on Cycle 1 Day 1. 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 every 9 weeks (± 7 days) and will be based on 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. After 
the completion or discontinuation of the study treatment, safety 
follow-up and survival follow-up will be performed. 
Considering the rareness of the disease, the patient accrual rate is 
expected to be approximately 2 patients per month. The total study 
duration is expected to be between 24-27 months with 6-month 
follow up.    
Inclusion Criteria 
1. Has histopathologically confirmed unresectable, locally 
advanced, recurrent or metastatic CUP. Patients must have 
undergone standard work-up to attempt to identify the primary 
tumor prior to enrollment. 
2. Is refractory or intolerant to at least one line of systemic 
chemotherapy. Patient ineligible for cytotoxic chemotherapy 
due to contraindications will be eligible.  
3. Is age ≥ 18 years. 
4. Has an ECOG PS of 0 - 2. 
5. Must be unsuitable for definitive treatment, such as definitive 
chemoradiotherapy and/or surgery. For subjects who have 
received (neo)adjuvant or definitive 
chemotherapy/chemoradiotherapy, time from the completion 
of last treatment to disease recurrence must be > 3 months. 
6. Is able to provide archival or fresh tissues for correlative 
analysis with obtainable results. 
7. Has at least one measurable lesion as per RECIST v1.1. 
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8. Has 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) ≥ 9.0 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 
(CrCl) ≥ 30 mL/min by Cockcroft-Gault formula: 
Female: 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶=
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×weight(kg)×0.85
72×serum creatinine(mg/dL) 
Male: 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶=
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×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. Is expected to survive ≥ 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. Is able to sign the informed consent form (ICF) and is able to 
comply with the scheduled follow-up visits and related 
procedures required in the protocol. 
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Exclusion Criteria 
1. Has 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. Is enrolled in another interventional clinical study. Current 
enrollment in an observational study (non-interventional) or in 
the follow-up phase of an interventional study is allowed. 
3. Has received palliative therapy for a local lesion within 2 
weeks prior to the first dose.  
4. Has received systemic treatment with Chinese traditional 
medicines with anti-cancer indications or immunomodulators 
(including thymosins, interferons, and interleukins) within 2 
weeks prior to the first dose of study treatment. 
5. Has received systemic immunosuppressants within 2 weeks. 
Allowed are 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. Has received a live attenuated vaccine within 4 weeks prior to 
the first dose of study treatment or is 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. Has undergone 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. Has 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. 
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9. Has 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. Has bone metastases and is at risk for paraplegia. 
11. Has known active autoimmune disease requiring treatment or 
a previous autoimmune 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. Has a known history of primary immunodeficiency diseases. 
13. Has a known active pulmonary tuberculosis. 
14. Has a known history of allogeneic organ transplantation or 
allogeneic hematopoietic stem cell transplantation. 
15. Is human immunodeficiency virus (HIV)-infected (has 
positive anti-HIV antibody). 
16. Has an active or poorly controlled serious infections. 
17. Has symptomatic congestive heart failure (NYHA Class II–
IV) or symptomatic or poorly controlled arrhythmia. 
18. Has uncontrolled hypertension (systolic blood pressure ≥ 160 
mmHg or diastolic blood pressure ≥ 100 mmHg) despite 
standard treatment. 
19. Had any arterial thromboembolic event within 6 months prior 
to enrollment, including myocardial infarction, unstable 
angina, cerebrovascular accident, or transient cerebral 
ischemic attack. 
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20. Has significant malnutrition, such as those requiring 
continuous parenteral nutrition ≥7 days. Allowed are those 
who received intravenous treatment for malnutrition that 
ended more than 4 weeks before the first dose of study 
treatment. 
21. Has a history of clinically significant deep venous thrombosis, 
pulmonary embolism, or other serious thromboembolic events 
within 3 months prior to enrollment (having an implantable 
port or catheter-related thrombosis or incidental pulmonary 
embolism detected on scan without symptoms or superficial 
venous thrombosis is not considered to be a "serious" 
thromboembolisms). 
22. Has 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. Has severe pulmonary dysfunction. 
24. Has hepatic encephalopathy, hepatorenal syndrome, or 
cirrhosis with Child-Pugh Class B or C. 
25. Has bowel obstruction or history of any 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. 
26. Has known acute or chronic active hepatitis B (positive 
HBsAg and hepatitis B (HBV) DNA viral load ≥ 103 
copies/mL or > 200 IU/mL), or acute or chronic active 
hepatitis C (positive hepatitis C [HCV] antibody and 
detectable HCV RNA). 
27. Has history of gastrointestinal (GI) perforation and/or fistula 
within 6 months prior to study enrollment (having a 
gastrostomy or enterostomy is allowed). 
28. Has interstitial lung disease requiring corticosteroids. 
29. Has history of other primary malignant tumors, excluding: 
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 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. 
30. Is pregnant or breastfeeding. 
31. Has an acute or chronic diseases, psychiatric disorders, or 
laboratory abnormality that may lead to the following 
consequences: increased investigational drug-related risks, or 
interference with interpreration of trial results, or is otherwise 
considered ineligible for participating in the trial by the 
investigators. 
Study Drugs, Strengths, 
and Administrations 
Sintilimab 
200 mg IV on day 1 and then every 3 weeks 
Evaluation Criteria 
 
 
Efficacy evaluation: 
 Primary endpoint: Confirmed ORR assessed by 
independent radiology review per RECIST v.1.1 
 Secondary endpoints: ORR (investigator assessed), DCR, 
DOR, PFS, OS, QOL 
Safety evaluation: 
 The incidence and severity of treatment-emergent adverse 
events (TEAEs), treatment-related adverse events 
(TRAEs), serious adverse events (SAEs), adverse events 
(AEs) leading to discontinuation, AEs leading to death, and 
immune-related adverse events (irAEs). 
 Changes in vital signs, physical examination, and 
laboratory tests results before, during, and after treatment. 
Biomarker evaluation: 
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 Correlation between biomarkers in the tumor tissue and 
efficacy, including PD-L1 expression level, transcriptome 
sequencing, single-cell sequencing, and IHC analyses; 
 Correlation between biomarkers in peripheral blood and 
efficacy, including the soluble form of PD-L1, ctDNA, and 
cytokines analyses. 
Statistical Analysis 
Method 
Primary efficacy endpoint: 
The primary efficacy endpoint will be confirmed ORR (confirmed 
complete response (CR) or partial response (PR) determined by 
RECIST 1.1). A Simon’s two-stage Minimax design will be used. 
The null hypothesis involves an ORR of 10% that will be tested 
against an ORR of 25%. In the first stage, 22 patients will be 
treated. If there are ≤ 2 patients who achieve objective response 
the study will be terminated. If the study moves forward to second 
stage, an additional 18 patients will be treated in stage 2 leading to 
a total of 40 patients. Eight or more responders out of the 40 
treated patients will be considered clinically relevant. The power 
of this design is 80% under the 1-sided type I error rate of 5%. 
Assuming a 10% dropout rate, we will need to enroll up to a total 
of 45 patients. The ORR and DCR and the corresponding 95% CIs 
will be estimated. The DOR, PFS and OS will be analyzed using 
Kaplan-Meier Method. QOL will be assessed through scales and 
reported using descriptive statistics.  
Safety data: 
The incidence and severity of AEs will be summarized, and 
laboratory abnormalities will be presented. 
Biomarkers: 
PD-L1 expression levels and distribution, and other potential 
biomarkers will be analyzed, and the potential correlation between 
these biomarkers and efficacy will be explored. 
Pharmacokinetics (PK) data: 
The PK analysis will include but is not limited to descriptive 
statistical analysis of trough concentrations of sintilimab. 
 
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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 
Signed ICF1 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History/Previous 
Medication2 
× 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs3 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
 
 
 
Weight/Height4 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
Physical Examination4 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
 
 
 
ECOG PS4 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
12-Lead ECG5 
× 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
Laboratory Tests 
CBC/Blood 
Biochemistry/Routine 
Urinalysis6 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
Coagulation Function7 
× 
 
 
 
 
 
 
 
 
× 
× 
 
 
Pregnancy Test8 
× 
 
 
× 
 
× 
 
× 
× 
× 
 
 
 
Thyroid Function9 
× 
 
 
× 
× 
× 
× 
× 
× 
× 
 
 
 
HIV, HBV, and HCV10 
× 
 
 
 
 
 
 
 
 
 
 
 
 
PK/ADA 
PK 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
ADA 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
Safety Evaluation 
AE Evaluation11 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
Concomitant 
× 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 

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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 diagnosed within the past 10 years that are clinically significant as determined by the investigator, 
including history of cigarette use, alcohol use, surgery, and drug allergy. Detailed disease information regarding cancer of unknown primary should be 
documented separately and not listed as a part of the disease history. All autoimmune diseases should be documented, regardless of the date of onset. All 
medications (including replacement/supplement drugs) used within 30 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), 
during end-of-treatment visit, and during the first safety follow-up. 
Medication 
Survival Status 
 
 
Subsequent Anti-
Tumor Therapy 
 
 
 
 
 
 
 
 
 
× 
× 
× 
× 
Efficacy Evaluation 
Tumor Imaging 
Evaluation12 
× 
 
 
 
 
× 
 
 
× 
× 
 
 
 
Study Drug Infusion 
Sintilimab13 
 
× 
 
× 
× 
× 
× 
× 
× 
 
 
 
 
Quality of Life Evaluation14 
EQ 5D-5L + QLQ-C30 
 
× 
 
  
 
× 
 
 
× 
× 
× 
 
 
PRO-CTCAE™ 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
Biomarker Study 
Archival/Fresh Tumor 
Tissue Sample15 
× 
 
 
× 
 
 
 
 
 
× 
 
 
 
Blood16 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
PK Sample21 
 
× 
× 
× 
 
× 
 
 
× 
 
 
 
 

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6. Complete blood count: red blood cell (RBC) count, HGB, white blood cell (WBC) count, platelet (PLT) count, WBC differentials [lymphocyte (LYM) 
count and absolute neutrophil count (ANC)]. Blood biochemistry: hepatic function [total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), γ-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), and lactate dehydrogenase (LDH)], 
renal function [urea (UREA) and creatinine (Cr)], electrolytes (Na, K, Cl, Mg, Ca, and P), amylase, and fasting blood glucose (FBG). Routine urinalysis: 
pH (PH), urine white blood cell (UWBC), urine protein (UPRO), urine red blood cell (URBC), and urine glucose (UGLU). complete blood count, blood 
biochemistry, and routine urinalysis 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: prothrombin time (PT) and international normalized ration (INR). The test will be conducted within 7 days prior to the first dose 
and during the safety follow-up. 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 including at end-of-treatment. 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, and during send-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. 
10. Hepatitis B panel (HBsAg, HBsAB, HBcAB, HBeAg, and HBeAb), 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 treatment can be accepted. Prophylactic antiviral therapy is suggested to be performed according to 
the local treatment guidelines for HBV carriers. HBV activity should be monitored regularly during the trial. Tests will be conducted in each local lab. 
11. Adverse events (AEs) 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. 
12. Tumor evaluations (CT chest/abdomen and pelvis w contrast unless contraindicated; MRI abdomen and pelvis w contrast can be used if CT contrast cannot 
be used; PET can be used as long as CT portion is done with contrast) will be performed based on RECIST v1.1 and the same imaging method 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 every 9 weeks (± 7 days) until initiation of a new anti-tumor therapy, PD, 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 should be performed within 28 days prior to the first dose. If the bone metastasis is confirmed at baseline, PET scan with contrast is recommended 
every 9 weeks or as clinical indicated. For subjects who discontinue the treatment for reasons other than imaging-confirmed PD, if the subject’s last 

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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. A baseline evaluation with MRI of the brain should be done for all patients to rule out brain metastases. 
13. Sintilimab: 200 mg, IV is given on cycle 1 day 1 and then every 3 weeks 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. 
14. Quality of life evaluation: on the day of the first dose, during each imaging evaluation, and during the first safety follow-up, including EQ 5D-5L, EORTC 
QLQ-C30. PRO-CTCAE™ will be administered day 1 of every cycle.  
15. Subjects are required to provide at least 10 slides of archived or fresh tumor tissue samples during screening for biomarkers. If not available, a fresh biopsy 
will be performed. A mandatory biopsy (if clinically feasible) within 7 days prior to C2D1 and an optional biopsy at progression will be performed with 
patient consent.  
16. Whole blood samples are required to be provided by subjects for biomarker testing at the following time points: prior to the first dose, C1D8, 1st day of 
every cycle, at each efficacy evaluation, and 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. 
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 (until death or end of study [section 6.2.6]). Telephone visits are allowed. 
21. PK sample (10 ml) 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 
Protocol Synopsis............................................................................................................................ 4 
Table of Contents .......................................................................................................................... 16 
List of Figures ............................................................................................................................... 21 
List of Abbreviations .................................................................................................................... 22 
1 Background ................................................................................................................................ 28 
1.1 Disease Background............................................................................................................ 28 
1.1.1 Scope of Problem ................................................................................................. 28 
1.1.2 Rationale for use of Immunotherapy in CUP ...................................................... 28 
1.2 Investigational Drug (Sintilimab) ....................................................................................... 28 
1.2.1 Mechanism of action ............................................................................................ 28 
1.2.2 Clinical study results of sintilimab ...................................................................... 29 
1.3 Risk/Benefit Assessment ..................................................................................................... 30 
1.3.1 Potential risks ....................................................................................................... 30 
1.3.2 Potential benefits .................................................................................................. 31 
2 Study Objectives ........................................................................................................................ 31 
2.1 Primary Objectives.............................................................................................................. 31 
2.2 Secondary Objectives.......................................................................................................... 31 
2.3 Exploratory Objectives: ...................................................................................................... 31 
3 Study Design .............................................................................................................................. 31 
3.1 Overall Design .................................................................................................................... 31 
Figure 1 Schematic of SiARa-CUP study design and administration .......................................... 32 
3.2 End of Study and Length of Study ...................................................................................... 33 
3.3 Rationale for Study Design ................................................................................................. 33 
3.3.1 Rationale for the Use of Immune-Modified RECIST ......... Error! Bookmark not 
defined. 
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3.3.2 Rationale for Biomarker Assessments ................................................................. 33 
3.3.3 Rationale for Allowing Patients to Continue Treatment until Loss of Clinical 
Benefit ........................................................................................................................... 34 
3.4 Definition of Study Completion ......................................................................................... 34 
3.5 Criteria for Study Discontinuation ...................................................................................... 34 
4 Study Population ........................................................................................................................ 35 
4.1 Inclusion Criteria ................................................................................................................ 35 
4.2 Exclusion Criteria ............................................................................................................... 36 
4.3 Method of Treatment Assignment ....................................................................................... 39 
4.4 Restrictions During the Study ............................................................................................. 39 
4.5 Criteria for Discontinuation/Withdrawal ............................................................................ 40 
4.5.1 Treatment discontinuation .................................................................................... 40 
4.5.2 Subject withdrawal............................................................................................... 41 
4.5.3 Lost to follow-up.................................................................................................. 41 
5 Study Drugs and Other Treatments............................................................................................ 42 
5.1 Treatment Regimens of Study Drugs .................................................................................. 42 
5.1.1 Sintilimab ............................................................................................................. 42 
5.2 Dose Adjustments ............................................................................................................... 43 
5.2.1 General principles ................................................................................................ 43 
5.2.2 Sintilimab dose adjustments ................................................................................ 44 
5.2.3 Management of sintilimab-related infusion reactions.......................................... 56 
5.3 Principles for Managing Immune Checkpoint Inhibitor Toxicities .................................... 58 
5.4 Concomitant Treatments ..................................................................................................... 59 
5.4.1 Prohibited treatments ........................................................................................... 59 
5.4.2 Permitted treatments ............................................................................................ 60 
5.4.3 Drug-drug interactions ......................................................................................... 61 
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5.5 Drug Management .............................................................................................................. 61 
5.5.1 Return and destruction ......................................................................................... 61 
5.6 Study Drug Records ............................................................................................................ 62 
6 Study Procedure ......................................................................................................................... 62 
6.1 Enrollment........................................................................................................................... 62 
6.1.1 Enrollment............................................................................................................ 62 
6.1.2 Enrollment error handling .................................................................................... 62 
6.2 Study Plan and Schedule ..................................................................................................... 62 
6.2.1 Screening.............................................................................................................. 62 
6.2.2 Baseline (prior to Day 1 of Cycle 1) .................................................................... 64 
6.2.3 Treatment visits .................................................................................................... 64 
6.2.4 End-of-treatment visits ......................................................................................... 65 
6.2.5 Safety follow-up................................................................................................... 66 
6.2.6 Survival follow-up ............................................................................................... 66 
6.2.7 Subsequent anti-tumor therapy ............................................................................ 67 
6.2.8 Unscheduled visits ............................................................................................... 67 
7 Study Evaluation ........................................................................................................................ 67 
7.1 Efficacy Evaluation ............................................................................................................. 67 
7.1.1 Tumor imaging and disease evaluations .............................................................. 67 
7.1.2 Tumor imaging during the study .......................................................................... 68 
7.2 Safety Evaluation ................................................................................................................ 69 
7.2.1 Physical Examination........................................................................................... 69 
7.2.2 Routine laboratory safety evaluations .................................................................. 70 
7.3 PK ....................................................................................................................................... 72 
7.4 Biomarker Analysis ............................................................................................................. 72 
7.4.1 Tissue and Serum biomarkers .............................................................................. 72 
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7.5 Storage and Destruction of Biological Samples ................................................................. 73 
8 Safety Reports and AE Management ......................................................................................... 74 
8.1 Definition of AEs ................................................................................................................ 74 
8.2 Evaluating Adverse Events ................................................................................................. 74 
8.3 AE Documentation .............................................................................................................. 79 
8.3.1 Collection and time of AEs .................................................................................. 79 
8.3.2 Follow-up of AEs ................................................................................................. 80 
8.3.3 Contents of AE documentation ............................................................................ 80 
8.4 Expedited Reporting of SAEs and Pregnancy .................................................................... 82 
8.5 Abnormal Hepatic Function ................................................................................................ 85 
8.6 Management of Drug-Related Toxicities ............................................................................ 86 
8.6.1 irAEs .................................................................................................................... 86 
9 Statistics ...................................................................................... Error! Bookmark not defined. 
9.1 Statistical Analysis Plan ....................................................... Error! Bookmark not defined. 
9.2 Statistical Analysis Population ............................................................................................ 87 
9.3 Statistical Analysis Methods ............................................................................................... 87 
9.3.1 General statistical analysis ................................................................................... 87 
9.3.2 Safety analysis ..................................................................................................... 89 
9.3.3 Compliance .......................................................................................................... 90 
9.3.4 Baseline characteristics and concomitant medications ........................................ 90 
9.3.5 Data lists of eligible subjects ............................................................................... 91 
9.3.6 Exploratory analysis............................................................................................. 91 
10 Quality Assurance and Quality Control ................................................................................... 91 
11 Data Management and Record Keeping .................................................................................. 92 
11.1 Electronic Case Report Forms .......................................................................................... 92 
11.2 Source Data Documentation ............................................................................................. 92 
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11.3 Use of Computerised Systems .......................................................................................... 92 
11.4 Retention of Records ......................................................................................................... 93 
11.5 Monitoring ........................................................................................................................ 93 
12 Ethics........................................................................................................................................ 93 
12.1 Compliance with Laws and Regulations........................................................................... 93 
12.2 Informed Consent.............................................................................................................. 93 
12.3 Institutional Review Board or Ethics Committee ............................................................. 94 
12.4 Confidentiality .................................................................................................................. 95 
12.5 Financial Disclosure ........................................................... Error! Bookmark not defined. 
13 Study Documentation, Monitoring and Administration .......................................................... 95 
13.1 Study Documentation........................................................................................................ 95 
13.2 Protocol Deviations ........................................................................................................... 95 
13.3 Administrative Structure ................................................................................................... 96 
13.4 Publication of Data and Protection of Trade Secrets ........................................................ 96 
13.5 Protocol Amendments ....................................................................................................... 97 
14 References ................................................................................................................................ 98 
15 Appendix .................................................................................................................................. 99 
Appendix 1: Signature Page for Investigator ............................................................................ 99 
Appendix 2: Schedule of Biomarker Samples ........................................................................ 100 
Appendix 3: ECOG PS ........................................................................................................... 101 
Appendix 4: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) ......................... 102 
Appendix 5: Immune-Modified Response Evaluation Criteria in Solid Tumors (Immune-
Modified RECIST)...................................................................................................................117 
Appendix 6: Biomarker Analysis ............................................................................................ 126 
List of Tables 
Table 1 Schedule of visits ............................................................................................................. 12 
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Table 2 Effective methods of contraception ................................................................................. 40 
Table 3 Dosage and administration ............................................................................................... 42 
Table 5 Sintilimab dose adjustments ............................................................................................. 44 
Table 6 Guidelines for the management of sintilimab-related infusion reactions ........................ 57 
Table 10 Routine laboratory safety evaluation ............................................................................. 71 
Table 11 Detailed rules of AE evaluation ..................................................................................... 76 
Table 12 Liver injuries required to be reported as SAEs .............................................................. 85 
Table 13 Time point response: subjects with target (with or without non-target) disease. ..........112 
Table 14 Time point response: subjects with non-target disease only. ........................................112 
Table 15 Best overall response when confirmation of CR and PR required. ..............................113 
 
 
List of Figures 
Figure 1 Schematic of study design and administration ............................................................... 32 
 
 
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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 
CK 
Creatine Kinase 
CNB 
Core needle biopsy 
CR 
Complete response 
CRA 
Clinical Research Associate 
CrCl 
Endogenous creatinine clearance rate 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating cell-free tumor DNA 
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Abbreviations 
Full Name 
CTLA4 
Cytotoxic T-lymphocyte-associated protein 4 
CUP 
Cancer of unknown primary 
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 
eCRF 
Electronic case report form 
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 
EPO 
Erythropoietin 
FAS 
Full analysis set 
FBG 
Fasting blood glucose 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin-fixed paraffin-embedded 
FT3 
Free triiodothyronine 
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Abbreviations 
Full Name 
FT4 
Free thyroxine 
GSF 
Granulocyte-colony stimulating factor 
GCP 
Good Clinical Practice 
γ-GT 
γ-glutamyltransferase 
H&E 
Hematoxylin and eosin 
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 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
ICPi 
Immune Checkpoint inhibitor 
IF 
Immunoflorescence 
iDMC 
Independent Data Monitoring Committee 
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Abbreviations 
Full Name 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IND 
Investigational New Drugs 
INR 
International normalized ratio 
IO 
Immuno-oncology 
irAE 
Immunity-related adverse event 
IRB 
Institutional review board 
ITT 
Intention to treat 
IV 
Intravenous 
LPLV 
Last patient last visit 
IRR 
Independent radiology review 
LCSS 
The Lung Cancer Symptom Scale 
MRI 
Magnetic resonance imaging 
MSI-H 
Microsatellite instability-high 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NAb 
Neutralizing antibody 
NGS 
Next-generation sequencing 
NSAIDS 
Nonsteroidal anti-inflammatory drugs 
NSCLC 
Non-small-cell lung cancer 
NYHA 
New York Heart Association 
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Abbreviations 
Full Name 
ORR 
Overall 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 
PET 
Positron emission tomography 
PEX 
Physical Examimation 
PFS 
Progression free survival 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PLT 
Platelet count 
PPS 
Per-protocol set 
PMBC 
Peripheral mononuclear blood cells 
PR 
Partial response 
PS 
Performance center 
PT 
Prothrombin time 
QOL 
Quality of life 
RBC 
Red blood cell count 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
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Abbreviations 
Full Name 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SD 
Stable disease 
SS 
Safety set 
TCR 
T-cell receptor 
TBIL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
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 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell count 
WES 
Whole exome sequencing 
WGS 
Whole genome sequencing 
 
 
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1 Background 
1.1 Disease Background 
1.1.1 Scope of Problem 
CUP is a rare malignancy which accounts for 3-5% of all cancers and is characterized by a 
heterogeneous group of cancers for which the anatomical site of origin remains occult after 
detailed investigations.1 CUP has been traditionally treated in first-line with empiric/putative 
site-specified combination chemotherapies with limited response rates of 25-35% and survival 
ranging from 6 to 16 months.1 Beyond, frontline therapy, no standard of care or FDA approved 
agents exist. Therefore, there is an unmet and critical need to develop novel agents for this 
orphan disease.  
1.1.2 Rationale for use of Immunotherapy in CUP 
Using a multiplex testing approach, 28% of CUP carry one or more predictive biomarkers (MSI-
H, PD-L1 and/or TML-H) to the immune checkpoint blockade, providing a novel option for 
treatment in patients with CUP.2 Our preliminary data has also shown, that using a 92-gene assay, 
as an objective platform, we can identify a subset of CUP patients (33%) who have the potential 
of responding to ICIs by identifying their gene-expression signature to known primaries where 
ICIs have established efficacy and FDA approved indication.Raghav and Varadhachary (unpublished). Two 
studies, with Nivolumab and Pembrolizumab in CUP have shown preliminary activity with RR 
of 21% and 23%, respectively.3,4 However, no immunotherapy drug is approved for use in CUP 
patients.    
Based on this information, we propose a study to explore activity of Sintilimab in CUP. 
Study Hypothesis: Sintilimab, fully humanized anti-PD1 antibody, can result in durable tumor 
responses in both advanced refractory CUP.        
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. 
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PD-L1 is the main ligand that is expressed on activated T-cells, antigen-presenting cells, and 
tumor cells.5 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 
and their ability to kill cancer cells can be restored by blocking the PD-1/PD-L1 interaction with 
drugs.6 
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 
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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 every 3 weeks 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 
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 the 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 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 
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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 esophageal cancer, 
supporting the conduct of clinical trials in subjects with advanced cancers. 
 
2 Study Objectives 
2.1 Primary Objectives 
 To evaluate the safety and efficacy of sintilimab in subjects with CUP 
2.2 Secondary Objectives 
 To evaluate the ORR (investigator assessed) and DOR, PFS, OS, DCR, DOR, and QOL 
of sintilimab in subjects with CUP who receive Sintilimab. 
2.3 Exploratory Objectives: 
 To evaluate the correlation between biomarkers in tumor tissue and efficacy, including 
but not restricted to PD-L1 expression level, 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), 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 
CUP. Subjects with unresectable, locally advanced, recurrent or metastatic CUP will be enrolled. 
Up to of 45 subjects will be enrolled. Subjects will be treated with sintilimab at 200 mg IV on 
Day 1 every 3 weeks. 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 
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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 every 9 weeks (± 7 days) and will be based on 
RECIST 1.1 per independent radiology review, until PD, 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 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 endpoint of the trial will be confirmed ORR assessed by 
IRR per RECIST v.1.1. Patients who discontinue treatment for reasons other than disease 
progression (e.g., toxicity) will continue scheduled tumor assessments until disease progression, 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first. All 
patients will be followed for survival unless consent is withdrawn. 
Treatment beyond initial investigator-assessed RECIST 1.1-defined progression will be 
considered in subjects experiencing investigator-assessed clinical benefit and tolerating study 
therapy (especially during the flare time-window of the first 12 weeks of treatment to account for 
expected delayed response). In such cases confirmation of progression is recommended at a 
minimum of 4 weeks after the first immune-related PD assessment. Such subjects must 
discontinue therapy when further progression is documented.  
All patients will be closely monitored for safety and tolerability during all cycles of therapy, at 
the treatment discontinuation visit, and during the follow-up period. The NCI CTCAE v5.0 will 
be used to characterize the toxicity profile of the study treatments for all patients. 
After discontinuation of study treatment, patients may receive any subsequent line therapy as 
directed by their treating physician. 
Figure 1 Schematic of SiARa-CUP study design and administration 
 
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3.2 End of Study and Length of Study 
The final analysis will occur after full enrollment, which is expected approximately 24-27 months 
after the first patient is enrolled. The end of this study is defined as the date when the last patient, 
last visit (LPLV) occurs or the date at which the last data point required for statistical analysis (i.e., 
ORR) or safety follow-up is received from the last patient, whichever occurs later. LPLV is 
expected to occur 30-33 months after the first patient is enrolled. In addition, the PI may decide to 
terminate the study at any time. 
3.3 Rationale for Study Design 
Study Hypothesis: Sintilimab, fully humanized anti-PD1 antibody, can result in durable tumor 
responses in advanced refractory CUP.          
3.3.1 Rationale for Biomarker Assessments 
Published results suggest that the expression of PD-L1 in tumors correlates with response to anti-
PD-1 and anti-PD-L1 therapy (Topalian et al. 2012; Herbst et al. 2014; Borghaei et al. 2015; 
Fehrenbacher et al. 2016; Herbst et al. 2016; Rosenberg et al. 2016). In the current study, archival 
or baseline tumor specimens will be collected from patients and tested for PD-L1 expression by a 
central laboratory during the screening period. In addition to the assessment of PD-L1 status, other 
exploratory biomarkers, such as potential predictive and prognostic biomarkers related to the 
clinical benefit of sintilimab, tumor immunobiology, mechanisms of resistance, or tumor type, 
may be analyzed. 
Patients will undergo mandatory tumor biopsy sample collection, if deemed clinically feasible by 
the investigator, prior to start of treatment and then after 3 weeks of therapy and an optional biopsy 
at the time of first evidence of radiographic disease progression. Tumor tissue biomarkers related 
to resistance, disease progression, and clinical benefit of sintilimab may be analyzed. 
Blood samples will be collected at baseline and during the study to evaluate changes in surrogate 
biomarkers. Changes in biomarkers such as cytokines associated with T cell activation, circulating 
tumor DNA (ctDNA) concentration, and lymphocyte subpopulations may provide evidence of 
biologic activity of sintilimab in humans. Correlations between these biomarkers and safety and 
efficacy endpoints will be explored to identify blood-based biomarkers that might predict which 
patients are more likely to benefit from sintilimab.   
Tumor tissue and blood samples collected at baseline and, if deemed clinically feasible, tumor 
tissue collected at 3 weeks of therapy and at the time of progression will enable NGS and RNA 
profiling to identify germline and/or somatic mutations that are predictive of response to study 
drug, are associated with progression to a more severe disease state, are associated with acquired 
resistance to study drug, are associated with susceptibility to developing adverse events, or can 
increase the knowledge and understanding of disease biology. 
Genomics is increasingly informing researcher's understanding of disease pathobiology. Whole 
genome sequencing (WGS) provides a comprehensive characterization of the genome and, along 
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with clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches.   
3.3.2 Rationale for Allowing Patients to Continue Treatment until Loss of Clinical Benefit 
Conventional response criteria may not adequately assess the activity of immunotherapeutic agents 
as increase in tumor size does not consistently reflect therapeutic failure (Wolchok et al. 2009). The 
phenomena of pseudo-progression or infiltration of the tumor by immune cells may mimic tumor 
progression. Therefore, as this study is evaluating an immunotherapy, we will allow patients to 
continue to receive study treatment after documented RECIST v1.1−defined radiographic disease 
progression, provided the benefit-risk ratio for the patient remains favorable as assessed by the 
physician and study monitor. In the absence of unacceptable toxicity, patients who meet criteria for 
disease progression per RECIST v1.1 while receiving sintilimab will be permitted to continue study 
treatment if they meet all of the following criteria: 
• Evidence of clinical benefit, as determined by the investigator following a review of all 
available data. 
• Absence of symptoms and signs (including laboratory values, such as new or worsening 
hypercalcemia) indicating unequivocal progression of disease. 
• Absence of decline in ECOG Performance Status that can be attributed to disease 
progression. 
• Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions. 
3.4 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. 
3.5 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 (PI) 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 
visit schedule. 
Reasons for study discontinuation or interruption include but are not limited to: 
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 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 are 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. Has histopathologically confirmed unresectable, locally advanced, recurrent or metastatic 
CUP. Patients must have undergone standard work-up to attempt to identify the primary 
tumor prior to enrollment. 
2. Is refractory or intolerant to at least one line of systemic chemotherapy. Patient ineligible for 
cytotoxic chemotherapy due to contraindications will be eligible.  
3. Is aged ≥ 18 years. 
4. Has an ECOG PS of 0 - 2. 
5. Must be unsuitable for definitive treatment, such as definitive chemoradiotherapy and/or 
surgery. For subjects who have received (neo)adjuvant or definitive 
chemotherapy/radiochemotherapy, time from the completion of last treatment to disease 
recurrence must be > 3 months. 
6. Is able to provide archival or fresh tissues for correlative analysis with obtainable results. 
7. Has at least one measurable lesion as per RECIST v1.1. 
8. Has an adequate organs 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) ≥ 9.0 g/dL. Note: Subjects cannot receive blood 
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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 (CrCl) ≥ 30 mL/min by Cockcroft-Gault formula: 
Female: 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶=
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×weight(kg)×0.85
72×serum creatinine(mg/dL) 
Male: 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶=
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×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. Is expected to survive ≥ 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. Is able to sign the ICF and be able to comply with the scheduled follow-up visits and related 
procedures required in the protocol. 
4.2 Exclusion Criteria 
1. Has 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. Is 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. Has received palliative therapy for local lesion within 2 weeks prior to the first dose.  
4. Has received systemic treatment with Chinese traditional medicines with anti-cancer 
indications or immunomodulators (including thymosins, interferons, and interleukins) within 
2 weeks prior to the first dose of study treatment. 
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5. Has received systemic immunosuppressants within 2 weeks prior to treatment, 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. Has 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. Has undergone 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. Has 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. Has 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. Has bone metastases and is at risk for paraplegia. 
11. Has known active autoimmune disease requiring treatment or a previous autoimmune 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. Has a known history of primary immunodeficiency diseases. 
13. Has known active pulmonary tuberculosis. 
14. Has a known history of allogeneic organ transplantation or allogeneic hematopoietic stem 
cell transplantation. 
15. Is HIV-infected subjects (has positive anti-HIV antibody). 
16. Has an active or poorly controlled serious infections. 
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17. Has symptomatic congestive heart failure (NYHA Class II–IV) or symptomatic or poorly 
controlled arrhythmia. 
18. Has uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 100 mmHg) despite of standard treatment. 
19. Has any arterial thromboembolic event within 6 months prior to enrollment, including 
myocardial infarction, unstable angina, cerebrovascular accident, or transient cerebral 
ischemic attack. 
20. Has 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. Has a 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. Has 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. Has severe pulmonary dysfunction. 
24. Has hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh Class B or 
C. 
25. Has 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. 
26. Has known acute or chronic active hepatitis B (positive HBsAg and HBV DNA viral load ≥ 
103 copies/mL or > 200 IU/mL), or acute or chronic active hepatitis C (positive HCV 
antibody and positive HCV RNA). 
27. Has a history of gastrointestinal (GI) perforation and/or fistula within 6 months prior to the 
enrollment, excluding gastrostomy or enterostomy. 
28. Has interstitial lung disease requiring corticosteroids. 
29. Has a 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. 
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 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. 
30. Is pregnant or breastfeeding. 
31. Has an acute or chronic diseases, psychiatric disorders, or laboratory abnormalities that may 
lead to the following consequences: increased investigational drug-related risks, or 
interference with interpretation of trial results, or is otherwise considered inappropriate for 
participating in the trial by the investigators. 
 If there are any uncertainties regarding the inclusion/exclusion, please contact the sponsor 
immediately and provide a complete medical history of the subject. The sponsor and 
principal investigator will discuss and determine the eligibility of the subject. 
4.3 Method of Treatment Assignment  
After written informed consent has been obtained and eligibility established, each patient will be 
assigned an identification number and enrolled on study and will receive study medications in this 
single-arm study. All participants will be registered in the Clinical Oncology Research System 
(CORe). 
4.4 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 and whose luteinizing hormone and follicle stimulating 
hormone levels are within the postmenopausal range are considered menopausal; 
 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 luteinizing hormone and follicle 
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stimulating hormone levels are within the postmenopausal range are considered 
menopausal. 
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 
4.5 Criteria for Discontinuation/Withdrawal 
4.5.1 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 
 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; 
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 Completion of 24-month of treatment with the study drugs. 
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. 
4.5.2 Subject withdrawal 
A subject has the right to withdraw from the study at any time for any reason. 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 (eCRFs). A 
subject who has signed the ICF and received any study interventions cannot be replaced after 
withdrawal or treatment discontinuation. 
4.5.3 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 study team is unable to contact the subject. 
 
5 Study Drugs and Other Treatments 
The study drug is sintilimab. The first dose of study treatment should start on Day 1 of Cycle 1. 
For the rest of the treatment cycles, the study treatment can be administered 3 day 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 
Sintilimab1 
200 mg 
Every 3 
week 
IV 
infusion 
on Day 1, every 21 days 
thereafter 
The study drugs in Table 3 is provided by the supporting company. The local labs are 
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 supporting company's information, etc. The label on the 
vial contains the same information as the outer package except for dosage form, precautions, and 
dosage and 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 
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quality issues such as turbidity and precipitation are observed in the vial, seal the vial 
immediately and notify the supporting company. 
The preparation and administration of sintilimab is as follows: 
1. The dose and regimen of sintilimab is 200 mg IV every 3 weeks. 
2. Calculate the volume of 0.9% (weight/volume) sodium chloride solution needed to dilute 
the sintilimab to a final concentration 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: 60 minutes for first 
infusion and if tolerated, 30 minutes thereafter). 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 hours. The prepared solution can be stored for 24 hours at 
2-8℃ protected from light, and can be stored up to 6 hours 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 
study drug must resolve to NCI CTCAE v5.0 grade 0 – 1 or baseline levels, excluding the 
following cases: 
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 Alopecia 
 Grade 2 fatigue 
 Hemoglobin (HGB) ≥ 8.0 g/dL 
 Grade 2 weight loss 
 All the dose adjustments should be documented, including the reasons and actions taken. 
 If further concerns exist about resolution of toxicities, the investigator should discuss 
these concerns with the sponsor prior to drug administration. 
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 
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 
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Drug-Related Toxicities 
Severity 
Management 
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 
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) 
/ 
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Drug-Related Toxicities 
Severity 
Management 
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 highstrength 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 
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 noncorticosteroid (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 
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Drug-Related Toxicities 
Severity 
Management 
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.  
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 
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Grade 3–4 
Interrupt study treatment until clinically stable, consult an 
endocrinologist, and provide symptom management 
Hyperthyroidism 
Grade 1 
Continue and monitor closely 
Grade 2 
Continue and monitor closely 
Grade 3–4 
Interrupt study treatment until clinically stable, consult an 
endocrinologist, and provide 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) for 
mineralocorticoid 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 
Interrupt study treatment until clinically stable, consult an 
endocrinologist, and provide symptom management. emergency 
department referral for normal saline (at least 2 L) and IV stress-
dose corticosteroids on presentation (hydrocortisone 100 mg or 
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 
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Drug-Related Toxicities 
Severity 
Management 
Grade 3–4 
Interrupt study treatment until clinically stable, consult an 
endocrinologist, and provide 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 
Interrupt study treatment until clinically stable 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 
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 
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Drug-Related Toxicities 
Severity 
Management 
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 Syndrome 
Grade 1 
Continue 
Grade 2 
Consider interruption until symptoms are controlled. prednisolone 
< 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 
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Drug-Related Toxicities 
Severity 
Management 
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) 
/ 
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 
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Drug-Related Toxicities 
Severity 
Management 
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 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 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 
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 
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Drug-Related Toxicities 
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Management 
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 
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 
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Drug-Related Toxicities 
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Management 
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 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 
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Drug-Related Toxicities 
Severity 
Management 
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 corticosteroids (IV prednisone 1-2 mg/kg or 
methylprednisolone 0.8-1.6 
mg/kg) and intravitreal/periocular/topical corticosteroids per 
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Management 
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 
For more detailed management guidelines regarding immune-related adverse events, please refer to ASCO 
guidance document (https://www.asco.org/sites/new-www.asco.org/files/content-files/practice-and-
guidelines/2018-management-of-irAEs-summary.pdf). 
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 may 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 in 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. 
 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 
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hypersensitivity reactions or allergic reactions. Signs and symptoms usually occur during or after 
drug infusion and usually resolve within 24 hours after the infusion completion. Refer to Table 5 
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).  
 
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.  
Pre-medications should be 
given for subsequent infusions.  
 
The following pre-medications 
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 pre-
medications, the study drugs 
should be permanently 
discontinued. 
Grade 3 or 4 
Discontinue the infusion. 
Not applicable. 
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NCI CTCAE Grades 
Treatments 
Premedications for 
Subsequent Infusions 
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 
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. 
 
 
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). 
5.2.4 Dose Modification Criteria for Hematological and Non-Hematological Toxicities that 
are Not Immune-related 
Dose adjustments for sintilimab are not permitted during the entire course of the study. Dose 
delay is allowed for any non-immune related hematological and non-hematological toxicities as 
per the following principles.  
• For grade 1-2 toxicity, treatment should continue with close follow-up of toxicities. 
• For grade 3-4 toxicity, interrupt treatment until toxicity resolves to grade ≤ 2. A thorough 
work-up should be initiated to ensure that the toxicity is not immune/sintilimab related. 
Once confirmed, treatment can be restarted once toxicity has resolved to grade ≤2. 
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Sintilimab treatment may 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. 
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 
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, Table 5 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 
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); 
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 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; 
 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 sponsor. 
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 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); 
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 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; 
 Prophylactic antiviral therapy is permitted for hepatitis B carriers. Refer to treatment 
guidelines for dosage and administration. 
 If a grade 3 or higher neutropenia occurs, prophylactic treatment with a granulocyte 
colony-stimulating factor is permitted starting from the next cycle. 
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 (also see section 
5.1.1). Do not freeze. Cold-chain management 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 supporting company 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. 
Used sintilimab should be stored under the same storage conditions before verification by the 
monitor. 
5.5.1 Return and destruction 
In this trial, the containers of used sintilimab should be returned. 
Upon the completion or discontinuation of the study, all unused or expired study drugs must be 
returned to the supporting company for destruction. Arrangements for the return of study drugs 
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will be made by the research team in GI Medical Oncology. 
5.6 Study Drug Records 
The designee of the study sites 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. 
 
6 Study Procedure 
6.1 Enrollment  
6.1.1 Enrollment  
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 medical monitor does not agree, the subject 
should not continue the study (regardless of receiving the study drugs or not). The investigator 
may not allow the improperly enrolled subject to continue with the study until they receive the 
written approval from the sponsor. 
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 
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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 
 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 (within 3 days prior to the first dose) 
 Thyroid function (results obtained within 28 days prior to treatment are also accepted) 
 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 treatment 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 within the past 10 years 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. 
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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 in medical record 
and CRF. 
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 in medical record and CRF. 
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) 
 AE evaluation 
 Concomitant medications 
 EQ 5D-5L 
 EORTC QLQ-C30 
 PRO-CTCAE 
 Blood sampling for biomarkers and PK sampling (for C1D1 and C1D8) 
 Survival status 
6.2.3 Treatment visits 
 Recording the vital signs  
 Weight. 
 Physical examination 
 ECOG PS 
 12-lead ECG 
 Complete blood count/blood biochemistry/routine urinalysis 
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 Thyroid function 
 AE evaluation 
 Concomitant medications 
 Tumor imaging evaluation (if applicable) 
 Administration of study drugs (tumor imaging evaluation should be performed prior to 
administration) 
 EQ 5D-5L (if applicable) 
 EORTC QLQ-C30 (if applicable) 
 PRO-CTCAE (if applicable) 
 Blood sampling for biomarkers and PK sampling (for C2D1) 
 Fresh tumor tissue (C2D1) (if clinically feasible) 
 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, immunogenicity 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 
 Coagulation function 
 Thyroid function 
 Pregnancy test 
 Tumor imaging evaluation (if applicable) 
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 AE evaluation 
 Concomitant medications 
 Survival status 
 Optional biopsy (can be done within 21 days but prior to any subsequent treatment) 
 Blood sampling for biomarkers (if applicable) and PK sampling 
 EQ 5D-5L 
 EORTC QLQ-C30 
 PRO-CTCAE 
 Subsequent anti-tumor therapy 
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 
 AE evaluation 
 Concomitant medications (for the 30-day safety follow-up only) 
 Document subsequent anti-tumor therapy  
 Survival status 
 EQ 5D-5L (for the 30-day safety follow-up only) 
 EORTC QLQ-C30 (for the 30-day safety follow-up only) 
 PRO-CTCAE (for the 30-day safety follow-up only) 
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. However, 
immunogenicity sampling should be obtained. 
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 
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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 end of study. 
6.2.7 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. 
6.2.8 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. Test results from the unscheduled 
visits should be documented in the eCRFs. 
7 Study Evaluation 
7.1 Efficacy Evaluation 
Tumor evaluations will be performed based on RECIST v1.1. Refer to Appendix 4 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 neck (if 
applicable), 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. A baseline evaluation with MRI of the 
brain should be performed for all patients to rule out brain metastases.  
During the screening, the investigator of the study site will confirm the presence of measurable 
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lesions based on RECIST v1.1 to determine the eligibility of the subject. According to RECIST 
v1.1, a maximum or 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 
every 9 weeks (± 7 days) until initiation of a new anti-tumor therapy, PD, withdrawal of informed 
consent, lost to follow-up, death, or completion of the study (whichever comes first). 
Patients who have radiographic PD will discontinue treatment, treatment beyond disease 
progression is not allowed. 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 absence 
of 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 
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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, PET scan 
is recommended at baseline and for follow-up.  
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 
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, including the respiratory tract, cardiovascular system, abdomen, skin, head and 
neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal system and 
nervous system. 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 treatment administration on 
Day 1 of each treatment cycle. All of the clinically significant abnormalities should be 
documented as AEs. 
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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. Blood pressure and pulse are measured 
in the supine/sitting position after resting for at least 5 min. The time and date of measurement 
should be documented in the appropriate section of the eCRF. Temperature, pulse, respiratory 
rate, and blood pressure should be measured prior to the administration of study drugs. 
Additional monitoring of vital signs is allowed based on standard clinical practice or clinical 
need, and should be documented in the eCRF when an AE/SAE occurs (if applicable). The time 
and date of measurement should be documented in the appropriate section of the eCRF. 
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, and document the results on the ECG. 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 eCRF. 
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. 
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7.2.2.1 Laboratory safety evaluation (complete blood count, routine urinalysis, and blood 
biochemistry) and PK/ADA sampling 
Refer to Table 6 for laboratory tests including complete blood count, routine urinalysis, and 
blood biochemistry. Separately, serum samples from 1 mL of blood will be collected and stored 
for future PK/ADA analysis. 
Table 4 Routine laboratory safety evaluation 
Complete blood count 
RBC, HGB, WBC, PLT, LYM, and ANC 
Blood Biochemistry 
TBIL, ALT, AST, γ-GT, ALP, ALB, TP, LDH, UREA, Cr, Na, K, Cl, Mg, Ca, P, 
amylase, and FBG 
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, HBeAg, HBeAb, HBV DNA, HCV antibody, HCV RNA, and 
HIV antibody 
ALB = albumin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
AST = aspartate aminotransferase; Cr = serum creatinine; FBG = fasting blood glucose; FT3 = free triiodothyronine; 
FT4 = free thyroxine; γ-GT = γ-glutamyltransferase; 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 (strating 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.  
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7.3 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 
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, 3.5 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. 
7.4 Biomarker Analysis  
7.4.1 Tissue and Serum biomarkers 
All the eligible subjects must provide blood samples and tumor tissue samples for exploratory 
research on biomarkers (See Appendix 6).  
a. Fresh tumor tissue sample (or archival tissue) will be collected at baseline for 
determination of PD L1 expression and for exploratory research on biomarkers 
 Tissue should be collected by excisional or core needle biopsy, typically 
using a 21-18 gauge needle. The biopsy should include at least 5 cores, 2 
will be formalin-fixed paraffin-embedded (FFPE) and 3 will be fresh 
frozen. Tissue should be collected within 28 days prior to initiation of 
protocol therapy. 
 For archival tissue: a representative FFPE tumor specimen in a paraffin 
block (preferred) or at least 10 slides containing unstained, freshly cut, 
serial sections need to be submitted along with an associated pathology 
report. Samples collected via resection, core-needle biopsy (CNB) (at least 
three cores, embedded in a single paraffin block), or excisional, incisional, 
punch, or forceps biopsy are acceptable.   
 Considering the benefit seen with immunotherapy in MSI-H cancer, we 
will perform MSI tests on all patients. 
b. Tumor tissue sample will also be collected at week 3 for exploratory research on 
biomarkers 
 Biopsies at week 3 should be performed within 7 days before 
administration of C2D1 of study therapy. Samples collected via resection, 
core-needle biopsy (at least three cores preferred), or excisional, 
incisional, punch, or forceps biopsy are preferred.  
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c. Tumor tissue sample will also be collected at time of progression for exploratory 
research on biomarkers 
 Biopsies at the time of progression should be performed within 40 days 
after progression or prior to the next anti-cancer therapy, whichever is 
sooner. Samples collected via resection, core-needle biopsy (at least three 
cores preferred), or excisional, incisional, punch, or forceps biopsy are 
preferred. 
Blood and tissue collections will be tracked by Tissue Station. Collection requests will be placed 
in the system, prior collections, and updated once completed including details of the process.  
Exploratory biomarker research may include, but will not be limited to, immunohistochemistry 
for PD-L1, multiplexed immunofluorescence for immune markers, flow cytometry, analysis of 
ctDNA concentration, genes or gene signatures associated with tumor immunobiology, PD-L1, 
lymphocyte subpopulations, T-cell receptor repertoire, or cytokines associated with T-cell 
activation and may involve DNA or RNA extraction, analysis of germline or somatic mutations, 
and use of WGS or NGS. 
For sampling procedures, storage conditions, and shipment instructions, see the laboratory 
manual. 
Biological samples will be destroyed when the final manuscript has been completed, with the 
following exceptions: 
• Blood samples collected for WGS will be stored until they are no longer needed or until 
they are exhausted. However, the storage period will be in accordance with the IRB/EC 
approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
• Blood, plasma, serum, and tumor tissue samples collected for biomarker research will 
be destroyed no later than 5 years after the final manuscript has been completed. 
When a patient withdraws from the study, samples collected prior to the date of withdrawal may 
still be analyzed, unless the patient specifically requests that the samples be destroyed or local 
laws require destruction of the samples. 
Data arising from sample analysis will be subject to the confidentiality standards. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data derived 
from these analyses will generally not be provided to study investigators or patients unless 
required by law. 
7.5 Storage and Destruction of Biological Samples 
If needed, certain analyses such as selectivity with incurred sample, parallelism with incurred 
sample, in-study cut point determination, et al., using pooled or individual samples which are 
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necessary for further evaluation and validation of analytical methods may also be performed. 
Results of these analysis may be included in the Clinical Study Report (CSR) or published 
separately from the CSR. 
Incured samples reanalysis will be assessed simultaneously with the biological samples. The 
results of these evaluations will not be recorded in the CSR, but will be presented separately in a 
biological analysis report. 
After all necessary analyses, subject information will be desensitized (including anonymized and 
pooled) and then disposed or destroyed. 
 
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. Any adverse event 
should be evaluated the attribution/relationship with study therapy. Any adverse event should be 
evaluated according to the NCI Common Terminology for Adverse Events (CTCAE), version 
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5.0. All adverse eventsmust 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 5 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);or 
 
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 †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 

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Action Taken  
Did the adverse event cause the investigational product to be discontinued? 
Relationship 
to Sponsor’s 
Product 
Did the investigational 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.) 
 
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. 

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(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 on the case report forms /worksheets 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 a 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 the first protocol intervention 
until 90 days after the last study drug administration, using medical terms and concepts. Avoid 
colloquialisms and abbreviations. All the AEs (including SAEs) should be documented on the AE 
forms in the eCRFs. 
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 III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
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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 does not resolve, a reasonable 
explanation should be documented in the eCRF. 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 drug(s). 
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. 
AEs secondary to other events 
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 eCRFs if they occur at different time from 
the primary event. If the relationship between events is unclear, document them as separate 
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events in the eCRFs. 
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 eCRFs.  
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 eCRFs. 
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 that happen during the entire course of the study, and after the last dose (including 
those that occur before Day 90), should be documented in the patient’s medical record, captured 
in  the eCRF 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 eCRF 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 
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 
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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 a subject’s 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 eCRF. Any adverse events 
resulting from the overdose should be recorded. If the adverse event 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. 
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 
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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. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with 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 30 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  
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Additionally, any serious adverse events that occur after the 30 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 The investigator 
must fill out the SAE Report Form provided by the supporting company, regardless of whether it 
is the initial report or a follow-up report. Besides, the investigator must report the SAE to the 
sponsor (drugsafety@innoventbio.com) by the time within 24 hours after noticing the event.  
For SAEs occurring beyond the above period, those considered related to sintilimab should also 
be reported. 
The investigator must submit the completed SAE report form to the supporting company within 
24 hours after noticing the event. The investigator should urgently collect all missing information 
and provide a complete SAE report.   
For an SAE, the investigator should 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. The investigator should provide 
a description of the SAE. In the SAE description, the following should also be included: the 
subject number, age, gender, height, and weight; indication for receiving the investigational drug, 
cancer staging, and overall condition; SAE occurrence, development, outcome, and result; 
laboratory results related to the SAE (the units, and normal ranges must be provided); medical 
history, onset and duration of concurrent diseases related to the SAE; medication history and 
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initiation, duration, and dosage of concomitant medications related to the SAE; initiation, 
duration, and dosage of the study drugs. 
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 hours 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 
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 6 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 
ALT or AST ≥ 8 × ULN 
and the increased value of TBIL ≥ 1× ULN 
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and ALP ≤ 2 × ULN 
and no hemolysis 
or TBIL ≥ 3× ULN 
After being notified of the abnormalities, the subject must return to the study site promptly 
(ideally within 48 hours) 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. These potential drug-induced liver injury should 
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 
During the course of the trial, the investigators will conduct regular safety review for the irAEs.  
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. 
 
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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 CUP. Up to 45 subjects with CUP will be enrolled. The goal for the number of 
evaluable subjects is 40.   
A detailed statistical analysis plan (SAP) will begin after the first enrollment and will be 
finalized prior to database locking. The SAP should contain details of all analyses and the 
presentation of results. 
9.2 Statistical Analysis Population 
Intention-to-treat set (ITT): all enrolled subjects who are treated. 
Evaluable set (EP): all enrolled subjects 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 treated 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 
9.3.1 General statistical analysis 
Continuous 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. 
All the statistical analyses will be performed with SAS 9.2 (or higher). 
9.3.1.1 Analysis of primary efficacy endpoints 
The primary efficacy endpoint is confirmed ORR, defined as the proportion of subjects with a 
best overall response (BOR) of confirmed complete response (CR) or confirmed partial response 
(PR), assessed by the IRR based on Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v.1.1) in the evaluable population. A 95% confidence interval will be provided for 
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observed ORR. 
Design and sample size/power 
The primary efficacy endpoint will be confirmed ORR. 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 25%, i.e. a 15% 
improvement. In the first stage, 22 patients will be treated. If there are ≤ 2 patients who achieve 
objective response in these 22 patients (by end of 6 cycles in the last enrolled patient), the study 
will be terminated. If the study moves forward to second stage, an additional 18 patients will be 
treated leading to a total of 40 patients. Eight or more responders out of the 40 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 62% if the ORR 
is 10% and the average sample size would be 28.8. Assuming a 10% dropout rate, we will need 
to enroll up to a total of 45 patients. 
9.3.1.2 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 22 evaluable subjects, complete 6 cycles of study treatment, and again after the 
total of 40 evaluable subjects, complete 6 cycles of therapy.  
9.3.1.3 Analysis of key and other secondary efficacy endpoints 
The key secondary efficacy endpoints are ORR (investigator assessed), DCR, DOR, PFS and OS 
in the evaluable and ITT populations. 
The ORR, DCR (defined as proportion of patients with CR+PR+SD) and corresponding exact 
95% CIs of the sintilimab arm will be estimated using binomial distribution.  
PFS is the time from treatment initiation to first date of progression (by imaging), or to death due 
to any cause. OS is the time from treatment initiation 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 registration. The mPFS amd mOS and corresponding 95% CI will be estimated via the 
Kaplan-Meier method, and survival curves will be plotted.7 Log-rank test will be performed to 
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test the difference in survival between groups.8 Regression analyses of survival data based on the 
Cox proportional hazards model (Cox, 1972) 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 (Jiang, 2007). 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. 
9.3.2 Safety analysis 
The safety analysis will use the SS. Safety parameters include AEs, laboratory tests, vital signs, 
ECG, immunogenicity, etc. Unless otherwise stated, all the safety analyses will be summarized . 
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 
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. 
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 
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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. A cross-classification table is 
used to describe ECG changes in PR and QTc from baseline before and after the treatment and 
data lists will be provided for other abnormalities. 
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. 
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. 
Other important baseline information such as region, choice of chemotherapies and time of 
enrollment will also be summarized. 
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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 changes in quality of life on treatment.  
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 
The University of Texas MD Anderson Cancer Center will be responsible for data management of 
this study, including quality checking of the data.  Data entered manually will be collected via 
EDC through use of eCRFs.  Sites will be responsible for data entry into the electronic data 
capture (EDC) system. The PI will perform oversight of the data management of this study.  
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  System 
backups for data stored at The University of Texas MD Anderson Cancer Center and records 
retention for the study data will be consistent with The University of Texas MD Anderson Cancer 
Center’s standard procedures, which mandate that data be maintained indefinitely.  
 
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11 Data Management and Record Keeping 
11.1 Electronic Case Report Forms 
eCRFs are to be completed through use of the MD Anderson Cancer Center Prometheus EDC 
system. All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. SAE data will be 
captured via eSAE in accordance with Sponsor policy. 
11.2 Source Data Documentation 
Study monitors will perform ongoing source data verification and review to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time.  They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, and records kept at pharmacies, 
laboratories, and medico-technical departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Trial Monitoring Plan. This includes any protocol data to be entered directly into 
the eCRFs (i.e., no prior written or electronic record of the data) and considered source data. 
Source documents that are required to verify the validity and completeness of data entered into the 
eCRFs must not be obliterated or destroyed and must be retained per the policy for retention of 
records described in Section 11.4. 
To facilitate source data verification and review, the investigators must provide the Sponsor 
direct access to applicable source documents and reports for trial related monitoring, Sponsor 
audits, and IRB/EC review. The study site will allow inspection by applicable health authorities. 
11.3 Use of Computerized Systems 
When clinical observations are entered directly into a study site’s computerized medical record 
system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research. An acceptable computerized data 
collection system allows preservation of the original entry of data. If original data are modified, 
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the system should maintain a viewable audit trail that shows the original data as well as the reason 
for the change, name of the person making the change, and date of the change. 
11.4 Retention of Records 
Records and documents pertaining to the conduct of this study and the distribution of the 
investigational medical product (IMP), including eCRFs, electronic patient-reported-outcomes 
(PRO) data (if applicable), Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator indefinitely, in accordance with 
the current policy of the MD Anderson Cancer Center IND office.   
Written notification should be provided to the Sponsor and Innovent Inc prior to transferring any 
records to another party or moving them to another location. 
11.5 Monitoring 
During the study, a study monitor from the University of Texas MD Anderson Cancer Center 
Investigational New Drug Office will have regular contacts with the investigator and team. 
 
12 Ethics 
12.1 Compliance with Laws and Regulations 
This study will be conducted in full conformance with the International Council on Harmonization 
(ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the ICH 
E2A guideline (Clinical Safety Data Management:  Definitions and Standards for Expedited 
Reporting).  Studies conducted in the United States or under a U.S. Investigational New Drug 
(IND) application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply with 
the E.U. Clinical Trial Directive (2001/20/EC). 
12.2 Informed Consent 
The investigator or qualified designee must obtain documented consent from each potential subject 
or each subject’s legally acceptable representative prior to participating in a clinical trial. If there 
are changes to the subject’s status during the trial (e.g., health or age of majority requirements), 
the investigator or qualified designee must ensure the appropriate consent is in place. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the objectives, 
methods, and potential risks associated with each optional procedure.  Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time for any reason.  
A separate, specific signature will be required to document a patient's agreement to participate in 
optional procedures.  Patients who decline to participate will not provide a separate signature. 
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The Consent Forms must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study.  The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the patient to participate.  
The final revised IRB/EC-approved Consent Forms must be provided to the Sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a significant 
new information/findings addendum in accordance with applicable laws and IRB/EC policy) 
during their participation in the study.  For any updated or revised Consent Forms, the case 
history or clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained using the updated/revised Consent Forms for continued 
participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative.  All signed and dated Consent Forms must remain in each patient’s 
study file or in the site file and must be available for verification by study monitors at any time. 
Each Consent Form may also include patient authorization to allow use and disclosure of 
personal health information in compliance with the U.S. Health Insurance Portability and 
Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization Form for 
patient authorization for use and disclosure of personal health information under the HIPAA 
regulations, the review, approval, and other processes outlined above apply except that IRB 
review and approval may not be required per study site policies. 
12.3 Institutional Review Board or Ethics Committee 
This protocol, the Informed Consent Forms, any information to be given to the patient, and relevant 
supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated.  In addition, any patient 
recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB/EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. Investigators are also responsible for promptly informing 
the IRB/EC of any protocol amendments (see Section 13.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, investigators must 
comply with requirements for reporting serious adverse events to the local health authority and 
IRB/EC.  Investigators may receive written IND safety reports or other safety related 
communications from the Sponsor.  Investigators are responsible for ensuring that such reports 
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are reviewed and processed in accordance with health authority requirements and the policies and 
procedures established by their IRB/EC, and archived in the site’s study file.  
12.4 Confidentiality 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number.  
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the Informed Consent Form (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or required by 
law. Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless required by 
law. The aggregate results of any conducted research will be available in accordance with the 
policy on study data publication (see Section 13). 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, Sponsor monitors, representatives, and collaborators, and the 
IRB/EC for each study site, as appropriate. 
 
13 Study Documentation, Monitoring and Administration  
13.1 Study Documentation 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented, including, but not limited to, the protocol, protocol amendments, Informed 
Consent Forms, and documentation of IRB/EC and governmental approval. In addition, at the end 
of the study, the investigator will receive the patient data, including an audit trail containing a 
complete record of all changes to data. 
The Investigator is responsible for completing the cohort summary report and submitting it to the 
IND office Medical Monitor for review. This should be submitted after the first 5 evaluable patients 
per cohort, and every 5 evaluable patients per cohort, thereafter. 
13.2 Protocol Deviations 
The investigator should document and explain any protocol deviations. The investigator should 
promptly report any deviations that might have an impact on patient safety and data integrity to 
the Sponsor and Innovent Inc and to the IRB/EC in accordance with established IRB/EC policies 
and procedures. 
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13.3 Administrative Structure 
This trial will be supported via the rare disease strategic alliance between The University of Texas 
MD Anderson Cancer Center and Innovent. The University of Texas MD Anderson Cancer Center 
will be the sole site, responsible for enrolling patients. The MD Anderson Cancer Center IND 
office will provide oversight of safety. 
After written informed consent has been obtained, the study team will generate a unique study 
identification number for the patient. 
Patient data will be recorded via an EDC system with use of eCRFs. 
Central laboratories, including those at Innovent collaborators and at The University of Texas MD 
Anderson Cancer Center, will be used for PD-L1 expression status determination and will provide 
kits for pharmacogenomic, tissue, whole blood, serum, and plasma sample analyses to be 
conducted at central laboratories or Innovent. 
Treatment decisions will be made on the basis of the local reading of ECGs obtained during the 
study. 
Imaging data will be retained at The University of Texas MD Anderson Cancer Center. 
13.4 Publication of Data and Protection of Trade Secrets 
Regardless of the outcome of a trial, the Sponsor and Innovent Inc is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific congresses 
and in peer-reviewed journals. The Sponsor will comply with all requirements for publication of 
study results.  
The results of this study may be published or presented at scientific congresses. For all clinical 
trials in patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the PI aims to submit a journal manuscript reporting primary clinical 
trial results within 6 months after the availability of the respective Clinical Study Report. In 
addition, for all clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the PI aims to publish results from analyses 
of additional endpoints and exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to Innovent Inc prior to 
submission for publication or presentation. This allows Innovent Inc to protect proprietary 
information and to provide comments based on information from other studies that may not yet be 
available to the investigator. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. Any formal publication of the study in which 
contribution of Innovent Inc personnel exceeded that of conventional monitoring will be 
considered as a joint publication by the investigator and the appropriate Innovent Inc personnel. 
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Any inventions and resulting patents, improvements, and/or know-how originating from the use 
of data from this study will become and remain the exclusive and unburdened property of Innovent 
Inc, except where agreed otherwise. 
13.5 Protocol Amendments 
Any protocol amendments will be prepared by the PI. Protocol amendments will be submitted to 
the MD Anderson IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects only 
(e.g., change in contact information). 
 
 
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14 References 
 
1. 
Varadhachary GR, Raber MN: Cancer of unknown primary site. N Engl J Med 371:757-65, 2014 
 
2. 
Gatalica Z, Xiu J, Swensen J, et al: Comprehensive analysis of cancers of unknown primary for the 
biomarkers of response to immune checkpoint blockade therapy. Eur J Cancer 94:179-186, 2018 
 
3. 
Naing A, Meric-Bernstam F, Stephen B, et al: Phase 2 study of pembrolizumab in patients with advanced 
rare cancers. J Immunother Cancer 8, 2020 
 
4. 
Tanizaki J, Yonemori K, Akiyoshi K, et al: NivoCUP: An open-label phase II study on the efficacy of 
nivolumab in cancer of unknown primary. Journal of Clinical Oncology 38:106-106, 2020 
 
5. 
Zou W, Chen L: Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8:467-
77, 2008 
 
6. 
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 
 
7. 
Kaplan EL, Meier P: Nonparametric Estimation from Incomplete Observations. Journal of the American 
Statistical Association 53:457-481, 1958 
 
8. 
Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. 
Cancer Chemother Rep 50:163-70, 1966 
1.  
2. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
Immunol 2008,8:467-477. 
3. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. 
Journal of Clinical Investigation 2015,125:3384-3391. 
4. Chen Y,Zhu Z,Zhao W et al. A randomized phase 3 trial comparing paclitaxel plus 5-
fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced 
esophageal carcinoma-the ESO-shanghai 1 trial protocol. Radiat Oncol.2018 Feb 27;13(1):33. 
5. Chang GC, Yang TY, Shih CM, Lin LY, Lee HS, Chiang CD. Serial-measured versus 
estimated creatinine clearance in patients with non-small cell lung cancer receiving cisplatin-
based chemotherapy. J Formos Med Assoc. 2003;102(4):257–261. 
 
 
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15 Appendix 
Appendix 1: Signature Page for Investigator 
Protocol Title: A Phase 2 Clinical Trial Evaluating the Efficacy and Safety of Sintilimab for 
Advanced Rare Cancers (SiARa Cancer Study) – Cancer of Unknown Primary (SiARa-CUP) 
Protocol Number: MD 2020-0902 
This protocol is a trade secret owned by The UT MD Anderson Cancer Center and 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:       ________________________________ 
 
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Appendix 2: Schedule of Biomarker Samples 
Visit 
Timepoint 
Sample Type 
Screening 
(Day −28 to Day –1) 
Baseline 
Biomarker (blood, plasma, and serum) 
Day 1 of Cycle 3 
Prior to infusion 
Biomarker (blood, plasma, and serum) 
Progression (≤ 40 days 
after progression is 
radiographically 
determined) 
NA 
Biomarker (blood, plasma, and serum) 
 
 
 
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Appendix 3: 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 4: 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, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1 Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm 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 non-
cystic 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 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 
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 
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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 
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. 
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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 
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 
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axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may 
be axial, sagittal or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20 mm × 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 
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 
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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 
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 
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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 
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 
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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 
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. 
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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 13 
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, Table 14 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 
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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 15. 
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 
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 eCRF. 
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 13 to Table 15. 
Conditions that define "early progression, early death and inevaluability" are study specific and 
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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 7 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 
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 8 Time point response: subjects with non-target disease only. 
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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 
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 9 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 
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Overall response 
first time point 
Overall response 
subsequent time point 
Best overall response 
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 
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 
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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 
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 
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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 
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 5: Immune-Modified Response Evaluation Criteria in Solid Tumors (Immune-
Modified RECIST) 
Conventional response criteria may not be adequate to characterize the anti-tumor activity of 
immunotherapeutic agents like sintilimab, which can produce delayed responses that may be 
preceded by initial apparent radiographic progression, including the appearance of new lesions.  
Therefore, immune-modified response criteria have been developed to incorporate new lesions 
into the assessment of total tumor burden and allow radiographic progression to be confirmed at a 
subsequent assessment.  Immune-modified Response Evaluation Criteria in Solid Tumors 
(RECIST), as described within this appendix, were adapted from RECIST, Version 1.1 (v1.1) 
(Eisenhauer et al 2009), in the same manner that immune-related response criteria were adapted 
from WHO criteria (Wolchok et al. 2009) and RECIST v1.0 (Nishino et al. 2014).  When not 
otherwise specified, RECIST v1.1 conventions will apply.  Differences between immune-
modified RECIST and RECIST v1.1 are summarized in Table 1. 
Table 1 
Comparison of RECIST v1.1 and Immune-Modified RECIST 
 
RECIST v1.1 
Immune-Modified RECIST 
Measurable new lesions Always represent 
progression 
Incorporated into the total tumor 
burden a and followed 
Non-measurable new 
lesions 
Always represent 
progression 
Do not represent progression, 
but preclude CR 
Non-target lesions 
Contribute to defining CR, 
PR, SD, and PD 
Contribute to defining CR only 
CR 
Disappearance of all lesions Disappearance of all lesions 
PR 
≥ 30% decrease in sum of 
diameters of target lesions, 
in the absence of CR, new 
lesions, and unequivocal 
progression in non-target 
lesions 
≥ 30% decrease in tumor 
burden, a in the absence of CR 
PD 
≥ 20% increase in sum of 
diameters of target lesions, 
unequivocal progression in 
non-target lesions, and/or 
appearance of new lesions 
≥ 20% increase in tumor burden 
a 
SD 
Neither sufficient shrinkage 
to qualify for CR or PR nor 
sufficient increase to qualify 
for PD 
Neither sufficient shrinkage to 
qualify for CR or PR nor 
sufficient increase to qualify for 
PD 
CR = complete response; PD = progressive disease; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease. 
a Tumor burden is the sum of diameters of target lesions and measurable new lesions. 
 
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TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below.  All measurable and non-measurable lesions should be assessed at screening 
and at subsequent protocol-specified tumor assessment timepoints.  Additional assessments may 
be performed as clinically indicated for suspicion of progression.   
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size as follows:  
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan (CT/MRI 
scan slice thickness/interval ≤ 5 mm) 
10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable) 
20 mm by chest X-ray 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in the 
short axis when assessed by CT scan (CT scan slice thickness recommended to be ≤ 5 mm).  
At baseline and follow-up, only the short axis will be measured and followed.  Additional 
information on lymph node measurement is provided below (see "Identification of Target and 
Non-Target Lesions," "New Lesions," and "Calculation of Sum of Diameters"). 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 mm but < 15 mm) 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, peritoneal spread, and abdominal mass/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
Bone Lesions: 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, and plain 
films are not considered adequate imaging techniques for measuring bone lesions.  
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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 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 malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered measurable lesions if 
they meet the definition of measurability described above.  However, if non-cystic lesions 
are present in the same patient, these are preferred for selection as target lesions. 
Lesions with Prior Local Treatment: 
Tumor lesions situated in a previously irradiated area or in an area subjected to other loco-
regional therapy are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  Lesions may include hepatic lesions previously treated with 
hepatic arterial therapy, or other solid masses previously treated with external beam 
radiotherapy. 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study.  Imaging-based evaluation should 
always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm in 
diameter as assessed using calipers (e.g., skin nodules).  For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions.  However, lesions 
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on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated 
lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment.  In this guideline, the definition of measurability of lesions on CT scan is based on 
the assumption that CT slice thickness is ≤ 5 mm.  When CT scans have slice thickness of > 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and during the 
study should be guided by the tumor type under investigation and the anatomic location of the 
disease.  For patients who develop contraindications to contrast after baseline contrast CT is done, 
the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed 
should also be based on the tumor type and the anatomic location of the disease, and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is possible and, 
if not, the patient should be considered not evaluable from that point forward.  Care must be taken 
in measurement of target lesions and interpretation of non-target disease or new lesions on a 
different modality, since the same lesion may appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, CYTOLOGY, 
HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be utilized 
for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
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. 
IDENTIFICATION 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 that, 
for instances in which patients have only one or two organ sites involved, a maximum of two 
lesions (one site) and four lesions (two sites), respectively, will be recorded.  Other lesions (albeit 
measurable) in those organs will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
be representative of all involved organs, but in addition should lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend 
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itself to reproducible measurement, in which circumstance the next largest lesion that can be 
measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be visible 
by imaging even if not involved by tumor.  As noted above, pathological nodes that 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.  Lymph node size is normally reported as two dimensions in the plane 
in which the image is obtained (for CT, this is almost always the axial plane; for MRI, the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node that 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.  All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions.  Nodes that have a short axis of < 10 mm are 
considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or non-measurable), 
including pathological lymph nodes, should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements are not required.  It is possible to record multiple 
non-target lesions involving the same organ as a single item on the Case Report Form (CRF) (e.g., 
"multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
NEW LESIONS 
New lesions identified after baseline will be evaluated for measurability with use of the same 
criteria applied to prospective target lesions at baseline per RECIST (e.g., non−lymph node lesions 
must be ≥ 10 mm on the longest diameter; new lymph nodes must be ≥ 15 mm on the short axis 
[see note below]).  All new lesions (measurable or non-measurable) must be assessed and 
recorded at the time of identification and at all subsequent tumor assessment timepoints.  
Up to a maximum of five measurable new lesions total (and a maximum of two lesions per organ) 
can be included in the calculation of tumor burden that is performed as part of the tumor response 
evaluation.  New lesion types that would not qualify as target lesions per RECIST cannot be 
included in the calculation of tumor burden and thus will not affect overall tumor response 
evaluation.  New lesions that are not measurable at first appearance but meet measurability 
criteria at a subsequent timepoint can be included in the tumor response evaluation from that point 
on, if the maximum number of measurable new lesions has not been reached. 
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph node 
lesion is ≥ 15 mm, it will be considered a measurable new lesion.  If at first appearance the short 
axis of a lymph node lesion is ≥ 10 mm and < 15 mm, the lymph node will not be considered 
measurable but will still be considered a new lesion and should be identified as a non-measurable 
new lesion.  If at first appearance the short axis of a lymph node is < 10 mm, the lymph node 
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should not be considered pathological and should not be considered a new lesion.  A lymph node 
can subsequently become measurable, when the short axis is ≥ 15 mm. 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non−lymph node lesions, short axis for lymph node 
lesions) will be calculated for all target lesions at baseline as a measure of tumor burden.  At each 
subsequent tumor assessment, a sum of the diameters (longest diameter for non-lymph node 
lesions, short axis for lymph node lesions) will be calculated for all target lesions plus measurable 
new lesions (up to five new lesions, with a maximum of two new lesions per organ) that have 
emerged after baseline.  Hence, each net percentage change in tumor burden per assessment 
accounts for the size and growth kinetics of both old lesions and new lesions as they appear. 
Measuring Lymph Nodes 
If at first appearance the short axis of a new lymph node lesion is ≥ 15 mm, it will be considered 
a measurable new lesion and may be included in the sum of the diameters.  If the new lymph 
node lesion is included in the sum of diameters, it will continue to be measured and included in 
the sum of diameters at subsequent timepoints, even if the short axis decreases to < 15 mm (or 
even < 10 mm).  However, if it subsequently decreases to < 10 mm and all other lesions are no 
longer detectable or have also decreased to a short axis of < 10 mm (if lymph nodes), a response 
assessment of complete response may be assigned. 
Lymph nodes should always have the actual short axis measurement recorded (measured in the 
same anatomical plane as the baseline examination), even if the node regresses to < 10 mm during 
the study.  Thus, when lymph nodes are included in the sum of diameters, the sum 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. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions and up to five measurable new lesions (lymph node and 
non−lymph node) should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g., 2 mm).  However, sometimes lesions or lymph nodes become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value be 
recorded on the CRF, as follows: 
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 and "too small to measure" should be ticked.  (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 
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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 and "too small to measure" should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measurement, that should be 
recorded, even if it is < 5 mm, and in that case "too small to measure" should not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When non−lymph node lesions fragment, the longest diameters of the fragmented portions should 
be added together to calculate the sum of diameters.  Similarly, as lesions coalesce, a plane 
between them may be maintained that would aid in obtaining maximal diameter measurements of 
each individual lesion.  If the lesions have truly coalesced such that they are no longer separable, 
the vector of the longest diameter in this instance should be the maximum longest diameter for the 
coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS AND NON-MEASURABLE NEW 
LESIONS 
Measurements are not required for non-target lesions or non-measurable new lesions.  Non-target 
lesions should be noted at baseline, and non-measurable new lesions should be noted at the time 
of identification.  At subsequent evaluations, non-target lesions and non-measurable new lesions 
will be categorized as "present" or "absent." 
After baseline, changes in non-target lesions or non-measurable new lesions (or measurable new 
lesions in excess of five total or two per organ) will contribute only in the assessment of complete 
response (i.e., a complete response is attained only with the complete disappearance of all tumor 
lesions, including non-target lesions and non-measurable new lesions) and will not be used 
to assess progressive disease. 
RESPONSE CRITERIA 
Definitions of the criteria used to determine objective tumor response are provided below: 
Complete response (CR):  Disappearance of all lesions 
Any pathological lymph nodes must have reduction in short axis to < 10 mm. 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target lesions 
plus measurable new lesions (up to a maximum of five total or two per organ), taking as 
reference the baseline sum of diameters, in the absence of CR 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of all target lesions 
plus measurable new lesions (up to a maximum of five total or two per organ), taking as 
reference the smallest sum of diameters on study (including baseline) 
In addition to the relative increase of 20%, the sum of diameters must also demonstrate 
an absolute increase of ≥ 5 mm. 
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New lesions alone do not qualify as progressive disease.  However, their contribution to 
total tumor burden is factored into the sum of the diameters, which is used to determine 
the overall immune-modified RECIST tumor response. 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor sufficient 
increase to qualify for PD 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response assessment 
timepoint for patients who have measurable disease at baseline. 
Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients with Target 
Lesions (with or without Non-Target Lesions) 
Target Lesions and 
Measurable New Lesions a 
Non-Target Lesions and 
Non-Measurable New 
Lesions b 
Overall Response 
CR 
Absent 
CR 
CR 
Present or not all evaluated 
PR 
PR 
Any 
PR 
SD 
Any 
SD 
Not all evaluated 
Any 
NE 
PD 
Any 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; 
PR = partial response; SD = stable disease. 
a Up to a maximum of five measurable new lesions total (and a maximum of two 
lesions per organ) can be included in the calculation of tumor burden, in addition 
to the target lesions identified at baseline. 
b Also includes measurable new lesions in excess of five total or two per organ. 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable 
at that timepoint.  If measurements are made on only a subset of target or measurable new lesions 
at a timepoint, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesions would 
not change the assigned timepoint response.  This would be most likely to happen in the case of 
PD.  For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
during the study only two lesions were assessed, but those gave a sum of 80 mm, the patient will 
have achieved PD status, regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as "symptomatic 
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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 patients 
is to be determined by evaluation of target and non-target lesions, as well as new lesions, as shown 
in Table 1. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228−47.   
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Can Res 2009;15:7412−20. 
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response assessment: 
does reducing the number of lesions impact response assessment in melanoma patients treated with 
ipilimumab? J Immunother Can 2014;2:17 
 
 
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Appendix 6: Biomarker Analysis 
• Samples Collection and Processing: 
• Core needle biopsy (CNB) or excisional biopsy:  A fresh CNB or excisional biopsy 
will be obtained with the purpose of research studies before and after treatment and 
sent to the MD Anderson Institutional Tissue Bank (ITB) immediately after collection.  
At least 5 tissue cores will be obtained from the CNB/surgical procedure. The number 
of cores obtained will be affected by the patient clinical condition at the time of biopsy 
and determined by the radiologist who is performing the procedure. It is important to 
note that in some patients, the biopsy sample will also be required for clinical diagnosis. 
In such case, the first specimen will be prioritized for clinical specimen processing. In 
most instances, a rapid on-site evaluation (ROSE) is available locally to evaluate the 
adequacy of clinical sample, thus additional biopsies may be procured for this research 
project. Nevertheless, the amount tissue available for correlative studies can be 
variable. Core biopsy is typically performed using 21-18 gauge needle and with 
condition permitting, up to 5 cores should be collected. 
• These cores/surgical excision pieces will be processed for (Figure 1): 
 
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 Cores or excision pieces 1 and 2: Immediate and overnight fixation in 10% 
buffered formalin for paraffin embedding, usually within 20-24 hour after 
fixation. For biopsies performed on Friday, fixation time may extend to 48 
hours (FFPE samples). The FFPE sample is important as it also provides a 
histological confirmation for the presence and cellularity of tumor cells. FFPE 
samples will also be prioritized for immune gene expression profiling by 
NanoString or other to be determined assays (Figure 1) 
 Cores or excision pieces 3 to 5: Flash freezing in liquid nitrogen will be 
obtained for RNA (RNA-sequencing) and DNA (targeted or whole exome 
sequencing (WES), among other analysis. Potentially, flow cytometry from 
fresh tissue tumor tissues could be performed in selected cases.  
• The tissue and blood will be processed as follows: 
 FFPE Tissues: Immediate and overnight fixation in 10% buffered formalin for 
paraffin embedding, usually within 20-24 hour after fixation. For biopsies 
performed on Friday, fixation time may extend to 48 hours (FFPE samples). For 
pathology evaluation, at least one sample per 1-cm of diameter will be 
submitted for FFPE processing and pathology analysis. Hematoxylin and eosin 
(H&E)-stained sections from all FFPE diagnostic slides (tumor and adjacent 
normal level) will be scanned in Aperio image analysis for pathological 
evaluation and biomarker analysis  
 Fresh Tissues: Flash freezing in liquid nitrogen for genomic studies including 
RNA-sequencing and Whole Exome Sequencing (WES). 
• Blood Specimens: 40 ml of blood will be collected at several time points (pre-treatment 
or baseline, cycle 1 day 15, and at the time of disease progression [+/- 1 week]) for:  
 Isolation of germ-line DNA from peripheral mononuclear blood cells (PMBCs) 
and TCR- T-cell receptor repertoire. 
 Isolation of plasma for cell free DNA analysis of genomic abnormalities using 
gene panels or analysis of cytokines associated with T-cell activation. 
 Isolation of circulating tumor cells (CTCs). 
 Potential flow cytometry analyses for phenotypic and functional studies.  
• Biomarker Analysis: 
• Histology evaluation of tumor tissue: H&E-stained sections from CNBs and surgical 
excisions will be used to confirm the presence of tumor cells, as well as their abundance 
(tumor cellularity), stromal components and lymphocytic infiltrates. Hematoxylin and 
eosin (H&E)-stained sections from all FFPE diagnostic slides (tumor, normal and 
lymph nodes) will be scanned in Aperio™ digital pathology scanner analysis for 
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pathological evaluation and selection of 1 or 2 blocks (depending on tumor availability) 
for biomarker analysis.   
From the tumor tissue specimens, the following pathological analysis will be 
performed: 1) tumor diagnosis using the World Health Organization (WHO) 
classification; 2) lowest degree of tumor differentiation; 3) percentage of areas of 
necrosis; 4) percentage of areas of fibrosis; 5) percentage of viable tumor tissue; and, 
6) percentage of viable malignant cells. 
Central Review: The scanned H&E-stained slides will be available for pathology 
analysis at the Translational Molecular Pathology and Biomarker Lab chaired by Dr. 
Ignacio I. Wistuba, MD Anderson Cancer Center.  
• Quality Control (QC) of tumor tissue: All tissue specimens collected will be reviewed 
by reference pathologists. At least, three types of QC activities for specimens collected 
will be performed: a) histology/cytology examination of the tissues and cells; b) tissue 
quality assessment of fresh specimens for extraction of DNA, RNA and proteins, and 
to prepare histology specimens such as whole sections for immunohistochemistry and 
immunofluorescence; and, c) quality assessment of DNA, RNA and protein extracted. 
All histology stained samples will be scanned and digital images will be available for 
review. 
• Immunohistochemistry (IHC) and Immunofluorescence (IF) analyses: Fresh frozen 
and FFPE tissues will be used for analysis of immune markers.  For 
immunohistochemistry (IHC) and multiplex immunofluorescence (IF) analyses, 
histology sections obtained from FFPE samples will be utilized (Figure 1). IHC and IF 
will be performed using autostainers. All antibodies used will be optimized for IHC/IF 
by examination of positive and negative controls and testing of the antibodies standard 
methods, including Western blotting. All pathology slides will be scanned into a digital 
image scanner and analyzed using image analysis software; IHC analysis will be 
performed using the Aperio Image Toolbox™ (Leica Biosystems) and IF analysis 
using, among pthers, the Vectra Inform™ (Perkin-Elmer) software. The following 
markers will be performed using optimized and validated protocols, as follows: 
 IHC assays: Staining of tumor tissue for PD-L1 will be conducted before and 
after treatment and be performed using the proper IHC assay. Briefly, 4µm-
thick histology sections will be used for IHC will be performed on autostainers 
(Leica Bond Max, Leica Biosystems, Vista, CA). All antibodies have been 
optimized for IHC by examination of positive and negative controls and testing 
of the antibodies by Western blotting. To perform quantitative image analysis if 
the expression of each marker, all IHC slides will be scanned into a digital 
image scanner (Aperio™ AT Turbo, Leica Biosystems, Buffalo Grove, IL), and 
analyzed using the Aperio Image Genie Toolbox™ software (Leica Biosystems, 
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Buffalo Grove, IL). Five random 1-mm square areas within the tumor region 
will be selected for analysis. The expression of IHC marker(s) in malignant cells 
will be evaluated using the Aperio™ digital H-score system which includes the 
percentage of positive cells (0 to 100) and intensity (0 to 3+), with a total score 
ranging from 0 to 300. The expression of markers in inflammatory cells will be 
examined using an infiltrate density score established by the number of cells 
expressing a determined marker by tissue area. 
 Multiplex IF Analysis: Up to 20 immune markers distributed in 3-4 panels will 
be utilized. For multiplex IF analysis, we will use the Opal chemistry and 
multispectral microscopy Vectra system (Perkin-Elmer) which includes the 
Nuance software; analysis will be performed using the InForm software. The 
expression of protein markers and inflammatory cells will be examined using 
an infiltrate density score established by the number of cells expressing a 
determined marker by tissue area. The data and digital images will be deposited 
in a central database for review by pathologists. Among other markers, we will 
study the expression of the following CD3, CD4, CD8, PD-L1, PD-1, FOXP3, 
CD45RO, CD57, CD68, and Granzyme B; additional markers will be selected 
according the results of the gene expression analysis and may include other 
immunotherapy targets (e.g., OX-40, Vista, GITR, TIM-3, LAG-3, 
NKp46/CD16, etc.) and proliferation markers (e.g., Ki67).  
• Nucleic acids and protein extraction: Blood (plasma and PMBCs), tumor (CNB and 
surgical excision specimens) samples will be subjected to DNA, RNA and protein 
extraction using standard methods. DNA and RNA quantity and integrity will be 
assessed using NanoDrop 1000 spectrophotometer (Nanodrop technologies) and Pico-
green analyses. Also, protein lysate will be extracted using standard methods. 
• Molecular analysis of tumor tissues: Using FFPE and/or fresh frozen for 
CNBs/surgical excisions (Figure 1), the following analysis will be performed:  
 Immuno-oncology (IO) gene expression signatures: Using FFPE tumor tissues, 
IO panels of genes will be examined using the Nanostring technology 
(nCounter). This assay will be used to measure expression levels of drug targets, 
tumor infiltrate composition, and total immune cell composition using a single 
section of FFPE tumor tissue. The Nanostring methodology offers a cost-
effective way to analyze the expression levels of up to 800 genes 
simultaneously, with precision superior to qPCR. The current Nanostring 
PanCancer Immune Profiling Panel includes  770  genes  and  combines  
markers  for  24  different  immune  cell  types  and populations, 30 
common cancer antigens and genes that represent all categories of immune 
responses including key checkpoint blockade genes. Alternatively, we will 
apply the HTG Edge Seq technology, also known as quantitative nuclease 
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protection assay or HTG Edge Chemistry that enables extraction and 
amplification-free quantitation of mRNA from FFPE tissues without RNA 
extraction. Their Immuno-Oncology Assay examines the expression of 549 
genes implicated in the host immune response to tumors.  
 Next Generation Sequencing (NGS) analysis: To study tumor molecular 
abnormalities, fresh, and alternatively, FFPE tumor tissues before and after 
treatment will be examined for targeted gene panel NGS (analysis of mutations, 
copy number, indels, translocations), whole exome sequencing (WES) and 
RNA sequencing. Targeted NGS: Different sequencing platforms can be used 
to sequence DNA extracted from clinical samples. These platforms have a 
minimum input of 10ng of sample which make it amenable to sequencing with 
minimal DNA. The panels available are, among others, CMS50, CMS400, 
Oncomine and Foundation Medicine. They range from 50 to 409 oncogenes and 
tumor suppressor genes, with coverage of hotspots and whole exomes. All these 
platforms are available at facilities at MD Anderson Cancer Center. WES and 
RNA-seq: Illumina Hi-seq platform is available at the Sequencing Facilities at 
MD Anderson Cancer Center 
• Flow cytometry Analysis: This type of analysis may be applied to two types of 
specimens. 
 Cryopreserved PBMCs: High order flow cytometry panels are available for 
analysis of tumor tissue and blood specimens. The panels will focus on 1) 
delineation of major immune cell types (T cells, B cells, NK cells, DC), 2) 
determination of T cell differentiation status and limited functionality (IFNγ, 
TNFα, GB) and 3) defining the expression level of costimulatory and co-
inhibitory molecules on T cells. The proposed studies may be conducted 
retrospectively on cryopreserved PBMCs. Briefly, 40 cc of heparinized 
peripheral blood from patients prior to the initiation of treatment, and at 3 time 
points throughout treatment (2 weeks, 8 weeks and at time of progression) will 
be processed fresh (within 24h of being drawn) for PBMC isolation. PBMCs 
will be cryopreserved and stored in liquid nitrogen until use.  
 Flow cytometry of freshly disaggregated tumor tissue. In selected cases, fresh 
tissue will be available for flow cytometry analysis. Tumor tissue will be stored 
in HBSS for up to 24h before processing for flow cytometry. Fresh tissue will 
be mechanically disaggregated or digested according to needs and panel design. 
The cells will be processed as a single cell suspension and stained according to 
each customized panel.  
• Liquid biopsy analysis: Liquid biopsies are non-invasive blood tests that detect tumor 
cell free DNA (cfDNA) that are shed into the blood from the primary tumor and from 
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metastatic sites. cfDNA testing offers the opportunity to take serial samples in order to 
monitor tumor genomic changes in real time. There are several platforms available at 
MD Anderson Cancer Center, including the application of droplet digital PCR (ddPCR) 
platform in a small panel of hot spots/genes or a larger panel of genes using NGS 
platform. Additionally, isolation of circulating tumor cells (CTCs) and exosomes for 
genotyping DNA purposes are available as optional analysis of blood compartments. 
• TCR receptor repertoire: TCR sequencing analysis may be performed using DNA from 
tumor tissues as well as PBMC. Briefly, 500 ng tumor DNA or 3-6 ug PBMC DNA will 
be subjected to high throughput TCR Vβ CDR3 sequencing on an Illumina HiSeq sequencer 
with at least 5-fold coverage by ImmunoSEQ™ sequencing 
(Adaptive 
Biotechnologies, Seattle, WA). TCR profile generated from treatment-refractory 
tumors at the time of disease progression will be compared to data from pre-treatment 
tumor samples to explore the TCR repertoire evolution of these tumors under 
therapeutic pressure. The dynamic changes of TCR from PMBC, when longitudinal 
blood samples are available, will be correlated to response to immune checkpoint 
blockade or chemotherapy and survival. 
• Cytokines analysis: For the detection of soluble factors in plasma we may use the 
SQ120 instrument from Meso Scale Discovery (MSD). This and other technologies 
allow for the detection of up to 40 analytes per well and uses a very low sample volume, 
with a sensitivity up to 1000-fold higher than traditional ELISA assays with a large 
linear range of 3-4 logs. These technologies can be utilized for either single agent 
detection or in multiplex format.  
 
 
 
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