Clinical trial NCT04194801
Conditions: Hepatocellular Carcinoma
Sponsor: CStone Pharmaceuticals
Start date: 2019-12-16; Completion date: 2021-10-20
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate the safety, tolerability, pharmacokinetic and efficacy of fisogatinib (formerly known as BLU-554) in combination with CS1001 in patients with locally advanced or metastatic hepatocellular carcinoma (HCC)

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Phase Ib: Fisogatinib (BLU-554) 400mg in combination with Sugemalimab (CS1001) 1200mg intervention 2: Phase Ib: Fisogatinib (BLU-554) 600mg in combination with Sugemalimab (CS1001) 1200mg intervention 3: Phase II: Fisogatinib (BLU-554) 600mg in combination with Sugemalimab (CS1001) 1200mg
Intervention descriptions: intervention 1: Phase Ib: participants received 400 mg Fisogatinib (BLU-554) once daily (QD), in combination with 1200mg fixed dose Sugemalimab (CS1001) once every 3 weeks (Q3W). Every 21 days (3 weeks) will be considered as one cycle. intervention 2: Phase Ib: participants received 600 mg Fisogatinib (BLU-554) QD, in combination with 1200mg fixed dose Sugemalimab (CS1001) Q3W. Every 21 days (3 weeks) will be considered as one cycle. intervention 3: Phase II: participants received 600 mg Fisogatinib (BLU-554) QD, in combination with 1200mg fixed dose Sugemalimab (CS1001) Q3W. Every 21 days (3 weeks) will be considered as one cycle.

Protocol documents:
Prot_000.pdf: 
Clinical Protocol CS3008(BLU-554)-101 
Fisogatinib 
ClinicalTrials.gov Document Cover Page 
Clinical Protocol  
Study CS3008(BLU-554)-101 
Study Title: A Muti-center, Open-label, Multiple-dose Phase Ib/II Study to Assess the Safety, 
Tolerability, Pharmacokinetics, Anti-tumor Efficacy of CS3008 (BLU-554) in Combination with 
CS1001 in Subjects with Locally Advanced or Metastatic Hepatocellular Carcinoma (HCC) 
Document Date: 28Jul2020 
NCT Number: NCT04194801 


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A Multi-center, Open-label, Multiple-dose Phase Ib/II Study to Assess the Safety, 
Tolerability, Pharmacokinetics, Anti-tumor Efficacy of CS3008 (BLU-554) in 
Combination with CS1001 in Subjects with Locally Advanced or Metastatic 
Hepatocellular Carcinoma (HCC) 
 
Version 2.1 


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Clinical Study Protocol 
 
 
Protocol Title: 
A Muti-center, Open-label, Multiple-dose Phase Ib/II 
Study to Assess the Safety, Tolerability, 
Pharmacokinetics, Anti-tumor Efficacy of CS3008 
(BLU-554) in Combination with CS1001 in Subjects 
with Locally Advanced or Metastatic Hepatocellular 
Carcinoma (HCC) 
Protocol No.: 
CS3008 (BLU-554) - 101 
Version Number: 
V. 2.1/Jul. 28, 2020 
Investigational Drug: 
CS3008(BLU-554); CS1001 
Study Phase: 
Phase Ib/II 
Sponsor: 
CStone Pharmaceuticals (Suzhou) Co., Ltd. 
CStone Pharmaceuticals (Shanghai) Co., Ltd. 
Unit E618, 2F, North Tower, Building A1, SIP BioBay, 
218 Xinghu Street, Suzhou Industrial Park, Suzhou, China 
Room 211-20, 2nd Floor, Building 1, No. 38, Debao Road, 
Experimental Zone, Free Trade Zone, Shanghai, China 
Blueprint Medicines Corporation 
45 Sidney Street Cambridge, MA 02139, USA 
Confidentiality Statement 
This confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee. Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written 
authorization from the sponsor. 


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Signature Page 
 
Protocol Title: 
A Muti-center, Open-label, Multiple-dose Phase Ib/II 
Study to Assess the Safety, Tolerability, 
Pharmacokinetics, Anti-tumor Efficacy of CS3008(BLU- 
554) in Combination with CS1001 in Subjects with 
Locally Advanced or Metastatic Hepatocellular 
Carcinoma (HCC) 
Protocol No.: 
CS3008 (BLU-554) - 101 
Version Number: 
V. 2.1/Jul. 28, 2020 
 
 
This protocol is a confidential document of CStone Pharmaceuticals (Suzhou) Co., Ltd. and 
CStone Pharmaceuticals (Shanghai) Co., Ltd. for confidential circulation. I confirm I have read 
through and understand this protocol and will follow the protocol in the study. Furthermore, I will 
abide by the ethics principles in Declaration of Helsinki and GLP and applicable laws and 
regulations during the study. By signing for this document, I agree that I will not make public or 
disclose any non-public information herein without prior written permission from CStone 
Pharmaceuticals (Suzhou) Co., Ltd. and CStone Pharmaceuticals (Shanghai) Co., Ltd. 
 
I have read through the full text of the protocol and agree to follow it in the study. 
 
 
Investigator Name: 
                            
 
 
 
 
Investigator Signature 
Date 
Note to investigator: Please sign your name and date on this signature page. Fill in the printed names of 
you and your site where this trial will be conducted. A copy of this signature page will be returned to 
CStone Pharmaceuticals (Suzhou) Co., Ltd. and CStone Pharmaceuticals (Shanghai) Co., Ltd. 


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Protocol Approval Page 
 
Protocol Title: 
A Muti-center, Open-label, Multiple-dose Phase Ib/II 
Study to Assess the Safety, Tolerability, 
Pharmacokinetics, Anti-tumor Efficacy of CS3008(BLU- 
554) in Combination with CS1001 in Subjects with 
Locally Advanced or Metastatic Hepatocellular 
Carcinoma (HCC) 
Protocol No.: 
CS3008 (BLU-554) - 101 
Version Number: 
V. 2.1/Jul. 28, 2020 
 
CStone Pharmaceuticals will carefully fulfill the duties of sponsors according to current Good 
Clinical Practice of relevant countries and regions and be responsible for the initiating, 
submitting, organizing, sponsoring and monitoring this clinical study. Patients with serious 
adverse events during the clinical study will be provided with active intervention and the 
corresponding treatment expense will be covered by sponsor according to applicable national 
regulatory requirements. Adequate financial compensation will be offered to subjects who 
experience damage confirmed to be consequence of investigational product-induced serious 
adverse effect. 
I have participated in the development of and discussion on this study protocol and agree to its 
contents. I have fully understood sponsor’s duties related with this trial protocol and agree to 
conduct clinical study per this protocol and applicable regulatory requirements. 
Sponsor: CStone Pharmaceuticals (Suzhou) Co., Ltd. 
CStone Pharmaceuticals (Shanghai) Co., Ltd. 
Blueprint Medicines Corporation 
 
 
 
 
 
 
 
                                                                 Date 
Senior Vice President, Chief Translational Medicine Officer   


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Table of Contents 
 
1. 
PROTOCOL SYNOPSIS ................................................................................................9 
1.1. 
SYNOPSIS ........................................................................................................................9 
1.2. 
SCHEDULE OF ACTIVITIES .......................................................................................23 
2. 
INTRODUCTION .........................................................................................................35 
2.1. 
INTRODUCTION OF THE INVESTIGATIONAL DRUG ...........................................35 
2.2. 
MECHANISM OF ACTION AND BACKGROUND ....................................................35 
2.3. 
PRECLINICAL STUDY .................................................................................................38 
2.3.1. 
PHARMACOLOGY .........................................................................................................38 
2.3.2. 
PHARMACOKINETICS ..................................................................................................43 
2.3.3. 
TOXICOLOGY .................................................................................................................44 
2.4. 
CLINICAL STUDIES .....................................................................................................48 
2.5. 
OVERALL BENEFIT/RISK ASSESSMENT .................................................................56 
3. 
OBJECTIVES AND ENDPOINTS ..............................................................................57 
3.1. 
PRIMARY OBJECTIVES AND PRIMARY ENDPOINTS OF THE STUDY .............57 
3.2. 
SECONDARY OBJECTIVES AND SECONDARY ENDPOINTS OF THE 
STUDY:  .........................................................................................................................................57 
4. 
STUDY DESIGN ...........................................................................................................59 
4.1. 
OVERALL STUDY DESIGN .........................................................................................59 
4.2. 
STUDY RATIONALE ....................................................................................................61 
4.2.1. 
Rationale for Study Design and Selection of Subjects .....................................................61 
4.2.2. 
Rationale for Dose Selection ...........................................................................................61 
4.2.3. 
Rationale for Biomarker Analysis ...................................................................................63 
4.3. 
DOSE ESCALATION .....................................................................................................63 
4.3.1. 
Dose Escalation ...............................................................................................................63 
4.3.2. 
Dose-Limiting Toxicity ....................................................................................................66 
4.3.3. 
Stopping Criteria For Dose Escalation ...........................................................................66 
4.3.4. 
MTD Definition ................................................................................................................66 
4.3.5. 
Recommended Phase II Dose (RP2D) Definition ...........................................................67 
4.4. 
END OF STUDY .............................................................................................................67 
4.5. 
TREATMENT AFTER END OF STUDY ......................................................................67 
5. 
STUDY POPULATION ................................................................................................67 
5.1. 
GENERAL CONSIDERATIONS ...................................................................................67 
5.2. 
INCLUSION CRITERIA ................................................................................................67 
5.3. 
EXCLUSION CRITERIA ...............................................................................................69 
5.4. 
SUBJECT SUPPLEMENTATION .................................................................................70 
5.5. 
PROCESS OF HANDLING INADEQUATE ENROLLMENT.....................................71 
5.6. 
TREATMENT DISCONTINUATION AND STUDY WITHDRAWAL ......................71 
5.6.1. 
Criteria for Study Treatment Discontinuation ................................................................71 
5.6.2. 
Follow-up of Subjects Who Discontinue Treatment ........................................................72 
5.6.3. 
Withdrawal From Study ...................................................................................................72 


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6. 
STUDY TREATMENTS ...............................................................................................73 
6.1. 
INVESTIGATIONAL PRODUCT .................................................................................73 
6.1.1. 
Investigational Product ...................................................................................................73 
6.1.2. 
Dosage Forms and Strenghts of Investigational Products ..............................................73 
6.1.3. 
Package and Label ..........................................................................................................73 
6.2. 
MANAGEMENT OF INVESTIGATIONAL PRODUCT ..............................................74 
6.2.1. 
Dispensing and Storage of Investigational Product ........................................................74 
6.2.2. 
Preparation and Administration of Investigational Product ...........................................74 
6.2.3. 
Return and Destruction of Study Drugs ...........................................................................75 
6.3. 
COMPLIANCE TO STUDY TREATMENT ..................................................................76 
6.4. 
STUDY TREATMRNT ADJUSTMENT .......................................................................76 
6.4.1. 
BLU-554 Dose Modifications ..........................................................................................77 
6.4.2. 
CS1001 Dose Suspension ................................................................................................77 
6.4.3. 
CS1001 Dose Resumption ...............................................................................................77 
6.4.4. 
CS1001 Permanent Discontinuation ...............................................................................78 
6.5. 
CONCOMTANT TREATMENT ....................................................................................79 
6.5.1. 
Prohibited Medications/Vaccines ....................................................................................79 
6.5.2. 
Permitted Treatment ........................................................................................................80 
6.6. 
SPECIAL PRECAUTIONS .............................................................................................80 
6.6.1. 
Infusion-Related Reaction ...............................................................................................80 
6.6.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms ............................................82 
6.6.3. 
Immune-Related Adverse Events .....................................................................................82 
6.6.4. 
Other Specific Adverse Events or Adverse Drug Reactions ............................................83 
7. 
STUDY ASSESSMENT AND PROCEDURES ..........................................................83 
7.1. 
SAFETY ASSESSMENTS .............................................................................................83 
7.1.1. 
Vital Signs ........................................................................................................................83 
7.1.2. 
Physical Examination and ECOG Performance .............................................................83 
7.1.3. 
Electrocardiogram (ECG) ...............................................................................................84 
7.1.4. 
Echocardiography ...........................................................................................................84 
7.1.5. 
Laboratory Tests ..............................................................................................................84 
7.1.6. 
Immunogenicity ...............................................................................................................86 
7.2. 
EFFICACY ASSESSMENTS .........................................................................................86 
7.3. 
PHARMACOKINETIC EVALUATION AND IMMUNOGENICITY 
ASSESSMENTS ................................................................................................................................86 
7.4. 
BIOMARKER EVALUATION ......................................................................................87 
7.5. 
STUDY PROCEDURES .................................................................................................87 
7.5.1. 
Screening Phase ..............................................................................................................87 
7.5.2. 
Treatment Phase ..............................................................................................................88 
7.5.3. 
End of Treatment (EOT) Visit ..........................................................................................92 
7.5.4. 
Follow-up Phase ..............................................................................................................93 
8. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT ........................................94 
8.1. 
DEFINITION OF AN ADVERSE EVENT ....................................................................94 
8.2. 
ABNORMAL LAB RESULTS .......................................................................................95 


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8.3. 
DEFINATION OF A SERIOUS ADVERSE EVENT ....................................................95 
8.4. 
DOCUMENTATION OF ADVERSE EVENTS ............................................................96 
8.4.1. 
Time of AE Collection ......................................................................................................97 
8.4.2. 
Follow-up of Unresolved Adverse Events .......................................................................97 
8.4.3. 
Events that Occur after Subject Withdraws from Study ..................................................97 
8.4.4. 
Variables collected ..........................................................................................................97 
8.4.5. 
Severity Analysis ..............................................................................................................98 
8.4.6. 
Causality Assessment .......................................................................................................98 
8.4.7. 
Disease Progression ........................................................................................................99 
8.4.8. 
New Cancers ....................................................................................................................99 
8.5. 
REPORTING OF ADVERSE EVENTS .........................................................................99 
8.5.1. 
Requirements for Serious Adverse Event Reporting .......................................................99 
8.5.2. 
Requirements for Non-serious Adverse Event Reporting ..............................................100 
8.6. 
OVERDOSE ..................................................................................................................101 
8.7. 
PREGNANCY ...............................................................................................................101 
8.7.1. 
Maternal Exposure ........................................................................................................101 
8.7.2. 
Paternal Exposure .........................................................................................................102 
9. 
QUALITY CONTROL ,QUALITY ASSURANCE AND DATA 
MANAGEMENT ............................................................................................................................102 
9.1. 
QUALITY CONTROL AND QUALITY ASSRANCE ...............................................102 
9.2. 
DATA MANAGEMENT AND CODING ....................................................................102 
10. 
QUALITY CONTROL AND QUALITY ASSRANCE ...........................................103 
10.1. 
SAMPLE SIZE DETERMINATION ............................................................................103 
10.2. 
UMMERIES OF CONDUCT OF STUDY ....................................................................104 
10.2.1. 
Analysis Populations .....................................................................................................104 
10.3. 
SAFETY ANALYSIS ....................................................................................................105 
10.4. 
EFFICACY ANALYSIS ...............................................................................................105 
10.5. 
PHARMACOKINETIC ANALYSES ...........................................................................106 
10.6. 
IMMUNOGENICITY ANALYSES .............................................................................107 
10.7. 
BIOMARKER ANALYSES .........................................................................................107 
11. 
ETHICAL, REGULATORY AND OTHER REQUIREMENT .............................107 
11.1. 
HEALTH AUTHORITY APPROVAL .........................................................................107 
11.2. 
ETHICAL CONDUCT OF THE STUDY AND ETHICAL APPROVAL ...................107 
11.3. 
INFORMED CONSENT PROCESS.............................................................................108 
11.4. 
CHANGES TO THE PROTOCOL AND INFORMED CONSENT FORM ................108 
11.5. 
PROTOCOL ADHERENCE AND DEVIATION ........................................................108 
11.6. 
STUDY CLOSURE .......................................................................................................109 
11.7. 
RECORDS RETENTION .............................................................................................109 
11.8. 
CLINICAL STUDY REPORT ......................................................................................110 
11.9. 
CONFIDENTIAL AND PRIVACY ..............................................................................110 
11.10. 
PUBLICATION PRIVACY ..........................................................................................110 
11.11. 
INSURANCE, REIMBURSEMENT AND COMPENSATION ..................................111 
11.12. 
(PREMATURE) TERMINATION OF THE STUDY ..................................................111 


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12. 
ABBREVIATIONS ......................................................................................................112 
13. 
REFERENCES ............................................................................................................114 
14. 
APPENDIX ...................................................................................................................116 
14.2. 
APPENDIX 2: THE LATEST REVISED RECIST GUIDANCE (VERSION 1.1) .....117 
14.3. 
APPENDIX 3: GUIDANCE FOR IMMUNE-RELATED ADVERSE REACTIONS 
MANAGEMEMT ............................................................................................................................126 
14.4. 
APPENDIX 4: ECOG PERFORMANCE STATUS .....................................................135 
14.5. 
PPENDIX 5: NEW YORK HEART ASSOCIATION (NYHA) ...................................136 
14.6. 
APPENDIX 6: Effective Controception Methods .........................................................137 
 
 
 
 


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1. 
PROTOCOL SYNOPSIS 
 
1.1. SYNOPSIS 
 
Sponsor: CStone Pharmaceuticals (Suzhou) Co., Ltd., CStone 
Pharmaceuticals (Shanghai) Co., Ltd., 
Blueprint Medicines Corporation 
Final product name: NA 
Investigational product: CS3008 (fisogatinib, BLU-554), CS1001 
Names of active substances: Fibroblast growth factor receptor 4 inhibitor, completely humanized 
IgG4-type recombinant anti- Programmed death ligand 1 (PD-L1) monoclonal antibody 
Title of study: 
A Muti-center, Open-label, Multiple-dose Phase Ib/II Study to 
Assess the Safety, Tolerability, Pharmacokinetics, Anti-tumor 
Efficacy of CS3008 (BLU-554) in Combination with CS1001 in 
Subjects with Locally Advanced or Metastatic Hepatocellular 
Carcinoma (HCC) 
CAT No.: 
JXHL1900045, CXSL900017 
Protocol No.: 
CS3008 (BLU-554) - 101 
Sites: 
20 sites as planned 
Duration of the study (first 
subject in to last subject out): 
Screening period (28 days prior to the initial administration), 
treatment period (at most 24 months) and follow-up period 
(safety follow-up period: at most 90 days; survival follow-up 
period: every 12 weeks until withdrawl of subjects or 
termination of study) 
Study Phase: 
Phase Ib/II 
This is a multi-center, open-label, multi-dose, dose-finding and extension study for evaluating the safety, 
tolerance, pharmacokinetics and antitumor efficacy profiles of BLU-554 in combination with CS1001 in 
subjects with locally advanced or metastatic HCC. 
The study consists of 2 parts, including a Part 1 (phase Ib) dose escalation and part 2 (phase II) dose 
expansion. Part 1 is a dose escalation study for determination of the MTD (Maximum tolerated dose) 
and/or RP2D (Recommended Phase II dose) of BLU-554 in the combination regimen and assess primary 
safety and tolerance of the combination regimen. Part 2 is a dose extension study in which preliminary 
evaluate the antitumor efficacy and the further evaluate the safety, tolerance, PK and immunogenicity of 
combination regimen. 
Phase 1b: Dose Escalation 
Primary Objectives 
Primary Endpoints 
 
To determine the maximum tolerated dose 
(MTD) and/or recommended Phase II dose 
(RP2D) of BLU-554 when being in 
combination with CS1001 in subjects with 
locally advanced or metastatic HCC. 
 
To evaluate the safety and tolerability of 
BLU-554 in combination with CS1001. 
 
Incidence of DLT (Dose-limiting toxicity) 
during the administration of BLU-554 in 
combination with CS1001. 
 
Safety: incidence and severity of AEs and 
SAEs, including laboratory tests, vital signs, 
and ECG 
 
Tolerance: discontinuation and reduction of 
study drug dose 
Secondary Objectives 
Secondary Endpoint 


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 To assess the pharmacokinetics (PK) profile 
of BLU-554 in combination with CS1001. 
Pharmacokinetic parameters include, but are not 
limited to: 
 
When being administered in combination 
with BLU-554, area under the serum 
concentration-time curve (AUC); Maximum 
serum concentration (Cmax); Time to 
maximum serum concentration (tmax); 
Clearance at steady state (CLss); 
accumulation ratio of CS1001. 
 
When being administered in combination 
with CS1001, AUC, Cmax, tmax, CLss/F, 
accumulation ratio of BLU-554. 
 
To assess the preliminary anti-tumor 
activity of BLU-554 in combination with 
CS1001. 
 
To assess Objective response rate (ORR), 
the duration of response (DOR), disease 
control rate (DCR), time to progression 
(TTP), progression free survival (PFS) and 
overall survival (OS) based on RECIST 
v1.1. 
 To assess the immunogenicity of CS1001 
when being administered in combination 
with BLU-554. 
 Occurrence of anti-CS1001 antibody 
 To correlate FGF19 and PD-L1 expression 
level with efficacy of BLU-554 in 
combination with CS1001 
 
ORR, DOR, DCR, TTP, PFS and OS by 
FGF19 protein and PD-L1 protein level 
Phase II: Dose expansion 
Primary Objectives 
Primary Endpoints 
 
To assess the anti-tumor activity of BLU- 
554 in combination with CS1001. 
 
To assess ORR based on RECIST v1.1. 
Secondary Objectives 
Secondary Endpoint 
 
To assess the anti-tumor activity of BLU- 
554 in combination with CS1001. 
 
To assess the DOR, DCR, TTP, PFS and OS 
based on RECIST v1.1 
 
To evaluate the safety and tolerability of 
BLU-554 in combination with CS1001. 
 
Safety: incidence and severity of AEs and 
SAEs, including laboratory tests, vital signs, 
and ECG 
 
Tolerance: discontinuation and reduction of 
study drug dose 
 To assess the pharmacokinetics (PK) profile 
of BLU-554 in combination with CS1001. 
Pharmacokinetic parameters include, but are not 
limited to: 
 
When being administered in combination 
with BLU-554, AUC, Cmax, tmax, CLss, 
accumulation ratio of CS1001. 
 
When being administered in combination 
with CS1001, AUC, Cmax, tmax, CLss/F, 
accumulation ratio of BLU-554. 
 To assess the immunogenicity of CS1001 
when being administered in combination 
with BLU-554. 
 Occurrence of anti-CS1001 antibody 
 To correlate FGF19 and PD-L1 expression 
level with efficacy of BLU-554 in 
combination with CS1001 
 
ORR, DOR, DCR, TTP, PFS and OS by 
FGF19 protein and PD-L1 protein level 


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Study design: 
Both Phase Ib and Phase II can be divided into 3 periods, screening period, treatment period and follow-up 
period: 
 
The screening period is the 28 days prior to the first dose. 
 
During the treatment period, the subjects will be administered the study drug once every 21 days (3 
cycles). BLU-554 is taken orally (PO) once daily (QD); CS1001 is administered intravenously once 
every 21 days (Q3W). Subjects with advanced stage solid tumor will be imageologically evaluated by 
the investigators every 9 weeks (i.e. every 3 dosing periods) during the 1st year of treatment and every 
12 weeks after treatment for more than 1 year against Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1). The investigator may increase evaluation frequency if clinically indicated. The drug 
may be administered continually until presence of intolerable adverse reaction, disease progression, 
withdrawal of informed consent, loss to follow up, death or study termination. The duration of 
treatment may be up to 24 months. 
 
Follow-up period consists of safety follow-up period and survival follow-up period. The safety follow-
up period includes 90 days after the last dose of study drug, or until the initiation of a new anti-tumor 
treatment, whichever occurs earlier. Survival follow-up period will be performed every 12 weeks for 
collection of the survival status, subsequent anti-tumor therapies and study drug-related SAEs of the 
subjects until the death, loss to follow-up, withdrawal or termination of study, whichever occurs first. 
Refer to the Section 1.2 SOA for the study schedule. 
Phase Ib: Dose Escalation 
The MTD and/or RP2D of BLU-554 in the combination regimen will be determined using a BOIN dose 
escalation design. 2 dose levels of BLU-554 will be assessed with CS1001 1,200 mg Q3W as the fixed 
dose (RP2D in single-dose study). The planned dose escalation scheme is shown in Table 1 with 400 mg 
QD as the starting dose of BLU-554. Every 21 days (3 weeks) will be considered as one cycle. DLT 
assessment will be done within 21 days (Cycle 1) after the administration. Using BOIN design, the target 
toxicity probability of the MTD is 0.3 with a maximum sample size of 12. The cohort size included 3 
enrolled and treated subjects. The number can be modified based on subject’s enrollment. As shown in 
Figure 13, the starting dose is dose level 1, i.e. BLU-554 400 mg QD in combination with fixed dose 
CS1001 1,200 mg Q3w. After complete DLT assessment for each cohort, the dose level for the next cohort 
was determined according to the dose escalation/decreasing rule in Table 7. Repeat the step with every 3 
subjects until a maximum sample size of 12 is reached, the dose escalation is ended (See Dose Escalation 
Flowchart for details). CS1001 is administered intravenously once every 3 weeks (21 days). BLU-554 is 
taken orally once daily from Day 1 to Day 21; In case that the two study drugs would be administered on 
the same day, BLU-554 should be administered firstly. 
Table 1:Planned Dose Escalation Scheme 
Cohort 
BUL-554 
CS1001 
1 
400 mg QD 
1,200 mg Q3W 
2 
600 mg QD 
1,200 mg Q3W 
 
During the study period, an SMC consisting of the principle investigator, the CRO's representatives (CRA 
and other relevant person) and the sponsor’s representative will be established to review the safety data, 
PK data, efficacy data from the study and determine the escalation dose level and dosage regimen in dose 
escalation study so as to determine the MTD and RP2D selected for the extension study. The SMC will 
also decide whether or not to include unscheduled dose levels for the study. 
Phase II: Dose expansion: 


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The primary objective of the dose expansion phase is to primarily evaluate the antitumor efficacy as well 
as to further evaluate the safety, tolerability, PK and immunogenicity of the combination regimen. In 
this part, subjects will be enrolled into 2 groups according to the expression of FGF19 
immunohistochemistry (IHC): Group 1 will be advanced hepatocellular carcinoma subjects with FGF19 
IHC-, the cancellation of which will be based on phase Ib data (see protocol 4.1 for details); Group 2 
will be advanced  hepatocellular carcinoma subjects with FGF19 IHC+. In case of being within the 
statistically pre-defined assessment range, additional subjects may be enrolled for further evaluation 
(see Protocol 4.1 for details). FGF19 expression will be determined at central laboratory by 
immunohistochemistry (IHC) with the inclusion criteria of FGF19 IHC+ defined as ≥ 1%. 
In Phase Ib and Phase II, archived or fresh tumor samples must be provided for FGF19 and PD-L1 IHC 
test which will be employed at central laboratory. 
The tumors shall be evaluated in accordance with RECIST v1.1. During the 1st year of the treatment, 
subjects will receive CT/MRI examination every 9 weeks (every 3 cycles). After 1 year of treatment, 
CT/MRI examinations shall be carried out once every 12 weeks (The investigator may increase the 
frequency of tumor evaluations where clinically indicated). 
The data from subjects on anti-tumor activity, safety, tolerability, PK profile and host immunogenicity 
will be reviewed from the day of first administration of study drugs up to 90 days after the last 
administration or up to two-year treatment period of combination regimen 
 
. 


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● 
Dose Escalation Process: 
 
Planned number of subjects: 
Phase Ib: Approximately 12 subjects will be enrolled 
Phase II: Approximately 40 subjects will be enrolled 
Dose limiting toxicity (DLT) 
definition: 
Definition of DLT: All toxicity or adverse events (AEs) are graded 
according to NCI-CTCAE 5.0. Any AE occurring during C1 (21 
days) that is not clearly caused by something other than 
investigational drug: 
Hematological toxicity: 
● 
Grade 4 neutropenia that lasts for ＞7 days; 
● 
Grade ≥3 febrile neutropenia (ANC<1,000/mm3, with a single 
temperature of ≥38.3°C or a sustained temperature of ≥38°C for 
more than one hour); 
● 
Grade 3 neutropenia with infection; 
● 
Grade 3 thrombocytopenia with clinically significantly 
bleeding; 


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● 
Grade 4 thrombocytopenia; 
● 
Grade ≥4 anemia 
Non-hematological toxicity: 
● 
Grade ≥4 toxicity; 
● 
Grade 3 toxicity that fails to be resolved to ≤Grade 2, with the 
exception of diarrhea, nausea and vomiting; 
● 
Grade ≥3 immune-related adverse event (irAE); 
● 
Any Grade 3 tumor flare reaction (local pain, irritation or rash 
at known or suspected tumor focus) that lasts for 7 days or 
above; 
● 
Grade 3 or Grade 4 non-hematological laboratory 
abnormalities, if meet any of the followings: 
– need medical intervention 
– require hospitalization 
– last for >7 days 
and other toxicity of any grade that requires premature termination 
of the study as determined by the investigator and the sponsor 
through discussion. 
Definition of MTD: Based on BOIN design, MTD is the highest 
dose level at which 30% of the subjects experience DLT within 21 
days (Cycle 1) among which at least 6 subjects are available for 
DLT evaluation. The RP2D will be determined by SMC based on 
comprehensive data of safety and tolerability, PK, 
pharmacodynamics, and preliminary anti-tumor efficacy obtained 
during the dose escalation phase. The RP2D will not exceed the 
MTD and will be determined at a dose escalation meeting. 
Study Population: 
Inclusion Criteria: 
To meet the conditions for participation in this clinical study, 
subjects must: 
1. Voluntarily participate in the clinical study. Fully 
understand and get informed of this study and sign the 
Informed Consent Form (ICF). 
2. 
≥18 years of age on day of signing the informed consent. 
3. 
Unresectable locally advanced or metastatic hepatocellular 
carcinoma as confirmed by histology or cytology. 
4. 
Stage B or C based on Barcelona Clinic Liver Cancer 
(BCLC) staging system; In case of Stage B, subject must be 
ineligible for surgery and/or local therapy, or has progressed 
after surgery and/or local therapy or refuses surgery and/or 


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local treatment. 
5. 
For Phase Ib, subject has failed after or is unsuitable for the 
standard systemic therapy against HCC. For Phase II, 
subject has not previously received systemic therapy 
[systemic therapies mainly include: chemotherapy, 
molecular target drugs (e.g. tyrosine kinase inhibitors, TKI), 
immunotherapy (e.g. anti PD-1/PD-L1, CTLA-4 etc.), 
biological therapy (e.g. tumor vaccine), cytokines, etc.)]. 
6. At least one measurable lesion as evaluable by RECIST 
version1.1, Target lesions within the field of prior efficacy 
irradiation or in the area of local treatment (intervention or 
ablation therapy) are considered measurable in case of 
confirmation of progression. 
7. 
Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) score of 0-1 point. 
8. 
A-level Child-Pugh score. 
9. 
Expected survival≥3 months. 
10. For Phase Ib and II, 9 formalin fixed-paraffin embedded and 
unstained tumor tissue slides should be provided for FGF19 
IHC and PD-L1 analysis in the central laboratory. 
 
Patients to be enrolled in the FGF19 IHC + arm in the Phase 
II study must be FGF19 IHC +; 
 
Patients to be enrolled in the FGF19 IHC - arm in the Phase 
II study must be FGF19 IHC – (whether this arm will be 
initiated or not will be decided based on Phase Ib data) 
11. Clinical laboratory screening criteria:  
  Absolute neutrophil count (ANC)≥1.5 × 
109/L  
 Platelet count≥ 75 × 109/L 
 Hemoglobin≥90 g/L 
 Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 5 × ULN 
 Total bilirubin ≤ 2 ×ULN 
 International normalized ratio (INR) or prothrombin time 
(PT) ≤ 1.5 ×ULN (INR ≤ 1.5 × ULN and PT ≤ 1.5 × ULN, 
if both available) 
 Serum creatinine ≤ 1.5 ×ULN or creatinine clearance 
(CL)≥60 mL/min (Cockcroft-Gault Formula) 
        Female: CrCl=(140-age) × weight (Kg) × 0.85  
                          72× serum creatinine (mg/dL) 
        Male: CrCl=(140-age) × weight (Kg) × 1.00      
                         72× serum creatinine (mg/dL) 
12. For subjects with hepatitis C virus (HCV) infection, treatment 
with locally approved and available anti-HCV therapy is 
required if HCV RNA is detected. 
13. For subjects with hepatitis B virus (HBV) infection, HBV 
DNA ≤ 2,000 IU/ml at Screening. 
 
Subject with HBV DNA (+), treatment with HBV antiviral 
therapy (as per the local standard of care) is required at least 
14 days prior to the initiation of study. 


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 
Subject with HBsAg (+) and/or HBcAb (+), based on 
investigator assessment, HBV antiviral therapy may be 
applied if needed. 
14. For female subjects of childbearing potential, serum pregnancy 
test must be negative within 7 days prior to randomization. 
Except for female subjects who have been recorded as 
surgically sterilized or who are postmenopausal, female 
subjects of childbearing potential or male subjects and their 
partners must agree to use effective contraception from the 
signature of the informed consent form (ICF) until at least 6 
months after the last dose of study drug. Appendix 6: Effective 
Contraceptive Methods 
Exclusion Criteria: 
Subjects who meet any of the following criteria will not be eligible 
to participate in the study: 
1. Portal vein tumor thrombosis in the main trunk or 
contralateral first branch (VP4), involvement of the 
inferior vena cava or the heart as revealed by imaging at 
baseline. 
2. Prior or current history of hepatic encephalopathy. 
3. History of liver surgery and/or local treatment for HCC 
(intervention, ablation therapy, absolute alcohol injection, etc.) 
or radiotherapy, etc. within 4 weeks prior to first dose. 
4. Active or documented gastrointestinal bleeding within 6 
months (e.g. esophageal or gastric varices, ulcer bleeding). 
5. Presence of ascites detected by physical examination or clinical 
symptoms caused by ascites during the screening period, or 
ascites that need for special treatment, such as repeated 
drainage, or intraperitoneal drug infusion, etc. (Note: subjects 
with a small amount of ascites that can only be detected by 
imaging may be enrolled). Presence of uncontrolled pleural 
effusion or pericardial effusion (with clinical symptoms, 
requiring repeated drainage, or intrapleural or pericardial drug 
infusion, etc.) during the screening period. 
6. Presence of meningeal metastasis or central nervous system 
(CNS) metastatic lesions. 
7. According to the New York Heart Association (NYHA) 
Classification, subject has clinically significant, uncontrolled 
cardiovascular disease, including Grade III or IV congestive 
heart failure; myocardial infarction or unstable angina 
(within 6 months), uncontrolled hypertension (systolic blood 
pressure≥150 mmHg and diastolic blood pressure≥100 
mmHg) or clinically significant uncontrolled arrhythmias, 
including bradycardia that may result in prolonged QT (e.g. 
Grade II or III heart block). Left ventricular ejection fraction 
(LVEF)<50%. QTc interval >480 msec (corrected using 
Fridericia’s formula). 
8. Subjects who have current interstitial lung disease or 
noninfectious pneumonitis, and prior history of interstitial 
lung disease or noninfectious pneumonitis that may affect 
the assessment or management of study drug-related 
pulmonary toxicity. Presence of active tuberculosis 


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infection. 
9. Any serious acute, chronic infections that require systemic 
antimicrobial, antifungal or antiviral therapy at screening, 
excluding viral hepatitis. 
10. Malabsorption syndrome or inability to take the study drug 
orally for other reasons. 
11. Had primary malignancies other than HCC within 5 years. 
The following prior malignancies were excluded: completely 
excised skin basal cells and squamous cell carcinoma, local 
prostate cancer responsive to treatment, and carcinoma in 
situ with complete resection at any site. 
12. Subject has had major surgery within 4 weeks prior to first 
dose (procedures such as central venous cannulation, biopsy, 
and feeding tube placement are not considered as major 
surgery). 
13. Previously received FGFR4 inhibitor treatment. 
14. Blood transfusion, use of hematopoietic stimulating factors 
[including G-CSF (granulocyte colony stimulating factor), 
GM- CSF (granulocyte-macrophage colony stimulating 
factor), EPO (erythropoietin) and TPO (thrombopoietin)] 
and human albumin preparations within 14 days prior to first 
dose. 
15. Requiring corticosteroids (dose equivalent to > 10 mg/day of 
Prednisone) or other immunosuppressive drugs within 14 
days prior to first dose for systemic therapy. 
Note: For the absence of active autoimmune disease, it is 
allowed to use inhaled or topical steroids or adrenal hormone 
replacement therapy with equivalent dose of ≤10 mg/day 
prednisone. Short-term (≤ 7 days) use of corticosteroids for 
prophylaxis (e.g., contrast allergy) or for the treatment of 
non- autoimmune diseases (e.g., delayed hypersensitivity 
reactions due to contact allergens) is permitted. For subjects 
requiring hormone therapy, the dose administration should 
be done at least two days before and after the injection of 
CS1001. 
16. Use of traditional Chinese medicine (elemene, Kanglaite, 
Cinobufacin, Xiaoaiping, Huaier granule, Ganfule, Jinlong 
capsule, Aidi, etc.) with anti-liver cancer indication within 
14 days prior to the first dose. 
17. Subject has received potent CYP3A4 inhibitors and/or 
inducers within 2 weeks prior to first dose. See Appendix 8: 
Strong Inhibitors and Inducers of CYP3A4. 
18. Concurrent HBV and HCV infection (History of HCV 
infection, but subjects with HCV RNA(-) can be considered 
as not being infected with HCV). 
19. Subjects with human immunodeficiency virus (HIV) 
infection. 
20. Pregnant or lactating women. 
21. Subjects with a history of hypersensitivity or 
hypersensitivity to any of the components of the 
investigational drug. 
22. Any previous or current clinically significant diseases, 
medical conditions, history of surgery, signs, or abnormal 
laboratory parameters that, in the opinion of the 
investigator, may increase the risks associated with study 
participation and study drug administration, or affect the 
subject's ability to receive study drug and reliability of 
study results; other circumstances that in the opinion of the 


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investigator would preclude participation in the study. 
23. Subjects who are unwilling or unable to follow the study 
procedures as defined. Subjects with no or limited 
disposing capacity and with psychiatric disorders that 
may affect study compliance. 
24. With the exception of alopecia, all toxicities from prior 
anticancer therapies and other therapies did not recover 
to ≤ Grade 1 (per CTCAE v5.0) prior to the first dose of 
study drug. 
25. Subjects who have received prior allogeneic stem cell or 
solid organ transplantation. 
Definition of end of study: 
All subjects completed the treatment period, EOT visit, disease 
progression follow-up and survival follow-up or the Sponsor 
terminated the study (whichever occurred first). 
Test product, dose and mode of 
administration: 
BLU-554 capsule 100 mg will be taken by oral administration once 
daily. 
CS1001 injection 600 mg/20 ml/Bottle will be given via 
intravenous infusion on the first day of each treatment 
cycle, once every 21 days (3 weeks). 
Planned trial and treatment 
duration per subject: 
No more than 35 cycles (24 months) of study treatment followed 
by a 90-day safety follow-up. 


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Statistical methods: 
Analysis Populations 
Safety analysis set: consists of all subjects receiving at least one 
dose of investigational product. 
Efficacy analysis set: consists of all subjects with measurable 
baseline disease who received at least one dose of investigational 
product. It will be the primary analysis set for efficacy in this study. 
Note: Subjects who were screened but never started treatment will 
be listed, but not included in any efficacy analysis set. Therefore, 
these subjects will not be included in any of the summary tables. 
Dose-determining set: consists of all subjects from the safety 
analysis set who, in Cycle 1, meet the minimum exposure criterion 
and complete the follow-up on Cycle 1 Day 21 or discontinue the 
treatment due to DLT. 
A subject is considered to have met the minimum exposure criterion 
if in Cycle 1 the subject has received ≥75% of the treatment (not 
necessarily consecutively). Subjects who do not meet these 
minimum safety evaluation requirements are considered to be 
ineligible for the dose-determining set. Determination of the MTD 
uses subjects eligible for the dose-determining set. 
Pharmacokinetic analysis set: consists of all subjects who received 
at least one dose of investigational product and had at least one 
post-baseline pharmacokinetic assessment. 
Immunogenicity analysis set: consists of all subjects receiving at 


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least one dose of investigational product and having available ADA 
data. 
Biomarker analysis set: consists of all subjects receiving at least 
one dose of investigational product and having available biomarker 
data. 
All analysis sets will be determined before the database is locked. 
Primary Analysis Method 
Safety: 
Safety assessments will include adverse events, vital signs, physical 
examination, electrocardiogram (ECG), echocardiography and 
laboratory tests. The incidence of DLT for each dose group will be 
assessed. All treatment-emergent adverse events (TEAEs) in each 
dose group are summarized by system organ classification and 
preferred terms. 
The relationship of the incidence and severity of all TEAEs to the 
investigational drug will be summarized. 
Descriptive summaries of laboratory tests and vital signs for each 
dose group will be made separately. Abnormal findings of 
laboratory tests, vital signs, ECG, echocardiograms will be listed. 
Efficacy: 
Efficacy assessments will be conducted according to RECIST v1.1, 
including ORR, PFS, DCR and DOR. The efficacy endpoint is the 
ORR assessed by the investigator and ORR for the subjects in each 
dose group and overall ORR will be summarized. OS and PFS will 
be expressed by a Kaplan-Meier curve. 
Sample Size Determination 
According to efficacy result of BLU-554-1101 study (data cut-off 
date: 16 Jun 2018), ORR was 17% (11/63) for FGF19 IHC+ 
subjects (1st line and above) and 0 (0/38) for FGF19 IHC- subjects. 
ORR of PD-1/PD-L1 monotherapy was reported around 10~20% 
for 1st line and 2nd line HCC subjects. Based on the data above, 
BLU-554 in combination with CS1001 is targeting 40% ORR for 
1st line and 2nd line FGF19 IHC+ subjects and 30% ORR for 1st line 
and 2nd line FGF19 IHC- subjects. Combining all subjects treated at 
RP2D in Phase Ib and Phase II, gating criteria in Bayesian 
framework are developed as the following: 
Gating based on 25 FGF19 IHC+ subjects 
• 
A non-informative ORR prior is assumed at Beta (0.45, 0.55). 
• 
Timing - when all 25 subjects finish at least two post-baseline 
tumor assessments 
• 
Go - 12 responses or more, corresponding ORR 48%, the 


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probability of combo ORR > 40% is 0.788. 
• 
No go - 8 (32%) responses or fewer, the probability of combo 
ORR<40% is 0.797. 
• 
Evaluate - 9 (36%) to 11 (44%) responses, evaluate other 
efficacy endpoints (DOR, DCR etc.) and safety. 
Gating based on 40 FGF19 IHC+ subjects (if enrichment of 15 
FGF19 IHC+ subjects as decided) 
• 
A non-informative ORR prior is assumed at Beta (0.45, 0.55). 
• 
Timing - when all 40 subjects finish at least two post-baseline 
tumor assessments 
• 
Go - 18 responses or more, corresponding ORR 45%, the 
probability of combo ORR > 40% is 0.737. 
• 
No go - 14 (35%) responses or fewer, the probability of combo 
ORR<40% is 0.744. 
• 
Evaluate - 15 (37.5%) to 17 (42.5%) responses, evaluate other 
efficacy endpoints (DOR, DCR, etc.) and safety. 
Gating based on FGF19 IHC - subjects treated at RP2D in Phase 
Ib 
• 
A non-informative ORR prior is assumed at Beta (0.2, 0.8). 
• 
Timing - only conducted if at least 6 FGF19 IHC- subjects are 
treated at RP2D in Phase Ib, when they finish at least two post- 
baseline tumor assessments 
• 
No go - 0 response, the probability of combo ORR<30% is 
greater than 0.99, Phase II will only include the FGF IHC+ 
cohort 
• 
Evaluate - 1 response or more, the cohort of FGF IHC- 
subjects will be included in Phase II 
Gating based on 15 FGF19 IHC- subjects 
• 
A non-informative ORR prior is assumed at Beta (0.2, 0.8). 
• 
Timing - when all 15 subjects finish at least two post-baseline 
tumor assessments 
• 
Go - 6 responses or more, corresponding ORR 40%, the 
probability of combo ORR > 30% is 0.757. If the final 
decision for FGF19 IHC+ subjects is “go” (Gating based on 15 or 40 
FGF19 IHC+ subjects, as above said), FGF19 IHC- subjects may also 
be included in the target population of future development. 
• 
No go - 3 (20%) responses or fewer, the probability of combo 
ORR<30% is 0.845. Future development will not include 
FGF19 IHC- subjects in the target population. 
• 
Evaluate - 4 (26.7%) to 5 (33.3%) responses, evaluate other 


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efficacy endpoints (DOR, DCR, etc.) and safety. 
The sample sizes of 25 or 40 FGF19 IHC+ subjects and 15 FGF19 
IHC- subjects are selected to have reasonably high probability of 
ORR exceeding the target when the go criteria are met or ORR 
being lower than the mono therapies when no-go criteria are met. 
The go and no-go criteria are set up to guide future development of 
the combination. They are not binding decision-making rules. 
If the actual numbers of evaluable subjects are different from those 
planned above, the same method will be used to calculate the 
posteriori probability that ORR will reach the predefined target for 
reference in subsequent development. 
 


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1.2.  SCHEDULE OF ACTIVITIES 
 
Table 2:tudy Assessments and Procedures Schedule in Dose Escalation Part (Phase Ib) 
Phase Iba 
Screenin 
g 
Treatment (21d for each cycle) 
Follow-up 
Cycle 1 
Cycle 2 
≥Cyc 
le 3 
EOT 
visit b 
Safety follow-up c 
Survival 
follow-up 
c 
1 
2 
3 
Days 
-28 to -1 
1 
2 
8 
15 
1 
15 
1 
0-7 
days 
post 
EOT 
date 
30 days 
post last 
dose 
60 days 
post last 
dose 
90 days 
post last 
dose 
Every 12 
weeks 
post last 
dose 
Time Window 
±2  
±2  
±4  
±4  
±4  
±7  
±7  
±7  
±7  
±7  
Informed Consent d 
X 
Inclusion/Exclusion Criteria 
X 
X 
Demographics 
X 
Medical History e 
X 
X 
Physical Examination f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy 
Test g 
X 
X h 
X 
X 
12-lead ECG i 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram j 
X 
As clinically indicated 
X 
Tumor Imaging k 
X 
Within 1 year: every 9 weeks ± 7 days (end of every 3 dose cycles), after 1 year: every 12 weeks ± 7 days; or based on 
the clinical needs. 
Blood test l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry, CK-MB l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, HBV, HCV m 
X 
X 
X 
X 
AFP m 
X 
X 
X 
Coagulation l 
X 
X 
X 
X 
X 
X 
Routine Urine Test 
X 
X 
X 
X 
X 
X 
Thyroid Function n 
X 
X 
X 
X 
X 
X 


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Tumor Sample 
X o 
CS1001 Administration p 
X 
X 
X 
BLU-554 Administration q 
X 
PK blood sample r 
X 
Immunogenicity Blood 
Sample r 
X 
Subsequent anti-tumor 
therapy s 
 
X 
X 
X 
X 
AE Monitoring 
X 
SAE Monitoring t 
X 
Concomitant Medications 
X 
Survival Status u 
X 
Abbreviations: AFP, Alpha-Fetoprotein; CT, computed tomography; CK-MB, creatine kinase-MB; ECOG, Eastern Cooperative Oncology Group; HBV, Hepatitis B 
Virus; HCV, Hepatitis C Virus; HIV, Human Immunodeficiency Virus; PK, pharmacokinetics. 
a. 
All visits should be performed as noted in Table 2. Additional safety tests (e.g., blood test, ECG) may be performed whenever clinically indicated, at the 
Investigator’s discretion. Unless otherwise indicated, all tests and procedures must be performed predose at each visit. Whenever a test result is questionable, it 
should be repeated immediately. Re-screening is permitted for one time, but need to decide by medical monitor and sponsor assessment. 
b. 
The date of the End of Treatment (EOT) visit is defined as the date on which the investigator decided to stop dosing. The EOT visit should be performed 0-7 
days post the EOT date. If the EOT visit and a treatment visit occur within 7 days, no tests are required for repeated items. If the EOT visit occurs within the 
safety follow-up window, no tests are required for repeated items. If an alternate treatment is started within 7 days of the EOT date, the EOT visit should be 
conducted prior to the first dose of alternate therapy. The last administration date is defined as the later last administration date of the two study drugs. It 
should be noted that the date on which the investigator decided to stop dosing may not coincide with the date of last dose. 
c. 
Safety visits: For subjects who have completed treatment, a safety visit should be conducted on the 30th day (±7 days), 60 days (±7 days), and 90 days (± 7 days) 
post the last dose; the safety follow-up at 90 day post the last dose can be conducted at the same day as that for the first survival follow-up. Survival follow-up: 
subjects will be contacted by telephone or in person every 12 weeks from the last dose of study drug to collect survival status, subsequent anti-tumor therapy, 
and study drug-related SAEs until the death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs first. 
d. 
Consent for the study may be obtained from the subjects by written. 
e. 
A complete medical history will be obtaining at the Screening visit. Only disease-related symptoms and changes from the previous visit need to be collected on 
C1D1. 
f. 
A complete physical examination will be performed at the Screening visit. Subsequent physical examinations will be disease- and AE-focused. 
g. 
To be performed for women with childbearing potential within 7 days of C1D1. A serum pregnancy test should be performed at Screening; thereafter, a serum 
or urine pregnancy test should be performed on every odd cycle (e.g., C3, C5). 
h. 
To be performed on D1 (±4 days) of every odd cycle starting with C3. 
i. 
ECGs (12-lead) exams will be performed after at least a 10 minute rest in the supine position. ECGs will be performed at Screening and during treatment, at 
EOT, and at Safety Follow-Up. In case of PK sampling, ECG should be performed for 3 consecutive times with an interval of 5 minutes each time in Cycle 1, 2 
and 4. Refer to Table 4 and Table 5 for specific time. For other treatment cycles ECG should be performed at predose of any Cycle Day 1 dosing. For C1D2, 


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ECG should be collected at predose. Frequency of ECGs may be increased if clinically indicated. 
j. 
To be performed as clinically indicated. 
k. 
Imaging assessment of tumors: Tumor assessment is conducted according to the standard RECIST v1.1. See the specific assessment standards in Appendix 2. 
The imaging assessment method of tumors may adopt CT or MRI as decided by the investigator, however, the assessment method, machine and technical 
parameters should remain consistent in the entire study period; if there is no contraindication, a contrast medium should be used. The imaging results will be 
interpreted by the investigator or radiologist of each site. In case a tumor assessment has been conducted within 28d before initial administration and by the 
same method and machine in the same hospital, the result can be adopted as baseline tumor assessment. Baseline tumor assessment should cover chest, abdomen, 
pelvic cavity and any other site suspected of tumor lesion (such as brain, bone lesions). Subjects with bone metastases during screening should be followed up 
using CT/MRI/X-ray at subsequent visits. Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days prior to the first dose (baseline 
assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter until (1) disease progression, (2) initiation of a new anti-tumor 
therapy, (3) withdrawal of informed consent, (4) loss of follow-up, (5) death, and (6) termination of the study, whichever occurs first. In case medication is 
discontinued permanently for a subject due to the reasons other than those above said (such as AEs), the tumor assessment will still be conducted as scheduled. 
The investigator can schedule additional imaging examination based on the subject's clinical condition. If an unscheduled tumor assessment is carried out and the 
disease has not progressed, subsequent tumor assessments should also be performed as scheduled. The confirmatory assessment must be completed 4 weeks after 
the efficacy is assessed as complete response (CR) or partial response (PR). If the investigator suspects that the progression of disease is pseudoprogression, then 
progression of disease must be confirmed in the imaging examination four weeks later or at the next scheduled imaging assessment time point (note: the  time 
point of the next imaging examination may not be later than 9 weeks after the initial confirmation of progression of disease). For a subject whose treatment is 
stopped before any clearly- disease progression, imaging examination results should be obtained as far as possible to conduct tumor efficacy assessment. In case 
a subject discontinues study treatment due to disease progression (excluding pseudoprogression), it will be unnecessary to repeat the step of imaging assessment 
in the last visit. If the subject has completed the imaging assessment of the tumor within 28 days prior to the EOT visit or safety visit, it is not required to repeat 
such examinations at the two visits. 
l. 
If the Screening visit tests are performed within 7 days of C1D1, clinical laboratory tests do not need to be repeated on C1D1 (i.e. there is a -7-day window for 
C1D1 labs). When laboratory tests (including blood test, blood biochemistry, myocardial enzyme, coagulation function, urinalysis, and thyroid function, if 
applicable) and study drug administration are scheduled to be conducted on the same day (e.g., Day 1 [D1] of each treatment cycle), the test results should be 
available before the administration can be scheduled. Except for the first dose, laboratory tests at each dosing visit should be completed within 3 days prior to 
dosing. If the subject has received relevant laboratory tests within the first 7 days of the EOT visit or safety visit 1, there is no need to repeat such tests at these 
two visits. 
m. 
Screening visit will be performed at the local laboratory, which includes HCV antibody, HBsAg, HIV antibodies. Subjects with HBsAg positive will further 
assess HBV DNA test, subject with HCV antibody positive will further assess HCV RNA test. Subjects with HBsAg positive need to be retested for HBV DNA 
every 12 weeks until safety follow-up 1; subjects with HCV antibody positive need to be retested for HCV RNA every 12 weeks until safety follow-up 1; 
APF test will be done every 12 weeks until the EOT visit. 
n. 
Thyroid function examination covers free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) analysis, conducted respectively 
in the screening period, dosing in the first and second administration cycle, dosing every two subsequent administration cycles, EOT and in the safety follow-
up visit. If the thyroid function test at screening is performed within 7 days prior to the first dose (C1D1), it does not need to be repeated before the first dose 
(i.e., there is a -7-day window for the thyroid function test on C1D1). When thyroid function tests and study drug administration are scheduled to be conducted 
on the same day (eg, on Day 1 [D1] of the respective treatment cycle for thyroid function tests), the test results should be available before the administration 
can be scheduled. Except for the first dose, the specified thyroid function tests performed at each dosing visit should be completed within 3 days prior to 


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dosing. If subjects have completed the thyroid function examination within 7 days prior to the end of treatment visit or safety visit 1, there is no need to repeat 
such at these two visits. 
o. 
The tumor tissue used for FGF19 and PD-L1 IHC test will be sampled at screening and be analyzed at central laboratory. 
p. 
CS1001 will be given on D1 of each 21-day cycle. Each infusion should be completed over 60-120 minutes. The recommended infusion time for PK blood 
sample collection is 90 minutes, as shown in table 4 and table 5. 
q. 
BLU-554 will be administered qd in the morning with no food intake from 2 hours before until 1 hour after study drug administration. On study visit days when 
PK samples are collected, subjects will take their BLU-554 dose at the site. When the 2 study drugs are administered on the same day, BLU-554 should be 
administered before CS1001 infusion completion. After BLU-554 is administered, the subject should be given with CS1001 through intravenous infusion as 
soon as possible. 
r. 
Blood samples for PK and immunogenicity assessment refer to Table 4 and Table 5. 
s. 
Subsequent anti-tumor treatment: Information on subsequent (after the end of study treatment) anti-tumor therapies will be collected, including the name of all 
components of the treatment and the start and end dates of administration. 
t. 
If the investigator learns of any SAE (including death) in a subject after the subject has completed safety follow-up or has withdrawn from the study, and there is a 
reasonable cause to believe that the event is possibly related to the study drug, the investigator should notify the sponsor's pharmacovigilance team or 
representative. 
u. 
Survival status: Subjects will be contacted by telephone or in person every 12 weeks from the last dose of study drug to collect survival status, subsequent anti-
tumor therapy, and study drug-related SAEs until death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs first. 


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Table 3:Study Assessments and Procedures Schedule in Expansion Part (Phase II) 
Phase I1a 
Screening 
Treatment (21d for each cycle) 
Follow-up 
Cycle 1 
Cycle 
2 
≥Cycle 
3 
EOT visit b 
Safety follow-up c 
Survival 
follow-up 
c 
1 
2 
3 
Days 
-28 to -1 
1 
2 
15 
1 
1 
0-7 days 
post EOT 
date 
30 days 
post last 
dose 
60 days 
post last 
dose 
90 days 
post last 
dose 
Every 12 
weeks 
post last 
dose 
Time Window 
±2  
±4  
±4  
±7  
±7  
±7  
±7  
±7  
Informed Consent d 
X 
Inclusion/exclusion Criteria 
X 
X 
Demographics 
X 
Medical History e 
X 
X 
Physical Examination f 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Test 
g 
X 
X h 
X 
X 
12-lead ECG i 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram j 
X 
As clinically indicated 
X 
Tumor Imaging k 
X 
Within 1 year: every 9 weeks ± 7 days (end of every 3 dose cycles), after 1 year: every 12 weeks ± 7 days; or based 
on the clinical needs. 
Blood testl 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry, CK-MB l 
X 
X 
X 
X 
X 
X 
X 
HIV, HBV, HCV m 
X 
X 
X 
X 
AFPm 
X 
X 
X 
Coagulation l 
X 
X 
X 
X 
X 
X 
Routine Urine Test 
X 
X 
X 
Thyroid Function n 
X 
X 
X 
X 
X 
X 
Tumor Sample 
X o 
CS1001 Administration p 
X 
X 
X 


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BLU-554 Administration q 
X 
PK Blood Sample r 
X 
Immunogenicity Blood Sample 
r 
X 
Subsequent anti-tumor therapy s 
 
X 
X 
X 
X 
AE Monitoring t 
X 
SAE Monitoring 
X 
Concomitant Medications 
X 
Survival Status u 
X 
Abbreviations: AFP, Alpha-Fetoprotein; CT, computed tomography; CK-MB, creatine kinase-MB; ECOG, Eastern Cooperative Oncology Group; HBV, Hepatitis B 
Virus; HCV, Hepatitis C Virus; HIV, Human Immunodeficiency Virus; PK, pharmacokinetics. 
a. 
All visits should be performed as noted in Table 3. Additional safety tests (e.g., blood test, ECG) may be performed whenever clinically indicated, at the 
Investigator’s discretion. Unless otherwise indicated, all tests and procedures must be performed predose at each visit. Whenever a test result is questionable, it 
should be repeated immediately. Re-screening is permitted for one time, but need to decide by medical monitor and sponsor assessment. Repeated screening 
is allowed for once and central laboratory-confirmed FGF19 IHC results obtained at screening # 1 may be used in the assessment of FGF19 IHC status at 
repeated screening without recollecting tumor samples for testing. It is recommended that the screening of FGF19 IHC status be performed first and then 
clinical screening continue when FGF19 IHC screening results are acceptable.  
b. 
The date of the End of Treatment (EOT) visit is defined as the date on which the investigator decided to stop dosing. The EOT visit should be performed 0-7 
days after the EOT date. If the EOT visit and a treatment visit occur within 7 days, no tests are required for repeated items. If the EOT visit occurs within the 
safety follow-up window, no tests are required for repeated items. If an alternate treatment is started within 7 days of the EOT date, the EOT visit should be 
conducted prior to the first dose of alternate therapy. The last administration date is defined as the later last administration date of the two study drugs. It 
should be noted that the date on which the investigator decided to stop dosing may not coincide with the date of last dose. 
c. 
Safety visits: For subjects who have completed treatment, a safety visit should be conducted on the 30th day (±7 days), 60 days (±7 days), and 90 days (± 7 days) 
post the last dose; the safety follow-up at 90 day post the last dose can be conducted at the same day as that for the first survival follow-up. Survival follow-up: 
Subjects will be contacted by telephone or in person every 12 weeks from the last dose of study drug to collect survival status, subsequent anti-tumor therapy, 
and study drug-related SAEs until death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs first. 
d. 
Consent may be obtained from the subjects by written. 
e. 
A complete medical history will be obtaining at the Screening visit. Only disease-related symptoms and changes from the previous visit need to be collected on 
C1D1. 
f. 
A complete physical examination will be performed at the Screening visit. Subsequent physical examinations will be disease- and AE-focused. 
g. 
To be performed for women of childbearing potential within 7 days of C1D1. A serum pregnancy test should be performed at Screening; thereafter, a serum or 
urine pregnancy test should be performed on every odd cycle (e.g., C3, C5). 
h. 
To be performed on D1 (±4 days) of every odd cycle starting with C3. 
i. 
ECGs (12-lead) exams will be performed after at least a 10 minutes rest in the supine position. ECGs will be performed at Screening and during treatment, at 
EOT, and at Safety Follow-Up. In case of PK sampling, ECG test should be perfomed for 3 consecutive times with an interval of 5 minutes each time in Cycle 1, 


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2 and 4. Refer to Table 4 and Table 5 for specific time.For other treatment cycles ECG should be performed at predose of any Cycle Day 1 dosing. For C1D2, 
ECG should be collected at predose. Frequency of ECGs may be increased if clinically indicated. 
j. 
To be performed as clinically indicated. 
k. 
Imaging assessment of tumors: Tumor assessment is conducted according to the standard RECIST v1.1. See the specific assessment standards in Appendix 2. The 
imaging assessment method of tumors may adopt CT or MRI as decided by the investigator, however, the assessment method, machine and technical parameters 
should remain consistent in the entire study period; if there is no contraindication, a contrast medium should be used. The imaging results will be interpreted by the 
investigator or radiologist of each site. In case a tumor assessment has been conducted within 28d before initial administration and by thesame method and machine 
in the same hospital, the result can be adopted as baseline tumor assessment. Baseline tumor assessment should cover head, chest, abdomen, pelvic cavity and any 
other site suspected of tumor lesion (such as brain, bone lesions). Subjects with bone metastases during screening should be followed up using CT/MRI/X- ray at 
subsequent visits. Subjects who have no brain metastases confirmed by imaging at screening will not be required to undergo regular brain imaging at subsequent 
visits, which may be scheduled by the investigator as clinically indicated. Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days 
prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter until (1) the disease progression, (2) 
initiation of a new anti-tumor therapy, (3) withdrawal of informed consent, (4) loss of follow-up, (5) death, and (6) the termination of the study, whichever occurs 
first. In case medication is discontinued permanently for a subject due to the reasons other than those above said (such as AEs), the tumor assessment will still be 
conducted as scheduled. The investigator can schedule additional imaging examination based on the subject's clinical condition. If an unscheduled tumor 
assessment is carried out and the subject has not progressed, subsequent tumor assessments should also be performed as scheduled. The confirmatory assessment 
must be completed 4 weeks after the efficacy is assessed as complete response (CR) or partial response (PR). If the investigator suspects that the progression of 
disease is pseudoprogression, then progression of disease must be confirmed in the imaging examination four weeks later or at the next scheduled imaging 
assessment time point (note: the time point of the next imaging examination may not be later than 9 weeks after the initial confirmation of progression of disease). 
For a subject whose treatment is stopped before any clearly- disease progression, imaging examination results should be obtained as far as possible to conduct 
tumor efficacy assessment. In case a subject discontinues study treatment due to the progression of disease (excluding pseudoprogression), it will be unnecessary 
to repeat the step of imaging assessment in the last visit. If the subject has completed the imaging assessment of the tumor within 28 days prior to the EOT visit or 
safety visit, it is not required to repeat such examinations at the two visits. 
l. 
If the Screening visit tests are performed within 7 days of C1D1, clinical laboratory tests do not need to be repeated on C1D1 (i.e. there is a -7-day window for 
C1D1 labs). When laboratory tests (including blood test, blood biochemistry, myocardial enzyme, coagulation function, urinalysis, and thyroid function, if 
applicable) and study drug administration are scheduled to be conducted on the same day (e.g., Day 1 [D1] of each treatment cycle), the test results should be 
available before the administration can be scheduled. Except for the first dose, laboratory tests at each dosing visit should be completed within 3 days prior to 
dosing. If the subject has received relevant laboratory tests within the first seven days of the EOT visit or safety visit 1, there is no need to repeat such tests at 
these two visits. 
m. 
Screening visit will be performed at the local laboratory, which includes HCV antibody, HBsAg and HIV antibodies. Subjects with HBsAg positive will further 
assess HBV DNA test, subject with HCV antibody positive will further assess HCV RNA test. Subjects with HBsAg positive need to be retested for HBV DNA 
every 12 weeks until safety follow-up 1; subjects with HCV antibody positive need to be retested for HCV RNA every 12 weeks until safety follow-up 1; 
AFP test is required at baseline, and will be done every 12 weeks until the EOT visit.. 
n. 
Thyroid function examination covers free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) analysis, conducted respectively 
in the screening period, dosing in the first and second administration cycle, dosing every two subsequent administration cycles, EOT and in the safety follow-
up visit. If the thyroid function test at screening is performed within 7 days prior to the first dose (C1D1), it does not need to be repeated before the first dose 
(i.e., there is a -7-day window for the thyroid function test on C1D1). When thyroid function tests and study drug administration are scheduled to be conducted 
on the same day (eg, on Day 1 [D1] of the respective treatment cycle for thyroid function tests), the test results should be available before the administration 


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can be scheduled. Except for the first dose, the specified thyroid function tests performed at each dosing visit should be completed within 3 days prior to 
dosing. If subjects have completed the thyroid function examination within 7 days prior to the end of treatment visit or safety visit, there is no need to repeat 
such at these two visits. 
o. 
The tumor issue used for FGF19 and PD-L1 IHC test will be sampled at screening and be analyzed at central laboratory. 
p. 
CS1001 will be given on D1 of each 21-day cycle. Each infusion at Cycle 1 should be completed over 60-120 minutes. The recommended infusion time for PK 
blood sample collection is 90 minutes, as shown in table 4 and table 5. 
q. 
BLU-554 will be administered qd in the morning with no food intake from 2 hours before until 1 hour after study drug administration. On study visit days when 
PK samples are collected, subjects will take their BLU-554 dose at the site. When the 2 study drugs are administered on the same day, BLU-554 should be 
administered before CS1001 infusion completion. After BLU-554 is administered, the subject should be given with CS1001 through intravenous infusion as 
soon as possible. 
r. 
Blood samples for PK and immunogenicity assessment refer to Table 4 and Table 5. 
s. 
Subsequent anti-tumor treatment: Information on subsequent (after the end of study treatment) anti-tumor therapies will be collected, including the name of all 
components of the treatment and the start and end dates of administration. 
t. 
If the investigator learns of any SAE (including the death) in a subject after the subject has completed safety follow-up or has withdrawn from the study, and there 
is a reasonable cause to believe that the event is possibly related to the study drug, the investigator should notify the sponsor's pharmacovigilance team or 
representative. 
u. 
Survival status: Subjects will be contacted by telephone or in person every 12 weeks from the last dose of study drug to collect survival status, subsequent anti-
tumor therapy, and study drug-related SAEs until death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs first. 


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Table 4: Schedule for PK and Immunogenicity Blood Sampling by Study Drugs in Phase Ib 
BLU-554a 
CS1001a 
ECGa, e 
Day 
Time 
Time window 
PK 
Samplin 
g 
Time 
Time window 
PK 
Samplin 
g 
ADA 
Sampling of 
CS1001 
Cycle 1 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 dosing 
b 
  
CS1001 dosingb 
30 min 
± 5 min 
X 
1h 
± 5 min 
X 
2hc, e 
± 10 min 
X 
EOI+30 minc, e 
± 15 min 
X 
X 
4h 
± 15 min 
X 
6h 
± 15 min 
X 
7.5h 
  
EOI+6h 
± 30 min 
X 
8h 
± 30 min 
X 
D2 
24hd 
± 1h 
X 
EOI+22.5hd 
± 1h 
X 
X 
D8 
168h 
  
EOI+168 h 
± 1 day 
X 
D15 
336h 
  
EOI+336h 
± 1 day 
X 
Cycle 2 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
  
CS1001 dosingb 
30 min 
± 5 min 
X 
1h 
± 5 min 
X 
2h 
± 10 min 
X 
X 
4h 
± 15 min 
X 
6h 
± 15 min 
8h 
± 30 min 
X 
D2 
24hd 
± 1h 
X 


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BLU-554a 
CS1001a 
ECGa, e 
Day 
Time 
Time window 
PK 
Sampling 
Time 
Time 
window 
PK 
Sampling 
ADA 
Sampling of 
CS1001 
Cycle 4 
D1 
 
0 (Predose 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
CS1001 dosingb 
 
EOI+30 min 
± 15 min 
X 
X 
EOI+6h 
± 30 min 
X 
D2 
EOI+22.5hd 
± 1 h 
X 
D8 
EOI+168 h 
± 1 d 
X 
D15 
EOI+336h 
± 1 d 
X 
Cycle 5 
D1 
0 (Predose) 
30 min prior 
to 
dosing 
X 
X 
C7, C10、 
C13 and 
C16, and 
every 8 
cycles 
afterwards 
D1 
0 (Predose) 
 
 
30 min prior 
to 
dosing 
X 
X 
Abbreviations: EOI, end of infusion; ADA, anti-drug antibody; PK, pharmacokinetics 
a. It is important that PK sampling occurs as close as possible to the scheduled time. PK and immunogenicity sampling and ECG collection should be performed 
on the same day. Detailed sequential procedures are: 1) Scheduled triplicate ECG with an interval of at least 5 mins; 2) Vital sign measurements; 3) PK blood 
sampling; and 4) Any other tests and assessment required by the study. 
b. After BLU-554 is administered, the subject should be intravenously infused with CS1001 as soon as possible. For PK blood sampling, the recommended 
infusion time of CS1001 is 90 minutes. 
c. Collect two samples at one time point with BLU-554 blood sample be collected firstly and then CS1001 blood sample. 
d. The 24h PK sample of BLU-554 and the EOI+22.5h PK sample of CS1001 must be collected prior to dosing on the same day. 
e. Cycle 1 Day 1: "2 hours post BLU-554 dosing" ECG collection is allowed at 1 - 4 h post BLU-554 dosing; "end of CS1001 infusion + 30 min" ECG collection is 
allowed from the time after the completion of CS1001 infusion to 2.5 h post the completion of CS1001 infusion. If the ECG collection windows for these two time 
points on C1D1 do not overlap, i.e. two sets of ECG data will be collected. 


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Table 5:Schedule for PK and Immunogenicity Blood Sampling by Study Drugs in Phase II 
BLU-554a 
CS1001a 
ECGa, e 
Day 
Time 
Time 
window 
PK sampling 
Time 
Time window 
PK 
sampling 
ADA sampling 
of CS1001 
Cycle 1 
D1 
0 (Predose) 
30 min 
prior to 
dosing 
X 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
CS1001 dosingb 
2hc, e 
±10 min 
X 
EOI+30 minc, e 
± 15 min 
X 
X 
D2 
24hd 
± 1h 
X 
EOI+22.5hd 
± 1h 
X 
X 
Cycle 2 
D1 
0 (Predose) 
30 min 
prior to 
dosing 
X 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
CS1001 dosingb 
30 min 
± 5 min 
X 
1h 
± 5 min 
X 
2h 
± 10 min 
X 
X 
4h 
± 15 min 
X 
6h 
± 15 min 
X 
8h 
± 30 min 
X 
D2 
24hd 
± 1h 
X 
Cycle 4 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
CS1001 dosingb 
EOI+30 min 
± 15 min 
X 
X 
EOI+6h 
± 30 min 
X 
D2 
EOI+22.5hd 
± 1 h 
X 
D8 
EOI+168 h 
± 1 d 
X 
D15 
EOI+336h 
± 1 d 
X 


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BLU-554a 
CS1001a 
ECGa, e 
Day 
Time 
Time 
window 
PK sampling 
Time 
Time window 
PK 
sampling 
ADA sampling 
of CS1001 
Cycle 5 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
C7, C10、 
C13 and 
C16, and 
every 8 
cycles 
afterwards 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
Abbreviations: EOI, end of infusion; ADA, anti-drug antibody; PK, pharmacokinetics 
a. It is important that PK sampling occurs as close as possible to the scheduled time. PK and immunogenicity sampling and ECG collection should be performed 
on the same day. Detailed sequential procedures are: 1) Scheduled triplicate ECG with an interval of at least 5 mins; 2) Vital sign measurements; 3) PK blood 
sampling; and 4) Any other tests and assessment required by the study. 
b. After BLU-554 is administered, the subject should be intravenously infused with CS1001 as soon as possible. For PK blood sampling, the recommended 
infusion time of CS1001 is 90 minutes. 
c. Collect two samples at one time point with BLU-554 blood sample be collected firstly and then CS1001 blood sample. 
d. The 24h PK sample of BLU-554 and the EOI+22.5h PK sample of CS1001 must be collected prior to dosing on the same day. 
e. Cycle 1 Day 1: "2 hours post BLU-554 dosing" ECG collection is allowed at 1 - 4 h post BLU-554 dosing; "end of CS1001 infusion + 30 min" ECG collection is 
allowed from the time after the completion of CS1001 infusion to 2.5 h after the completion of CS1001 infusion. If the ECG collection windows for these two time 
points on C1D1 do not overlap, i.e. two sets of ECG data will be collected. 


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2. 
INTRODUCTION 
2.1. INTRODUCTION OF THE INVESTIGATIONAL DRUG 
BLU-554 capsules, also known as BLU111362 or X439161, are a highly potent selective small 
molecule inhibitor of FGFR4, which are developed by Blueprints for the treatment against HCC 
and other solid tumors with positive FGF19 expression. 
CS1001 injection is a completely humanized IgG4-type recombinant anti-Programmed death 
ligand 1 (PD-L1) monoclonal antibody developed by CStone Pharmaceutical, which exerts an anti-
tumor effect by recovering T-cell immune killer function after blocking the PD-L1 signaling 
pathway. It is currently developed for indications of advanced solid tumors such as HCC, lung 
cancer, gastric cancer, esophageal cancer etc. 
2.2. MECHANISM OF ACTION AND BACKGROUND 
 
Background 
Hepatocellular Carcinoma 
Primary liver cancer mainly includes three different pathological types, which include 
Hepatocellular Carcinoma (HCC), Intrahepatic Cholangiocarcinoma (ICC) and HCC-ICC, with 
great differences in the terms of pathogenesis, biological behavior, histologicalmorphology, 
treatment method and prognosis, with hepatocellular carcinoma accounting for > 85-90%[2] 
HCC is the sixth most common cancer and the second leading cause of death in subjects with cancer, 
which accounts for 7% of all cancers worldwide. Each year, 750,000 subjects could be present with 
HCC, among which almost 700,000 cases of subjects die [1] HCC is the fourth most common 
malignant tumor in China and the third leading cause of death in subjects with tumor [2]. Each 
year, 466 thousand cases of subjects could be present with newly diagnosed HCC in China, among 
which, about 422 thousands cases of subjects could die[3], which significantly threats to the lives 
and well-beings of the people in China. 
Treatment of HCC 
Treatment of HCC is based on the staging of the disease. The Barcelona Clinic Liver Cancer 
(BCLC) staging criteria [4], having been validated in a large series of subjects[5], have become 
the standard by which treatment decisions are made. At this time, only tumor resection and liver 
transplantation are curative for HCC. It has been estimated that, in the US, 20–30% of subjects 
who present with HCC may fall into the very early, or early stages of the 
BCLC criteria[1], and so would be candidates for surgical treatment. However, only about 5% of 
subjects present with very early HCC, where resection and transplant have had the best results, 
and in many others presenting with early stage disease, chronic liver disease and cirrhosis preclude 
the use of surgery as a treatment modality. Even in subjects who are thought to be good candidates 
and successfully undergo resection, recurrence rates can be 55% at 2 years, and may reach 60-
100% by 5 years[6]. Localized therapies such as trans-arterial chemo-embolization have had some 
long-term success, but only in very select groups of subjects. 
The majority of subjects with HCC ultimately require systemic therapy, but development of 
systemic treatment for HCC has been severely limited. The current standard of care is sorafenib, 
a multikinase inhibitor, which received marketing approval in 2007. Sorafenib was evaluated in 
two Phase 3 trials against a control of best supportive care (BSC), with one trial conducted in 


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Western subjects with HCC, and the other in subjects from the Asia-Pacific region. In the 
Western trial, median overall survival (OS) improved from 7.9 months in the BSC arm to 10.7 
months in the sorafenib arm (hazard ratio 0.69, p <0.001) reflecting an improvement of 30% [7]. 
In the Asia-pacific trial, a similar degree of improvement was seen, although with a subject 
population with more advanced disease, the actual survival times were different (4.2 months in 
the BSC arm vs. 6.5 months in the sorafenib arm) [8]. 
Although other multi-kinase inhibitors including linifanib, sunitinib and brivanib have been 
tested as first-line treatment for HCC, none has shown a statistically significant improvement 
in OS compared to sorafenib in Phase 3 studies [9][10][11]. Lenvatinib was approved by the 
FDA as first-line treatment for HCC in August 2018. In a non-inferiority Phase III study of 
lenvatinib versus sorafenib, the results showed that the median survival was 13.6 months in the 
lenvatinib arm and 12 months in the sorafenib arm (HR, 0.92; 95% CI, 0.79-1.06), indicating 
that the lenvatinib was not inferior to sorafenib [12]. However, this was accompanied by 
significant toxicity and frequent dose interruptions and reductions [13]. 
In the second-line treatment for HCC in subjects who have received prior sorafenib, the multi-
kinase inhibitor, regorafenib, and the PD-1 inhibitor, nivolumab have shown clear clinical 
activity and gained approval in the second line setting [14][15]. However, ORR and 
OS remain low with these agents and there are no diagnostics to select subjects more likely to 
benefit. Thus, there remains a substantial medical need for novel agents for the systemic 
treatment for HCC in both the first and second line settings. 
Immune checkpoint is a class of molecules that are immunosuppressed. Their physiological 
function is to regulate the intensity and breadth of immune response, thereby avoiding damage 
of normal tissue. While tumor cells tend to utilize such profile of the immune checkpoints to 
evade attacks of the immune cells. Currently, the immune checkpoints that have been clinically 
validated include CTLA-4 and PD1/PD-L1, and the immune checkpoint inhibitors targeting the 
PD1/PD-L1 have better clinical application prospect due to their better safety and broader 
indications. The combination with many types of drugs is possible due to the good safety and 
potential improvement of immune micro-environment properties of PD1/PD-L1 inhibitors. 
PD1/PD-L1 inhibitors in combination with many types of drugs has also been explored in 
multiple clinical studies, including anti-PD1/PD-L1 inhibitors in combination with CTLA-4 
inhibitors such as nivolumab in combination with ipilimumab, durvalumab in combination with 
tremepilimumab; PD1/PD-L1 inhibitors in combination with molecular targeted agents such as 
lenvatinib in combination with pembrolizumab, PDR- 001 in combination with sorafenib. It was 
reported that lenvatinib in combination with pembrolizumab had a response rate of 52. 2% in 
subjects with advanced endometrial cancer and 63% in subjects with renal cell carcinoma, 
indicating that the combination regimen has the more prospective clinical treatment prospects 
[16] 
 
BLU-554 
BLU-554 was designed as a highly potent, selective small molecule inhibitor of FGFR4 and has 
a unique selectivity profile for the FGFR family. 
In normal physiology, FGF19 controls bile acid homeostasis and promotes hepatocyte 
survival and proliferation via binding to FGFR4 and co-receptor, Klotho-beta (KB), which 
initiates activation of the extracellular signal-regulated kinase (ERK) signaling pathway 
(Figure 1) [17]. Extracellular signal-regulated kinase activation attenuates bile acid 


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production by repressing expression of cholesterol-7α-hydroxylase (CYP7A1), an enzyme 
which catalyzes the first and rate-limiting step of bile acid production from cholesterol. 
Extracellular signal-regulated kinase additionally promotes hepatocyte proliferation via 
EGR1 and hepatocyte survival via anti-apoptotic mechanisms. 


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Figure 1:FGF19-FGFR4 Pathway in Normal Physiology and HCC 
 
The FGF19 pathway normally functions as an endocrine system in which post-prandial bile acids 
trigger FGF19 production in the ileum for delivery to the liver via the portal circulation. Liver 
expresses high levels of FGFR4 and KLB, which bind the released FGF19 and initiate signaling. 
Hepatocellular carcinomas likely to remain FGF19 responsive, suggesting that targeting the 
FGF19 pathway may have therapeutic benefit in HCC. 
 
CS1001 
PD-L1, primarily expressed on the surface of tumor cells and antigen presenting cells, is the 
main ligand of T-cell inhibitory receptor PD-1 [18]. Binding of PD-L1 on tumor cells to PD-1 
on the surface of T cell may cause signaling cascade reaction, inhibiting the proliferation of T 
cells and secretion of activated cytokines, reducing the activity of T cells, and reducing the 
tumor-cell killing ability of T cells; PD-L1 inhibitors impair the activity of T cells and tumor- 
cell killing ability by blocking the interaction between PD-1 and PD-L1 [19]. 
CS1001 is a completely humanized IgG4-type recombinant anti-Programmed death ligand 1 
(PD-L1) monoclonal antibody, which exerts an anti-tumor effect by recovering T-cell immune 
killer function after blocking the PD-L1 signaling pathway. 
2.3.   PRECLINICAL STUDY 
 
2.3.1. 
PHARMACOLOGY 
2.3.1.1. BLU-554 
Inhibition of FGFR4 In Vitro 
BLU-554 was designed as a highly potent, selective small molecule inhibitor of FGFR4 and 
has a unique selectivity profile for the FGFR family. BLU-554 forms a covalent interaction 
with cysteine 552 of FGFR4. This cysteine is located near the adenosine triphosphate (ATP) 


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binding site in FGFR4 and is unique among FGFR family members as well as rare among other 
kinases. It demonstrated biochemical in vitro activity on the FGFR4 kinase domain at a half-
maximal inhibitory concentration (IC50) of 5 nM and is at least 100-fold less active against the 
other FGFR paralogs. No kinases outside of the FGFR family are significantly bound by BLU-
554.Figure 2 below shows the high selectivity of BLU-554 across the human kinome. 
Figure 2:The Activity of BLU-554 against the Human Kinome 
 
 
 
 
 
Each branch of the dendrogram above represents an individual human kinase. BLU-554 was screened at 3 μM 
against each kinase. Kinases inhibited at 3 μM are indicated by red circles on the kinome tree. The degree of 
inhibition corresponds to the size of the circle. No kinases outside of the FGFR family are significantly bound 
by BLU-554. Kinome illustration reproduced courtesy of Cell Signaling Technology, Inc 
(www.cellsignal.com). 
In vitro, in human breast cancer cell line MDA-MB-453, BLU-554 exhibited dose-dependent 
inhibition of FGFR4 activity as well as modulation of key effector pathways known to be 
involved in tumorigenesis. 
Inhibition of FGFR4 In Vivo 
In vivo, anti-tumor efficacy with BLU-554 was demonstrated in a Hep3B human HCC 
xenograft model (genomic amplification and overexpression of FGF19) and in a LIX-066 
subject-derived tumor xenograft model (overexpression of FGF19 without amplification). In 
the Hep3B model Figure 3), tumor regression was observed following administration of BLU-
554 on both once daily (qd) and twice daily (bid) dosing schedules with no corresponding 
weight loss. In the LIX-066 primary human tumor model (Figure 4), tumor stasis was observed 
with a significant reduction in tumor growth upon administration of BLU-554; efficacy and 
tolerability were improved compared to sorafenib. Together, these data provide a rationale for 
selecting subjects with FGF19 overexpression and/or gene amplification for treatment with 
BLU-554. 


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Figure 3:BLU-554 Efficacy in a Xenograft Tumor Model with Amplified FGF19 
 
Mice bearing Hep3B xenograft tumors were dosed orally on a once daily (qd) or twice daily (bid) schedule 
with 30, 100, or 200 mg/kg BLU-554. The Hep3B xenograft models HCC tumors that are IHC+, FISH+. 
BLU-554 100 mg/kg bid and 200 mg/kg qd resulted in equivalent tumor growth inhibition. Data points 
represent group mean and error bars represent standard error of the mean (SEM). 
Figure 4:Efficacy Measurements for BLU-554 in a Subject-derived Xenograft Tumor Model 
with FGF19 Up-regulation in the Absence of Genomic Amplification 
Mice bearing LIX-066 xenograft tumors were dosed orally with 30, 100, or 200 mg/kg BLU- 554 bid. The 
LIX-066 xenograft models HCC tumors that are IHC+, FISH-. A significant decrease in tumor growth was 
observed. Data points represent group mean, and error bars represent standard error of the mean (SEM). 
Safety pharmacology studies revealed that BLU-554 inhibits human ether-a-go-go-related gene 
(hERG) channel activity in vitro with an average IC50 of 6.26 μM by single cellular 
electrophysiological recordings. The pharmacologic specificity of BLU-554 was assessed 
against a panel of 55 pharmacological targets including receptors, transporters, and enzymes. 
Compound binding was calculated as percentage inhibition of the binding of a radioactively 
labeled ligand specific for each target. Assays for the following targets showed >50% inhibition 
by BLU-554 at 10 µM screening concentration: A3 adenosine receptor, α2 adrenergic receptor, 
cholecystokinin A receptor, chloride ion channel, κ-opioid receptor, 
1000 


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melatonin receptor MT1, sodium ion channel site 2, and the nociceptin receptor. The 
relevance of this binding was not apparent in the dog and mouse 28-day Good Laboratory 
Practice (GLP) toxicology studies and so the clinical significance of these interactions is 
unknown. 
2.3.1.2. CS1001 
In Vitro Pharmacology 
In vitro pharmacology studies were conducted, including: the binding capacity with cell surface 
human PD-L1, the binding capacity with recombinant PD-L1 protein in human, cynomolgus 
monkey or mouse, the binding kinetics to recombinant PD-L1 protein, the binding capacity with 
human PD-L2 protein, the member of PD-L1 family, competitive blocking of ligation of PD-L1 
with PD-1/CD80, activation on human CD4+ T cells, ADCC and CDC. 
In the binding assay of PD-L1 on the cell surface, CS1001 antibody effectively bound to PD- 
L1-transfected CHO cells with an EC50 value being 1.10 nM. 
Cross-species reactivity test showed that CS1001 specifically binds to human and cynomolgus 
monkey PD-L1 protein with the comparable binding capacity, but cannot bind to mouse PD-L1 
protein. 
The calculated result of affinity with WBP315.hPro1.ECD.mFc showed that CS1001 has 
strong affinity with PD-L1 protein and its affinity constant is 1.38 nM. 
Cross-reactivity assay with proteins of PD-L1 family showed that CS1001 specifically binds to 
human PD-L1 protein but not to human PD-L2, indicating that this PD-L1 antibody would not 
potentially cause side effects due to non-specific binding. 
From the results of competitive inhibition of PD-L1/PD-1 ligation, it is clear that CS1001 can 
effectively block the ligation of PD-L1 with PD-1 protein with IC50 value being 1.93 nM. It is 
also showed that CS1001 can effectively block the ligation of PD-L1 with CD80 similarly as 
the reference antibody WBP315BMK1 (BMS). 
Together, above results showed that CS1001 can inhibit the PD-1/PD-L1 interaction via specific 
binding to PD-L1. Its effect on T cell immune function was further studied in in vitro functional 
experiments. 
The effect of CS1001 on T lymphocyte activation was tested using mixed lymphocyte reaction 
(MLR). The results showed that CS1001 can significantly enhance the secretion of IL-2 and 
IFN-γ by CD4+ T lymphocytes, and promote the proliferation of CD4+ T lymphocytes. 
On the other hand, the ADCC and CDC effect of CS1001 were tested. The results indicated 
that CS1001 had no ADCC and CDC on PD-L1-positive lymphocytes, thereby without 
potential damage to surrounding immune cells in vivo. 
In Vivo Pharmacology 
Because CS1001 does not recognize mouse PD-L1, the activity of CS1001 was evaluated in a 
syngeneic mouse tumor model humanized with human PD-L1 in the tumor graft (MC38- B7H1) 
and human PD-1 in animal host (i.e. B-hPD-1 C57BL/6 humanized mouse). The drug was 


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administered through intraperitoneal injection, once every 2 days for 6 consecutive doses. The 
results (Figure 5) showed that the tumor volume in the solvent control group increased rapidly 
during the test period (the mean tumor volume was 2359 mm3 at the end of the study), while the 
tumor volumes were substantially lower in the CS1001 low (3mg/kg), medium (10 mg/kg), and 
high (30 mg/kg) dose groups than the control group (the mean tumor volumes were 949 mm3, 
1416 mm3, and 1115 mm3, respectively), and all 3 doses showed effective anti-tumor activity 
(Tumor Growth Inhibition [TGIs] were 62.8%, 42.0%, and 55.4%, respectively; p=0.019, 0.149, 
and 0.039, respectively). On the other hand, mice in different groups showed no significant 
difference in body weight changes during administration (Figure 6), and were in good state of 
activity and food consumption, indicating that the mice were well tolerated with CS1001. The 
consistent results were achieved in a repeated study using the same animal model. 
Figure 5:Tumor Growth in Each Group during the Test 


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Figure 6: Body Weight Changes of Mice in Each Group during the Administration 
 
2.3.2. PHARMACOKINETICS 
2.3.2.1. BLU-554 
Single-Dose Pharmacokinetics 
Upon single dose administration in nonclinical species, plasma clearance upon IV 
administration was moderate in mouse and rat, at ~ 20% liver blood flow. Plasma clearance in 
nonrodent species, dog, and monkey, was low at ≤20% liver blood flow. The volume of 
distribution at steady state was low-to-moderate in all species, either approximating or slightly 
higher than published values for the volume of total body water. The oral bioavailability of 
BLU-554 dosed as a solution was moderate in mouse, rat, and dog, ranging from 62% to 82%, 
and was low in monkey (29%). 
Repeat-dose Pharmacokinetics 
In repeat-dose toxicology studies in mice, plasma exposure to BLU-554 increased less than 
proportionally to dose upon repeat-dosing for 7 or 28 days. Systemic exposure to BLU-554 
was similar in both sexes of mice (Report WIL-124511). 
In repeat-dose toxicology studies in dogs, BLU-554 exposure in terms of Cmax increased in a 
dose proportional manner, but AUC0-24 increased greater than proportionally to dose upon 
repeat-dosing for 28 days. Exposure was similar in both sexes of dogs (Report WIL-124512). 
2.3.2.2. CS1001 
Single-Dose Pharmacokinetic Study 


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Serum PK characteristics and ADA on CS1001 were assessed when 18 male and 18 female 
navïe cynomolgus monkeys were administered intravenously once at 10, 30 and 90 mg/kg. 
The results showed that in the dose range of 10 mg/kg to 90 mg/kg, the C0 of CS1001 increased 
in a dose-dependent manner, and the rate of AUC0-last increased greater than proportional over 
the above-mentioned dose range. 
The female: male ratio of CS1001 systemic exposure (AUC0-last) (Table 2) was 0.58, 0.94 and 
0.85 in the low, medium and high dose groups respectively, all of which were within 2 folds, 
suggesting that no significant gender difference on CS1001 systemic exposure in cynomolgus 
monkeys. 
ADA was mainly occurred at 648, 984 and 1320 hours after administration; in the 10 mg/kg 
treatment group, the number (%) of monkeys with a positive ADA sample was 22.2% for both 
male and female, and in the 30 mg/kg treatment group, the number (%) of monkeys with a 
positive ADA sample was 22.2% for the male and 11.1% for the female. No monkeys had 
positive ADA sample in the 90 mg/kg treatment group. The data showed that compared with the 
low-dose group, the positive rate of ADA in the high-dose group showed a decreasing trend. No 
abnormalities were observed in all the experimental animals during the whole experiment. 
Please refer to Investigator’s brochure (IB) of CS1001. 
2.3.3. TOXICOLOGY 
2.3.3.1. BLU-554 
The toxicity profile of BLU-554 was evaluated in vitro in a bacterial reverse mutation assay and 
in vivo in CD-1 mice, Sprague-Dawley rats, and Beagle dogs. CD-1 mice and Beagle dogs were 
chosen as the nonclinical test species for assessing chemical structure- and pharmacology-
mediated toxicity of BLU-554 on the basis of the following criteria: a) these species are 
pharmacologically responsive to the effects of BLU-554; b) these species have historically been 
utilized to assess potential human adverse effects, and; c) these species are qualitatively similar 
in hepatocyte metabolism profiles to humans. 
Repeat-Dose Toxicity 
In the 28-day GLP-compliant repeat-dose toxicology study in CD-1 mice, only minimal effects 
were noted at a limit dose of 2,000 mg/kg/day. Resultant end-of-study sex-averaged maximum 
plasma concentration (Cmax) and area under the plasma concentration versus time curve from 0 
to 24 hours (AUC0-24) in the mouse were higher than the predicted Cmax and AUC0-24 at the 
projected human efficacious dose of 1,000 mg/day; (581 mg/m2/day). 
In the 28-day GLP-compliant repeat-dose toxicology study in Beagle dogs, the lethal dose 
effects, the highest non-severely toxic dose (HNSTD) effects, and the dose-limiting toxicities 
(DLT) have been carefully characterized. In the dog, the DLT is attributed to inanition, 
gastrointestinal malfunction, and metabolic perturbations evidenced by changes in body weights, 
food consumption, serum, and urine chemistry values, and contributed to by hematologic and 
tissue effects. The severely toxic dose (STD) in the dog is 50 mg/kg/day (1,000 mg/m2/day) and 
the HNSTD is 25 mg/kg/day (500 mg/m2/day). At the HNSTD, the predominant change in serum 
biochemistry was hyperphosphatemia. However, this was modest (maximum increase of 30% 
on Day 15) and readily reversible, with complete recovery by Day 42. Hyperphosphatemia was 


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associated with minimal to mild tissue mineralization as detailed in the Investigator’s Brochure. 
Effects noted in dogs are considered to be related to the pharmacologic activity of FGFR4 
signaling by BLU-554 or the sequelae of these effects, except for the myxomatous change noted 
in the heart. All adverse effects are monitorable. All adverse effects were resolving or resolved 
after the 14-day recovery period,except effects in the stomach, heart, and aorta. No functional 
effects on the cardiovascular system were noted based on electrocardiogram (ECG) analyses 
and in-life examinations. 
Genotoxicity 
BLU-554 was negative in the bacterial reverse mutation and micronucleus in vitro assays with 
and without metabolic activation (rat liver S9). 
Developmental and Reproductive Toxicity 
Reproductive toxicology studies have not been initiated. Studies on the potential toxicity of 
BLU-554 on reproductive function and fetal development are not available. No information is 
available on the safety or efficacy of BLU-554 in pregnant or lactating females. In the GLP- 
compliant 28-day repeat-dose toxicity studies in CD-1 mice (Study WIL-124511) and Beagle 
dogs (Study WIL-124512), adverse effects in reproductive tissues were noted only in male dogs 
(effects in the testes and epididymis). Pregnant women will not be enrolled in the Phase 1 clinical 
trial and lactating women will be instructed not to nurse while receiving BLU-554. 
Local Tolerance 
Local tolerance was assessed by reviewing the digestive tract changes in the GLP-compliant 
28-day toxicology studies in mouse (Study WIL-124511) and dog (Study WIL-124512). No 
evidence of local gastrointestinal effects occurred in the CD-1 mouse even at the highest tested 
dose of 2,000 mg/kg/day at which local mucosal surface concentrations would be anticipated 
to be high relative to human exposure. In the Beagle dog at lethal doses, esophageal effects 
were attributed to gavage trauma and gastric mucosal effects to stress. 
BLU-554 did induce emesis and diarrhea in the dog at the HNSTD, without any 
gastrointestinal tissue histologic correlate. 
Other Toxicity Studies 
Phototoxicity Studies: Definitive tissue distribution studies have yet to be performed. In GLP- 
and non-GLP-compliant toxicology studies in CD-1 mice and Beagle dogs, there were no 
lesions in the epidermis of the skin or in the eye. In a non-GLP in vitro neutral red uptake 
photoxicity assay in 3T3 fibroblasts, BLU-554 was classified as a compound with 
phototoxicity potential. On the basis of the molar extinction coefficient of BLU-554, the in 
vitro neutral read uptake photoxicity assay in 3T3 fibroblasts, and the lack of definitive tissue 
distribution data, a risk of phototoxicity cannot be ruled out. Subjects should therefore use 
clothing and sunscreen to avoid direct sun exposure. 
Toxicokinetics 
The allometrically scaled HNSTD in the dog is 500 mg/m2 (25 mg/kg/day). The highest 
nontoxic dose in the mouse is 2,000 mg/kg/day or 6,000 mg/m2. Based on allometrically scaled 
dosages as well as on systemic exposures (AUC0-24), the dog is the most sensitive species. The 


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mouse tolerates these exposures without toxic consequences. The mean exposure in the dog at 
the HNSTD approximates the steady state AUC0-24 and Cmax values at the human MTD/RP2D 
of 600 mg/day (370 mg/m2/day), while the STD exposure AUC0-24 and Cmax values exceed the 
maximum tolerated human exposure. 
See Investigator’s brochure (IB) of BLU-554 for more details. 
2.3.3.2. CS1001 
Single-Dose Toxicity Test 
To evaluate the potential toxicity and the MTD of CS1001, following single intravenous infusion 
to cynomolgus monkeys, and to assess the reversibility, persistence, or delayed occurrence of 
toxic effects following a 14-day observation period. In conclusion, administration of CS1001 to 
cynomolgus monkeys by a single intravenous infusion at dose levels of 100, 300, and 1,000 
mg/kg followed by a 14-day observation period was well tolerated and did not result in any 
treatment-related mortality, and any effects in clinical signs, changes in body weight, food intake, 
or gross pathology. Under the conditions of the study, the MTD was considered to be no less 
than 1,000 mg/kg. 
Repeat-Dose Toxicity Test 
To determine the potential toxicity to cynomolgus monkey of CS1001, by intravenous infusion 
once weekly for a total of 5 doses and to assess the reversibility, persistence, or delayed 
occurrence of toxic effects following a 4-week recovery period. 
CS1001 was given via intravenous infusion by the doses of 30, 75 and 200 mg/kg, and, at the 
end of the trial, no CS1001-related significant change was observed in survival rate, clinical 
symptoms, weight, food intake, temperature or clinical pathology (blood test, coagulation 
parameters, biochemistry and urine analysis). One case of retinal depigmentation was observed 
in the 200 mg/kg dose group, and the possibility of drug-related pigmentary degeneration of the 
retina could not be excluded; no other CS1001-related ophthalmological change was seen. 
The results of pathological test showed that, in the late administration period and late recovery 
period, no CS1001-related obvious lesion visible to naked eyes was observed; there was no 
significant change in the weight of any organ; the microscopic examination of various organs 
also showed no CS1001-related histopathological change. 
Consequently, under the conditions of the study, the NOAEL was considered to be 200 mg/kg. 
Safety Pharmacology Evaluation 
The safety pharmacological parameters (cardiovascular and respiratory systems) were evaluated 
in the repeated dose toxicity test. 
According to the results, in the repeated dose toxicity test, the changes in the blood pressure, 
heart rate, ECG and respiratory system parameters of cynomolgus monkeys in various 
administration groups all fell within the ranges of normal physiological fluctuations, and no 
CS1001-related significant change was observed. 
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Local irritation was evaluated in repeated dose toxicity study. The results showed that during the 
administration period, very slight to obvious erythema could be observed at the injection site of 
animals in all groups (including the control group). The histopathological examination showed 
hemorrhage and/or neutrophil-dominated inflammatory infiltration in blood vessels/peripheral 
tissues. No obvious dose dependence was observed regarding the severity, duration or incidence. 
Local reactions at injection sites lasted for different durations in various administrations, but all 
of them disappeared within 7d after administration. Therefore, these findings were considered 
related to the dose administration procedure and not related to CS1001. 
In Vitro Hemolysis Studies 
The in vitro hemolysis test was conducted to detect whether two concentrations of CS1001 
injection could incur hemolysis and/or RBC coagulation. There was no hemolysis or coagulation 
of red blood cell in negative control group (sodium chloride), and obvious hemolysis in positive 
control group (purified water), which indicated the study system was valid. No hemolysis or red 
blood cell coagulation was noted in CS1001 (6 and 30.3 mg/mL) or CS1001 placebo. 
Anaphylaxis Study 
An active systemic anaphylaxis study was performed in guinea pigs to determine the potential 
anaphylaxis of CS1001. According to the results, the animals in the positive control group 
showed the allergic reactions of piloerection, nose scratching, dyspnea and gait instability 5 min 
after challenge dosing; however, no allergic reaction was observed after provocation and 
administration on any animal in the negative control group or the administration groups. No 
animal showed any CS1001-related change in clinical symptoms or weight in either the 
induction phase or the challenge phase, and there was no unexpected death during the trial. 
Immunotoxicity/Immunogenicity Test 
The immunological characteristic assessment was also carried out during the repeated dose 
toxicity test, and mainly consisted of four aspects, i.e., ADA analysis, B, T lymphocyte 
phenotype analysis, cytokine analysis, and immune globulin & complement. 
As shown by the ELISA method-based detection in this study, no positive anti-CS1001 antibody 
result was detected on any animal, suggesting that CS1001 had no immunogenicity for 
cynomolgus monkeys under these doses. Flow cytometry was employed for B, T lymphocyte 
phenotype detection, and the results showed that, no statistical difference or dose-related change 
was observed in the peripheral blood and immune organ lymphocyte subset percentage before 
and after administration or among various dose groups. Trace- sample multi-index flow 
cytometry-based protein quantitative counting (Becton-Dickinson FACSCanto II flow 
cytometry) was used to analyze the TNF-α, IL-2, IL-4, IFN-γ, IL-5 and IL-6 in the peripheral 
blood, and the results showed that no CS1001-related change was observed in cytokines and 
that all cytokine changes fell within the ranges of normal physiological fluctuations. 
Immunoturbidimetry was adopted to analyze the immune globulin & complement in serum via 
the detection indexes of C3c, C4, IgG, IgA and IgM, and the results showed that no CS1001-
related change was observed in immune globulin & complement and that all the changes fell 
within the ranges of normal physiological fluctuations. 
Tissue Cross-reactivity Study 
Immunohistochemistry was employed to analyze the tissue cross-reactivity of CS1001 in human, 
cynomolgus monkey and rat tissues. According to the results: Immunohistochemistry was 


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employed to analyze the binding activity of biotinylated CS1001 and biotinylated control (135-
Human Ctrl) in 33 kinds of fresh frozen normal rat tissues, cynomolgus monkey tissues and 
human tissues (each kind of tissues coming from three individuals). At 1 μg/mL and 10 μg/mL, 
specific staining by biotinylated CS1001 was observed only on the cell membrane of CHO PD-
1 positive cell line (positive control). No specific staining by biotinylated CS1001 or biotinylated 
135-Human Ctrl was seen in any fresh frozen rat tissue; no specific staining by biotinylated 
CS1001 or biotinylated 135-Human Ctrl was seen in any fresh frozen cynomolgus monkey 
tissue; no specific staining by biotinylated 135-Human Ctrl was seen in any fresh frozen human 
tissue, and only specific staining by biotinylated CS1001 was seen in the placenta tissue. 
Toxicokinetic study 
Toxicokinetics was studied in a repeated dose trial in cynomolgus monkeys. 40 cynomolgus 
monkeys were randomly assigned into four groups, that is, the placebo group and the dose 
groups of CS1001 30 mg/kg, 75 mg/kg and 200 mg/kg; the drug was given once a week for a 
total of five times (respectively on D1, D8, D15, D22 and D29), and the blood would be 
sampled at the planned time for the serum concentrations of CS1001 and ADA test. See Table 
3 for the summary of the toxicokinetic parameters of CS1001. 
According to the results of CS1001 administered to male and female cynomolgus monkeys 
through repeated intravenous infusion, the Tmax median of CS1001 occurred between 0.3 and 8.0 
hours postdose. No significant gender difference was observed among various dose groups in 
term of the systemic exposure; as the dose was increased from 30 mg/kg to 200 mg/kg, systemic 
exposures of both female and male cynomolgus monkeys on Days 1 and 22 increased 
proportionally. Based on the change in AUC0-168h, the ratio of systemic exposure on Day 22 to 
that on Day 1 ranged between 2.2 and 3.0 and the growth in systemic exposure of CS1001 in the 
test animals of any dose group indicated the existence of drug accumulation. No ADA was 
observed in the animals of any dose group. 
See the Investigator’s brochure (IB) of CS1001for more details. 
2.4.   CLINICAL STUDIES  
2.4.1.1. BLU-554 
As of 16 June 2018 (data cut-off), there is 1 ongoing Phase 1 study in subjects with BLU-554 
Study BLU-554-1101 is a Phase 1, open-label, FIH study designed to evaluate the safety, 
tolerability, PK, PD, and preliminary antineoplastic activity of BLU-554 administered orally in 
subjects with HCC. The study consists of 3 parts. Part 1 consists of dose escalation employing a 
3+3 design to determine MTD/RP2D by exploring both QD and BID dosing schedules. 
Additional accrual to dose levels that had been declared safe was allowed to further assess the 
safety, PK, PD, and preliminary antitumor activity of BLU-554. Part 2 consists of dose 
expansion exploring the MTD/RP2D for the QD dosing schedule. Part 3 is a continuation of 
expansion for the QD dosing schedule in subjects with FGF19 immunohistochemistry positive 
(IHC+) HCC who have not received prior TKI therapies such as sorafenib, regorafenib, 
lenvatinib, or other kinase inhibitor (TKI-navï e). Part 1 and Part 2 of the study have completed 
enrollment. Part 3 (Expansion FGF19 IHC+, TKI-navï e) is ongoing with BLU-554 being 
administered at the RP2D of 600 mg QD. At the time of the data cut-off date (16 June 2018), 
115 subjects have received BLU-554, including 34 subjects in Part 1 (QD and BID dosing) and 
81 subjects in Part 2 (QD dosing). 
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A total of 25 subjects received BLU-554 according to the QD dose escalation schedule during 
Part 1 of the study at doses ranging from 140 mg to 900 mg. In the QD dose schedule, no DLTs 
were observed at doses ranging from 140 to 600 mg QD. Two DLTs were noted at 900 mg QD 
including 1 subject with Grade 3 abdominal pain and 1 subject with Grade 3 fatigue lasting more 
than 7 days. BLU-554 600 mg QD was determined to be the MTD. Based on the safety profile, 
PK, and preliminary antitumor activity, 600 mg QD was considered the recommended dose for 
Part 2 (dose expansion). 
A total of 9 subjects received BLU-554 according to the BID dose escalation schedule during 
Part 1 of the study at doses of 200 mg or 300 mg. In the BID dose schedule, 2 DLTs were noted 
at 200 mg BID, including 1 subject with Grade 3 fatigue lasting greater than 7 days and 1 subject 
with clinically important AEs (Grade 1 headache, nausea, diarrhea, abdominal pain, and Grade 
3 fatigue) that were determined by the Investigator to be a DLT. At 300 mg BID, 1 DLT was 
noted in 1 subject with Grade 3 pulmonary edema. Pharmacokinetic modelling suggested that 
100 mg BID would provide exposure below xenograft efficacy levels as well that of the 280 mg 
QD dose level. Therefore, further study of the BID schedule is not planned. 
Part 2 Expansion 
A total of 81 subjects have received BLU-554 at the RP2D of 600 mg QD in Part 2 QD dose 
expansion. 
Pharmacokinetics 
The single dose (Cycle 1 Day 1 [C1D1]) and steady state (Cycle 1 Day 15 [C1D15]) 
pharmacokinetics of BLU-554 following QD and BID oral administration have been 
evaluated in subjects in Study BLU-554-1101. The mean plasma BLU-554 concentration- 
time profiles for each dose level on C1D1 and C1D15 are shown in Figure 7 
Following administration of single oral doses of BLU-554 ranging from 140 to 900 mg, the 
median time to peak concentration (Tmax) ranged from 1.5 to 2 hours postdose, and the mean 
(of all dose groups) plasma elimination half-life (t½) of BLU-554 was 16.5 hours. After a single 
dose and repeat dosing of BLU-554, systemic exposure increased in a dose-dependent manner. 
No significant drug accumulation (Rac ≤1.6) was observed after repeat dosing of BLU-554 
(dose range: 140 – 900 mg QD; 200 and 300 mg BID), consistent with the observed half-life. 
The steady state (C1D15) geometric mean (%CV; n) Cmax and AUC0-τ of BLU-554 at the RP2D 
of 600 mg QD was 8733 ng/mL (36.1%; n=72) and 91386 h•ng/mL (41.8%; n=65), 
respectively. 


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Figure 7: Mean (+StdDev) Plasma Concentration-Time Profiles of BLU-554 on C1D1 (Single 
Dose) and C1D15 (Steady State) Following Once Daily or Twice Daily Oral Administration 
(Study BLU-554-1101) 
Abbreviations: BID = twice daily; C1D1 = Cycle 1, Day 1; C1D15 = Cycle 1, Day 15; QD = once daily; 
StdDev = standard deviation. 
Data cut-off date: 22 June 2018. 
Safety 
As of the data cutoff, a total of 115 subjects were evaluable for the safety analysis evaluation. Most 
adverse events (AEs) observed in these subjects were Grade 1 or 2. The most common (≥20%) 
suspected to be related to study drug include diarrhea (N = 87, 76%), nausea (N = 48, 42%), ALT 
increased (N = 38, 33%), vomiting (N = 42, 37%), AST increased (N = 33, 29%), fatigue (N = 32, 
28%) and decreased appetite (N = 22, 19%). Serious adverse events (SAEs) were reported in 49 
(43%) subjects, and SAEs considered related to study drug occurred in 18 (16%) subjects, mainly 
including vomiting, anemia, hyponatremia, and pyrexia, etc. 
At the time of the data cut-off, 10 of 115 subjects remained on treatment, including 9 subjects 


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who are FGF19 IHC+. Of the 105 subjects (91%) who discontinued treatment with BLU-554,78 
subjects ended treatment due to disease progression, 18 due to AEs, 6 due to withdrawal of 
consent, and 3 due to Investigator decision. No deaths due to drug-related AEs have been 
reported. 
Efficacy 
A total of 101 subjects were evaluated for disease assessment per RECIST 1.1 (Investigator- 
assessed response). Of the 38 subjects who were FGF19 IHC–, there were no responders. Eleven of 
63 (17%) subjects who were FGF19 IHC+ had documented responses per RECIST1.1. One subject 
had an unconfirmed complete response before disease progression, which was documented at the 
subsequent assessment due to a new lesion. Best response is shown in Table 7. Maximum tumor 
reduction as measured by shrinkage in target lesions in 63 FGF19 IHC+ subjects is shown in Figure 
8. Twenty-seven (43%) subjects have had a reduction in tumor burden, including 5 of the 7 TKI 
navïe subjects (71%) as shown in Figure 9 
Table 7: 
Best Response (Response-Evaluable Population, N=101) 
 
Best Response 
FGF19 IHC+ 
N=63 
N (%) 
FGF19 IHC- 
N=38 
n (%) 
Complete response 
1 (2)a 
0 
Partial response 
10 (16) 
0 
Stable disease 
30 (48) 
21 (55) 
Disease progression 
22 (35) 
17 (45) 
Abbreviations: IHC = immunohistochemistry. 
Data cut-off date: 16 June 2018. 
 
 


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Figure 8:Waterfall Plot of Maximum Tumor Reduction in Target Lesions (Response- 
Evaluable Population, IHC+, N=63) 
 
Abbreviations: CR = complete response; IHC = immunohistochemistry; PR = partial response; TKI = 
tyrosine kinase inhibitor. 
Data cut-off date: 16 June 2018. 


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Figure 9:Spider Plot of Tumor Reduction and Study Duration in Tyrosine Kinase Inhibitor 
Naïve Subjects (Response-Evaluable Population, IHC+, N=7) 
 
Abbreviations: C = cycle; IHC = immunohistochemistry; Scr = Screening; TKI = tyrosine kinase inhibitor; 
x = treatment discontinuation. 
Data cut-off date: 16 June 2018. 
 
Pharmacodynamics 
During BLU-554 dose escalation in both the QD and BID dosing schedules, plasma-based PD 
markers are collected predose, and 1 hour, 2 hours, and 15 days thereafter. Cholesterol and the 
bile acid precursor, 7α-hydroxy-4-cholesten-3-one (C4), were selected as biomarkers as they 
constitute reactants of the FGFR4-regulated bile acid synthesis pathway under physiologic liver 
conditions. Cholesterol and C4 are substrate and product respectively of CYP7A1 and 
CYP17A1 catalytic conversion that are repressed by FGFR4 signaling. As shown in Figure 10 
inhibition of FGFR4 by BLU-554 leads to a release of the CYP7A1/CYP17A1 expression 
blockade and subsequently to the accumulation of C4 and depletion of total cholesterol as 
expected. This relationship is apparent starting from the lowest 30 mg BLU-554 dose and 
becomes more pronounced with increasing dose levels. No change of magnitude is apparent 
beyond 600 mg, which indicates that pathway modulation plateaued. This indicates adequate 
FGFR4 target coverage. 
Gut-derived endocrine FGF19 represents a feedback loop to prevent oversupply of bile acids. 
Due to the perturbance of the bile acid homeostasis by BLU-554, FGF19 levels rise accordingly 
(data not shown). 


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Figure 10: Plasma-Based Pharmacodynamic Markers (Once Daily Dosing) 
Please refer to the latest Investigator's Brochure for the latest data from clinical study of 
BLU-554. 
 
2.4.1.2. 
CS1001 
Study CS1001-101 has been conducted in Mainland China since October 2017. CS1001-101 
is an ongoing Phase 1a/1b, multi-center, open-label, multiple-dose, dose finding and expansion 
first in human (FIH) study for assessing the safety, tolerability, PK profile and anti-tumor 
efficacy of CS1001 in subjects with advanced solid tumors or lymphoma. Phase 
1a part was a dose finding study and used a classic 3+3 design. Phase 1a part is a dose finding 
study in which subjects received CS1001 intravenously across 5 cohorts at 3 mg/kg, 10 mg/kg, 
20 mg/kg, 1,200 mg fixed dose and 40 mg/kg once every 3 weeks (Q3W). Phase Ib part is an 
expansion study conducted in subjects with different solid tumors and subjects with lymphoma. 
As of November 30, 2018, a total of 29 subjects were enrolled into each of the dose- escalation 
groups and began to receive CS1001 at 5 dose levels, i.e. 3 mg/kg, 10 mg/kg, 20 mg/kg, fixed 
dose 1,200 mg and 40 mg/kg from October 19, 2017 to June 5, 2018 for dose finding. No dose 
limiting toxicity (DLT) was observed in all dose groups after assessment by the Safety 
Monitoring Committee (SMC) and maximum tolerated dose (MTD) was not reached. As of 30 
November 2018, the overall safety and tolerability were good. Based on data on safety, PK and 
preclinical pharmacology, the fixed dose 1,200 mg as infused every 3 weeks was identified as 
the study drug dose for CS1001 in Phase Ib and subsequent studies. Preliminary safety data and 
antitumor activity supported the subsequent studies of CS1001 in subjects with advanced tumors. 
As the design of Phase Ib study, it was planned to enroll 250- 300 subjects. 162 subjects had 
been enrolled as of 15 March 2019 and the study is still ongoing. 
Pharmacokinetics 
As of 30 November 2018, serum concentrations of CS1001 were observed from 29 subjects in 


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5 dose groups in the Phase Ia study of CS1001-101. Pharmacokinetic (PK) analysis indicated 
that the median Tmax was between 2.05 to 4.55 hours after a single intravenous infusion (3 mg/kg, 
10 mg/kg, 20 mg/kg, 40 mg/kg, fixed dose 1,200 mg). The exposure of CS1001 (Cmax and AUC) 
increased proportional to dose escalation with moderate individual variability. Calculated based 
on plasma concentration profile after single dose, the arithmetic mean t1/2 ranged from 12.19 to 
17.56 days; geometric mean Vss ranged from 3.29 to 4.43 L, indicating that CS1001 was mainly 
distributed in blood and extracellular fluid; mean t1/2 and Vss were comparable across dose 
groups. The in vivo pharmacokinetic property of CS1001 is consistent with the IgG4-type 
antibodies. In addition, PK values after multiple intravenous infusions (every 3 weeks, Q3W) 
showed a consistent proportional increase in exposure compared with the Cycle 1 with 
moderate individual variability. 
Safety 
As of 30 November 2018, the safety profile of all subjects at 5 different dose levels in the 
dose escalation phase (Phase Ia) CS1001 was summarized. 
All 5 dose levels had been assessed by the Safety Monitoring Committee (SMC). No dose 
limiting toxicity (DLT) was observed in all dose groups, and the maximum tolerated dose 
(MTD) was not reached. 
As of the data cutoff, enrolled subjects had received a median of 6 cycles of CS1001, with a 
range from 1 cycle to 20 cycles; the median duration of CS1001 treatment was 126 days, 
ranging from 21 days to 408 days. No subjects experienced treatment-emergent adverse events 
(TEAEs) leading to study drug infusion interruption, TEAEs leading to death, and infusion-
related TEAEs. 
29 (100%) subjects experienced TEAEs during the study. The most common (≥ 20.0%) TEAEs 
were anemia (48.3%), proteinuria (44.8%), blood bilirubin increased (27.6%), alanine 
aminotransferase increased (24.1%), aspartate aminotransferase increased (24.1%), conjugated 
bilirubin increased (24.1%), white blood cell count decreased (24.1%) and appetite decreased 
(20.7%). TEAE will be replaced with AE (adverse event) in the following description. 
Most subjects (93.1%) experienced CS1001-related AEs during the study. The most frequent 
CS1001-related AEs were anemia (48.3%), followed by proteinuria (44.8%), blood bilirubin 
increased (27.6%), alanine aminotransferase increased (24.1%), aspartate aminotransferase 
increased (20.7%), conjugated bilirubin increased (20.7%), white blood cell count decreased 
(20.7%), etc. 
Of the CS1001-related AEs, most were Grade 1 to 2 in severity according to Common 
Terminology Criteria for Adverse Events (CTCAE), and Grade 3 events included platelet 
count decreased (1 in group 20 mg/kg) and anemia (2 in group 1,200 mg fixed dose). There 
were no Grade 4 or 5 CS1001-related AEs. 
Of the 29 subjects enrolled, 6 (20.7%) experienced serious adverse reactions (SAEs), none of 
which were related to CS1001. 2 (6.9%) subjects experienced AEs that led to permanent 
treatment discontinuation, which were abnormal hepatic function (3.4%) and pulmonary 
tuberculosis (3.4%) respectively. Both were in group 1,200 mg fixed dose and both were judged 
to be unrelated to CS1001. 
13 (44.8%) subjects experienced AEs leading to delayed treatment cycle, which occurred in 


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groups 3 mg/kg (2 subjects), 10 mg/kg (2 subjects), 20 mg/kg (2 subjects) and 1,200 mg fixed 
dose (7 subjects), respectively. 2 (6.9%) of these subjects reported increased conjugated bilirubin 
(in groups 3 mg/kg and 1,200 mg fixed dose, respectively), and the incidence of other AEs 
leading to delayed treatment cycle was 3.4%. 
7 (24.1%) subjects experienced immune-related adverse reactions (irAEs), which occurred in 
groups 10 mg/kg (1 subject), 20 mg/kg (3 subjects) and 1,200 mg fixed dose (3 subjects), all of 
which were CTCAE grade 1 or 2 in severity. IrAEs with an incidence of ≥ 5.0% included 
hypothyroidism (13.8%) and pruritus (6.9%). 
A total of 8 (27.6%) cases of death occurred during the study across all the groups, with the 
exception of group 20 mg/kg. 7 cases were due to the subject's disease, and 1 case with 
unknown cause. No subject died due to study treatment. 
Efficacy 
A total of 29 subjects in the CS1001-101 phase Ia study began treatment with CS1001 every 3 
weeks from October 19, 2017 to June 05, 2018. As of November 30, 2018, 20 subjects had 
discontinued the treatment and 9 subjects continued to receive CS1001 in this study. Of these 
29 subjects, 7 subjects achieved partial responses, of which 6 subjects were with confirmed 
responses and one subject was with unconfirmed response due to failure to reach the next 
imaging assessment follow-up time. All 7 subjects who achieved objective responses remained 
in sustained response with unreached median time to response. The median progression-free 
survival (PFS) for all subjects was 4.3 months and the 6-month progression- free survival rate 
was 42.0%; the median survival time (OS) was not reached and the 6-month overall survival rate 
was 75.1%. 
Findings from the phase Ia study demonstrated that CS1001 demonstrated preliminary 
efficacy in subjects with advanced solid tumors or lymphoma. 
Please refer to the latest Investigator's Brochure for the latest data from clinical study of 
CS1001. 
2.5.   OVERALL BENEFIT/RISK ASSESSMENT  
HCC is a highly fatal tumor in the world. Most HCC subjects have lost their opportunities to 
receive curative treatment at the time of the first diagnosis and the recurrence rate at 2 years and 
5 years after surgery remains high (see 2.2 for details), seriously threating to the lives and well-
beings of the subjects in China. Most HCC subjects in China are complicated with underlying 
liver disease (e.g., chronic hepatitis B, chronic hepatitis C, cirrhosis, etc.) which makes the 
treatment more difficult[2]. Existing available therapies are limited with not good efficacies, so 
there is still a huge unmet clinical need. Therefore, a new combination regimen is urgently 
needed. 
BLU-554 showed highly selectivity in non-clinical, phase I BLU-554-1101 study and showed a 
better response rate in subjects in group FGF19 IHC + (see Section 2.4.1.1). For the safety of 
BLU-554, reactions mainly are gastrointestinal system disorders or increased hepatic 
transaminase, of which, nausea, vomiting, diarrhea and abdominal pain can be relieved by 
supportive treatments while for transaminase and bilirubin elevation, liver function should be 
monitored closely. 
Anti-PD-1 and anti-PD-L1 monoclonal antibodies targeting PD-1 and PD-L1 have achieved 


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major advances in treatment for various advanced malignancies. Opdivo ® (nivolumab) has been 
approved by the US FDA as the second-line therapy for treatment against advanced 
hepatocellular carcinoma, providing breakthrough advancement to anti-PD-1/PD-L1 antibody 
drug in the treatment for liver cancer. The results of the recently reported KEYNOTE-224 study 
also showed encouraging efficacy and acceptable safety of pembrolizumab in subjects with 
advanced hepatocellular carcinoma who had previously failed sorafenib treatment, or who were 
intolerant to sorafenib. 
Based on the mechanism of action of CS1001 and the clinical safety information of the like 
product, it is expected that the adverse events that may occur during clinical trials mainly include 
various inflammation caused by the activation of the immune system, such as pneumonia, colitis, 
hepatitis, nephritis and inflammation of endocrine system, etc. According to the available 
clinical data of anti-PD-L1 and anti-PD-1 monoclonal antibody drugs, although the incidence of 
adverse reactions is high, such drugs are well tolerated, and only a small proportion of subjects 
have discontinued the drugs due to adverse reactions, and most adverse reactions can be relieved 
after treatment. Due to the variable early symptoms of immune-related adverse reactions, 
investigators should pay special attention to the early signs and symptoms of various immune-
related reactions in clinical study, make timely judgments and adjust the dose according to the 
protocol and provide corresponding effective therapy, so as to reduce the medication risk in 
subjects. 
Based on the current clinical data and pre-clinical pharmacological and toxicological profiles, it 
is expected that the combination regimens would show positive risks and benefits balance, and 
will provide more safe and effective treatment options for HCC subjects in China. 
3.   OBJECTIVES AND ENDPOINTS 
3.1. PRIMARY OBJECTIVES AND PRIMARY ENDPOINTS OF THE STUDY 
 
Objectives: 
Endpoints: 
Primary 
Phase Ib: 
 To determine the MTD and/or RP2D of 
BLU- 554 when being in combination 
with CS1001 in subject with advanced 
HCC. 
 To evaluate the safety and tolerability of 
BLU- 554 in combination with CS1001. 
 Incidence of DLT during the 
administration of BLU-554 in 
combination with CS1001. 
 Safety: incidence and severity of AEs 
and SAEs, including laboratory tests, 
vital signs, and ECG 
 Tolerance: discontinuation and 
reduction of study drug dose 
Phase II: 
 To assess the anti-tumor efficacy of 
BLU-554 in combination with CS1001 
 
 To assess ORR based on RECIST v1.1 
3.2.  SECONDARY OBJECTIVES AND SECONDARY ENDPOINTS OF THE STUDY:  
Objectives: 
Endpoints: 


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Secondary 
Phase Ib 
 To assess the pharmacokinetics (PK) 
profile of BLU-554 in combination 
with CS1001. 
Pharmacokinetic parameters include, but are 
not limited to: 
 When combination with BLU-554, 
AUC, Cmax, tmax, CLss , 
accumulation ratio of CS1001. 
 
When combination with CS1001, AUC, 
Cmax, tmax, CLss/F, accumulation 
ratio of BLU-554 
 To preliminary assess the anti-tumor 
activity of BLU-554 in combination 
with CS1001 
 To assess ORR, DOR, DCR, TTP, PFS 
and OS based on RECIST v1.1 
 To assess the immunogenicity of CS1001 
when administered in combination 
with BLU-554 
 Occurrence of anti-CS1001 antibody 
 To correlate FGF19 and PD-L1 expression 
 
level with efficacy of BLU-554 in 
combination with CS1001 
 ORR, DOR, DCR, TTP, PFS and 
OS by FGF19 protein and PD-L1 
protein level 
Phase II 
 
To assess the anti-tumor activity of BLU-
554 in combination with CS1001. 
 To assess DOR, DCR, TTP, PFS and OS 
based on RECIST v1.1 
 
To evaluate the safety and tolerability of 
BLU- 554 in combination with CS1001. 
 Safety: incidence and severity of AEs 
and SAEs, including laboratory tests, 
vital signs, and ECG 
 Tolerance: discontinuation and reduction 
of study drug dose 
 
To assess the pharmacokinetics (PK) 
profile of BLU-554 in combination with 
CS1001. 
Pharmacokinetic parameters include, but are 
not limited to: 
 When combination with BLU-554, 
AUC, Cmax, tmax, CLss, accumulation 
ratio of CS1001. 
  When combination with CS1001, AUC, 
Cmax, tmax, CLss/F, accumulation ratio 
of BLU-554. 
 
To assess the immunogenicity of CS1001 
when 
 
administered in combination with BLU-
554. 
 Occurrence of anti-CS1001 antibody 
 
To correlate FGF19 and PD-L1 
expression level with efficacy of BLU-
554 in combination 
 
with CS1001 
 ORR, DOR, DCR, TTP, PFS and 
OS by FGF19 protein and PD-L1 
protein level 
 


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4. 
STUDY DESIGN  
4.1.  OVERALL STUDY DESIGN 
 
This is a multi-center, open-label, multi-dose and Phase I study for evaluating the safety, 
tolerance, pharmacokinetic profiles and efficacy profiles of BLU-554 in combination with 
CS1001 in subjects with advanced HCC. 
The study consists of 2 parts, including Phase Ib dose escalation and Phase II dose expansion. 
Phase Ib is a dose escalation study for determination of the MTD and/or RP2D of BLU-554 in 
the combination regimen and the primary safety and tolerance of the combination regimen. 
Phase II is a dose extension study in which preliminary evaluation of the antitumor efficacy and 
the further evaluation of the safety, tolerance, PK and immunogenicity of combination regimen. 
Both Phase Ib and Phase II can be divided into 3 periods, screening period, treatment period 
and follow-up period (See Figure 11) 
• The screening period is the 28 days prior to the first dose. 
• During the treatment period, the subjects will be administered the study drug once 
every 21 days (3 cycles). BLU-554 is taken orally (PO) once daily (QD); CS1001 is 
administered intravenously once every 21 days (Q3W). Subjects with advanced stage 
solid tumor will be imageologically evaluated every 9 weeks (i.e. every 3 dosing 
periods) during the 1st year of treatment and every 12 weeks after treatment against 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (See Appendix错误!未
找到引用源。). The investigator may increase evaluation frequency if clinically 
indicated. The drug may be administered continually until presence of intolerable 
adverse reaction, disease progression, withdrawal of consent, loss to follow up, death 
or study termination. The duration of treatment may be up to 24 months. For subjects 
suspected of developing a pseudoprogression, if the subjects meet the criteria set forth 
in the protocol (see Section错误!未找到引用源。) it is recommended to continue 
receiving the study drug before confirmation by imaging. During the period of first 
documented PD and confirmed PD, subjects will be advised to continue study drug if 
they meet the following criteria. 
• Follow-up period consists of safety follow-up period and survival follow-up period. 
The safety follow-up period includes 30 days, 60 days and 90 days after the last 
dose of study drug, or until the initiation of a new anti-tumor treatment, whichever occurs 
earlier. Survival follow-up will be performed every 12 weeks to collect survival status, 
subsequent anti-tumor therapy, and study drug-related SAEs until the death, loss of follow-
up, withdrawal from the study, or study termination, whichever occurs first.. See Section 错
误!未找到引用源。 


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Figure 11:. Study flowchart 
 
During the study period, an SMC consisting of the principle investigator, the CRO's 
representatives (CRA and other relevant person) and the sponsor’s representative will be 
established to review the safety data, PK data, efficacy data from the study and determine the 
escalation dose level and dosage regimen in dose escalation study so as to determine the MTD, 
recommend the dose levels selected for the extension study, and determine the RP2D. The SMC 
will also decide whether or not to include unscheduled dose levels for the study. 
Phase Ib: Dose Escalation 
The MTD and/or RP2D of two dose levels and preliminary safety evaluation of BLU-554 in the 
combination regimen will be determined with the starting dose of 400 mg QD (once daily). 
CS1001 1,200 mg Q3W (every 3 weeks) as the fixed dose will be the RP2D in the monotherapy 
phase I study CS1001-101. The dose escalation part will use the BOIN design. (See Section 错
误!未找到引用源。 for details). 
Phase II: Dose Expansion 
The primary objective of the dose expansion phase is to further evaluate the antitumor efficacy 
as well as the safety, tolerability, PK and immunogenicity of the combination regimen. Subjects 
will be enrolled into 2 groups based on FGF19 IHC expression: Group 1 will be HCC subjects 
with FGF19 IHC-, approximately 15 subjects will be enrolled; Group 2 will be HCC subjects 
with FGF19 IHC+, approximately 25 subjects will be enrolled, approximately total 40 subjects 
in expansion part. Data on phase Ib evaluation at RP2D will be used as the basis to determine 
whether to continue to enroll subjects with FGF19 IHC- in the dose expansion phase. If the 
statistically pre-specified continuous evaluation range is reached, additional subjects with 
FGF19 IHC+ may be enrolled for further evaluation. FGF19 IHC test will be performed at central 
laboratory with FGF19 IHC+ defined as ≥ 1% for inclusion assessment. 
Archived or fresh tumor samples must be provided for FGF19 and PD-L1 IHC test which will 
be performed at central laboratory. (See Section 错误!未找到引用源。) 


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The imaging examinations of tumors shall be evaluated in accordance with RECIST v1.1. 
During the 1st year of the treatment, subjects will receive CT/MRI examination in the screen 
period and every 9 weeks (at the end of every 3 cycles). After 1 year of study, CT/MRI 
examinations shall be carried out once every 12 weeks (The investigator may increase the 
number of tumor evaluations where clinically indicated). 
Subjects will be monitored for anti-tumor activity, safety, tolerability, PK profile and host 
immunogenicity throughout the study from the day of first administration of study drugs up to 
90 days after the last administration or up to two-year treatment period of combination regimen. 
Figure 12:Study Procedure 
 
 
4.2.   STUDY RATIONALE 
 
4.2.1. Rationale for Study Design and Selection of Subjects 
This trial is an open-label study to evaluate the safety, tolerability and PK of the two doses 400 mg, 
600 mg QD in a phase Ib BLU-554-1101 study) of BLU-554 in the combination regimen using a 
dose escalation trial in Phase Ib. Based on the available data, the reasonable dose would be obtained 
as the recommended dose in the dose extension study (Phase II). In Phase II, a preliminary 
assessment of the efficacy of the combination regimen will be performed in HCC subjects without 
prior systemic treatment and further assessment of safety, tolerability, PK and immunogenicity 
would also be conducted in order to carry out subsequent clinical studies. 
4.2.2. Rationale for Dose Selection 
The two doses of BLU-554 (400 mg QD, 600 mg QD) and fixed dose of 1,200 mg Q3W of CS1001 
(see 错误!未找到引用源。) will be selected as the exploratory dose in the dose escalation phase 
of this study based on the safety and PK data of BLU-554 (BLU-554-1101) and CS1001 (CS1001-
101) monotherapy phase Ib studies. Dose escalation phase data will be used to determine the 
recommended dose in the dose extension phase. The dose selection of the two study drugs were 
based on the following: 
BLU-554 
In Study BLU-554-1101, the MTD/RP2D was determined in the dose escalation phase of the 
BLU-554 QD and BID dosing regimens, respectively. In the QD dose schedule, a total of 25 


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subjects received BLU-554 according to the QD dose escalation schedule during Part 1 of the 
study at doses ranging from 140 mg to 900 mg as outlined in Table 8. No DLTs were observed 
at doses ranging from 140 to 600 mg QD. Two DLTs were noted at 900 mg QD including 1 
subject with Grade 3 abdominal pain and 1 subject with Grade 3 fatigue lasting more than 7 
days. Of the 25 subjects in dose escalation, 4 were FGF19 IHC+, 10 were FGF19 IHC-, and 11 
were unknown. All 3 responders in Part 1 were FGF19 IHC+, 1 at 280 mg and 2 at 420 mg. 
Based on the safety profile, PK, and preliminary antitumor activity, 600 mg QD was considered 
the recommended dose for Part 2 (dose expansion). 
Table 8 Dose Escalation Summary for Study BLU-554-1101 (Part 1, QD Dosing 
Schedule) 
Dose 
Subjects Treated 
(N=25) 
DLT 
140 mg QD 
3 
0 
280 mg QD 
3 
0 
420 mg QD 
6 
0 
600 mg QD（MTD） 
6 
0 
900 mg QD 
7 
2 
Abbreviations: DLT = dose limiting toxicity; MTD = maximum tolerated dose; QD = once daily. 
In the BID dose schedule, a total of 9 subjects received BLU-554 at doses of 200 mg or 300 mg. 
Two (2) DLTs were noted at 200 mg BID, including 1 subject with Grade 3 fatigue lasting greater 
than 7 days and 1 subject with clinically important AEs (Grade 1 headache, nausea, diarrhea, 
abdominal pain, and Grade 3 fatigue) that were determined by the Investigator to be a DLT. At 
300 mg BID, 1 DLT was noted in 1 subject with Grade 3 pulmonary edema. Pharmacokinetic 
modeling suggested that 100 mg BID would provide exposure below xenograft efficacy levels 
as well that of the 280 mg QD dose level. Therefore, further study of the BID schedule is not 
planned. 
As of the data cutoff, a total of 115 subjects were evaluable for the safety analysis evaluation. 
Most adverse events (AEs) observed in these subjects were Grade 1 or 2. The most common 
(≥20%) suspected to be related to study drug include diarrhea (N = 87, 76%), nausea (N = 48, 
42%), ALT increased (N = 38, 33%), vomiting (N = 42, 37%), AST increased (N = 33, 29%), 
fatigue (N = 32, 28%) and decreased appetite (N = 22, 19%). Serious adverse events (SAEs) were 
reported in 49 (43%) subjects, and SAEs considered related to study drug occurred in 18 (16%) 
subjects, mainly including vomiting, anemia, hyponatremia, and pyrexia, etc. 
CS1001: 
The CS1001-101 study evaluated the safety and PK profile of CS1001 at 5 dose levels (3 mg/kg, 
10 mg/kg, 20 mg/kg, 1,200 mg, 40 mg/kg). As of 08 April 2018, the Safety Monitoring Committee 
(SMC) completed all 5 dose level assessments for the dose escalation phase CS1001. No DLTs 
were observed in any dose group, and MTD was not reached. Total of 16 subjects experienced 
treatment-emergent adverse events (TEAEs), of whom 15 subjects experienced treatment-related 
TEAEs. No deaths, permanent discontinuations or dose reductions due to TEAEs were reported 
in the study. The most frequent TEAEs were Grade 1/2 anaemia (n = 7), nausea (n = 6), decreased 
appetite (n = 5), blood bilirubin increased (n = 4), protein urine present (n = 4), white blood cell 
count decreased (n = 4) and proteinuria (n = 4). Grade 3 TEAEs were observed in 5 subjects, 
including bilirubin conjugated increased, gastric haemorrhage, bone pain, ascites and platelet 
count decreased; 1 of which (platelet count decreased) was considered as treatment-related by 
investigators. No Grade 4/5 TEAEs were reported. Two (2) serious AEs (SAEs) were reported in 


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2 subjects, 1 is Grade 3 gastric haemorrhage, the other is Grade 3 ascites. None of them was 
considered as treatment-related by investigators. 
irAEs occurred in 5 subjects, including diarrhea, adrenal insufficiency, hyperthyroidism, 
hypothyroidism, platelet count decreased, blood thyroid stimulating hormone decreased, blood 
thyroid stimulating hormone increased, thyroxine free decreased, thyroxine free increased, tri-
iodothyronine decreased and tri-iodothyronine free increased. All irAEs were Grade 1-3. 
Overall, there were no significant toxicity overlap observed from the two investigation 
products.280 mg QD estimated to be the minimally efficacious dose, to limit the number of 
subjects treated at subtherapeutic doses, based on the data on tolerance, preliminary anti- tumor 
efficacy, safety, PK and pharmacodynamics, this study will employ BLU-554 400 mg QD as 
starting dose in combination with CS1001 1,200 mg Q3W. 
4.2.3. Rationale for Biomarker Analysis 
The primary biomarkers analyzed in this study are the expression levels of FGF19 and PD-L1 
protein. The ORR of BLU-554 mono in the BLU-554-1101 study was 17% in subjects with 
positive FGF19 protein expression, while the ORR was 0% in the subjects with negative FGF19 
protein expression, suggesting that the expression of FGF19 protein is critical to the effect of 
BLU-554. PD-L1 expression, as predictive biomarkers of PD-(L) 1 antibody, have been 
demonstrated in multiple tumors (e.g. lung cancer), and preliminary evidence is also shown in 
liver cancer (e.g. Keynote-224, DOI: http://dx.doi.org/10.1016/S1470- 2045(18)30351-6). 
4.3. 
  DOSE ESCALATION 
 
4.3.1. Dose Escalation 
The dose escalation part of the study employs a BOIN [20] design to determine the MTD and 
RP2D of BLU-554 in the combination regimen. Two dose levels of BLU-554 will be assessed and 
the dose of CS1001will be fixed (RP2D in the monotherapy study). See Table 9 for the details 
about the dose escalation scheme of combination regimen. Every 21 days (3 weeks) will be 
considered as one cycle. DLT assessment will be done within 21 days (Cycles1) after the 
administration. 
Table 6:Planned Dose Escalation Scheme 
Dose Level 
BUL-554 
CS1001 
1 
400 mg QD 
1,200 mg Q3W 
2 
600 mg QD 
1,200 mg Q3W 
Using BOIN design, the target toxicity probability of the MTD is 0.3 with a maximum sample 
size of 12. The cohort size included 3 enrolled and treated subjects. See Figure 13 for the study 
design with the description as below: 
1. 
The starting dose for dose escalation was dose level 1, i.e. BLU-554 400 mg QD in 
combination with CS1001 1,200 mg Q3W. 
2. 
The dose level for the next cohort was determined according to the dose 
escalation/decreasing rule in Table 7. Under this rule, the likelihood of a dose dispensing 
error is lowest. When using Table 7, pay attention to: 
a. 
"Excluded dose" refers to any current dose and all higher doses that should be 
excluded from the trial to avoid the treatment for the newly enrolled subjects at these 


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higher toxic doses. 
b. 
When a dose is excluded, the dose for the next cohort will be decreased by one level. 
If the minimum dose planned for evaluation is excluded, the trial will be ended for 
safety reasons and the MTD will be considered as not determinable. 
c. 
In case that all the actions in the table (increase, decrease, exclusion) are not eligible, 
the current dose will be remained for the next cohort. 
d. 
If the current dose is the lowest dose planned for assessment, and such dose should be 
reduced according to rule, the current dose will be remained for the next cohort. 
However, if, based on the number of DLTs, the criteria for excluding dose has met, 
the trial should be terminated for safety reasons. 
e. 
If the current dose is the highest dose planned for assessment, and such dose should 
be increased according to rule, the current dose will be remained for the next cohort. 
3. 
Repeat step 2 until a maximum sample size of 12 is reached, the dose escalation is ended. 
After the end of the dose escalation, the MTD will be determined using a monotonic regression 
method: the dose for which the monotonic estimation of the toxicity probability would be the 
most approximate the target toxicity probability would be selected as the MTD. If the 
monotonic estimates of toxicity probability for two or more doses are equal and less than the 
target toxicity probability, the highest dose will be selected as the MTD; if the monotonic 
estimates of toxicity probability for two or more doses are equal and greater than the target 
toxicity probability, the lowest dose will be selected as the MTD. 
Table 7: BOIN STUDY DESIGN DOSE ESCALATION/DECREASING RULES 
Measures 
Number of subjects treated at current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Elevate the 
dose: if the 
cases of 
DLT <= 
0 
0 
0 
0 
1 
1 
1 
1 
2 
2 
2 
2 
Decrease 
the dose: if 
the cases of 
DLT>= 
1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
4 
5 
Decrease 
the dose: if 
the cases of 
DLT >= 
NA 
NA 
3 
3 
4 
4 
5 
5 
5 
6 
6 
7 


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Figure 13： Flow Chart of Dose Escalation Phase Ib Study with BOIN Design 
 
 
MTD = Maximum Tolerated Dose 
During the study period, an SMC consisting of the principle investigator, the CRO's 
representatives (CRA and other relevant person) and the sponsor’s representative will be 
established to review the safety data, PK data, efficacy data from the study and determine the 
escalation dose level and dosage regimen in dose escalation study so as to determine the MTD, 
recommend dose levels in the extension study, and determine the RP2D. The SMC will also 
decide whether or not to include unscheduled dose levels for the study. 
Once the RP2D is determined in phase Ib, the protocol will be amended to explore the safety 
and efficacy of the combination regimen in HCC subjects. Currently, Phase Ib study has been 
completed for subject recruitment on May 20, 2020, and SMC has confirmed the RP2D as 


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BLU-554 600 mg QD combined with CS1001 1200 mg IV Q3W on June 18, 2020 by 
reviewing the relevant safety, PK and efficacy data of subjects enrolled in Phase Ib study. 
4.3.2. 
Dose-Limiting Toxicity 
Definition of DLT: All toxicity or adverse events (AEs) are graded according to NCI-CTCAE 
5.0. Any AE occurring during C1 (21 days) that is not clearly caused by something other than 
investigational drug: 
Hematological toxicity: 
● 
Grade 4 neutropenia that lasts for ＞7 days; 
● 
Grade ≥3 febrile neutropenia (ANC<1,000/mm3, with a single temperature of ≥38.3°C 
or a sustained temperature of ≥38°C for more than one hour); 
● 
Grade 3 neutropenia with infection; 
● 
Grade 3 thrombocytopenia with clinically significantly bleeding; 
● 
Grade 4 thrombocytopenia; 
● 
Grade ≥4 anemia 
Non-hematological toxicity: 
● 
Grade ≥4 toxicity; 
● 
Grade 3 toxicity that fails to be resolved to ≤Grade 2, with the exception of diarrhea, 
nausea and vomiting; 
● 
Grade ≥3 immune-related adverse event (irAE) 
● 
Any Grade 3 tumor flare reaction (local pain, irritation or rash at known or suspected 
tumor focus) that lasts for 7 days or above; 
● 
Grade 3 or Grade 4 non-hematological laboratory abnormalities, if meet any of the 
followings: 
– need medical intervention 
– require hospitalization 
– last for >7 days 
and other toxicity of any grade that requires premature termination of the study as determined 
by the investigator and the sponsor through discussion. 
4.3.3. Stopping Criteria For Dose Escalation 
To adequately monitor safety of subjects, when subjects reached 12, study enrollment will be 
held pending data review by SMC. The SMC is established for the determination of dose levels 
to be administered during dose escalation and dose regimens in this study. The SMC consists 
of the principal investigator, the CRO's representatives (CRA and other relevant person) and 
the sponsor’s representatives. 
In the event that an MTD is not identified, RP2D will be determined by the SMC and the sponsor 
based on the pharmacokinetics, tolerability and preliminary antitumor activities observed in the 
dose escalation period, as well as other available data. 
4.3.4. MTD Definition 


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MTD is the highest dose level at which 30% of the subjects experience DLT within Cycle 1 in 
which at least 6 subjects are available for DLT evaluation. The MTD will be determined using 
a monotonic regression method: The dose for which the monotonic estimation of the toxicity 
probability would be the most approximate the target toxicity probability would be selected as 
the MTD. If the monotonic estimates of toxicity probability for two or more doses are equal and 
less than the target toxicity probability, the highest dose will be selected as the MTD; if the 
monotonic estimates of toxicity probability for two or more doses are equal and greater than the 
target toxicity probability, the lowest dose will be selected as the MTD. 
4.3.5. Recommended Phase II Dose (RP2D) Definition 
The RP2D will be determined by SMC based on comprehensive data of safety and tolerability, PK, 
pharmacodynamics, and preliminary anti-tumor efficacy obtained during the dose escalation phase. 
The RP2D will not exceed the MTD and will be determined at a dose escalation meeting. 
Additionally, observations related to PK, PD, and any cumulative toxicity observed after multiple 
cycles may be included in the rationale supporting the RP2D below the MTD. A minimum of 6 
subjects must be treated at the potential RP2D to confirm that it is the RP2D. 
4.4. END OF STUDY 
Definition of “End of study”: all subjects completed the treatment period, EOT, disease 
progression follow-up and survival follow-up or the Sponsor terminated the study (whichever 
occurred first). Completion of survival follow-up is defined as at least 80% of subjects died, loss 
to follow-up or followed up until at least 18 months after the first dose of drug.  
4.5. TREATMENT AFTER END OF STUDY 
For subjects who are able to benefit from study medication, at the end of the treatment period 
(up to 2 years), the study drug treatment will be continued after consultation with sponsor. 
The therapeutic dose that subjects continue to use is the same as the most recent dose prior to 
their enrollment into the follow-up period. Different doses are allowed only upon approval of 
the sponsor and the investigator (based on clinical trial data and subject's conditions at that time). 
 
 
5. 
STUDY POPULATION 
5.1. GENERAL CONSIDERATIONS 
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the 
trial as subjects. Prior to performing any trial assessments, the investigator will ensure that the 
subject or the subject’s legal representative has provided written informed consent following 
the procedure described in Section错误!未找到引用源。. 
The investigators or their designees must ensure that all subjects who meet the following 
inclusion and exclusion criteria. 
5.2. INCLUSION CRITERIA 
To meet the conditions for participation in this clinical study, subjects must:  
1. Voluntarily participate in the clinical study. Fully understand and get informed of this 


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study and sign the Informed Consent Form (ICF). 
2. ≥18 years of age on day of signing the informed consent. 
3. Unresectable locally advanced or metastatic hepatocellular carcinoma as confirmed by 
histology or cytology. 
4. Stage B or C based on Barcelona Clinic Liver Cancer (BCLC) staging system; In case of 
Stage B, subject must be ineligible for surgery and/or local therapy, or has progressed 
after surgery and/or local therapy or refuses surgery and/or local treatment. 
5. For Phase Ib, subject has failed after or is unsuitable for the standard systemic therapy 
against HCC. For Phase II, subject has not previously received systemic therapy 
[systemic therapies mainly include: chemotherapy, molecular target drugs (e.g. tyrosine 
kinase inhibitors, TKI), immunotherapy (e.g. anti PD-1/PD-L1, CTLA-4 etc.), biological 
therapy (e.g. tumor vaccine), cytokines, etc.)]. 
6.  At least one measurable lesion as evaluable by RECIST version 1.1. Target lesions 
within the field of prior efficacy irradiation or in the area of local treatment (intervention 
or ablation therapy) are considered measurable in case of confirmation of progression. 
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1 point. 
8. A-level Child-Pugh score. 
9. Expected survival≥3 months. 
10. For Phase Ib and II, 9 formalin fixed-paraffin embedded and unstained tumor tissue 
slides should be provided for FGF19 IHC and PD-L1 analysis in the central laboratory. 
 
Patients in the FGF19 IHC+ arm enrolled in the Phase II study must be FGF19 IHC+ as 
confirmed by the central laboratory 
 
Patients in the FGF19 IHC- arm enrolled in the Phase II study must be FGF19 IHC– 
as confirmed by the central laboratory (whether this arm will be initiated or not will 
be decided based on Phase Ib data) 
11. Clinical laboratory screening criteria: 
● 
Absolute neutrophil count (ANC)≥1.5 × 109/L 
● 
Platelet count≥ 75 × 109/L 
● 
Hemoglobin≥90 g/dL 
● 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN 
● 
Total bilirubin ≤ 2 ×ULN 
● 
International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 ×ULN (INR ≤ 1.5 
× ULN and PT ≤ 1.5 × ULN, if both available) 
● 
Serum creatinine ≤ 1.5 ×ULN or creatinine clearance (CL)≥60 mL/min (Cockcroft- 
Gault Formula) 
Female: CrCl=(140-age) × weight (Kg) × 0.85 
72× serum creatinine (mg/dL) 
Male: CrCl=(140-age) × weight (Kg) × 1.00 
72× serum creatinine (mg/dL) 
12. For subjects with hepatitis C virus (HCV) infection, treatment with locally approved 
and available anti-HCV therapy is required if HCV RNA is detected. 
13. For subjects with hepatitis B virus (HBV) infection, HBV DNA ≤ 2,000 IU/ml at Screening. 
 
Subject with HBV DNA (+), treatment with HBV antiviral therapy (as per the local 
standard of care) is required at least 14 days prior to the initiation of study. 
 
Subject with HBsAg (+) and/or HBcAb (+), based on investigator assessment, HBV 
antiviral therapy may be applied if needed. 


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14. For female subjects of childbearing potential, serum pregnancy test must be negative 
within 7 days prior to randomization. Except for female subjects who have been recorded 
as surgically sterilized or who are postmenopausal, female subjects of childbearing 
potential or male subjects and their partners must agree to use effective contraception 
from the signature of the informed consent form (ICF) until at least 6 months after the last 
dose of study drug. Appendix 6: Effective Contraceptive Methods 
5.3.  EXCLUSION CRITERIA 
 
Subjects who meet any of the following criteria will not be eligible to participate in the study: 
1. Portal vein tumor thrombosis in the main trunk or contralateral first branch (VP4), 
involvement of the inferior vena cava or the heart as revealed by imaging at 
baseline. 
2. Prior or current history of hepatic encephalopathy. 
3. History of liver surgery and/or local treatment for HCC (intervention, ablation therapy, 
absolute alcohol injection, etc.) or radiotherapy, etc. within 4 weeks prior to first dose. 
4. Active or documented gastrointestinal bleeding within 6 months (e.g. esophageal or 
gastric varices, ulcer bleeding). 
5. Presence of ascites detected by physical examination or clinical symptoms caused by 
ascites during the screening period, or ascites that need for special treatment, such as 
repeated drainage, or intraperitoneal drug infusion, etc. (Note: subjects with a small 
amount of ascites that can only be detected by imaging may be enrolled). Presence of 
uncontrolled pleural effusion or pericardial effusion (with clinical symptoms, requiring 
repeated drainage, or intrapleural or pericardial drug infusion, etc.) during the screening 
period. 
6. Presence of meningeal metastasis or central nervous system (CNS) metastatic lesions. 
7. According to the New York Heart Association (NYHA) Classification, subject has 
clinically significant, uncontrolled cardiovascular disease, including Grade III or IV 
congestive heart failure; myocardial infarction or unstable angina (within 6 months), 
uncontrolled hypertension (systolic blood pressure≥150 mmHg and diastolic blood 
pressure≥100 mmHg) or clinically significant uncontrolled arrhythmias, including 
bradycardia that may result in prolonged QT (e.g. Grade II or III heart block). Left 
ventricular ejection fraction (LVEF) <50%. QTc interval >480 msec (corrected 
using Fridericia’s formula). 
8. Subjects who have current interstitial lung disease or noninfectious pneumonitis, 
and prior history of interstitial lung disease or noninfectious pneumonitis that may 
affect the assessment or management of study drug-related pulmonary toxicity. 
Presence of active tuberculosis infection. 
9. Any serious acute, chronic infections that require systemic antimicrobial, antifungal or 
antiviral therapy at screening, excluding viral hepatitis. 
10. Malabsorption syndrome or inability to take the study drug orally for other reasons. 
11. Had primary malignancies other than HCC within 5 years. The following prior 
malignancies were excluded: completely excised skin basal cells and squamous cell 
carcinoma, local prostate cancer responsive to treatment, and carcinoma in situ with 
complete resection at any site. 


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12. Subject has had major surgery within 4 weeks prior to first dose (procedures such as 
central venous cannulation, biopsy, and feeding tube placement are not considered as 
major surgery). 
13. Previously received FGFR4 inhibitor treatment. 
14. Blood transfusion, use of hematopoietic stimulating factors [including G-CSF 
(granulocyte colony stimulating factor), GM-CSF (granulocyte-macrophage colony 
stimulating factor), EPO (erythropoietin) and TPO (thrombopoietin)] and human albumin 
preparations within 14 days prior to first dose. 
15. Requiring corticosteroids (dose equivalent to > 10 mg/day of Prednisone) or 
other immunosuppressive drugs within 14 days prior to first dose for systemic 
therapy. 
Note: For the absence of active autoimmune disease, it is allowed to use inhaled or topical 
steroids or adrenal hormone replacement therapy with equivalent dose of ≤10 mg/day 
prednisone. Short-term (≤ 7 days) use of corticosteroids for prophylaxis (e.g., contrast 
allergy) or for the treatment of non-autoimmune diseases (e.g., delayed hypersensitivity 
reactions due to contact allergens) is permitted. For subjects requiring hormone therapy, the 
dose administration should be done at least two days before and after the injection of 
CS1001. 
16. Use of traditional Chinese medicine (elemene, Kanglaite, Cinobufacin, Xiaoaiping, 
Huaier granule, Ganfule, Jinlong capsule, Aidi, etc.) with anti-liver cancer indication 
within 14 days prior to the first dose. 
17. Subject has received potent CYP3A4 inhibitors and/or inducers within 2 weeks prior to 
first dose. See Appendix 8: Strong Inhibitors and Inducers of CYP3A4. 
18. Concurrent HBV and HCV infection (History of HCV infection, but subjects with HCV RNA(-) 
can be considered as not being infected with HCV). 
19. Subjects with human immunodeficiency virus (HIV) infection. 
20. Pregnant or lactating women. 
21. Subjects with a history of hypersensitivity or hypersensitivity to any of the components of 
the investigational drug. 
22.  Any previous or current clinically significant diseases, medical conditions, history of 
surgery, signs, or abnormal laboratory parameters that, in the opinion of the 
investigator, may increase the risks associated with study participation and study drug 
administration, or affect the subject's ability to receive study drug and reliability of 
study results; other circumstances that in the opinion of the investigator would preclude 
participation in the study. 
23. Subjects who are unwilling or unable to follow the study procedures as defined. Subjects 
with no or limited disposing apacity and with psychiatric disorders that may affect study 
compliance. 
24. With the exception of alopecia, all toxicities from prior anticancer therapies and other 
therapies did not recover to ≤ Grade 1 (per CTCAE v5.0) prior to the first dose of 
study drug. 
25. Subjects who have received prior allogeneic stem cell or solid organ transplantation. 
5.4.  SUBJECT SUPPLEMENTATION 


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Phase Ib: Subjects with first cohort of each dose level will be supplemented if meet below 
criteria, the following cohort subjects of each dose level will depend on SMC decision. 
 
Subjects receive <75% of the prescribed amount of study drug within 21 days 
after the first dose, and those without observed DLT will be supplemented. 
Phase II: Subjects may be supplemented to have efficacy evaluable subjects (defined as 
having at least one post-baseline disease response assessment). 
5.5.  PROCESS OF HANDLING INADEQUATE ENROLLMENT 
Subjects who do not meet the inclusion criteria are not permitted to enroll and receive the study 
drug at any time. No exceptions are allowed under this clause. 
If a subject does not meet all inclusion criteria but has accidentally started the study treatment, 
the investigator should inform the sponsor immediately and discuss with the sponsor regarding 
continuing or terminating the study drug treatment of that subject. The sponsor must ensure that 
all decisions are accurately recorded. 
5.6.  TREATMENT DISCONTINUATION AND STUDY WITHDRAWAL 
5.6.1. Criteria for Study Treatment Discontinuation 
Subjects will discontinue the study drug treatment if any of the following occurs: 
1. 
Study protocol-specified discontinuation criteria (see Section 错误!未找到引用源。 
and6.4.4). 
2. 
Any clinical adverse events (AEs) or concurrent diseases that, in the opinion of the 
investigator, indicate continued participation is not in the best benefit of the subject 
3. 
Disease progression (subjects who meet the criteria for re-challenge after disease 
progression may continue medication until the progression is confirmed by imaging 
evaluation) 
4. 
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
5. 
Poor compliance from subjects, untimely and quantitative medication, failure of 
communication by investigators, or may lead to large deviation of test results and 
can’t be remedied, these will result in the discontinuation of study drug after 
confirmation of investigators and the sponsor. 
6. 
During the study treatment, for any subject who receives any prohibited 
comedications and/or concomitant treatments that affect the tolerance judgment, the 
investigators and the sponsor can make subjects withdraw from the study drug 
treatment after confirmation. 
7. 
Subjects, who are reluctant to continue the clinical trial, can inform to doctor in 
charge at any time, and can withdraw from it immediately. In accordance with the 
Helsinki Declaration and other applicable statutes and regulations, subjects are 
entitled to withdraw from the study at any time for any reason, and the doctor or site 
can’t hold prejudice against his future medical care. 


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8. 
Other cases that the investigators consider unsuitable for continued medication. 
9. 
Female subject becomes pregnant 
10. Death 
11. Follow-up 
If a subject fails to complete the study for non-drug related reasons, it will be considered that the 
subject did not finish the study; if the sponsor considers it is necessary, and then the number of 
subjects should be supplemented. The decision of subjects should be recorded. 
In all cases, all the reasons and primary reason for withdrawal will be recorded in the electronic 
case report form (eCRF). For the subject who have received at least one dose of the 
investigational drug, in case that they withdraw from the study with any reason, then the 
investigators should try their best to persuade subjects to undergo the end-of-study visit and 
should keep track of subjects with unresolved AE. 
5.6.2. 
Follow-up of Subjects Who Discontinue Treatment 
Subjects who discontinue the study drug must continue to be followed, and outcome and/ or 
survival follow-up data will be collected as required until death, loss to follow-up or end of study. 
Subjects who stopped treatment before clearly documented disease progression will continue to 
undergo imaging examination and tumor evaluation every 9 weeks (±7 days) within 1 year and 
every 12 weeks (±7 days) after 1 year until presence of any of the followings: (1) disease 
progression, (2) initiation of new anti-cancer therapy, (3) withdrawal of informed consent, (4) 
loss to follow-up, (5) death, (6) termination of study, whichever occurs first. 
Loss to follow-up is that the contact cannot be established with the subject, and there is 
insufficient information to determine the status of the subject at that time. Subjects who refuse 
survival follow-up should be defined as withdrawal of consent instead of loss to follow-up. 
For loss to follow-up subjects, the site should contact the subject as much as possible to 
determine the reasons for loss to follow-up and try to reschedule the visit. The process of 
attempting to contact the subject should also be documented and the date contacting the subject 
and the contact information used will be documented in the study file. 
5.6.3. 
Withdrawal From Study 
Subjects have the right to withdraw from the study at any time for any reason. If subjects 
withdraw from the study, they will not be given the study drug or will not be followed up as 
defined in any protocol. 
Subjects may withdraw or be withdrawn from study treatments for any of the following reasons: 
 
Withdrawal of consent. 
 
Death; 
 
Loss to follow-up. 
If the subject withdraws consents for the trial and the disclosure of subsequent information, 
he or she will no longer be treated with the study drug, nor receive visits according to the 


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protocol schedule, or no subsequent data will be collected. The sponsor will retain the use 
right of data and information prior to withdrawal of consent by the subject. If the subject 
withdraws consent for the trial, but does not withdraw consent for disclosure of subsequent 
information, information related to survival of the subject will continue to be collected and, 
where possible, until the end of the study. 
6. 
STUDY TREATMENTS 
6.1. INVESTIGATIONAL PRODUCT 
6.1.1.  Investigational Product 
 
BLU-554 will be provided as capsules for oral administration and be manufactured 
and provided by Blueprint Medicines. 
 
CS1001 is an injection, which is manufactured by WuXi AppTec Group. 
All study drugs are for investigational use only and should only be used within the context of 
this study. 
6.1.2. 
Dosage Forms and Strenghts of Investigational Products 
See Table 8 for the dosage form and strength of investigational products 
Table 8 Dosage Form and Strength of Investigational Products 
BLU-554 
Dosage Form: Capsule 
Strength: 100 mg 
Excipients in the Drug Product: polyvinylpyrrolidone, microcrystalline cellulose, 
mannitol, croscarmellose sodium, sodium lauryl sulfate. 
Expiration Date: 36 Months 
Storage Condition: Stored in the provided container at room temperature (15 to 
30 °C, 59 ° – 86 °F), protected from direct sunlight. 
CS1001 
Dosage Form: Injection. 
Strength: 600 mg/20 mL/vial. 
Excipients in the Preparation Formulation: Histidine/ Histidine Hydrochloride, 
Mannitol, Sodium Chloride, Polysorbate 80 and pH5.5. 
Expiration Date: 36 months tentatively. 
Storage Condition: 2 ℃ to 8 ℃. 
6.1.3. Package and Label 
All study drugs will be labeled according to the requirements of Good Clinical Practice (GCP). The 
label text will be approved in accordance with the procedures of the sponsor agreement, and the site 
may obtain a copy of the label upon request. All drugs are transported as study-specific main 
materials. 
Drug labels should utilize a unified format, and packaging label contents include: protocol 
number, clinical trial drug name (marked “specifically used for clinical trial”), strength, 
storage, batch number, expiration date, sponsor and so on. 
The complete records of batch numbers and expiration dates of all study drug and drug labels 


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will be kept in the sponsor’s study folder. 
6.2.   MANAGEMENT OF INVESTIGATIONAL PRODUCT 
 
The responsibilities for the Management of Investigational Product are in accordance with 
requirements specified in Appendix 7: Reponsibility For Medication Management 
6.2.1. Dispensing and Storage of Investigational Product 
The study drug is provided by the sponsor and distributed to the sites as planned. A designated 
person of the clinical trial unit is responsible for management and distribution, and 
investigational product should be stored in a medicine cabinet with locks. 
A designated person of the site is responsible for the unified preservation, management and 
distribution of the study drug. The responsible person of the site will confirm that the study drug 
has been received in writing and that the study drug is used within the framework of the clinical 
study as requested by the protocol. The receipt, distribution and return of the study drug will be 
documented. 
The study drug will be distributed by a member of the study group. The member shall ensure 
and record that the subjects receive the dispensed drugs as planned and record the number and 
date of drug dispensing and recovery in the original medical record 
6.2.2. Preparation and Administration of Investigational Product 
When BLU-554 and CS1001 are administered on the same day, BLU-554 is administered first, 
followed by intravenous CS1001. The subject should be given with CS1001 through 
intravenous infusion as soon as possible after BLU-554 administration. 
 
BLU-554 
BLU-554 doses should be administered with a glass of water in a fasted state, with no food 
intake from 2 hours before until 1 hour after study drug administration. Each dose should be 
administered at approximately the same time each day. Subjects should take BLU-554 in the 
morning. Subjects should be instructed to swallow capsules whole and to not chew the capsules. 
If the subject forgets to take a dose, he/she should take BLU-554 until 4 pm that day (the BLU-
554 dose should be administered with a glass of water in a fasted state, with no food intake from 
2 hours before until 1 hour after study drug administration). If the dose has not been taken by 4 
pm, then that dose should be omitted and the subject should resume treatment with the next 
scheduled dose. 
If a subject vomits during or after taking BLU-554, re-dosing is not permitted until the next 
scheduled dose. 
A temporary discontinuation (up to 3 weeks) in BLU-554 dosing is allowed for subjects who 
require an interruption (e.g., for surgery or another procedure) during the treatment period.BLU-
554 should be discontinued 48 hours before the procedure and resumed 48 hours after the 
procedure is completed. 
 
CS1001 


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The route of administration for CS1001 is intravenous infusion, the infusion process shall be in 
accordance with local clinical practices (recommend to use infusion set fitted with a 0.2 micron 
embedded or additional filter). Specific drug preparation and other unique requirements can be 
found in the drug manual. 
As a routine precautionary measure, the subject should be observed for 2 hours in the area with 
resuscitation equipment and first aid medicines after receiving the first two doses of test drug 
infusion. 
Drug Dilution Methods: 
 
Use 250 mL of sterile physiological saline (0.9% sodium chloride solution) to 
dilute the total dose of the drug to be administered. 
Drug Use Instructions: 
 
CS1001 is administered by intravenous infusion rather than IV bolus. 
 
Ensure that the study drug solution is clear, transparent, and free of visible particles. 
 
Draw the study drug injection with a syringe. The volume of the injection is 40 
mL (3 mL/bottle: 13.33 bottles, or 20 mL/bottle: 2 bottles; do not mix the two 
strengths of injections during one infusion configuration). Inject it into a 250 mL 
saline intravenous infusion bag. 
 
Turn upside-down gently when mixing, and prohibit shaking. 
 
Visually inspect the prepared solution. If it is not clear or has precipitation, the 
solution should be discarded and be recorded in the responsibility log of drug 
management. 
 
Record the time and the corresponding dose (in mg) of CS1001 on the 
intravenous infusion bag label. 
 
The infusion of the study drug should be completed within 60 - 120 minutes. 
According to Section错误!未找到引用源。, if the infusion reaction occurs, the 
infusion time can be prolonged. Do not use the same infusion intravenous catheter 
while administering other drugs. 
 
At the end of infusion, the infusion tube should be rinsed with a sufficient 
amount of saline. 
 
It is recommended that the study drug should be given to the subject immediately 
after preparation to avoid exposure of the prepared drug to room temperature over 
the recommended 6-hour limit. Among them, the 6-hour time limit includes 
storage time of DP bottles at room temperature, storage time of infusion solution in 
the intravenous infusion bag and infusion duration. If you need to delay the use of 
prepared drugs, you can place it in a refrigerator (2-8 ℃), but not more than 24 
hours. 
6.2.3. Return and Destruction of Study Drugs 
In this study, the study drug will be recovered. All unused and/or partially used study drugs 
will be returned to the sponsor-designated third party for destruction upon completion of 


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complete accountability records at the study site (please refer to the drug manual and 
corresponding instructions for specific instructions on drug distribution, accountability and 
recovery). Relevant personnel of the trial shall ensure that the disposal of study drug is 
reasonably arranged, appropriate handling procedures are formulated according to applicable 
regulations, guidelines and rules and regulations, and relevant records are made. Study drugs 
will be destroyed after approval of the sponsor. 
6.3. COMPLIANCE TO STUDY TREATMENT  
• 
BLU-554 
Subjects will be dispensed the appropriate number of study drug bottles to allow for dosing for 
a full cycle, or until the next scheduled visit. Subjects are to bring back all unused capsules (or 
the empty bottles) on D1 of each treatment cycle or at the next scheduled visit. Compliance with 
the dosing regimen will be assessed based on brought back of unused drug (or empty bottles). 
• 
CS1001 
In order to ensure the treatment compliance, the dosage will be monitored by the primary 
investigator or his/her designees. Accurate medication (at the initiation and end of the infusion) 
time and dosage should be recorded. If the infusion is interrupted, the cause of the interruption 
must also be recorded in the eCRF. 
• 
Overdose 
An overdose is defined as: the subject (intentionally or accidentally) takes a drug dose that 
exceeds 20% of the protocol specified dose. Subjects who are suspected to have an overdose 
must receive appropriate supportive care as determined by the investigator and medical monitor 
after consultation. Any adverse event resulting from an overdose should be reported to the 
medical monitor and included in the standard adverse event report. 
6.4.    STUDY TREATMRNT ADJUSTMENT 
 
These guidelines should be followed by clinical Investigators, however, for an individual subject, 
dose interruptions, reductions, and treatment discontinuation should also be based on the clinical 
circumstance. Deviation from these guidelines must be documented and communicated with the 
sponsor. Adverse events are to be graded according to NCI CTCAE version 5.0. 
• 
For the Phase Ib dose escalation, dose reductions for BLU-554 during the evaluation 
period of DLTs are only allowed if a DLT is observed. 
• 
Dose reduction is not permitted for CS1001. If a subject experience a CS1001 
related toxicities, then the subject must suspend or permanently discontinue CS1001 
treatment. 
• 
During the study treatment, if Investigator can judge AE is associated with one of 
the investigation products, the IP can be suspended, another IP could continue to be 
administrate. If cannot judge, both of the IPs should be suspended. 
• 
If the study treatment is delayed according to the scheduled administration time for 
any reason (BLU-554 interrupted 2 weeks, CS1001 interrupted 9 weeks), the study 
treatment will no longer continue to be given (if the investigator considers that the 
subject is still benefiting, the subject may continue to receive the treatment with the 
consent of the medical monitor, i.e. the sponsor). 
• 
Two administration delays are allowed due to toxicity. If the need for third delayed 


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administration of toxicity occurs, after consultation with the sponsor, the study 
treatment will be permanently terminated. 
6.4.1. BLU-554 Dose Modifications 
• 
Any Grade 1 or Grade 2 BLU-554-related AE no dose modification required 
• 
Any Grade 3 or Grade 4 BLU-554-related AE, suspend (for at most 2 weeks) until 
event is ≤ Grade 1, or has returned to baseline, then resume by reducing 1 dose 
level. (if returned to ≤ Grade 1 or baseline within 14 days, and Investigator believes 
that it is in the subject’s best interest, treatment may resume without dose reduction, 
with the written approval of the sponsor). If not resolved or returned to ≤ Grade 1 or 
baseline within 14 days, subjects should discontinue the treatment with BLU-554. 
• 
After reducing the dose of BLU-554 due to BLU-554-related adverse events, 
subjects should maintain such reduced dose during the subsequent treatment. The 
dose can be reduced as low as 300 mg. 
* In case immune mediated etiology cannot be excluded; consider following the guidelines in Section 14.3. 
6.4.2. CS1001 Dose Suspension 
CS1001 will be suspended for any of the following CS1001-related adverse reactions: 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
− 
Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 
–   Grade 2 drug-related hypothyroidism/hyperthyroidism do not require a 
treatment delay 
• 
Any Grade 3 skin, drug-related adverse event 
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions: 
− 
Grade 3 lymphopenia does not require dose delay 
− 
For a subject who has Grade ≥ 2 drug-related AST, ALT, or total bilirubin 
elevation, dose delay is required 
− 
Any Grade ≥3 drug-related amylase or lipase abnormalities not associated with 
symptoms or manifestations of pancreatitis do not require dose delay. If such 
Grade ≥ 3 amylase or lipase abnormalities occur, the sponsor's medical monitor 
should be consulted 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of CS1001. 
6.4.3. CS1001 Dose Resumption 
Subjects may resume treatment with CS1001 when the CS1001-related AE(s) resolve to Grade 
≤ 1 or baseline within 9 weeks from the scheduled dosing, with the following exceptions: 
• 
Subjects may resume treatment in the presence of Grade 2 fatigue. 
• 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 


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treatment if the event recovers to Grade ≤ 2 skin toxicity. 
• 
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued. 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis must be completely resolved to 
baseline level before treatment is resumed. For patients with Grade 1 pneumonitis 
despite steroid tapering for at least 1 month, treatment may be resumed after 
discussion with and approval by the sponsor's medical monitor. 
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the sponsor medical 
monitor. 
Two dose delays are allowed due to toxicity. If the need for third delayed administration of 
toxicity occurs, after consultation with the sponsor, the study treatment will be permanently 
terminated. 
6.4.4. CS1001 Permanent Discontinuation 
Subjects will be required to permanently discontinued CS1001 for the following drug 
relatedadverse events: 
• 
Any Grade 2 CS1001-related uveitis, eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment. 
• 
≥ Grade 3 infusion-related reaction during or after CS1001 infusion see Section 
错误!未找到引用源。 
• 
Grade 3-4 severe pneumonitis 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions: 
− 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation. 
− 
Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation. 
− 
Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
○ 
Grade 3 drug-related thrombocytopenia >7 days or serious uncontrollable 
bleeding event requires discontinuation; 
○ 
any drug-related liver function test (LFT) abnormalities that meet the 
following criteria requires discontinuation: 
‒ AST or ALT > 5-10 × ULN for 2 weeks 
‒ AST or ALT > 10 × ULN 
‒ Total bilirubin > 5 × ULN 
‒ Concurrent AST or ALT > 3× ULN and total bilirubin > 2 × ULN 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
− 
Grad4 neutropenia ≤ 7 days 


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− 
Grade 4 lymphopenia or leukopenia 
− 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset. 
− 
Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the sponsor Medical Monitor. 
• 
Any event that leads to delay in dosing lasting > 9 weeks from the scheduled dosing 
requires discontinuation, with the following exceptions: 
− 
Dose delays to allow for prolonged steroid tapers to manage drug-related 
adverse events may be allowed if approved by the sponsor medical monitor. 
Prior to re-initiating treatment in a subject with a dosing delay lasting > 9 
weeks from the scheduled dosing, the sponsor medical monitor must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should 
also continue, more frequently study visit should take if clinically indicated 
during such dosing delays. 
− 
Dosing delays lasting > 9 weeks from the scheduled dosing that occur for non-
drug-related reasons may be allowed if approved by the sponsor medical 
monitor. Prior to re-initiating treatment in a subject with a dosing delay 
lasting > 9 weeks, the sponsor medical monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed. Periodic 
study visits to assess safety and laboratory studies should also continue, more 
frequently study visit should take if clinically indicated during such dosing delays. 
6.5.  CONCOMTANT TREATMENT 
 
All concomitant medication used throughout the treatment period and safety follow-up period 
(30, 60 and 90 days after the last dose of the study drug) should be recorded starting from the 
signature of the ICF by the subjects, which should include the dose, regimen, route, indications, 
starting date and end date of the concomitant drug. 
6.5.1. Prohibited Medications/Vaccines 
The following medications and procedures are prohibited during the study: 
 
use of strong CYP3A4 inhibitors and inducers is prohibited during the study (Please 
refer to Section 错误!未找到引用源。 
 
Do not use any anti-tumor drugs other than the study drug (irrespective of those 
approved by the Health Authority or investigational treatment), including but not 
limited to chemotherapy, radiotherapy, immunotherapy, bio-targeted therapy, 
hepatic intervention, local therapy and traditional Chinese medicines with anti-
hepatocellular carcinoma indication. 
−   Palliative local therapy (including surgery and radiation therapy) to extra-
hepatic non-target lesions may be allowed. 


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 
Immunosuppressive agents, including but not limited to systemic corticosteroids, etc. 
(the dose higher than 10 mg/day prednisone or equivalent dose), with the exception 
of special circumstances requiring such agents for the treatment of an AE, in which 
the investigator must discuss with the sponsor's medical monitor. 
 
The use of live vaccines should be prohibited during the study period. 
 
For Phase Ib, prophylactic medications, such as prophylactic anti-emetic, 
prophylactic colony-stimulating factor, erythropoietin etc., are not permitted during 
the DLT observation period (D1 to D21 of Cl). Drugs or treatments that correct 
hematologic toxicity are not allowed. 
6.5.2. Permitted Treatment 
The permitted treatments for this study include: 
 
After discussion and consultation with the medical monitor, the investigator can perform 
supportive treatment (e.g. local radiotherapy against pain (extra-hepatic non-target 
lesions only)), or thoracic puncture and drainage to relieve the subject's symptoms). 
 
Bisphosphonates indicated for bone metastases are permitted during the study period. 
 
Local, ocular, intraarticular, intranasal and inhaled glucocorticoids therapies (with 
extremely low systemic absorption) in subjects are also acceptable; ≤ 10 mg/day of 
prednisone or equivalent dose of the similar drugs as the adrenal alternative therapy 
are also acceptable; short-term (＜3 weeks) use of glucocorticoids for prophylactic 
treatment (e.g. to prevent allergy to contrast medium) or for the treatment of non- 
autoimmune diseases (e.g., delayed type hypersensitivity caused by contact with 
allergen) is also allowable. 
6.6.   SPECIAL PRECAUTIONS 
 
Subjects should be closely observed and monitored during the administration of CS1001 up to 
30 minutes after completion of the infusion. 
If a grade 2 or higher hypersensitivity reaction, inflammatory reaction or infusion-related 
reaction occurs, the CS1001 infusion will be discontinued. Recommendations for treatment of 
infusion-related reactions and severe hypersensitivity reactions according to NCI are presented 
in sections错误!未找到引用源。 and错误!未找到引用源。 respectively. 
6.6.1. Infusion-Related Reaction 
Infusion-related reaction symptoms include fever, chills, nausea, itching, angioedema, 
hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness or high 
blood pressure. Severe reactions include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation and cardiogenic shock. The subjects should be closely 
monitored for such reactions. Please refer to Table 9 for treatment adjustments for infusion- 
related reactions caused by administration of CS1001. 
The site must have conditions for the treatment of serious infusion-related reactions, such as 
immediate access to the intensive care unit (ICU) or the equal environment and availability of 
appropriate treatment (including adrenaline, corticosteroids, intravenous antihistamines, 
bronchodilators and oxygen). In the event of an infusion-related allergic reaction or an allergic 


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reaction of ≥ 2 level, the CS1001 infusion will be stopped. 
In the event of hypersensitive reactions, the best available medical treatment must be taken for 
these subjects. Based on the guidelines for emergency treatment of allergic reactions published 
by Resuscitation Association Working Group (UK), it is recommended that subjects should 
immediately report any delayed response to the investigator. 
Table 9:Treatment adjustments for infusion-related reaction symptoms after administration 
of CS1001 
NCI-CTCAE Classification 
Treatment Adjustment for CS1001 
Level 1 - Mild 
Mild and transient reactions; no need to interrupt 
infusion; and no intervention required. 
When the infusion rate of CS1001 decreases by 
50%, it is necessary to closely monitor any 
worsening reaction until the reaction disappears. 
Medical treatment can be given on demand. 
Level 2 - Moderate 
The need of treatment or infusion interruption, and 
timely relief after symptomatic treatment (e.g., 
antihistamines, NSAIDs, anesthetics, intravenous 
fluids, etc.); and the need of prophylactic treatment 
with treatment time ≤ 24 hours. 
CS1001 infusion should be suspended. Once the 
infusion-related reaction disappears or the severity 
drops to level 1 or below, the infusion may be 
restarted at a rate reduced to 50% of the previous 
rate, and any worsening reaction should be closely 
monitored. Appropriate medical management 
strategies should be established based on the 
following text. 
Level 3 or Level 4 - Severe or life-threatening 
Level 3: The delay of symptom relief (e.g., 
symptomatic administration and/or the failure of 
timely relief after transient interruption of the 
infusion); the symptomatic relapse after initial 
improvement; and hospitalization or clinical 
consequences (e.g., kidney damage, pulmonary 
infiltration, etc.) due to clinical sequelae. 
Level 4: life-threatening; and the need of 
emergency intervention (e.g., the need of ventilator 
support, etc.). 
The CS1001 infusion should be discontinued 
immediately and the infusion tube connected to the 
subject should be disconnected. Whether to 
continue the study treatment will be determined by 
the investigator. Appropriate medical management 
strategies should be established, as described below; 
The subject should immediately withdraw from 
CS1001 treatment group and should not receive 
additional CS1001 treatment. Appropriate medical 
management strategies should be established based 
on the following text. 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NSAIDs = 
Non-Steroidal Anti-Inflammatory Drugs. 
Once the infusion rate of CS1001 is reduced by 50% or the infusion is suspended due to infusion-
related reactions, the reduced infusion rate must be maintained at all subsequent infusions. If the 
subject occurs the infusion-related reaction (≥ level 2) for the second time at a slower infusion 
rate, the infusion should be discontinued, and the subject should withdraw from CS1001 
treatment group. 
Infusion Reactions of CTCAE Level 1 or Level 2: Appropriate medical treatment strategies 
should be established according to the reaction type. It includes but is not limited to antihistamines 
(e.g., diphenhydramine or equivalent drugs), antipyretic agents (e.g., paracetamol or equivalent 
drugs), oral or intravenous corticosteroids on demand, epinephrine, bronchodilators and oxygen. 
Bedside monitoring must be continued until symptom relief is achieved. In the subsequent dosing 
period, the subject will receive prophylactic oral antihistamines (e.g., diphenhydramine or 


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equivalent drugs) and antipyretic agents (e.g., paracetamol or equivalent drugs) at least 30 minutes 
prior to infusion and will be closely monitored for infusion-related clinical signs and symptoms. 
Infusion Reactions of CTCAE Level 3 or 4: The infusion should be discontinued immediately. 
Appropriate medical management strategies should be established immediately according to 
severity and type of the reaction. It includes but is not limited to oral or intravenous 
antihistamines, antipyretic agents, corticosteroids, epinephrine, bronchodilators and oxygen. 
Whenever the subject occurs an infusion-related reaction of Level 4, CS1001 must be 
discontinued. 
If an infusion-related reaction of Level 3 occurs, whether to continue the study treatment will 
be determined by the investigator after consulting with the sponsor. If it is decided to continue 
the treatment, the infusion time of CS1001 should be at least 1 hour for the next dosing period. 
Prophylactic antihistamines (e.g., diphenhydramine 50 mg or equivalent drugs) and antipyretic 
agents (e.g., paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) or equivalent drugs) 
will be given within 30 to 60 minutes prior to infusion. The subject will be closely monitored 
for infusion-related clinical signs and symptoms. 
6.6.2. Severe Hypersensitivity Reactions and Flu-Like Symptoms 
In the event of hypersensitive reactions, the best available medical treatment must be taken for these 
subjects. It is recommended that subjects should immediately report any delayed response to the 
investigator. 
In the event of generalized allergic reactions/anaphylactoid reactions (typical 
manifestations occur within a few minutes after dosing and are characterized by respiratory 
distress, laryngeal edema and/or intense bronchial spasm; subsequent vascular collapse or shock 
in general but without previous dyspnea; skin manifestations such as itching and urticaria, 
with/without edema; and gastrointestinal symptoms such as nausea, vomiting, abdominal 
cramps and diarrhea), the infusion must be discontinued and the subject should discontinue 
study drug administration. 
In the event of hypersensitive reactions, the subject will be given infusions of adrenaline and 
dexamethasone, followed by immediate monitoring, and the ICU should be prepared for a 
ready-to-use state when needing to be transferred to the ICU. 
If the subject appears the above reactions after receiving the treatment for the first time, it is 
advisable to administer prophylactic 25 mg indomethacin or a similar dose of NSAIDs (NSAIDs) 
(e.g., 600 mg ibuprofen and 500 mg naproxen sodium) within 30 to 60 minutes prior to each 
subsequent CS1001 infusion. Or according to the investigator's judgment, other fever treatment 
may be given to the subject (e.g., paracetamol). 
6.6.3. Immune-Related Adverse Events 
If an immune-mediated AE is suspected, the investigator should ensure that the evidence of etiology 
is conclusive or other causes may be excluded. 
For any irAE of ≥ Grade 3 or irAE of Grade 2 with the requirement of drug suspension or 
permanent withdrawal, the investigator should inform the sponsor as soon as possible and 
consult with the sponsor if necessary. 


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Based on the severity of AE, CS1001 will be suspended and corresponding treatment will be 
given. For subjects who use corticosteroids, corticosteroid dose will be gradually reduced within 
at least 1 month after the adverse reaction is improved to grade 1 or better. Short-term 
immunosuppressive agents such as tumor necrosis factor antagonists, mycophenolate mofetil or 
other drugs may be used if needed. If the severity of AE is maintained at grade 1 or better, CS1001 
treatment can be restarted. In the event of an immune-mediated persistent, worsening or recurrent 
adverse event of Grade 3, or an immune- mediated event of Grade 4, CS1001 treatment should 
be discontinued permanently. For the identification, diagnosis, management and dose adjustment 
of irAE, please refer to APPENDIX 3: GUIDANCE FOR IMMUNE-RELATED ADVERSE 
REACTIONS MANAGEMEMT 
6.6.4. Other Specific Adverse Events or Adverse Drug Reactions 
The light absorption characteristics of BLU-554 suggest the possibility that BLU-554 treatment will 
be associated with phototoxicity. Therefore, subjects should use clothing and sunscreen to avoid 
direct sun exposure. 
7. 
STUDY ASSESSMENT AND PROCEDURES 
7.1.  SAFETY ASSESSMENTS  
Throughout the study, safety assessments should be performed at all study site visits. The 
severity, time, and correlation with study treatment will be assessed. 
Subjects’ vital signs, physical examination, ECOG performance status score, ECG, and safety 
laboratory tests will be measured and assessed at specified intervals throughout the study. 
Subjects’ medical histories are collected during the screening period to understand the 
underlying diseases. Special attention should be paid to immune-related adverse reactions (e.g. 
gastrointestinal tract, skin, lung, liver, kidney, endocrine organs, etc.). 
Adverse events and laboratory test results will be graded according to NCI-CTCAE v5.0 
throughout the study. The characteristics of toxicity events include severity, duration, and onset 
time. Safety endpoints included all types of adverse events, safety laboratory assessments, ECG, 
and vital signs, etc. 
Subjects will continue to be evaluated for safety. Subjects will be evaluated for safety if they 
take any study medication. 
7.1.1. 
Vital Signs 
Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure. 
Additional vital sign assessment monitoring may be performed at the discretion of the 
investigator based on clinical needs. 
7.1.2. 
Physical Examination and ECOG Performance 
A comprehensive physical examination includes the examination of the head, eyes, ears, nose, throat, 
skin, thyroid, nervous system, respiratory, cardiovascular, abdomen (liver and spleen), lymph nodes 
and extremities. Height and weight should be measured and recorded. 
Brief physical examination includes examination of the skin, respiratory, cardiovascular system, 
and abdomen (liver and spleen). 


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The investigator must assess the abnormal changes in ECOG scores. 
7.1.3. 
Electrocardiogram (ECG) 
A 12-lead ECG will be collected at the scheduled time in the SoA. Whenever possible, the same 
electrocardiograph should be used throughout the study. The subject should rest for at least 10 
minutes for collection of 12 lead ECGs at a supine position. All ECG safety must be assessed 
by a qualified physician. In case of any abnormalities, ECG must be repeated. 
7.1.4. Echocardiography 
Left ventricular ejection fraction and ventricular function will be assessed byechocardiography 
at the time points described in the SOA. 
7.1.5. Laboratory Tests 
The blood and urine samples used for clinical laboratory assessment will be collected as 
specified by the protocol. The specific collection time points are described in the SOA. Details 
of sample preparation and analysis will be provided by local laboratories. The reference ranges 
for all safety parameters will be provided by local laboratories.


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This study will detect the following parameters; 
Blood test 
Platelet Count 
RBC Indices: 
WBC count with Differential: 
RBC Count 
MCV 
Neutrophils 
Hemoglobin 
MCH 
Lymphocytes 
Hematocrit 
Monocytes 
Eosinophils 
Basophils 
Serum Chemistry 
BUN/Urea1 
Potassium 
AST 
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT 
Total protein 
Glucose 
Calcium 
Alkaline 
phosphatase 
Albumin 
Total cholesterol 
Triglyceride 
CK-MB 
CK-MB 
HBV、HCV1、HIV 
HCV antibody, HBsAg and HIV antibody 
AFP 
AFP 
Coagulation 
PT, INR and aPTT 
Routine Urine Test 
pH, Specific gravity, Glucose, ketones, WBC, protein 
Thyroid Function 
FT3, FT4 and TSH 
immunogenicity 
ADA level 
FGF19、PD-L1 expression 
FGF19 IHC、PD-L1 
Pregnancy test2 
β-hCG 
1. The detection of this test item for the same patient in the same study site should be consistent throughout 
the study. 
2. Subjects with HBsAg positive will further assess HBV DNA test, subject with HCV antibody positive will 
further assess HCV RNA test. 
3. A serum pregnancy test should be performed for female subjects at Screening; thereafter, a serum or urine 
pregnancy test should be performed on every odd cycle (e.g. C3, C5). 


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As for unexpected clinical laboratory detection values or values with unknown cause, if the 
investigator judges them as clinically significant, they should be repeatedly detected within 24h 
and continuously followed up until the detection results return to their normal value range and/or 
a rational explanation is found for such abnormality. The clinical laboratory will clearly mark 
the detection values beyond the normal value range, and the principal investigator needs to judge 
whether these abnormal values are clinically significant one by one, record those clinically 
significant ones as AEs and elaborate their relationship with treatment. 
7.1.6. Immunogenicity 
Immunogenicity involves the immune response to CS1001 itself, and is characterized through 
CS1001-related antibodies which may appear in subjects. These antibodies may cause CS1001 to 
be more quickly eliminated from the blood, or cause subjects receiving CS1001 treatment again at 
a later point of time to show infusion-related reactions. Blood samples used for immunogenicity 
analysis are respectively collected at the points of time provided in Table 4 and Table 5. The samples 
collected will be used to assess the anti-drug antibody (ADA) level of subjects (including 
assessment of neutralizing antibody Nab levels). 
7.2.   EFFICACY ASSESSMENTS  
Efficacy assessments will be performed by the investigator and BICR, respectively, according to 
RECIST v1.1. 
Radiographic (CT or MRI) assessments will be performed within 28 days prior to the first dose 
(baseline assessment), every 9 weeks during the first year of the study and every 12 weeks thereafter, 
according to RECIST v1.1 (APPENDIX 2: THE LATEST REVISED RECIST GUIDANCE 
(VERSION 1.1))) until 1) disease progression, 2) initiation of new anti-cancer therapy, 3) 
withdrawal of informed consent, 4) loss of follow-up, 5) death, 6) termination of study, whichever 
occurs first. In addition to subjects who discontinue treatment due to disease progression as 
determined by radiographic assessment, additional subjects should continue to undergo 
radiographic assessments at the scheduled time. Baseline tumor assessment should include brain 
(phase II study only), chest, abdomen, pelvis and other sites suspected of tumor lesions, and 
subsequent evaluations should include all sites evaluated at baseline (phase II study: subjects who 
have no brain metastases confirmed by imaging at screening will not be required to undergo regular 
brain imaging at subsequent visits, which may be scheduled by the investigator as clinically 
indicated), and should be performed using the same imaging method used at baseline.. If a subject 
has undergone a bone scan within three months of baseline assessment and was determined to be 
negative, the bone scan was not required for the baseline assessment. For subjects with bone 
metastases at screening, bone lesions should be followed up at subsequent visits. For subjects 
without bone metastases at baseline, follow-up with bone lesions is not required, unless the subject 
develops symptoms. The same detection technique as the baseline was used throughout the study. 
If an unscheduled tumor assessment occurs and the subject does not experience disease progression, 
subsequent tumor assessments should also be performed as scheduled. 
All radiographic results in this study will be interpreted by the sites or radiologists. The subjects 
will be clinically managed (including continuation or discontinuation of study treatment) based on 
the investigator's assessment of tumor imaging and the investigator's clinical judgment during the 
study. 
7.3. PHARMACOKINETIC EVALUATION AND IMMUNOGENICITY ASSESSMENTS 
Blood for the pharmacokinetic profile of CS1001 and BLU-554 will be collected by venipuncture. 
According to the time points specified in Table 4 and Table 5, venous cannulation will be performed 
to collect plasma for detection of blu-554 and serum for detection of CS1001 respectively. PK 
samples shall not be sampled from the ipsilateral arm that has been injected with the drug. The 
actual sampling time (to the exact minute) of each sample will be recorded in the eCRF and in the 


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database. 
See the central laboratory manual for the handling of PK samples, including labeling and shipment. 
The corresponding labeling provided by the Sponsor must be applied on the collection tubes and 
sample storage tubes prior to sampling. For ease of reading, the label must be applied longitudinally 
along the tube. Labeling shall use high quality materials to ensure that it will not fall off the tube 
under extreme conditions. 
During shipping, the samples must be kept frozen in a freezer at -80 °C and placed in a box with 
dry ice. The samples were shipped to a bioanalytical laboratory, and the serum concentration of 
CS1001 was analyzed by the validated ELISA method, and the plasma concentration of BLU-554 
was analyzed by the validated LC-MS/MS method. 
7.4.   BIOMARKER EVALUATION 
 
Biomarkers related to this study include FGF19 and PD-L1. 
Where permitted by the Ethics Committee, all subjects who sign the informed consent form are 
required to provide 9 formalin fixed-paraffin embedded and unstained tumor tissue slides for the 
FGF19 and PD-L1 protein expression test during screening. Biomarker test (may include different 
methods for detecting FGF19 protein expression) will be applied in central lab. Detailed instructions 
for the collection, handling, and shipping of biomarker samples will be described in the applicable 
study laboratory manual. 
7.5.  STUDY PROCEDURES 
 
7.5.1. Screening Phase 
Written informed consent for the subject's signature must be obtained prior to the start of the 
screening period assessments and prior to the start of any study-related assessments. 
Screening will be Days -28 to -1, and all subjects will undergo screening procedures to determine 
eligibility. All subjects should provide archived or fresh tumor samples for an ICH assessment prior 
to enrollment. 
Required tumor tissue samples: 
Subjects must provide 9 formalin fixed-paraffin embedded and unstained tumor tissue slides for 
FGF19 and PD-L1 assessment at central laboratory. 
The following procedures will also be performed at the Screening visit: 
 Obtain demographic data, including gender, date of birth/age, race, and ethnicity; 
 Complete medical history, including a history of HCC and other malignancies, 
concurrent illnesses, prior treatments and the response to each treatment if available. 
The medical history obtained at C1D1 will be focused on disease-related symptoms 
and changes from the previous visit; 
 Complete physical examination, including ECOG PS; 
 AFP; 
 Tumor imaging (MRI or CT); 
 Vital signs including weight, temperature, pulse, and systolic/diastolic blood pressure. 
Height and weight will also be measured at Screening; 
 12-lead ECG; 


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 Echocardiogram; 
 Clinical laboratory assessment (blood test, coagulation, serum chemistry, CK-MB, 
urinalysis); 
 HBV, HCV, HIV; 
 Thyroid Function; 
 Serum pregnancy test within 7 days prior to dosing on C1D1 (women of childbearing 
potential only); 
 AE, SAE (only collect AEs and SAEs as specified in the electronic case report 
completion guidelines (eCCI)) 
 Concomitant medication. 
Re-screening is permitted for one time, but need to decide by investigator and sponsor assessment. 
Central laboratory-confirmed FGF19 IHC results obtained at screening # 1 may be used in the 
assessment of FGF19 IHC status at re-screening without recollecting tumor samples for testing. 
7.5.2. 
Treatment Phase 
For treatment phase of the study, all tests are performed at the time points specified in the dosing 
cycles. Subjects eligible for enrollment receive every 21 days (every 3 weeks) of BLU-554 in 
combination with CS1001 treatment as a cycle. 
The items to be completed during the treatment phase are as follows: 
C1D1: 
 
Checking inclusion/exclusion criteria 
 
Check/collect medical history 
 
Body weight, vital sign examination: body temperature, pulse, systolic and diastolic 
blood pressures are measured before and after infusion 
 
ECOG performance status score (prior to infusion) 
 
Physical examination 
 
12-lead ECG 
 
Echocardiogram 
 
Blood test, coagulation, blood biochemistry, CK-MB and urinalysis (when laboratory 
tests and study drug administration are scheduled on the same day, the results should be 
available before administration can be scheduled. Clinical laboratory tests do not need 
to be repeated on C1D1 if the screening visit tests are performed within 7 days prior to 
first dose (C1D1) (i.e., there is a -7 day window for laboratory tests on C1D1).) 
 
AFP 
 
Thyroid function (when thyroid function tests and study drug administration are 
scheduled on the same day, the results should be available before the administration 
can be scheduled. If the thyroid function test in the screening period is performed 
within 7 days prior to the first dose, it does not need to be repeated before the first dose 
(i.e., there is a -7 day window for thyroid function tests on C1D1).) 
 
PK blood, immunogenicity blood samples 


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 
Study drug administration, medication compliance 
 
DLT evaluation (Phase Ib only) 
 
AE，SAE, concomitant medications 
C1D2: 
 
12-lead ECG 
 
Echocardiogram (if clinically 
indicated) 
 
PK blood, immunogenicity blood samples 
 
BLU-554 administration, medication compliance 
 
DLT evaluation (Phase Ib only) 
 
AE, SAE, concomitant medications 
C1D8 (Phase Ib only): 
 
Body weight, vital sign examination: body temperature, pulse, systolic and diastolic 
blood pressure are measured before and after infusion 
 
Physical examination 
 
Echocardiogram (if clinically 
indicated) 
 
Blood test, blood biochemistry and 
CK-MB (The laboratory tests should 
be completed within 3 days pre-
dosing. When the laboratory tests 
and study drug administration are 
scheduled on the same day, the 
results should be available before the 
administration can be scheduled.) 
 
PK blood, immunogenicity blood samples 
 
BLU-554 administration, medication compliance 
 
DLT evaluation (Phase Ib only) 
 
AE，SAE, concomitant medications 
C1D15: 
 
Body weight, vital sign examination: body temperature, pulse, systolic and diastolic 


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blood pressure are measured before and after infusion 
 
Physical examination 
 
Echocardiogram (if clinically 
indicated) 
 
Blood test, blood biochemistry and 
CK-MB (The laboratory tests should 
be completed within 3 days pre-
dosing. When the laboratory tests 
and study drug administration are 
scheduled on the same day, the 
results should be available before the 
administration can be scheduled.) 
 
PK blood, immunogenicity blood samples 
 
BLU-554 administration, medication compliance 
 
DLT evaluation (Phase Ib only) 
 
AE，SAE, concomitant medications 
C2D1: 
 
Body weight, vital sign examination 
 
ECOG performance status score (before infusion) 
 
Physical examination 
 
12-lead ECG 
 
Echocardiogram (if clinically indicated) 
 
Blood test, coagulation, blood biochemistry, CK-MB and urinalysis (The laboratory 
tests should be completed within 3 days pre-dosing. When laboratory tests and study 
drug administration are scheduled on the same day, the results should be available 
before the administration can be scheduled.) 
 
Thyroid function (It should be completed within 3 days pre-dosing. When thyroid 
function tests and study drug administration are scheduled on the same day, the results 
should be available before the administration can be scheduled.) 
 
AE, SAE, concomitant medications 
 
PK blood, immunogenicity blood samples 
 
Study drug administration, medication compliance 
C3D1: 
 
Body weight, vital sign examination 


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 
ECOG performance status score (before infusion) 
 
Serum/urine pregnancy test (It is performed on D1 (± 4 days) of each odd cycle 
thereafter for women of childbearing potential) 
 
Physical examination 
 
12-lead ECG 
 
Echocardiogram (if clinically indicated) 
 
Blood test, coagulation, blood biochemistry, CK-MB and urinalysis (The laboratory 
tests should be completed within 3 days pre-dosing. When laboratory tests and study 
drug administration are scheduled on the same day, the results should be available 
before the administration can be scheduled.) 
 
AE, SAE, concomitant medications 
 
PK blood, immunogenicity blood samples 
 
Study drug administration, medication compliance 
C4D1: 
 
Body weight, vital sign examination 
 
ECOG performance status score (before infusion) 
 
Physical examination 
 
Tumor imaging examination 
 
Blood test, coagulation, blood biochemistry, CK-MB and urinalysis (The laboratory 
tests should be completed within 3 days pre-dosing. When laboratory tests and study 
drug administration are scheduled on the same day, the results should be available 
before the administration can be scheduled.) 
 
Thyroid function (It should be completed within 3 days pre-dosing. When thyroid 
function tests and study drug administration are scheduled on the same day, the results 
should be available before the administration can be scheduled.) 
 
AE, SAE, concomitant medications 
 
PK blood, immunogenicity blood samples 
 
Study drug administration, medication compliance 
C5D1 and D1 of subsequent cycles: 
 
Body weight, vital sign examination 
 
ECOG performance status score (before infusion) 
 
Serum/urine pregnancy test (It is performed on D1 (± 4 days) of each odd-numbered 
cycle thereafter for women of childbearing potential) 
 
Physical examination 
 
Tumor imaging examination (Imaging (CT or MRI) assessments are performed per 
RECIST v1.1 for Cycle 5 as clinically required, and every 9 weeks during year 1 and 
every 12 weeks thereafter for subsequent cycles) 
 
Blood test, coagulation, blood biochemistry, CK-MB and urinalysis (The laboratory 


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tests should be completed within 3 days pre-dosing. When laboratory tests and study 
drug administration are scheduled on the same day, the results should be available 
before the administration can be scheduled.) 
 
Thyroid function (The test is not required in Cycle 5, and thyroid function test is 
performed before dosing every 2 cycles in subsequent cycles (C6, C8, C10 … ). It 
should be completed within 3 days pre-dosing. When thyroid function tests and study 
drug administration are scheduled on the same day, the results should be available 
before the administration can be scheduled.) 
 
HBV, HCV (HBV DNA should be retested every 12 weeks for subjects with HBsAg 
positive, HCV RNA should be retested every 12 weeks for subjects with HCV antibody 
positive, i.e. C5, C9, C13 …) 
 
AFP (every 12 weeks, i.e. C5, C9, C13…) 
 
AE, SAE, concomitant medications 
 
PK blood, immunogenicity blood samples 
 
Study drug administration, medication compliance 
For subjects suspected of developing a pseudoprogression, if the subjects meet the following criteria, 
it is recommended to continue receiving the study drug before confirmation by imaging. Subjects 
will sign the informed consent for subsequent treatments of disease progression. 
a) Have clinical benefits as assessed by the investigator, e.g., no clinical signs and 
symptoms of significant disease progression (including worsening laboratory findings); 
b) Tolerance to study drug; 
c) Sable Eastern Cooperative Oncology Group (ECOG) performance status score; 
d) No rapid disease or tumor progression requiring urgent alternative medical intervention 
at critical anatomical sites (such as spinal cord compression). 
It is the responsibility of the investigator to determine if the subject may benefit from the subsequent 
treatment. Decisions should be made carefully to maximize the availability of further treatment for 
subjects who potentially benefit from it and to avoid long-term use of ineffective therapy. 
In rare cases, if the investigator considers subjects can benefit from the treatment, subjects may 
continue the treatment after disease progression determined by the confirmatory tumor imaging 
assessment, and subjects must sign the informed consent again. In that case, it’s necessary to consult 
with the sponsor first. 
7.5.3. 
End of Treatment (EOT) Visit 
The date of EOT visit is defined as the date when the investigator decides to discontinue the 
administration. The EOT visit should be performed 0-7 days after the EOT date. If the EOT visit 
and a treatment visit occur within 7 days, the repeat items do not need to be conducted. If the EOT 
visit occurs within the safety follow-up window, repeat items do not need to be conducted. If an 
alternate treatment is started within 7 days of the EOT date, the EOT visit should be conducted prior 
to the first dose of alternate therapy. The last administration date is calculated as the later last 
administration date of the two study drugs. It should be noted that the date on which the investigator 
decided to stop dosing may not coincide with the date of last dose. 
The following items to be completed for the EOT visit are as follows: 
 
Body weight, vital signs 


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 
ECOG score, physical examination 
 
Blood test, coagulation, blood biochemistry, CK-MB and urinalysis 
 
Thyroid function 
 
12-lead ECG 
 
Echocardiogram 
 
Tumor imaging (if the subject discontinue treatment due to disease progression 
(excluding pseudoprogression), it is not necessary to repeat the imaging assessment at 
last visit. If the subject has completed tumor imaging assessment within 28 days prior 
to EOT visit or safety visit, it is not required to repeat such examinations at the two 
visits.) 
 
Serum/urine pregnancy test (It is performed for women of childbearing potential) 
 
HBV、HCV 
 
AFP 
 
PK blood samples, immunogenicity blood samples 
 
AE, SAE, concomitant medications 
7.5.4. Follow-up Phase 
The follow-up phase includes safety follow-up phase and survival follow-up phase. 
Safety follow-up phase consists of 30 days, 60 days and 90 days after the last dose of study drug or 
until the start of a new antineoplastic treatment, whichever occurs first. 
Safety follow-up phase consists of 3 visits: 
(Note: safety visit 2 and safety visit 3 may be conducted by telephone follow-up)  
Safety Visit 1 (30 ± 7 days after last dose) : 
 
12-lead ECG 
 
Serum/urine pregnancy test (It is performed for women of childbearing potential) 
 
Examination of vital signs 
 
Physical Examination 
 
ECOG performance status score 
 
Tumor imaging examination (if applicable) 
 
HBV, HCV tests 
 
Clinical laboratory tests (blood test, blood biochemistry, urinalysis, 
coagulation, CK-MB) 
 
Thyroid function test 
 
Concomitant medications 
 
AE, SAE 
 
Subsequent anti-tumor therapy (if any) 


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Safety Visit 2 (60 ± 7 days after last dose) 
 
AE, SAE, concomitant medications 
 
Subsequent antineoplastic therapies (if any) 
Safety Visit 3 (90 ± 7 days after last dose) 
 
AE, SAE, concomitant medications 
 
Subsequent antineoplastic therapies (if any)  
Survival follow-up: 
From the last dose of study drug, subjects will be contacted by telephone or face-to-face every 12 
weeks, to collect subject survival status, subsequent anti-tumor therapy and study drug-related SAEs 
until the death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs 
first. 
8. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
It is the principal investigator's responsibility to ensure that all participants are familiar with the 
content of this section. 
8.1.  DEFINITION OF AN ADVERSE EVENT 
An adverse event (AE) is any untoward medical occurrence after clinical study subjects receive a 
drug, which need not necessarily have a causal relationship with the treatment. AEs include any 
unfavorable and abnormal sign (e.g., abnormal laboratory tests), symptom, or disease temporally 
associated with the use of a (investigational) drug, whether or not related with the (investigational) 
drug (as defined by ICH).  
It includes new events, exacerbation of underlying conditions, or increased frequency, and abnormal 
diagnostic results including abnormal laboratory values. 
Examples of AEs include, but not limited to: 
 
Abnormal laboratory test results; 
 
Clinically relevant symptoms and signs; 
 
Physical examination result change; 
 
Hypersensitivity reactions. 
In addition, symptoms or signs attributable to the following events are also included 
 
Overdosage; 
 
Drug discontinuation; 
 
Drug abuse; 
 
Drug misuse; 
 
Drug interactions; 
 
Drug dependence 
 
Drug leakage; 


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 
Pregnancy 
AEs include serious adverse events (SAEs) and non-serious AEs. 
8.2.    ABNORMAL LAB RESULTS 
The following criteria should be used to determine whether laboratory results should be reported as 
adverse events: 
 
Accompanied by symptoms, and (or); 
 
Require further diagnostic examination or pharmacological/surgical intervention, 
and (or); 
 
Lead to study treatment modifications (out of protocol-specified dose modification) 
or; 
 
Considered to be an adverse event by the Investigator or Sponsor. 
If any of the above criteria is not met, only the repeat test for abnormal findings is needed and it 
does not constitute an adverse event. Reporting error test results does not need to be reported as an 
adverse event. 
8.3.    DEFINATION OF A SERIOUS ADVERSE EVENT 
 
An SAE is any event that meets any of the following criteria as per the ICH definition: 
 
Death. 
 
Life-threatening ("life-threatening" means that the subjects are exposed to the risk 
of death in the event rather than the case it may theoretical lead to death in more 
serious event.) 
 
Inpatient hospitalization or prolongation of existing hospitalization (the reason for 
this condition is due to adverse events rather than the elective surgery, non-medical 
reasons, etc., as described below). 
 
Persistent or significant disability/incapacity. 
 
Causing congenital malformations or birth defects in offspring (congenital 
malformations or birth defects in the offspring of the subject); 
 
Significant medical events. 
Important medical events that may not necessarily result in death, be life-threatening or require 
hospitalization may be considered as an SAE when, based upon appropriate medical and scientific 
judgment, they may jeopardize the subject and may require intervention measures to prevent one of 
the outcomes listed in this definition. 
Examples of such events are: Intensive treatment in an emergency room or at home for allergic 
bronchospasm; Blood abnormalities or convulsions that do not result in inpatienthospitalization; 
Development of drug dependency or drug abuse. If the investigator considers that clinical symptoms 
and signs of an adverse event have a clinically significant impact, the AE is classified as a serious 
adverse event. Important medical events assessed by medical data and clinical experience of the 
investigator should be handled with reference to expedited reporting of serious adverse events. In 
addition, any suspected transmission of an infectious substance potentially via a medicinal product 
is also considered as an important medical event. 
Unlisted (Unexpected) Adverse Event 


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Unlisted adverse events refer to those whose nature or severity does not correspond to the reference 
safety information of the respective medicinal product. For investigational medicinal products, the 
expectedness of an adverse event will be judged on the basis of whether they are listed in the 
Investigator's Brochure. For comparator products approved for marketing, the expectedness of an 
adverse event will be judged based on whether it is listed in the package leaflet. 
Hospitalization 
Adverse events leading to hospitalization or prolonged hospitalization during the study are 
classified as serious adverse events. Any new hospitalization in medical institutions (even if the 
hospital stay is less than 24 hours) meets the criteria. Hospitalization also includes intra-hospital 
transfer to an urgent/intensive care unit (e.g., from pediatrics to the medicine, medicine to the 
intensive care unit for coronary heart disease, and from neurology department to the TB ward, etc.). 
The hospitalization in following institutions is not included: 
 
Rehabilitation; 
 
Hospice care; 
 
Short-term care (e.g. nursing care); 
 
Professional nursing; 
 
Home care; 
 
Admission to the general emergency department; 
 
Surgery on the same day (outpatient/ day surgery/ day-to-day operation). 
Hospitalization or prolonged hospitalization due to following reasons is not a serious adverse event: 
 
Hospitalization that is not associated with a new onset of an adverse event or 
exacerbation of a pre-existing AE (e.g., an examination of pre-existing ongoing 
laboratory abnormalities); 
 
Hospitalization for a non-medical reason (e.g., the subject is homeless); 
 
Transactional hospitalizations (e.g., annual physical examinations); 
 
Study protocol-specified hospitalization (e.g., for procedures required by the 
study protocol); 
 
Voluntary hospitalization not leading to clinical adverse events (e.g. for elective 
cosmetic surgery); 
 
Pre-scheduled hospitalizations or procedures (Entire study protocol and (or) 
pre-planned treatments or procedures by subjects should be documented in the 
baseline files); 
 
Hospitalization only for the use of study medication. 
Diagnosis and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as adverse events. However, the disease treated by such procedures should be reported as 
an adverse event if it meets the definition of an adverse event. For example, acute appendicitis that 
occurs during the adverse event reporting period should be reported as an adverse event and the 
appendectomy procedure to treat this disease should be recorded as the treatment of the adverse 
event. 
8.4. DOCUMENTATION OF ADVERSE EVENTS 
 


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All AEs spontaneously reported by subjects or answered by them after an open-label question "Do 
you have any health problem from the last visit/asking a question to the present?" by the investigator, 
or AEs observed should be collected and recorded. When collecting AE data, it is preferable to 
record the diagnosis (if possible) rather than to record a series of signs and symptoms. However, if 
a diagnosis is known, and the subject still has other signs or symptoms not belonging to the 
diagnosis, each symptom or sign should be recorded separately. 
8.4.1. Time of AE Collection 
AEs and SAEs will be collected from time of signature of main informed consent, throughout the 
treatment period and including the follow-up period. 
Documentation of AEs and SAEs from time of signature of informed consent through the first 
dose of study drug is described in the electronic case report completion guidelines (eCCI). 
Note: If the investigator gets known of any SAEs (including deaths) after the subjects have 
completed the safety follow-up or withdrawn from the study, the investigator should inform the 
sponsor's Pharmacovigilance team or representatives if, in his/her discretion, there is a 
reasonable possibility that such event is possibly correlated with the investigational drug. 
8.4.2. Follow-up of Unresolved Adverse Events 
During the course of the study all AEs and SAEs should be proactively followed up for each subject. 
Every effort should be made to follow up until all events are resolved, even though the event still 
exists after the discontinuation of treatment or termination of the study. As indicated medically, the 
investigator should follow up any AE that is not resolved at last visit by investigator. 
The sponsor retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
8.4.3. Events that Occur after Subject Withdraws from Study 
After the subject has been permanently discontinued from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring after the safety follow-up 
period. However, if an investigator learns of any SAEs, including death, at any time after the subject 
has been permanently discontinued from study, and he/she considers there is a reasonable possibility 
that the event is related to the investigational product, the investigator should notify the sponsor PV 
group or its representative. 
8.4.4. Variables collected 
The following variables will be collected for each AE: 
 
AE (verbatim) 
 
The date when the AE started and stopped 
 
Change of CTCAE grade 
 
Whether the AE is serious or not 
 
Investigator causality attribution against the Investigational Product 
 
Action taken with regard to investigational product 
 
Administration of treatment for the AE 
 
Outcome 


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In addition, the following variables will be collected for SAEs: 
 
Date AE met criteria for serious AE 
 
Date investigator became aware of SAE 
 
AE is serious due to 
 
Date of discharge (if applicable) 
 
Probable cause of death (if applicable) 
 
Date of death (if applicable) 
 
Autopsy performed (if applicable) 
 
Causality assessment in relation to study procedure(s) 
 
Causality assessment in relation to other medication 
 
Description of SAE 
8.4.5. Severity Analysis 
It is important to distinguish between serious and severe AEs. An AE of severe intensity need not 
necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE. On the other hand, a stroke that results in only a limited 
degree of disability may be considered a mile stroke but would be a SAE. 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study. AEs and SAEs should be assessed and graded based upon the NCI-
CTCAE Version 5.0. 
8.4.6. Causality Assessment 
The investigator’s assessment of causality must be provided for all adverse events (serious and non-
serious); the investigator must record the causal relationship and answer ‘yes’ or ‘no’ to the question 
‘Do you consider that there is a reasonable possibility that the event may have been caused by the 
investigational product?’ 
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an adverse event. 
If the investigator does not know whether or not investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor. If the investigator’s causality assessment is “unknown but not related to 
investigational product”, this should be clearly documented on study records. 
For SAEs causal relationship will also be assessed for other medication and study procedures. 
This includes non-treatment-emergent SAEs (e.g., SAEs that occur prior to the administration 
of investigational product) as well as treatment-emergent SAEs. A protocol-related SAE may 
occur as a result of a procedure or intervention required during the study (e.g., blood collection). 
The following guidelines should be used by investigators to assess the relationship of SAEs to 
the protocol: 
 
Protocol related: The event occurred due to a procedure/intervention that was 
described in the protocol for which there is no alternative etiology present in the 


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subject’s medical record. 
 
Not protocol related: The event is related to an etiology other than the 
procedure/intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record). 
8.4.7. Disease Progression 
Disease progression can be considered as a worsening of subject’s condition attributable to the 
disease for which the investigational product is being studied. Symptomsand/or signs associated 
with disease progression should neither be documented as an AE nor be reported as a SAE in an 
expedited fashion. But according to CTCAE 5.0, death due to disease progression needs to be 
reported as SAE in an expedited fashion. 
8.4.8. 
New Cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the investigational product and have been 
identified after the subject’s inclusion in this study. 
8.5.   REPORTING OF ADVERSE EVENTS 
 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events. If a serious adverse event occurs, expedited reporting will follow local and international 
regulations, as appropriate. 
8.5.1. 
Requirements for Serious Adverse Event Reporting 
All serious adverse events occurring during clinical study must be reported to the sponsor or its 
designated representative by investigational staff immediately within 24 hours of when he/she 
becomes aware of it. This timeframe also applies to additional new information (follow-up) on 
previously forwarded serious adverse event reports as well as to the initial and follow-up reporting 
of pregnancy cases. 
The sponsor representative works with the investigator to ensure that all the necessary 
information is provided within above timeline. 
For all serious adverse events, the investigator is obligated to pursue and provide information 
to the sponsor in accordance with the timeframes for reporting specified above. In addition, an 
investigator may be requested by the sponsor to obtain specific additional follow-up information 
in an expedited fashion. This information may be more detailed than that captured on the 
adverse event case report form. In general, this will include a description of the adverse event 
in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. 
In the case of a subject death, a summary of available autopsy findings must be submitted as 
soon as possible to the sponsor or its designated representative. 
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated sponsor representative. 
In case EDC is down, facsimile transmission/encrypted email of the filled paper Adverse Event 
Report form is the preferred backup method to transmit this information to the project contact 


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for SAE receipt. In rare circumstances and in the absence of facsimile equipment, notification 
by telephone is acceptable, with a hardcopy of the Adverse Event Report form sent by encrypted 
mail. Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the paper Adverse Event Report form within 24 hours when he/she aware of 
the event. 
The contact information for assistance with SAE reporting, specific to the site, are listed in the 
investigator folder provided to each site. The original copy of the Adverse Event Report form 
and the fax confirmation sheet must be kept with the case report form documentation at the 
study site. 
For details, please refer to the study specific Safety Management Plan (SMP). 
The sponsor representative will advise the investigator/study site personnel how to proceed. 
The sponsor has a legal responsibility to notify, as appropriate, both the local Health Authority 
and other regulatory agencies about the safety of a product under clinical investigation. Prompt 
notification of SAEs by the investigator to the appropriate project contact for SAE receipt is 
essential so that legal obligations and ethical responsibilities towards the safety of other subjects 
are met. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory 
authorities and the Institutional Review Board (IRB) /Independent Ethics Committee (IEC). 
Abnormal Liver Function Tests 
Abnormal liver function that meets the following conditions will be considered as SAE, which 
shall be reported by the investigator according to the SAE reporting process. If no other 
criteria are applicable, the important medical serious event criterion could be used for 
judgment. 
● 
For subjects with normal baseline of AST and ALT and total bilirubin: Treatment- 
emergent AST or ALT >3 × ULN, total bilirubin >2 × ULN, ALP < 2 × ULN (or 
not available) with no evidence of hemolysis; 
● 
For subjects with abnormal baseline ALT or AST or total bilirubin: Treatment- 
emergent AST or ALT >2 ×baseline values and >3 × ULN, or >8 × ULN 
(whichever is smaller) with total bilirubin level increased by at least 1 × ULN from 
baseline or if the value reaches > 3 × ULN (whichever is smaller). 
Disease progression 
Death due to disease progression requires expedited reporting as an SAE per CTCAE 5.0. 
New onset of tumors  
New onset of tumors should be classified as SAEs. New primary tumor is defined as a tumor 
found after study enrollment that is not primarily attributable to the use of study drug. 
8.5.2. Requirements for Non-serious Adverse Event Reporting 
All adverse events will be reported on the adverse event page(s)/module of the eCRF. It should be 
noted that the form for collection of serious adverse event information is not the same as the adverse 


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event CRF. Where the same data are collected, the forms must be completed in a consistent manner. 
For example, the same adverse event term should be used on both forms. Adverse events should be 
reported using concise medical terminology on the CRFs as well as on the form for collection of 
serious adverse event information. 
8.6. 
 OVERDOSE  
Overdose is defined as: the subject has taken (accidentally or intentionally) a dose exceeding the 
dose prescribed in the protocol by 20%. Subjects with a suspected overdose should be managed 
with symptomatic treatment or appropriate supportive therapy. 
For any drug overdose (whether or not it causes an AE), the investigator should complete a paper 
Adverse Event Report form within 24 hours of being informed and report it to the sponsor's 
pharmacovigilance representative. For drug overdoses with AE, AE information shall be recorded 
and reported together with drug overdose information in accordance with the requirement of Section 
8.5. 
8.7.   PREGNANCY  
To ensure subject safety, each pregnancy during study must be reported by the investigator or 
other site personnel to the sponsor’s representatives within 24 hours after being aware of its 
occurrence. The Sponsor's representatives together with the investigator will ensure that all 
relevant information is reported to the Sponsor's Pharmacovigilance Representative and the 
pregnancies and the outcome of each pregnancy in subjects who have been treated with the 
investigational drug should be reported. Abnormal pregnancy outcomes should be considered as 
SAEs, which should be reported in the Serious Adverse Event Reporting Form within the 
appropriate reporting timelimit for SAE. 
8.7.1. 
Maternal Exposure 
A female becomes, or is found to be, pregnant either while receiving or having been directly exposed 
to (e.g., environmental exposure) the investigational product, or after discontinuing and/or being 
directly exposed to the investigational product. 
If a subject is found to be pregnant during the study, the study drug should be discontinued 
immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled 
as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the subject was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate sponsor representatives within 24 hours of when he/she becomes aware 
of it. 
The same timelines apply when outcome information is available. 
The Pregnancy report module in the CRF is used to report the pregnancy (in case of failure of 
EDC system, the Pregnancy Report Form of sponsor could be filled out for reporting before 
accessing into the EDC system for supplementation when the EDC system has recovered) and 


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the Pregnancy Outcome Report is used to report the outcome of the pregnancy. 
Pregnancies occurring up to 180 days after the completion of study medication must also be 
reported to the investigator. 
8.7.2. 
Paternal Exposure 
A male has been exposed, either due to treatment or environmental, to the investigational product 
prior to or around the time of conception and/or is exposed during his partners’ pregnancy. 
Information on the pregnancy of a subject’s partner must be obtained directly from the subject’s 
partner. Therefore, prior to obtaining information on the pregnancy, the investigator must obtain 
the consent of the subject’s partner. 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
180 days following the last dose. 
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should, if possible, be followed up and documented. 
To capture information about a pregnancy from the partner of a male subject, the male subject’s 
partner consent must be obtained to collect information related to the pregnancy and outcome; 
the male subject should not be asked to provide this information. A consent form specific to this 
situation must be used. The outcome of any conception occurring from the date of the first dose 
until 180 days after the last dose should be followed up and documented. 
9. 
QUALITY CONTROL ,QUALITY ASSURANCE AND DATA 
MANAGEMENT 
9.1.    QUALITY CONTROL AND QUALITY ASSRANCE 
During trial conduct, CStone or its agent will conduct periodic monitoring visits to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed. The monitors will review 
source documents to confirm that the data recorded on CRFs is accurate. The investigator and 
institution will allow CStone monitors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification. The trial site may be subject to review 
by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC), and/or to 
Quality Assurance audits performed by CStone, and/or to inspection by appropriate regulatory 
authorities. Such audits/inspections can occur at any time during or after completion of the study. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
9.2.    DATA MANAGEMENT AND CODING 
Data Management will be performed by the sponsor delegated Data Management Vendor. 
An electronic data capture (EDC) system will be used for this study. All eCRF data will be entered 
in electronic forms at the site. Data collection, including all entries, corrections and alterations are 
to be made by investigator or authorized site personnel designated by the investigator. The eCRF 


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records will be automatically appended with the identification of the creator, by means of their 
unique User ID. By entering his/her electronic signature, the investigator confirms that all 
recorded data have been verified as accurate. All entries to the study database and changes will 
be fully recorded in a protected audit trail. 
The eCRF is essentially considered a data entry form and should not constitute the original 
(or source) medical records unless otherwise specified. The monitor will review the eCRFs 
and evaluate them for completeness and consistency by source document verification. 
The data will be validated as defined in the Data Management Plan. Data queries will be raised 
for inconsistent, impossible or missing data. Quality control procedures will be applied to each 
stage of data handling to ensure that all data are reliable and have been processed correctly. The 
Data Management Plan will also clarify the roles and responsibilities of the various functions 
and personnel involved in the data management process. 
Adverse events and medical/ surgical history will be coded using the most current version of 
Medical Dictionary for Regulatory Activities (MedDRA). Medications will be coded using the 
World Health Organization Drug Dictionary (WHO-DD). All coding will be performed by the 
vendor. 
10. 
QUALITY CONTROL AND QUALITY ASSRANCE 
10.1.  SAMPLE SIZE DETERMINATION 
It is planned to enroll not more than 12 subjects in the phase-Ib dose-escalation study. The 
observed toxicity will decide the actual sample size. 
According to efficacy result of BLU-554-1101 study (data cut-off date: 16 Jun 2018), ORR was 
17% (11/63) for FGF19 IHC+ subjects (1st line and above) and 0 (0/38) for FGF19 IHC-subjects. 
ORR of PD-1/PD-L1 monotherapy was reported around 10~20% for 1st line and 2nd line HCC 
subjects. Based on the data above, BLU-554 in combination with CS1001 is targeting 40% ORR 
for FGF19 IHC+ subjects and 30% ORR for FGF19 IHC- subjects. Combining the subjects 
treated at RP2D in Phase Ib and those in Phase II, gating criteria in Bayesian framework are 
developed as the following: 
Gating based on 25 FGF19 IHC+ subjects 
• 
A non-informative ORR prior is assumed at Beta (0.45, 0.55). 
• 
Timing - when all 25 subjects finish at least two post-baseline tumor assessments 
• 
Go - 12 responses or more, corresponding ORR 48%, the probability of combo ORR > 
40% is 0.788. 
• 
No go - 8 (32%) responses or fewer, the probability of combo ORR<40% is 0.797. 
• 
Evaluate - 9 (36%) to 11 (44%) responses, evaluate other endpoints, DOR, DCR, safety, 
etc., and additional 15 FGF19 IHC+ subjects may be enrolled for further evaluation. 
Gating based on 40 FGF19 IHC+ subjects (if enrichment of 15 FGF19 IHC+ subjects as 
decided) 
• 
A non-informative ORR prior is assumed at Beta (0.45, 0.55). 
• 
Timing - when all 40 subjects finish at least two post-baseline tumor assessments 
• 
Go - 18 responses or more, corresponding ORR 45%, the probability of combo ORR > 
40% is 0.737. 
• 
No go - 14 (35%) responses or fewer, the probability of combo ORR<40% is 0.744. 
• 
Evaluate - 15 (37.5%) to 17 (42.5%) responses, evaluate other endpoints, DOR, DCR, etc. 


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Gating based on FGF19 IHC- subjects treated at RP2D in Phase Ib 
• 
A non-informative ORR prior is assumed at Beta (0.2, 0.8). 
• 
Timing - only conducted if at least 6 FGF19 IHC- subjects are treated at RP2D in Phase 
Ib, when they finish at least two post-baseline tumor assessments 
• 
No go - 0 response, the probability of combo ORR<30% is greater than 0.99, Phase II 
will only include the FGF IHC+ cohort 
• 
Evaluate - 1 response or more, the cohort of FGF IHC- subjects will be included in Phase 
II 
Gating based on 15 FGF19 IHC- subjects 
• 
A non-informative ORR prior is assumed at Beta (0.2, 0.8). 
• 
Timing - when all 15 subjects finish at least two post-baseline tumor assessments 
• 
Go - 6 responses or more, corresponding ORR 40%, the probability of combo ORR > 30% 
is 0.757. If the final decision for FGF19 IHC+ subjects is “go”, FGF19 IHC- subjects 
may also be included in the target population of future development. 
• 
No go - 3 (20%) responses or fewer, the probability of combo ORR<30% is 0.845. future 
development will not include FGF19 IHC- subjects in the target population. 
• 
Evaluate - 4 (26.7%) to 5 (33.3%) responses, evaluate other endpoints, DOR, DCR, etc. 
The sample sizes of 25 or 40 FGF19 IHC+ subjects and 15 FGF19 IHC- subjects are selected 
to have reasonably high probability of ORR exceeding the target when the go criteria are met 
or ORR being lower than the mono therapies when no-go criteria are met. 
The go and no-go criteria are set up to guide future development of the combination. They are 
not binding decision-making rules. 
If the actual numbers of evaluable subjects are different from those planned above, the same 
method will be used to calculate the posteriori probability that ORR will reach the predefined 
target for reference in subsequent development. 
10.2.   UMMERIES OF CONDUCT OF STUDY  
10.2.1. Analysis Populations 
Safety analysis set: consists of all subjects receiving at least one dose of investigational product. 
Efficacy analysis set: consists of all subjects with measurable baseline disease who received at 
least one dose of investigational product. It will be the primary analysis set for efficacy in this 
study. 
Note: Subjects who were screened but never started treatment will be listed, but not included in 
any efficacy analysis set. Therefore, these subjects will not be included in any of the summary 
tables. 
Dose-determining set: consists of all subjects from the safety analysis set who, in Cycle 1, 
meet the minimum exposure criterion and complete the follow-up on Cycle 1 Day 21 or 
discontinue the treatment due to DLT. 
A subject is considered to have met the minimum exposure criterion if in Cycle 1 the subject 


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has received ≥75% of the treatment (not necessarily consecutively). Subjects who do not meet 
these minimum safety evaluation requirements are considered to be ineligible for the dose-
determining set. Determination of the MTD uses subjects eligible for the dose- determining set. 
Pharmacokinetic analysis set: consists of all subjects who received at least one dose of 
investigational product and had at least one post-baseline pharmacokinetic assessment. 
Immunogenicity analysis set: consists of all subjects receiving at least one dose of 
investigational product and having available ADA data. 
Biomarker analysis set: consists of all subjects receiving at least one dose of investigational 
product and having available biomarker data. 
All analysis sets will be determined before the database is locked. 
Demographics and baseline profiles will be summarized in the safety analysis set, e.g. age, 
gender, baseline disease characteristics, ECOG status and prior anti-tumor therapeutic regimens. 
Baseline values refer to data obtained in the last measurement prior to administration of the first 
dose of the investigational product. 
Continuous data will be summarized using descriptive statistics (mean, median, standard 
deviation and range), and frequencies and percentages will be described for categorical data. 
10.3.   SAFETY ANALYSIS 
 
Adverse events and toxicities will be evaluated according to NCI-CTCAE v5.0. Safety assessment 
will be conducted through medical review of adverse events and laboratory values. The incidence 
of DLT in the DLT population will be evaluated by dose group. 
Treatment emergent adverse events (TEAE) will be summarized by preferred term, system organ 
class, NCI-CTCAE severity grade and causality with investigational product. 
TEAE is defined as (regardless of severity) 
• 
Any adverse event following initiation of treatment 
• 
Adverse event that exists at the time of initiation of treatment but begins to worsen 
following initiation of treatment 
• 
Adverse event that has occurred and remitted prior to treatment but recurs following 
initiation of treatment 
Vital signs (including weight changes) and clinical laboratory values will be descriptively 
summarized by dose. ECG data will be evaluated and any abnormality will be listed. A tabular 
listing and summary of subjects in whom treatment with the investigational product is 
discontinued due to AE will be provided. A listing of death data will be provided. 
10.4.   EFFICACY ANALYSIS 
 
Response based on investigators’ assessment will be collected while on study every 9 weeks 
within 1 year, and every 12 weeks thereafter according to RECIST v1.1. 
10.2.2 Demographics and Baseline 


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 
Objective Response: The number and proportion of subjects who achieve objective 
tumor response (CR or PR) will be summarized. Objective response rate will be 
determined along with 95% confidence interval. 
 
Progression Free Survival (PFS): PFS is defined as the time from the date of first 
study dose to disease progression or death (whichever occurs first). Subjects without 
event (no disease progression or death) will be censored at the date of “last tumor 
assessment”. Kaplan-Meier methodology will be used to estimate median PFS, PFS 
rate at various time points, and their 95% confidence intervals. Kaplan-Meier curves 
will be constructed to provide a visual description of the PFS change with time. 
 
Duration of Response: Duration of response for responders (CR or PR) is defined as 
the time interval between the date of the earliest qualifying response and the date of 
PD or death for any cause (whichever occurs earlier). For subjects who are alive 
without progression following the qualifying response, duration of response will be 
censored on the date of last evaluable tumor assessment or last follow-up for 
progression of disease. 
 
Time to Progression (TTP): TTP is defined as the time from the date of first study 
dose to disease progression. Subjects without event (no disease progression) will be 
censored at the date of “last tumor assessment”. Kaplan-Meier methodology will be 
used to estimate median TTP and 95% confidence interval. 
 
Disease Control Rate: Disease control rate (DCR) is defined as the proportion of 
subjects who achieve CR, PR, and SD based on RECIST v1.1. 
 
Overall Survival: Overall survival is defined as the time interval between the date of 
the first investigational product dose to the date of death from any cause. 
Kaplan-Meier methodology will be used to estimate median OS, OS rate at various time 
points, and their 95% confidence intervals. 
10.5.  PHARMACOKINETIC ANALYSES 
 
Pharmacokinetic parameters will be analyzed by standard non-compartmental methods with 
Phoenix WinNonlin (Version 6.3 or higher). Actual sampling times will be used in the final 
PK parameter calculations. 
PK parameters will include but not limited to: 
Single dose: peak concentration (Cmax, single), time to maximum serum concentration (Tmax), area 
under the concentration-time curve after drug administration (AUC0-τ); 
Repeated dose: peak concentration (Cmax, ss) at steady state, trough concentration (Ctrough, ss) at 
steady state, area under the concentration-time curve (AUCτ, ss), clearance rate at steady state 
(CLss/F (BLU-554), CLss (CS1001)). 
In order to evaluate the extent of accumulation after repeated doses, accumulation ratio will 
be calculated as below formulas: 
Accumulation coefficient of AUC = AUCτ, ss/AUC0-τ 
Accumulation coefficient of Cmax = Cmax, ss/Cmax, single 


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Where, ALU0-τ for BLU-554 and CS1001 refers to AUC0-24h, single and AUC0-21d, single respectively, 
AUCτ, ss refers to AUC0-24h, ss and AUC0-21d, ss respectively. Pharmacokinetic data will be presented in 
graphical and/or tabular form and will be summarized descriptively. 
Summary statistics including number, arithmetic mean, SD, geometric mean and coefficient of 
variation will be calculated for all PK parameters (for Tmax, only median and range will be 
calculated). 
10.6. IMMUNOGENICITY ANALYSES 
Immunogenicity assessment data will be summarized by dose level, including:  
Number and percentage of subjects with positive ADA assays at baseline 
Number and percentage of subjects with at least one positive ADA assay at any time point 
following administration of the first dose 
The relationship between CS1001 concentrations and ADA assessment results will be explored. 
10.7. BIOMARKER ANALYSES 
Measurement of biomarkers, such as the expression of FGF19 and PD-L1 in tumor cells and tumor-
infiltrating immune cells prior to treatment, will be presented based on available data. The 
correlation between measurement of the above indicators and clinical outcomes (e.g., antineoplastic 
efficacy) will be described in graphical and tabular forms. 
11. ETHICAL, REGULATORY AND OTHER REQUIREMENT 
11.1. HEALTH AUTHORITY APPROVAL 
The Sponsor will obtain approval from the appropriate regulatory authorities prior to initiating the 
study at study sites of this country, in accordance with the applicable country- specific regulatory 
requirements. 
11.2. ETHICAL CONDUCT OF THE STUDY AND ETHICAL APPROVAL 
This study will be conducted in accordance with (ICH)/ GCP and all applicable regulatory 
requirements, including, where applicable, the current Declaration of Helsinki. The investigator (or 
sponsor, if applicable) is responsible for obtaining the review and approval of the study protocol, 
informed consent form of site, and any other information provided to the potential subjects (e.g., 
advertisements or information supporting or supplementing the informed consent form). The 
investigator agrees that the Ethics Committee can obtain all relevant documents directly. The 
composition of the Ethics Committee must comply with all applicable regulatory requirements. The 
Sponsor will provide the investigator with relevant documents/ materials necessary for the review 
and approval of the study by the Ethics Committee. 
If the study protocol, informed consent form or any other information that have been available 
for potential subjects after approval of the Ethics Committee, is revised during the study, the 
investigator will be responsible for ensuring the approval of the Ethics Committee for these 
amendments (if applicable). The investigator must comply with all applicable regulatory 
requirements regarding the use of the revised informed consent form, including access to prior 


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approval of the revised informed consent form by the Ethics Committee before a new subject 
uses a new form to agree to participate in the study. The approval for revised ICF/ other 
information from the Ethics Committee and copies for approved revised ICF/ 
other information must be sent to the applicant in a timely manner. 
11.3. INFORMED CONSENT PROCESS 
The principal investigator at each site will: 
 
Ensure that each subject is provided with complete and adequate oral or written 
information about the nature, purpose, possible risks and benefits of the study. 
 
Ensure that each subject knows he/she can voluntarily discontinue the study at any 
time. 
 
Ensure that each subject is given an opportunity to ask questions and given the 
appropriate explanation by the investigator, and given sufficient time to consider the 
information provided. 
 
Ensure that each subject provides signed and dated informed consent forms prior to 
performing any study-related procedure. 
 
Ensure that the original signed informed consent form is maintained in the 
investigator’s study file. 
 
Ensure that a copy of the signed informed consent form is provided to the subject. 
11.4. CHANGES TO THE PROTOCOL AND INFORMED CONSENT FORM 
The study procedures may be modified only after the principal investigator is in consultation 
with the sponsor. 
If there are any significant changes to the study protocol, these changes must be documented in 
the amendment of the latest clinical study protocol if needed. The amendment should be 
approved by the appropriate Ethics Committee and national regulatory authorities (if applicable) 
prior to implementation. The protocol amendment should comply with local requirements. The 
sponsor will issue the latest version of the protocol and any amendment to each principal 
investigator. 
If a modification to the site’s Informed Consent is required for the protocol amendment, the 
sponsor and the Ethics Committee of the site will approve the informed consent amendment 
prior to using it. If requested by local authorities, any administrative change should be informed 
to and approved by each ethics committee. 
11.5. PROTOCOL ADHERENCE AND DEVIATION 
Please read the protocol completely and follow the instructions. Exceptions can be made, 
however, in emergency situations where the investigator or trained study personnel believe there 
is a need for immediate intervention for the protection, safety and well-being of the subject. 
In case of major protocol deviations due to emergency, accident or negligence, the investigator 
or designee must contact the medical monitor by telephone at earliest convenience. This makes 
a decision on whether or not the subject should continue the study as early as possible. The 
investigator, sponsor, and medical monitor will document the decision. 


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11.6.  STUDY CLOSURE  
At the end of the study, the monitor will perform the following activities with the investigator or 
study site personnel (if applicable): 
 
Return all study data to the sponsor. 
 
Data queries. 
 
Count, verification and disposition of study drugs not used. 
 
Check the integrity of the study records. 
 
Return all treatment numbers to the sponsor. 
 
Sending PK samples to the testing laboratory. 
In addition, the sponsor will reserve the right to suspend or permanently discontinue clinical 
trials at a study site or all sites at any time, including, but not limited to, for the reason of safety, 
ethical issues, or serious non-compliance. If the sponsor decides to take this action, the sponsor 
will fully discuss with the investigator (including the reason for action). If feasible, the sponsor 
will inform the investigator in advance of the measures taken. 
In the event of suspension or termination of the study for safety reasons, the sponsor will 
promptly inform all other participating investigators and/ or the study sites and will inform 
the regulatory authorities of the suspension or termination of the study and reasons for this 
action. If required by applicable regulations, the investigator must inform the Ethics 
Committee in a timely manner and provide reasons for suspension or termination. 
All study data must be returned to the sponsor if the study is terminated prematurely. In 
addition, all unused study drugs will be disposed of according to the sponsor's study-related 
procedures. 
Corresponding financial compensation will be provided to the investigator and/or site 
according to the agreement between the investigator and the sponsor. 
11.7. RECORDS RETENTION 
 
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken. The investigator 
must assure that all reproductions are legible, are a true and accurate copy of the original, and 
meet accessibility and retrieval standards, including re-generating a hard copy, if required. 
Furthermore, the investigator must ensure there is an acceptable back up of these reproductions 
and that an acceptable quality control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that site, as dictated by any site requirements or local laws or regulations, 
or the sponsor’s standards/procedures; otherwise, the retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility, transfer of ownership of the 


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records in the event that the investigator leaves the site. 
11.8. CLINICAL STUDY REPORT 
At the end of the trial a summary of the clinical study report will be provided to all Ethics 
Committees/Institutional Review Boards, to Health Authority concerned and to Investigators. 
11.9. CONFIDENTIAL AND PRIVACY 
The ICF will incorporate wording that complies with relevant data protection and privacy legislation. 
In some cases, such wording will be in a separate accompanying document. 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor and their treatments. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held 
in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All study activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IEC/IRB, 
regulatory agencies or pharmaceutical company supplying study product may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the subjects in this study. The clinical 
study site will permit access to such records. 
The study subject’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for 
as long a period as dictated by the reviewing IEC/IRB, institutional policies, or sponsor 
requirements. 
11.10. PUBLICATION PRIVACY 
For multi-center studies, the first publication or disclosure of study results shall be a complete, 
joint multi-center publication or disclosure coordinated by the sponsor. Thereafter, any secondary 
publications will reference the original publication(s). 
Prior to submitting for publication, presentation, use for instructional purposes, or otherwise 
disclosing the study results generated by the site (collectively, a “Publication”), the investigator 
shall provide the sponsor with a copy of the proposed publication and allow the sponsor a period 
of at least 30 days (or, for abstracts, at least 5 working days) to review the proposed publication. 
Proposed publications shall not include any sponsor information or any personal data on any 
subject other than the study results, such as name or initials. 
At the sponsor’s request, the submission or other disclosure of a proposed publication will be 
delayed a sufficient time to allow the sponsor to seek patent or similar protection of any 
inventions, know-how or other intellectual or industrial property rights disclosed in the proposed 
Publication. 
If a written contract for the conduct of the study, which includes publication provisions 
inconsistent with this statement is executed, that contract’s publication provisions shall apply 


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rather than this statement. 
11.11. INSURANCE, REIMBURSEMENT AND COMPENSATION 
CStone holds and will maintain an adequate insurance policy covering damages arising out of 
CStone’s sponsored clinical studies. 
CStone will indemnify the Investigator and hold him/her harmless for claims for damages 
arising out of the investigation, in excess of those covered by his/her own professional liability 
insurance, providing that the drug was administered under his/her or deputy’s supervision and 
in strict accordance with accepted medical practice and with the study protocol. 
The Investigator must notify CStone immediately in case of any claims or lawsuits. 
11.12.  (PREMATURE) TERMINATION OF THE STUDY 
• Both the Sponsor and the Investigator reserve the right to terminate the study at any 
time. Should this be necessary, the procedures for an early termination or temporary 
halt will be arranged after consultation by all involved parties. 
• Premature termination of this study may occur as the result of a Health Authority 
decision, change in opinion of the IRB/EC, or investigational product safety problems. 
In addition, CStone retains the right to discontinue development of this investigational 
product at any time. 
If a study is prematurely terminated, CStone will promptly notify the investigator. After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within (a time period set by CStone). As directed by CStone, all study materials 
must be collected and all eCRFs completed to the greatest extent possible. 
 
 


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12. ABBREVIATIONS 
 
Abbreviation 
Definition 
AASLD 
American Association for the Study of Liver Disease 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
ATP 
Adenosine triphosphate 
AST 
Aspartate aminotransferase 
AUC 
Area under the serum concentration 
BCLC 
Barcelona clinic liver cancer 
β-hCG 
Beta - human chorionic gonadotropin 
BID 
Bis in die 
BSC 
Best supportive care 
C 
Cycle 
CBC 
Complete blood count 
CL 
Clearance 
CNS 
Central nervous system 
Cmax 
Maximum observed serum concentration 
CR 
Complete response 
CRO 
Contract research organization 
CT 
Computed tomography 
Ctrough 
Minimum observed serum concentration 
CYP3A4 
Cytochrome P450 3A4 
CYP7A1 
Cholesterol 7-alpha hydroxy-lase 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
EASL 
European Association for the Study of the Liver 
EC50 
Effective concentration for 50% of maximal activity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCCI 
Electronic case report form completion guidelines 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOT 
End of treatment 
ERK 
Extracellular signal-regulated kinase 
FGF 
Fibroblast growth factor 
FGFR4 
Fibroblast growth factor receptor 4 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HCC 
Hepatocellular carcinoma 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest Non-Severely Toxic Dose 
IB 
Investigator's Brochure 


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Abbreviation 
Definition 
ICC 
Intrahepatic cholangiocarcinoma 
ICF 
Informed consent form 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
irAE 
Immune-related adverse event 
MTD 
Maximum tolerated dose 
Nab 
Neutralizing antibody 
NCI-CTCAE 
NCI Common Terminology Criteria for Adverse Event 
NSAID 
Nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PD-1 
Programmed cell death receptor-1 
PD-L1 
Programmed cell death factor ligand-1 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PO 
Peros 
PR 
Partial response 
 
 
PS 
Performance status 
PT 
Prothrombin time 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended Phase II dose 
SAE 
Serious adverse event 
SMC 
Safety monitoring committee 
t½ 
Half-life 
TKI 
Tyrosine kinase inhibitor 
TTP 
Time to progression 
UNL 
Upper normal limit 
Vss 
Apparent volume of distribution at steady state 


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13. REFERENCES 
 
[1] 
EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. 
J Hepatology 2012;56(4):908-43. 
[2] 
原发性肝癌诊疗规范（2017年版）. 
[3] 
胡韵清、顾思萌、叶丁等. 慢性乙型肝炎发生肝细胞癌风险预测模型的研究进展. 
中华传染病杂志. 2018, Vol 36(3):185-188. 
[4] 
Llovet JM, Bru C, Bruix J. prognosis of hepatocellular carcinoma: the BCLC staging 
classification. Semin Liver Dis 1999;19 (3):329-38. 
[5] 
Cillo U, Vitale A, Grigoletto F, Farinati F, Brolese A, Zanus G, et al. Prospective 
validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol 
2006;44(4):723-31. 
[6] 
Earl TM and Chapman WC. Hepatocellular carcinoma: Resection versus Transplantation. 
Semin Liv Dis 2013;33(3):282-92. 
[7] 
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in 
advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-90. 
[8] 
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of 
sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: 
a phase III randomized, double-blind, placebo-controlled trial. Lancet Oncol 
2009;10(1):25-34. 
[9] 
Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus sorafenib 
in patients with advanced hepatocellular carcinoma: results of a randomized phase III 
Trial. J Clin Oncol 2015;33(2):172-9. 
[10] Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib 
in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 
2013;31(32)4067-75. 
[11] Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et al. Brivanib versus 
sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular 
carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 
2013;31(28):3517-24. 
[12] Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of 
patients with unresectable hepatocellular carcinoma: a randomized phase 3 non- 
inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. 
[13] Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, et al. Phase 2 study of 
lenvatinib in patients with advanced hepatocellular carcinoma. J Gsatroenterol 
2017;52(4):512-519. 
[14] Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G et al. Regorafenib for patients 
with hepatocellular carcinoma who progressed on sorafenib treatment(RESORCE): a 
randomized , double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389(10064):56-
6. 
[15] El-Khouiery AB, Sangro B, Yau T, Crocenzi T, Kudo M, Hsu C, et al. Nivolumab in 
patients with advanced hepatocellular carcinoma(CheckMate 040): an open-label, non- 
comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017 
Apr;389(10088):2492-2502. 


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[16] Masafumi Ikeda, Chigusa Morizane, Makoto Ueno, et al. Japanese Journal of Clinical 
Oncology. 2018,48(2):103-11. 
[17] Degirolam C, Sabba C, and Moschetta A. Therapeutic potential of the endocrine 
fibroblast growth factors FGF19, FGF21 ans FGF23. Nat Rev Drug Discov. 2016 
Jan;15(1):51-69. 
[18] GLOBOCAB 2012: Estimated Cancer Incidence, Mortality and prevalence Worldwide 
in 2012. 
[19] Lake RA, et al. Immunotherapy and chemotherapy-a practical partnership. Nat Rev 
Cancer 2005; 26:141-148. 
[20] Liu S. and Yuan, Y. (2015). Bayesian Optimal Interval Designs for Phase I Clinical 
Trials, Journal of the Royal Statistical Society: Series C , 64, 507-523. 


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14.  APPENDIX  
14.1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.2.   APPENDIX 2: THE LATEST REVISED RECIST GUIDANCE (VERSION 1.1)  
The following text is from: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, 
Ford R, et al. New response evaluation criteria in solid tumors: revised RECIST guideline 
(Version 1.1). 
Definition 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). 
Changes in only the largest diameter (uni-dimensional measurement) of the tumor lesions are 
used in the RECIST criteria. Note: Lesions are either measurable or non-measurable using the 
criteria provided below. The term “evaluable” in reference to measurability will not be used 
because it does not provide additional meaning or accuracy. 
Measurable lesion 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm). 
• 10 mm caliper measurement by clinical exam (when superficial). 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
Unmeasurable lesion 
All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to <15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques 
are all non-measurable. 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable.  


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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same 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 subject to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Trial protocols should detail the conditions under 
which such lesions would be considered measurable. 
Target Lesions 
● 
During the assessment at baseline, all measurable lesions up to a maximum of 2 lesions 
per organ and 5 lesions in total should be identified as target lesions and be recorded and 
measured. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organ, but in addition should be those 
that are subject to reproducible repeated measurements. 
● 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. The short axis of the node is the diameter normally used by radiologists 
to judge if a node is involved by solid tumor. Nodal size is normally reported as 2 
dimensions in the plane in which the image is obtained (for CT scan this is almost always 
the axial plane; for MRI the plane of acquisition may be axial, saggital, or coronal). The 
smaller of these measures is the short axis. For example, an abdominal node which is 
reported as being 20 mm x 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 <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 to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
Non-target Lesions 
● 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are 
not required and these lesions should be followed as “present”, “absent”, or in rare cases 
“unequivocal progression” (more details to follow). In addition, it is possible to record 


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multiple non-target lesions involving the same organ as a single item on the case record 
form (e.g., “multiple enlarged pelvic lymph node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
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 follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are accessible by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm 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. As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the trial. 
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 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 or less. 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 is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review 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 complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are above the upper normal limit at baseline, 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 CA125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup has 


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developed CA125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
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. Case report 
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 eCRF. 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 


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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 in this instance 
should be the maximal longest diameter for the “coalesced lesion”. 
Evaluation 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. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing 
non-target lesions. (Note: the appearance of one or more new lesions is also considered 
progression). 
When the subject also has measurable disease: In this setting, for the determination of 
“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 has only non-measurable disease: This circumstance arises in some Phase III 
trials when it is not one of the inclusion criteria to have measurable disease. The same general 
concept as noted above applies here, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
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”. If “unequivocal progression” is seen, 


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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 very nature of that disease makes 
it impossible to do so, therefore the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
evaluations 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: i.e., not 
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 trial in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on trial 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. 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. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the investigational product 
treatment until the end of treatment taking into account any requirement for confirmation. On 
occasion that 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 


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of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the trial and the protocol requirements, it may 
also require confirmatory measurement. 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”. 
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 unevaluable. 
CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease. 
Note: 
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 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
 
SD 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-
PD Not 
evaluated Non-
PD or not all 
evaluated 
Non-PD or not 
all evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
 
 
No  
 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
SD 
NE 
PD 
PD 
PD 


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without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and in-evaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) 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 both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/ sensitivity. 
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. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure that the 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 clinical trials (phase II or III) or trials 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 review by the sites to protect against bias, in particular in trials 
which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at 
a minimum interval (in general not less than 6 weeks). 
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 progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 


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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 stable disease varies in different studies and diseases. If 
the proportion of subjects achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 


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14.3. APPENDIX 3: GUIDANCE FOR IMMUNE-RELATED ADVERSE REACTIONS 
MANAGEMEMT 
Identification, diagnosis, management of immune-related adverse events and dose adjustment 
method are listed in detail as following: 
 
irAE 
Potential 
signs and 
symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
Pneumonitis 
Symptomatic
: dyspnea, 
cough, 
pleuritic 
chest pain, 
hypoxia 
Asymptomati
c: lung 
infiltrates that 
mimic severe 
bacterial 
pneumonia 
• 
Radiographic 
imaging of chest 
• 
Observe the 
specimen of tissues 
and lavage fluids 
used in 
bronchoscopy to 
investigate 
infectious 
pathogens and 
perform a 
pathologic 
evaluations on them 
Moderate (Grade 2): 
administration of 
corticosteroids at a 
dose of 1-2 mg/kg/day 
prednisone equivalents 
Withhold the 
administration of 
CS10
until 
resolved to ≤ 
Grade 1 
Severe (≥ Grade 3): 
high dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
along with antibiotics; 
in-patient 
hospitalization; 
consultation with a 
respiratory physician; 
additional 
immunosuppression 
with infliximab can be 
considered 
Permanent 
discontinuation 
from the study 
Colitis 
Watery 
diarrhea, 
mucus or 
blood in 
stool, 
abdominal 
pain, 
nausea/vomiti
ng, 
dehydration, 
peritoneal 
signs, bowel 
perforation 
• 
Stool cultures 
• 
Endoscopy or 
colonoscopy to rule 
out infection 
• 
Biopsy to rule out 
alternative etiology 
Moderate (≤Grade 2) 
diarrhea: antidiarrheal 
medication, oral 
hydration, electrolyte 
supplement 
Continue dosing 
Persistent Moderate 
(Grade 2) diarrhea: 
administration of 
corticosteroids at a 
dose of 1-2 mg/kg/day 
prednisone equivalents 
Withhold the 
administration of 
CS1001 until 
resolved to ≤ 
Grade 1 
Severe (Grade 3) 
diarrhea: high dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
along with antibiotics; 
infliximab can be 
Withhold the 
administration of 
CS1001 until 
resolved to ≤ 
Grade 1 


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considered for steroid 
refractory diarrhea 
Recurrent severe 
(Grade 3) or life- 
threatening (Grade 4): 
high dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
along with antibiotics; 
Permanent 
discontinuation 
from the study 


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irAE 
Potential signs 
and symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
infliximab can be 
considered for steroid 
refractory diarrhea; in- 
patient hospitalization 
If bowel perforation is 
suspected, steroid 
should be withheld, 
and surgical opinion 
should be explored; in- 
patient hospitalization; 
Infliximab should not 
be administered 
Permanent 
discontinuation 
from the study 
Hepatitis 
Symptomatic: 
fever, fatigue, 
nausea, 
abdominal pain, 
hepatomegaly, 
Asymptomatic: 
elevation of liver 
function tests 
(hepatic 
transaminases, 
bilirubin) 
• 
Chemistry: 
elevated levels 
of hepatic 
transaminases 
• 
Serologic 
testing: should 
be performed to 
rule out viral 
hepatitis 
(including 
hepatitis A and 
B), 
cytomegaloviru 
s, and Epstein- 
Barr virus 
• 
Ultrasonograms 
of the liver 
• 
Biopsy or 
radiologic 
• 
Grade 2: 
administration of 
corticosteroids at 
a dose of 1-2 
mg/kg/day 
prednisone 
equivalents 
• 
For subjects with 
liver metastasis or 
HCC who entered 
the study with 
Grade 2 elevation 
of AST/ALT, 
investigational 
drug will be 
withheld if 
AST/ALT 
increase ≥ 50% 
relative to 
baseline. 
Withhold the 
administration of 
CS1001 until 
resolved to ≤ 
Grade 1 


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imaging to 
distinguish 
from other 
etiologies of 
hepatic injury, 
such as 
neoplastic 
disease 
progression in 
the liver, 
infections, and 
effects of other 
medications or 
alcohol intake 
• 
Severe (≥ Grade 
3): administration 
of high dose 
corticosteroids (2- 
4 mg/kg/day IV 
methylprednisolon 
e); if not improved 
after 48-72 hours, 
alternative 
immunosuppressi 
on agents 
(mycophenolate 
mofetil) should be 
considered; in- 
patient 
hospitalization; 
consultation with 
a hepatologist 
• 
For subjects with 
liver metastasis or 
HCC who entered 
Permanent 
discontinuation 
from the study 


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irAE 
Potential signs 
and symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
the study with 
Grade 2 elevation 
of AST/ALT, 
investigational 
drug will be 
permanently 
discontinued if 
AST/ALT 
increase ≥ 50% 
relative to 
baseline and 
lasting ≥1 week 
• 
Total serum 
bilirubin >3 times 
upper limit of 
normal 
Hypophysitis 
Headache 
refractory to 
nonsteroidal 
anti- 
inflammatory 
drugs or other 
analgesics; 
weakness; 
fatigue, weight 
gain or weight 
loss; changes in 
mood or 
behavior; 
hypotension; 
electrolyte 
disturbances; 
abdominal pain; 
loss of libido; 
adrenal crisis; 
hypogonadism 
• 
Clinical 
chemistry tests 
• 
Endocrinologic 
laboratory test, 
ACTH, thyroid 
function test, 
• 
Magnetic 
resonance 
imaging (MRI) 
of the brain: 
enlargement of 
the pituitary 
with variable 
contrast 
enhancement 
characteristics 
Grade 2 without 
adrenal crisis: high- 
dose corticosteroids 
(methylprednisolone 1 
to 2 mg/kg/day or the 
equivalent); initiate 
appropriate hormone 
replacement therapy; 
consultation with an 
endocrinologist 
Withhold the 
administration of 
CS1001 until 
resolved to ≤ 
Grade 1 
Severe (≥ Grade 3) or 
adrenal crisis: high- 
dose corticosteroids 
(methylprednisolone 1 
to 2 mg/kg/day or the 
equivalent); 
consultation with an 
endocrinologist 
Permanent 
discontinuation 
from the study 
Nephritis 
Hematuria, 
peripheral 
edema, elevated 
serum creatinine 
• 
Clinical 
chemistry tests 
• 
Urine test 
• 
Biopsy if 
necessary 
Moderate (Grade 2): 
administration of 
corticosteroids at a 
dose of 1-2 mg/kg/day 
prednisone equivalents 
Withhold the 
administration of 
CS1001 until 
resolved to ≤ 
Grade 1 


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Severe (≥ Grade 3): 
administration of 
corticosteroids at a 
dose of 1-2 mg/kg/day 
prednisone equivalents 
Permanent 
discontinuation 
from the study 
Hypothyroidism 
/hyperthyroidism 
Typically 
asymptomatic 
and is identified 
by lab tests 
T3, T4, TSH test 
results 
Asymptomatic 
Moderate (≤ Grade 2) 
hypothyroidism: 
thyroxine replacement 
therapy 
Continue dosing 
Asymptomatic 
Moderate (≤ Grade 2) 
Continue dosing 


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irAE 
Potential signs 
and symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
hyperthyroidism: 
consider beta blockade 
Severe (≥ Grade 3) 
hypothyroidism: 
replacement therapy 
Withhold the 
administration of 
CS1001 until 
resolved to 
asymptomatic 
Grade 2 or ≤ 
Grade 1 or 
baseline 
Severe (Grade 3) 
hyperthyroidism 
lasting ≥ 6 weeks 
despite active 
management: 
administration of 
corticosteroids at a 
dose of 1-2 mg/kg/day 
prednisone equivalents 
Withhold the 
administration of 
CS1001 until 
resolved to 
asymptomatic 
Grade 2 or < 
Grade 1 or 
baseline 
Life-threatening 
(Grade 4) 
hyperthyroidism 
Permanent 
discontinuation 
from the study 
Dermatitis 
Maculopapular 
rash or 
erythroderma, 
pruritus, skin 
ulceration, 
bullous 
dermatitis, 
Stevens-Johnson 
syndrome 
• 
Unless an 
alternative 
etiology is 
identified, it 
should be 
considered 
immune-related 
• 
Pathologic 
evaluation of 
skin biopsy can 
be performed to 
rule out 
alternative 
etiology 
Moderate (≤ Grade 2, 
up to 30% of body 
surface area): topical 
corticosteroids and 
oral over-the-counter 
antihistamines and 
systemic 
corticosteroids if no 
improvement within 7 
days 
Continue dosing 
Severe (Grade 3, > 
30% of body surface 
area): administration 
of corticosteroids at a 
dose of 1-2 mg/kg/day 
prednisone equivalents 
Withhold the 
administration of 
CS1001 until 
resolved to ≤ 
Grade 2 


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Life-threatening 
(Grade 4, Stevens- 
Johnson syndrome, 
toxic epidermal 
necrosis, full-thickness 
dermal ulceration, 
necrosis or 
hemorrhage): high 
dose corticosteroids 
(2-4 mg/kg/day IV 
methylprednisolone); 
in-patient 
hospitalization; 
consultation with a 
dermatologist 
Permanent 
discontinuation 
from the study 
Neuromuscular 
toxicity 
Peripheral 
sensory 
• 
Physical exam 
Moderate (≤ Grade 2): 
administration of 
Withhold the 
administration of 


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irAE 
Potential signs 
and symptoms 
Diagnosis and 
differential 
diagnosis 
Recommended 
management 
Dose modification 
neuropathy, 
muscle 
weakness, 
Guilliain-Barre 
syndrome, 
transverse 
myelitis, 
myasthenia 
gravis 
of sensory 
change, loss of 
deep-tendon 
reflexes 
• 
Neuroimaging, 
nerve 
conduction 
exam, 
• 
Nerve/muscle 
biopsy 
corticosteroids at a 
dose of 1-2 mg/kg/day 
prednisone equivalents 
CS1001 until 
resolved to ≤ 
Grade 1 
Severe (≥ Grade 3): 
high dose 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
Permanent 
discontinuation 
from the study 
Ocular toxicity 
Photosensitivity, 
pain or dryness 
of the eyes, 
blurred vision, 
uveitis, iritis, 
episcleritis 
• 
ophthalmic 
exam 
Moderate (≤ Grade 2): 
topical steroids (1% 
prednisolone) 
Withhold the 
administration of 
CS1001 until 
resolved to ≤ 
Grade 1; if not 
resolved ≤ Grade 1 
within 14 days 
with topical 
steroids or 
initiation of 
systemic 
treatment, 
permanent 
discontinuation 
from the study 
Severe (≥ Grade 3): 
high dose systemic 
corticosteroids (2-4 
mg/kg/day IV 
methylprednisolone) 
Permanent 
discontinuation 
from the study 
Other irAEs, 
such as arthritis, 
pancreatitis, 
hemolytic 
anemia, adrenal 
insufficiency, 
myasthenic 
syndrome, and 
rhabdomyolysis 
Moderate (Grade 2) 
Withhold the 
administration of 
CS1001 until 
resolved to ≤ 
Grade 1 
Severe (≥ Grade 3) 
Permanent 
discontinuation 
from the study 


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14.4.   APPENDIX 4: ECOG PERFORMANCE STATUS 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group 
Chair* 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but able to carry out work of a light or sedentary nature, 
e.g. light house work, 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 
Dead 
*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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14.5.   PPENDIX 5: NEW YORK HEART ASSOCIATION (NYHA) 
 
When there is a reasonable uncertainty that the symptoms or signs are not of cardiac origin, the 
diagnosis should be No heart disease. 
Functional Capacity 
Objective Assessment 
Class I. Subjects with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
A. No objective evidence 
of cardiovascular disease. 
Class II. Subjects with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
B. Objective evidence 
of mild cardiovascular 
disease. 
Class III. Subjects with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderate 
cardiovascular disease. 
Class IV. Subjects with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
*The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 


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14.6.   APPENDIX 6: Effective Controception Methods 
  
The following measures are considered to be effective conception methods: 
 
Diaphragm 
 
Intrauterine device 
 
Cervical cap 
 
Female condom 
 
Condom 
 
Spermicide 


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rate.  


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data) 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 


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study. 


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hemistry and urine routine, CK-MB 
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death, at any time after the subject has been permanently discontinued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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2019  
After revision: Version No.: 2.0; Version Date: 
Jun 26, 2019 
 


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SAP_001.pdf: 
Statistical Analysis Plan CS3008(BLU-554)-101 
Fisogatinib 
 
ClinicalTrials.gov Document Cover Page 
Statistical Analysis Plan 
Study CS3008(BLU-554)-101 
Study Title: A Muti-center, Open-label, Multiple-dose Phase Ib/II Study to Assess the Safety, 
Tolerability, Pharmacokinetics, Anti-tumor Efficacy of CS3008 (BLU-554) in Combination with 
CS1001 in Subjects with Locally Advanced or Metastatic Hepatocellular Carcinoma (HCC) 
Document Date: 09Nov2021 
NCT Number: NCT04194801 


1 
Statistical Analysis Plan 
 
Protocol Title 
A Muti-center, Open-label, Multiple-dose Phase Ib/II 
Study to Assess the Safety, Tolerability, Pharmacokinetics, 
Anti-tumor Efficacy of CS3008 (BLU-554) in Combination 
with CS1001 in Subjects with Locally Advanced or 
Metastatic Hepatocellular Carcinoma (HCC) 
Protocol No.:  
CS3008(BLU-554)-101 
Investigational Drug: 
CS3008（BLU-554）; CS1001 
Version Number: 
1.0 
Sponsor: 
CStone Pharmaceuticals (Suzhou) Co., Ltd. 
CStone Pharmaceuticals (Shanghai) Co., Ltd. 
Blueprint Medicines Corporation 
Written by: 
Hangzhou Tigermed Consulting Co., Ltd. 
Finalization date: 
November 09, 2021  
Revision date 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes an agreement that you will not disclose the 
information contained herein to others without written authorization from the sponsor. 
 
 


2 
Signature Page 
 
 
A Muti-center, Open-label, Multiple-dose Phase Ib/II Study to Assess the 
Safety, Tolerability, Pharmacokinetics, Anti-tumor Efficacy of 
CS3008(BLU-554) in Combination with CS1001 in Subjects with Locally 
Advanced or Metastatic Hepatocellular Carcinoma (HCC) 
 
CS3008(BLU-554)-101 
 
Statistical analysis plan 
 
Version No.: 1.0 
 
 
Written by: 
 
 
  
 
 
Date：November 9, 2021 
Senior Statistician 
Hangzhou Tigermed Consulting Co., Ltd. 
 
 
Reviewed by: 
  
 
 
 
 
 
 
Date：November 9, 2021 
 
Deputy General Manager of Data Statistics Business Unit 
Hangzhou Tigermed Consulting Co., Ltd. 
 
 
Approved by: 
 
 
 
 
 
 
Date：November 9, 2021 
Senior Biostatistician 
CStone Pharmaceuticals (Suzhou) Co., Ltd.  
 


3 
Table of Contents 
1. 
BACKGROUND .........................................................................................................5 
2. 
STUDY DESIGN.........................................................................................................5 
2.1 
PROTOCOL SYNOPSIS  ..............................................................................5 
2.2 
SAMPLE SIZE DETERMINATION ..............................................................5 
2.3 
TIME OF ANALYSIS 
 ..............................................................................7 
2.4 
OBJECTIVES AND ENDPOINTS .................................................................8 
2.4.1 Primary Objectives and Primary Endpoints of the Study ........................8 
2.4.2 Secondary Objectives and Secondary Endpoints of the Study ................8 
3. 
STATISTICAL METHODS ........................................................................................9 
3.1 
GENERAL PRINCIPLE  ..............................................................................9 
3.2 
ANALYSIS SETS 
 ..............................................................................9 
3.2.1 Safety Analysis Set (SAS) .......................................................................9 
3.2.2 Efficacy Analysis Set (EAS) ....................................................................9 
3.2.3 Dose-determining Set (DDS) ...................................................................9 
3.2.4 Immunogenicity Analysis Set (IMAS) ..................................................10 
3.2.5 Biomarker Analysis Set .........................................................................10 
3.3 
ANALYSIS OF STUDY IMPLEMENTATION...........................................10 
3.3.1 Subject Distribution  ............................................................................10 
3.3.2 Protocol Deviations  ............................................................................10 
3.3.3 Combined Medications ..........................................................................10 
3.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .......................11 
3.4.1 Demographics 
 ............................................................................11 
3.4.2 Medical History 
 ............................................................................11 
3.4.3 History of Antitumor Therapy ...............................................................11 
3.5 
SAFETY ANALYSIS 
 ............................................................................11 
3.5.1 Study Drug Exposure  ............................................................................11 
3.5.2 Dose-Limiting Toxicity .........................................................................11 
3.5.3 Adverse Event 
 ............................................................................12 
3.5.4 Dead 
 ............................................................................12 


4 
3.5.5 Laboratory Data 
 ............................................................................12 
3.5.6 12-lead ECG 
 ............................................................................13 
3.5.7 Echocardiogram 
 ............................................................................13 
3.5.8 ECOG Score 
 ............................................................................13 
3.5.9 Vital Signs 
 ............................................................................13 
3.6 
EFFICACY ANALYSIS  ............................................................................13 
3.7 
PHARMACOKINETIC AND IMMUNOGENICITY ANALYSES ............14 
3.7.1 Pharmacokinetic Analyses .....................................................................14 
3.7.2 Immunogenicity Analyses .....................................................................14 
3.8 
BIOMARKER ANALYSES ..........................................................................15 
3.9 
Missing Values 
 ............................................................................15 
3.10 
Interim Analysis 
 ............................................................................15 
4. 
LIST OF ABBREVIATIONS ....................................................................................16 
APPENDIX 1: PROTOCOL SYNOPSIS ..........................................................................17 
APPENDIX 2： SCHEDULE OF ACTIVITIES ..............................................................30 
APPENDIX 3 PROCESSING OF MISSING DATES ......................................................42 
 


5 
1. 
BACKGROUND 
This is a multi-center, open-label, multi-dose, dose-finding and extension study for evaluating the 
safety, tolerance, pharmacokinetics and antitumor efficacy profiles of BLU-554 in combination 
with CS1001 in subjects with locally advanced or metastatic HCC. 
The study consists of 2 parts, including a Part 1 (phase Ib) dose escalation and part 2 (phase II) dose 
expansion. Part 1 is a dose escalation study for determination of the MTD (Maximum tolerated dose) 
and/or RP2D (Recommended Phase II dose) of BLU-554 in the combination regimen and assess 
primary safety and tolerance of the combination regimen. Part 2 is a dose extension study in which 
preliminary evaluate the antitumor efficacy and the further evaluate the safety, tolerance, PK and 
immunogenicity of combination regimen. 
This Statistical Analysis Plan has been written based on the CS3008 (BLU-554)-101 study protocol 
(version number: 2.1, version date: July 28, 2020), and describes the content and methods of 
statistical analysis in this study in detail. 
2. 
STUDY DESIGN 
2.1 PROTOCOL SYNOPSIS 
For the protocol synopsis, see Appendix 1. For more details, see the Study Flowchart in Appendix 2. 
For study indicators, see the Protocol Synopsis. 
2.2 SAMPLE SIZE DETERMINATION 
It is planned to enroll not more than 12 subjects in the phase-Ib dose-escalation study. The observed 
toxicity will decide the actual sample size. 
According to efficacy result of BLU-554-1101 study (data cut-off date: 16 Jun 2018), ORR was 17% 
(11/63) for FGF19 IHC+ subjects (1st line and above) and 0 (0/38) for FGF19 IHC-subjects. ORR 
of PD-1/PD-L1 monotherapy was reported around 10~20% for 1st line and 2nd line HCC subjects. 
Based on the data above, BLU-554 in combination with CS1001 is targeting 40% ORR for FGF19 
IHC+ subjects and 30% ORR for FGF19 IHC- subjects. Combining the subjects treated at RP2D in 
Phase Ib and those in Phase II, gating criteria in Bayesian framework are developed as the 
following: 
Gating based on 25 FGF19 IHC+ subjects 
• 
A non-informative ORR prior is assumed at Beta (0.45, 0.55). 
• 
Timing - when all 25 subjects finish at least two post-baseline tumor assessments 
• 
Go - 12 responses or more, corresponding ORR 48%, the probability of combo ORR > 40% is 
0.788. 
• 
No go - 8 (32%) responses or fewer, the probability of combo ORR<40% is 0.797. 
• 
Evaluate - 9 (36%) to 11 (44%) responses, evaluate other endpoints, DOR, DCR, safety, etc., 
and additional 15 FGF19 IHC+ subjects may be enrolled for further evaluation. 
 


6 
Gating based on 40 FGF19 IHC+ subjects (if enrichment of 15 FGF19 IHC+ subjects as 
decided) 
• 
A non-informative ORR prior is assumed at Beta (0.45, 0.55). 
• 
Timing - when all 40 subjects finish at least two post-baseline tumor assessments 
• 
Go - 18 responses or more, corresponding ORR 45%, the probability of combo ORR > 40% is 
0.737. 
• 
No go - 14 (35%) responses or fewer, the probability of combo ORR<40% is 0.744. 
• 
Evaluate - 15 (37.5%) to 17 (42.5%) responses, evaluate other endpoints, DOR, DCR, etc. 
Gating based on FGF19 IHC- subjects treated at RP2D in Phase Ib 
• 
A non-informative ORR prior is assumed at Beta (0.2, 0.8). 
• 
Timing - only conducted if at least 6 FGF19 IHC- subjects are treated at RP2D in Phase Ib, 
when they finish at least two post-baseline tumor assessments 
• 
No go - 0 response, the probability of combo ORR<30% is greater than 0.99, Phase II will 
only include the FGF IHC+ cohort 
• 
Evaluate - 1 response or more, the cohort of FGF IHC- subjects will be included in Phase II 
Gating based on 15 FGF19 IHC- subjects 
• 
A non-informative ORR prior is assumed at Beta (0.2, 0.8). 
• 
Timing - when all 15 subjects finish at least two post-baseline tumor assessments 
• 
Go - 6 responses or more, corresponding ORR 40%, the probability of combo ORR > 30% is 
0.757. If the final decision for FGF19 IHC+ subjects is “go”, FGF19 IHC- subjects 
may also be included in the target population of future development. 
• 
No go - 3 (20%) responses or fewer, the probability of combo ORR<30% is 0.845. future 
development will not include FGF19 IHC- subjects in the target population. 
• 
Evaluate - 4 (26.7%) to 5 (33.3%) responses, evaluate other endpoints, DOR, DCR, etc. 
The sample sizes of 25 or 40 FGF19 IHC+ subjects and 15 FGF19 IHC- subjects are selected to 
have reasonably high probability of ORR exceeding the target when the go criteria are met or ORR 
being lower than the mono therapies when no-go criteria are met. 
The go and no-go criteria are set up to guide future development of the combination. They are not 
binding decision-making rules. 
If the actual numbers of evaluable subjects are different from those planned above, the same 
method will be used to calculate the posteriori probability that ORR will reach the predefined target 
for reference in subsequent development. 


7 
2.3 TIME OF ANALYSIS 
Phase Ib: Dose Escalation 
The MTD and/or RP2D of two dose levels and preliminary safety evaluation of BLU-554 in the 
combination regimen will be determined with the starting dose of 400 mg QD (once daily). CS1001 
1,200 mg Q3W (every 3 weeks) as the fixed dose will be the RP2D in the monotherapy phase I 
study CS1001-101. The dose escalation part will use the BOIN design. 
During the study period, an SMC consisting of the principle investigator, the CRO's representatives 
(CRA and other relevant person) and the sponsor’s representative will be established to review the 
safety data, PK data, efficacy data from the study and determine the escalation dose level and 
dosage regimen in dose escalation study so as to determine the MTD and RP2D selected for the 
extension study. The SMC will also decide whether or not to include unscheduled dose levels for 
the study. 
Phase II: Dose Expansion 
The primary objective of the dose expansion phase is to further evaluate the antitumor efficacy as 
well as the safety, tolerability, PK and immunogenicity of the combination regimen. Subjects will 
be enrolled into 2 groups based on FGF19 IHC expression: Group 1 will be HCC subjects with 
FGF19 IHC-, approximately 15 subjects will be enrolled; Group 2 will be HCC subjects with 
FGF19 IHC+, approximately 25 subjects will be enrolled, approximately total 40 subjects in 
expansion part. Data on phase Ib evaluation at RP2D will be used as the basis to determine whether 
to continue to enroll subjects with FGF19 IHC- in the dose expansion phase. If the statistically pre-
specified continuous evaluation range is reached, additional subjects with FGF19 IHC+ may be 
enrolled for further evaluation. FGF19 IHC test will be performed at central laboratory with FGF19 
IHC+ defined as ≥ 1% for inclusion assessment. 
Archived or fresh tumor samples must be provided for FGF19 and PD-L1 IHC test which will be 
performed at central laboratory. 
The imaging examinations of tumors shall be evaluated in accordance with RECIST v1.1. During 
the 1st year of the treatment, subjects will receive CT/MRI examination in the screen period and 
every 9 weeks (at the end of every 3 cycles). After 1 year of study, CT/MRI examinations shall be 
carried out once every 12 weeks (The investigator may increase the number of tumor evaluations 
where clinically indicated). 
Subjects will be monitored for anti-tumor activity, safety, tolerability, PK profile and host 
immunogenicity throughout the study from the day of first administration of study drugs up to 90 
days after the last administration or up to two-year treatment period of combination regimen. 
 
 
 


8 
 
2.4 OBJECTIVES AND ENDPOINTS 
2.4.1 Primary Objectives and Primary Endpoints of the Study 
Objectives: 
Endpoints: 
Primary 
Phase Ib: 
 To determine the MTD and/or RP2D of BLU- 
554 when being in combination with CS1001 in 
subject with advanced HCC. 
 To evaluate the safety and tolerability of BLU- 
554 in combination with CS1001. 
 Incidence of DLT during the administration of 
BLU-554 in combination with CS1001. 
 Safety: incidence and severity of AEs and 
SAEs, including laboratory tests, vital signs, 
and ECG 
 Tolerance: discontinuation and reduction of 
study drug dose 
Phase II: 
 To assess the anti-tumor efficacy of BLU-554 in 
combination with CS1001 
 
 To assess ORR based on RECIST v1.1 
2.4.2 Secondary Objectives and Secondary Endpoints of the Study 
Objectives: 
Endpoints: 
Secondary 
Phase Ib 
 
To assess the pharmacokinetics (PK) profile of 
BLU-554 in combination with CS1001. 
Pharmacokinetic parameters include, but are not 
limited to: 
 When combination with BLU-554, AUC, 
Cmax, tmax, CLss , accumulation ratio of 
CS1001. 
 
When combination with CS1001, AUC, 
Cmax, tmax, CLss/F, accumulation ratio of 
BLU-554 
 
To preliminary assess the anti-tumor activity of 
BLU-554 in combination with CS1001 
 To assess ORR, DOR, DCR, TTP, PFS and OS 
based on RECIST v1.1 
 
To assess the immunogenicity of CS1001 when 
administered in combination with BLU-554 
 Occurrence of anti-CS1001 antibody 
 
To correlate FGF19 and PD-L1 expression 
 
level with efficacy of BLU-554 in combination with 
CS1001 
 ORR, DOR, DCR, TTP, PFS and OS by 
FGF19 protein and PD-L1 protein level 
Phase II 
 
To assess the anti-tumor activity of BLU-554 in 
combination with CS1001. 
 To assess DOR, DCR, TTP, PFS and OS based on 
RECIST v1.1 
 
To evaluate the safety and tolerability of BLU- 
554 in combination with CS1001. 
 Safety: incidence and severity of AEs and 
SAEs, including laboratory tests, vital signs, 
and ECG 
 Tolerance: discontinuation and reduction of study 
drug dose 
 
To assess the pharmacokinetics (PK) profile of 
BLU-554 in combination with CS1001. 
Pharmacokinetic parameters include, but are not 
limited to: 
 When combination with BLU-554, AUC, Cmax, 
tmax, CLss, accumulation ratio of CS1001. 
  When combination with CS1001, AUC, Cmax, 
tmax, CLss/F, accumulation ratio of BLU-554. 
 
To assess the immunogenicity of CS1001 when 
 
administered in combination with BLU-554. 
 Occurrence of anti-CS1001 antibody 


9 
 
To correlate FGF19 and PD-L1 expression level 
with efficacy of BLU-554 in combination 
 
with CS1001 
 ORR, DOR, DCR, TTP, PFS and OS by 
FGF19 protein and PD-L1 protein level 
3. 
STATISTICAL METHODS 
3.1 GENERAL PRINCIPLE 
For statistical analysis, all calculations will be performed using SAS statistical analysis software 
version 9.4 and above. 
For quantitative indicators, descriptive statistics include the number of cases, mean, standard 
deviation, median, minimum, and maximum, and all of which, as well as geometric mean and 
coefficient of variation, are included in the pharmacokinetic analysis. Unless otherwise specified, 
the decimal places of minimums and maximums are consistent with the original data recorded in 
the database. Means, medians, and geometric means have one more decimal place than the original 
data recorded in the database, and standard deviations and coefficients of variation have two more 
decimal places than the original data recorded in the database. All statistics have a maximum of 
four decimal places. 
For categorical indicators, descriptive statistics include the number and percentage of cases. 
Percentages are rounded to one decimal place, and the percentage is not reported if the frequency is 
0. 
In the statistical test, if the P value is greater than or equal to 0.0001, 4 decimal places will be 
retained, and if the P value is less than 0.0001, “<.0001” will be used. 
Baseline is defined as the last valid measurement or recording prior to the first study treatment. 
Phase Ib data will be summarized and analyzed by dose group. Phase II data will be summarized 
and analyzed on an aggregate basis. 
3.2 ANALYSIS SETS 
All analysis sets will be identified prior to database lock. 
3.2.1 Safety Analysis Set (SAS) 
Safety analysis set consists of all subjects receiving at least one dose of investigational product. 
Subjects will be divided according to the treatment they receive. 
3.2.2 Efficacy Analysis Set (EAS) 
Efficacy analysis set consists of all subjects with measurable baseline disease who received at least 
one dose of investigational product. 
3.2.3 Dose-determining Set (DDS) 
Dose-determining set consists of all subjects from the safety analysis set who, in Cycle 1, meet the 
minimum exposure criterion and complete the follow-up on Cycle 1 Day 21 or discontinue the 
treatment due to DLT. 


10 
A subject is considered to have met the minimum exposure criterion if in Cycle 1 the subject has 
received ≥75% of the treatment (not necessarily consecutively). Subjects who do not meet these 
minimum safety evaluation requirements are considered to be ineligible for the dose-determining 
set. Determination of the MTD uses subjects eligible for the dose- determining set. 
3.2.4 Immunogenicity Analysis Set (IMAS) 
Immunogenicity analysis set consists of all subjects receiving at least one dose of investigational 
product and having available ADA data. 
3.2.5 Biomarker Analysis Set 
Biomarker analysis set consists of all subjects receiving at least one dose of investigational product 
and having available biomarker data. 
3.3 
ANALYSIS OF STUDY IMPLEMENTATION 
3.3.1 Subject Distribution 
The number of subjects who have signed the informed consent form, the number of subjects who 
have failed the screening, and the number of subjects who have used the study drug will be 
calculated. 
The number and percentage of subjects who have ended treatment with the study drugs BLU-554 
and CS1001, as well as the number and percentage of subjects who have ended treatment due to 
various reasons, will be calculated respectively. The number and percentage of subjects who have 
withdrawn from the study, as well as the number and percentage of subjects who have withdrawn 
from the study for various reasons will be calculated, and the reasons for ending treatment and 
withdrawing from the study will be tabulated. 
The number and percentage of subjects included in each analysis set will be calculated and 
tabulated. 
3.3.2 Protocol Deviations 
Based on the safety analysis set, important protocol deviations will be summarized and tabulated. 
3.3.3 Combined Medications 
The analysis will be based on the safety analysis set. 
According to the time of the use of combined medications and study drugs, combined medications 
will be classified into past medications and concomitant medications. 
Past medication refers to non-study medication that was started and ended before the first dose of 
study drug. 
Concomitant medication refers to a non-study medication that meets one of the following 
conditions: 
• 
Started at the same time or after the first dose of study drug. 
• 
Started before the first dose of study drug and continued after the first dose of study drug. 


11 
Concomitant medications will be coded according to the World Health Organization Drug 
Dictionary (WHO-DD) WHODrug-Global-B3 Version 202103. Past medications and concomitant 
medications will be summarized by 2-level Anatomical Therapeutic and Chemical classification 
system (ATC) and Preferred Term (PT). If a subject experiences multiple occurrences of the same 
ATC2 and PT, the subject will be counted only once under the ATC2 and PT. 
3.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
The analysis will be based on the safety analysis set. 
3.4.1 Demographics 
Demographic data including age, sex, race, height, weight, baseline Eastern Cooperative Oncology 
Group (ECOG) score, and other demographic data will be described and tabulated. 
3.4.2 Medical History 
Tumor diagnosis will be statistically described and tabulated. 
Medical histories other than tumors will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 24.0 and summarized by System Organ Class (SOC) and Preferred 
Term (PT) thereunder. 
3.4.3 History of Antitumor Therapy 
The history of antitumor drug treatment will be coded and summarized according to the WHO-DD 
WHODrug-Global-B3 202103 Version. 
Previous antitumor treatment regimens, including previous systemic treatment regimens, 
radiotherapy history, and history of tumor-related surgery/operation will be statistically described. 
3.5 
SAFETY ANALYSIS 
3.5.1 Study Drug Exposure 
The analysis will be performed based on the safety analysis set. 
The number of cycles of CS1001 treatment received by patients will be summarize and statistically 
described, and the cumulative exposure, time of exposure (weeks), dose intensity [cumulative 
exposure/time of exposure (weeks)], relative dose intensity (dose intensity/planned dose 
intensity*100%), and dose adjustment of the study drugs CS1001 and BLU-554 will be summarized 
respectively. 
The planned dose, the actual dose, the action taken before or during the injection, and the reason for 
the action will be tabulated. 
3.5.2 Dose-Limiting Toxicity 
The analysis will be performed based on the dose-determining set. 
Dose-limiting toxicity categories will be summarized and tabulated. 


12 
3.5.3 Adverse Event 
The analysis will be performed based on the safety analysis set. 
Adverse events will be coded using MedDRA Version 24.0 and graded according to the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 
The overall occurrences of treatment-emergent adverse events (TEAEs) will be summarized, and 
the overall incidence of various TEAEs will be calculated. 
For all treatment-emergent adverse events, grade 3 and above TEAEs, serious adverse events 
(SAEs), TEAEs related to the study drug, SAEs related to the study drug, immune-related TEAEs, 
infusion-related reactions, and TEAEs leading to discontinuation of the study drug, the number and 
percentage of subjects will be summarized by System Organ Class (SOC) and Preferred Term (PT). 
In addition, TEAEs will be summarized by System Organ Class, Preferred Term, and NCI-CTCAE 
severity. 
TEAE is defined as (regardless of severity) 
 
Any adverse event following initiation of treatment 
 
Adverse event that exists at the time of initiation of treatment but begins to worsen following 
initiation of treatment 
 
Adverse event that has occurred and remitted prior to treatment but recurs following initiation 
of treatment 
TEAEs leading to the adoption of actions related to the study drug need to be summarized 
separately based on being related or not related to the study drug. 
The incidences of various treatment-emergent adverse events will be calculated by SOC and PT 
thereunder. The default order of adverse event incidences is an inverted order of overall incidence, 
by SOC first and then by PT thereunder. If the overall incidence of two adverse events is the same, 
the adverse events will be sorted alphabetically. If a subject experiences multiple occurrences of an 
adverse event with the same SOC and PT, the subject will be counted only once under the SOC and 
PT. The incidences of treatment-emergent adverse events will be calculated by SOC, PT and 
severity. If a subject experiences multiple occurrences of an adverse event with the same PT, the 
subject will be counted only once under the PT and only the most severe occurrence will be counted. 
All adverse events, serious adverse events, grade 3 and above adverse events, adverse events related 
to the study drug, immune-related adverse events, adverse events leading to discontinuation of the 
study drug, and adverse events leading to death will be tabulated. 
3.5.4 Dead 
The analysis will be performed based on the safety analysis set. 
All death events will be summarized and tabulated. 
3.5.5 Laboratory Data 
The analysis will be performed based on the safety analysis set. 


13 
At each visit, changes from baseline in quantitative laboratory test results will be summarized, and 
qualitative results will be summarized for specific laboratory tests. 
Specific laboratory findings will be graded according to NCI CTCAE v5.0, and then a cross-
tabulation of NCI CTCAE grades for the worst post-baseline measurements versus baseline will be 
generated. 
For liver function laboratory data, the following will be summarized: alanine aminotransferase 
(ALT) or/and aspartate aminotransferase (AST) >= 3*upper limit of normal (ULN), and total 
bilirubin (TBIL) > 2*ULN or TBIL > 1.5*ULN; ALT and/or AST, ALT, AST >= 3*ULN, 5*ULN, 
10*ULN, 20*ULN; TBIL > 1.5*ULN, > 2*ULN; alkaline phosphatase (ALP) > 1.5*ULN. 
Abnormal clinical laboratory data results will be tabulated. 
3.5.6 12-lead ECG 
The analysis will be performed based on the safety analysis set. 
At each visit, the overall ECG evaluation will be summarized. 
All abnormal and clinically significant 12-lead ECG findings will be tabulated. 
3.5.7 Echocardiogram 
The analysis will be performed based on the safety analysis set. 
Echocardiographic findings will be summarized. 
All abnormal and clinically significant echocardiographic findings will be tabulated. 
3.5.8 ECOG Score 
The analysis will be performed based on the safety analysis set. 
Crosstabs summarizing the highest post-baseline ECOG scores relative to baseline scores will be 
summarized. 
3.5.9 Vital Signs 
The analysis will be performed based on the safety analysis set. 
Vital signs at each visit from baseline and their changes from baseline will be statistically described. 
3.6 
EFFICACY ANALYSIS 
The analysis will be performed based on the safety analysis set.  
The investigator will perform efficacy assessments according to the Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST v1.1). 
Objective Response (ORR): The number and proportion of subjects who achieve objective tumor 
response (CR or PR) will be summarized. Objective response rate will be determined along with 95% 
confidence interval. (Clopper-Pearson method). 


14 
Progression Free Survival (PFS): PFS is defined as the time from the date of first study dose to 
disease progression or death (whichever occurs first). Subjects without event (no disease 
progression or death) will be censored at the date of “last tumor assessment”. Kaplan-Meier 
methodology will be used to estimate median PFS, PFS rate at various time points, and their 95% 
confidence intervals. Kaplan-Meier curves will be constructed to provide a visual description of the 
PFS change with time. 
Duration of response (DOR): Duration of response (complete response or partial response) for 
responders is defined as the time interval between the date of the earliest qualifying response and 
the date of PD or death for any cause (whichever occurs earlier). For subjects who do not have 
progressive disease following the qualifying response, duration of response will be censored on the 
date of last evaluable tumor assessment. Subjects without tumor assessment records after the 
earliest date of qualifying response will be censored on the earliest date of qualifying response. The 
analysis method is the same as that of PFS. 
Time to Progression (TTP): TTP is defined as the time from the date of first study dose to disease 
progression. Subjects without event (no disease progression) will be censored at the date of “last 
tumor assessment”. The analysis method is the same as that of PFS. 
Disease Control Rate: Disease control rate (DCR) is defined as the proportion of subjects who 
achieve CR, PR, and SD based on RECIST v1.1. The disease control rate and its 95% confidence 
interval (Clopper-Pearson method) will be calculated. 
Overall Survival (OS): Overall survival is defined as the time interval between the date of the first 
investigational product dose to the date of death from any cause. Subjects who are still alive at the 
analysis cutoff date will be censored at the date of the last known survival. The analysis method is 
the same as that of PFS. 
3.7 
PHARMACOKINETIC AND IMMUNOGENICITY ANALYSES 
3.7.1 Pharmacokinetic Analyses 
See the dedicated PK SAP. 
3.7.2 Immunogenicity Analyses 
Based on the immunogenicity analysis set, the immunogenicity assessment data will be presented 
according to the following categories. 
 
Number and percentage of subjects with positive ADA assays at baseline 
 
Number and percentage of subjects with at least one positive ADA assay at any time point 
following administration of the first dose 
 
Number and percentage of subjects with a positive treatment-induced ADA test at any time 
point after the first dose 
 
Number and percentage of subjects with a positive treatment-enhanced ADA test result at any 
time point after the first dose 
 
Number and percentage of subjects with a treatment-independent ADA test result at any time 
point after the first dose 


15 
 
Number and percentage of subjects with an unevaluable ADA test result at any time point after 
first dose 
 
Overall ADA prevalence: total number and percentage of subjects with a positive treatment-
induced ADA test result, a positive treatment-enhanced ADA test result, a treatment-
independent ADA test result and an unevaluable ADA test result 
 
Overall ADA incidence: total number and percentage of subjects with a positive treatment-
induced ADA test result and a positive treatment-enhanced ADA test result 
Note: Treatment-induced ADA: The patient is ADA negative at baseline and ADA positive at any 
time after the first dose; 
Treatment-enhanced ADA: The patient is ADA positive at baseline and has an enhanced ADA 
detection signal at any time point after the first dose (the immunogenicity titer is 4 times the 
baseline immunogenicity titer); 
Treatment-independent ADA: The patient is ADA positive at baseline, and there is no enhancement 
in the ADA detection signal from the baseline titer at any time point after the first dose (the 
immunogenicity titer does not exceed the baseline immunogenicity titer), or the patient is ADA 
positive at baseline, and has all negative or deficient ADA test results after the first dose. 
Unevaluable ADA: The patient is ADA deficient at baseline and ADA positive at least once at any 
time point after the first dose. 
Those confirmed to be anti-CS1001 antibody positive were presented in the following categories. 
 
Number and percentage of subjects with a positive ADA neutralizing antibody (Nab) test 
result at baseline. 
 
Number and percentage of subjects with at least one positive Nab test result at any time point 
after the first dose. 
3.8 
BIOMARKER ANALYSES 
Measurement of biomarkers, such as the expression of FGF19 and PD-L1 in tumor cells and tumor-
infiltrating immune cells prior to treatment, will be presented based on available data. The 
correlation between measurement of the above indicators and clinical outcomes (e.g., antineoplastic 
efficacy) will be described in graphical and tabular forms. 
3.9 
MISSING VALUES 
Processing of missing values: Missing values will not be imputed. The processing and censoring of 
missing data for the efficacy portion is described in Section 3.5. For missing dates, please refer to 
Appendix 3 for the specific imputation method for calculation. The dates in the list will be listed as 
filled on the eCRF. 
3.10 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 


16 
4. 
LIST OF ABBREVIATIONS  
Abbreviation 
Full name of abbreviations 
Chinese Name 
ADA 
Anti-drug Antibody 
抗药抗体 
AE 
Adverse Event 
不良事件 
ALP 
Alkaline Phosphatase 
碱性磷酸酶 
ALT 
Alanine Transaminase 
丙氨酸氨基转移酶 
AST 
Aspartate Transaminase 
天冬氨酸氨基转移酶 
ATC 
Anatomical Therapeutic Chemical 
解剖学治疗学及化学分类系统 
CI 
Confidence Interval 
置信区间 
CR 
Complete Response 
完全缓解 
CT 
Computed Tomography 
计算机断层 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
不良反应通用术语事件标准 
CV 
Coefficient of Variation  
变异系数 
DCR 
Disease Control Rate 
疾病控制率 
DLT 
Dose-Limiting Toxicity  
剂量限制性毒性 
DOR 
Duration of Response 
缓解持续时间 
EAS 
Efficacy Analysis Set  
有效性分析集 
ECOG 
Eastern Cooperative Oncology Group 
美国东部肿瘤协作组 
ECG 
Electrocardiography 
12 导联心电图 
eCRF 
Electronic Case Report Form 
电子病例报告表 
IMAS 
Immunogenicity Analysis Set 
免疫原性分析集 
MedDRA 
Medical Dictionary for Regulatory Activities 
国际医学用语词典 
MTD 
Maximum Tolerated Dose 
最大耐受剂量 
MRI 
Magnetic Resonance Imaging 
磁共振 
Nab 
Neutralizing Antibodies 
中和抗体 
NCI 
National Cancer Institute 
国立癌症研究所 
ORR 
Objective Response Rate 
客观缓解率 
OS 
Overall Survival 
总生存期 
PD 
Progression 
疾病进展 
PD-L1 
Programmed Death Ligand-1 
程序性死亡受配体-1 
PFS 
Progression-Free Survival 
无进展生存期 
PK 
Pharmacokinetics 
药代动力学 
PKAS 
Pharmacokinetics Analysis Set 
药代动力学分析集 
PR 
Partial response 
部分缓解 
PT 
Preferred Term 
首选术语 
RECIST 
Response Evaluation Criteria in Solid Tumors  
实体瘤疗效评价标准 
RP2D 
Recommended Phase II Dose 
II 期临床推荐剂量 
SAS 
Safety Analysis Set 
安全性分析集 
SD 
Standard Deviation 
标准差 
SMC 
Safety Monitoring Committee 
安全监查委员会 
SOC 
System Organ Class 
系统器官分类 
TBIL 
Total Bilirubin 
总胆红素 
TEAE 
Treatment-Emergent Adverse Event 
治疗期间不良事件 
TTP 
Time to Progression 
至疾病进展时间 
ULN 
Upper Limit of Normal 
正常值上限 
WHO-DD 
WHO Drug Dictionary 
世界卫生组织药物词典 
 
 
 


17 
 
APPENDIX 1: PROTOCOL SYNOPSIS 
Sponsor: CStone Pharmaceuticals (Suzhou) Co., Ltd., CStone 
Pharmaceuticals (Shanghai) Co., Ltd., 
Blueprint Medicines Corporation 
Final product name: NA 
Investigational product: CS3008 (fisogatinib, BLU-554), CS1001 
Names of active substances: Fibroblast growth factor receptor 4 inhibitor, completely humanized 
IgG4-type recombinant anti- Programmed death ligand 1 (PD-L1) monoclonal antibody 
Title of study: 
A Muti-center, Open-label, Multiple-dose Phase Ib/II Study to 
Assess the Safety, Tolerability, Pharmacokinetics, Anti-tumor 
Efficacy of CS3008 (BLU-554) in Combination with CS1001 in 
Subjects with Locally Advanced or Metastatic Hepatocellular 
Carcinoma (HCC) 
CAT No.: 
JXHL1900045, CXSL900017 
Protocol No.: 
CS3008 (BLU-554) - 101 
Sites: 
20 sites as planned 
Duration of the study (first 
subject in to last subject out): 
Screening period (28 days prior to the initial administration), 
treatment period (at most 24 months) and follow-up period 
(safety follow-up period: at most 90 days; survival follow-up 
period: every 12 weeks until withdrawl of subjects or 
termination of study) 
Study Phase: 
Phase Ib/II 
This is a multi-center, open-label, multi-dose, dose-finding and extension study for evaluating the safety, 
tolerance, pharmacokinetics and antitumor efficacy profiles of BLU-554 in combination with CS1001 in 
subjects with locally advanced or metastatic HCC. 
The study consists of 2 parts, including a Part 1 (phase Ib) dose escalation and part 2 (phase II) dose 
expansion. Part 1 is a dose escalation study for determination of the MTD (Maximum tolerated dose) and/or 
RP2D (Recommended Phase II dose) of BLU-554 in the combination regimen and assess primary safety and 
tolerance of the combination regimen. Part 2 is a dose extension study in which preliminary evaluate the 
antitumor efficacy and the further evaluate the safety, tolerance, PK and immunogenicity of combination 
regimen. 
Phase 1b: Dose Escalation 
Primary Objectives 
Primary Endpoints 
 
To determine the maximum tolerated dose 
(MTD) and/or recommended Phase II dose 
(RP2D) of BLU-554 when being in 
combination with CS1001 in subjects with 
locally advanced or metastatic HCC. 
 
To evaluate the safety and tolerability of 
BLU-554 in combination with CS1001. 
 
Incidence of DLT (Dose-limiting toxicity) 
during the administration of BLU-554 in 
combination with CS1001. 
 
Safety: incidence and severity of AEs and 
SAEs, including laboratory tests, vital signs, 
and ECG 
 
Tolerance: discontinuation and reduction of 
study drug dose 
Secondary Objectives 
Secondary Endpoint 


18 
 To assess the pharmacokinetics (PK) profile 
of BLU-554 in combination with CS1001. 
Pharmacokinetic parameters include, but are not 
limited to: 
 
When being administered in combination 
with BLU-554, area under the serum 
concentration-time curve (AUC); Maximum 
serum concentration (Cmax); Time to 
maximum serum concentration (tmax); 
Clearance at steady state (CLss); 
accumulation ratio of CS1001. 
 
When being administered in combination 
with CS1001, AUC, Cmax, tmax, 
CLss/F, accumulation ratio of BLU-
554. 
 
To assess the preliminary anti-tumor 
activity of BLU-554 in combination with 
CS1001. 
 
To assess Objective response rate (ORR), 
the duration of response (DOR), disease 
control rate (DCR), time to progression 
(TTP), progression free survival (PFS) and 
overall survival (OS) based on RECIST 
v1.1. 
 To assess the immunogenicity of CS1001 
when being administered in combination 
with BLU-554. 
 Occurrence of anti-CS1001 antibody 
 To correlate FGF19 and PD-L1 expression 
level with efficacy of BLU-554 in 
combination with CS1001 
 
ORR, DOR, DCR, TTP, PFS and OS by 
FGF19 protein and PD-L1 protein level 
Phase II: Dose expansion 
Primary Objectives 
Primary Endpoints 
 
To assess the anti-tumor activity of BLU- 
554 in combination with CS1001. 
 
To assess ORR based on RECIST v1.1. 
Secondary Objectives 
Secondary Endpoint 
 
To assess the anti-tumor activity of BLU- 
554 in combination with CS1001. 
 
To assess the DOR, DCR, TTP, PFS and OS 
based on RECIST v1.1 
 
To evaluate the safety and tolerability of 
BLU-554 in combination with CS1001. 
 
Safety: incidence and severity of AEs and 
SAEs, including laboratory tests, vital signs, 
and ECG 
 
Tolerance: discontinuation and reduction of 
study drug dose 
 To assess the pharmacokinetics (PK) profile 
of BLU-554 in combination with CS1001. 
Pharmacokinetic parameters include, but are not 
limited to: 
 
When being administered in combination 
with BLU-554, AUC, Cmax, tmax, CLss, 
accumulation ratio of CS1001. 
 
When being administered in combination 
with CS1001, AUC, Cmax, tmax, CLss/F, 
accumulation ratio of BLU-554. 
 To assess the immunogenicity of CS1001 
when being administered in combination 
with BLU-554. 
 Occurrence of anti-CS1001 antibody 
 To correlate FGF19 and PD-L1 expression 
level with efficacy of BLU-554 in 
combination with CS1001 
 
ORR, DOR, DCR, TTP, PFS and OS by 
FGF19 protein and PD-L1 protein level 


19 
Study design: 
Both Phase Ib and Phase II can be divided into 3 periods, screening period, treatment period and follow-up 
period: 
 
The screening period is the 28 days prior to the first dose. 
 
During the treatment period, the subjects will be administered the study drug once every 21 days (3 
cycles). BLU-554 is taken orally (PO) once daily (QD); CS1001 is administered intravenously once 
every 21 days (Q3W). Subjects with advanced stage solid tumor will be imageologically evaluated by 
the investigators every 9 weeks (i.e. every 3 dosing periods) during the 1st year of treatment and every 
12 weeks after treatment for more than 1 year against Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1). The investigator may increase evaluation frequency if clinically indicated. The drug 
may be administered continually until presence of intolerable adverse reaction, disease progression, 
withdrawal of informed consent, loss to follow up, death or study termination. The duration of 
treatment may be up to 24 months. 
 
Follow-up period consists of safety follow-up period and survival follow-up period. The safety follow-
up period includes 90 days after the last dose of study drug, or until the initiation of a new anti-tumor 
treatment, whichever occurs earlier. Survival follow-up period will be performed every 12 weeks for 
collection of the survival status, subsequent anti-tumor therapies and study drug-related SAEs of the 
subjects until the death, loss to follow-up, withdrawal or termination of study, whichever occurs first. 
Refer to the Section 1.2 SOA for the study schedule. 
Phase Ib: Dose Escalation 
The MTD and/or RP2D of BLU-554 in the combination regimen will be determined using a BOIN dose 
escalation design. 2 dose levels of BLU-554 will be assessed with CS1001 1,200 mg Q3W as the fixed 
dose (RP2D in single-dose study). The planned dose escalation scheme is shown in Table 1 with 400 mg 
QD as the starting dose of BLU-554. Every 21 days (3 weeks) will be considered as one cycle. DLT 
assessment will be done within 21 days (Cycle 1) after the administration. Using BOIN design, the target 
toxicity probability of the MTD is 0.3 with a maximum sample size of 12. The cohort size included 3 
enrolled and treated subjects. The number can be modified based on subject’s enrollment. As shown in 错
误!未找到引用源。, the starting dose is dose level 1, i.e. BLU-554 400 mg QD in combination with 
fixed dose CS1001 1,200 mg Q3w. After complete DLT assessment for each cohort, the dose level for the 
next cohort was determined according to the dose escalation/decreasing rule in 错误!未找到引用源。. 
Repeat the step with every 3 subjects until a maximum sample size of 12 is reached, the dose escalation is 
ended (See Dose Escalation Flowchart for details). CS1001 is administered intravenously once every 3 
weeks (21 days). BLU-554 is taken orally once daily from Day 1 to Day 21; In case that the two study 
drugs would be administered on the same day, BLU-554 should be administered firstly. 
Table 1:Planned Dose Escalation Scheme 
Cohort 
BUL-554 
CS1001 
1 
400 mg QD 
1,200 mg Q3W 
2 
600 mg QD 
1,200 mg Q3W 
 
During the study period, an SMC consisting of the principle investigator, the CRO's representatives (CRA 
and other relevant person) and the sponsor’s representative will be established to review the safety data, 
PK data, efficacy data from the study and determine the escalation dose level and dosage regimen in dose 
escalation study so as to determine the MTD and RP2D selected for the extension study. The SMC will 
also decide whether or not to include unscheduled dose levels for the study. 
Phase II: Dose expansion: 


20 
The primary objective of the dose expansion phase is to primarily evaluate the antitumor efficacy as 
well as to further evaluate the safety, tolerability, PK and immunogenicity of the combination 
regimen. In this part, subjects will be enrolled into 2 groups according to the expression of FGF19 
immunohistochemistry (IHC): Group 1 will be advanced hepatocellular carcinoma subjects with 
FGF19 IHC-, the cancellation of which will be based on phase Ib data (see protocol 4.1 for details); 
Group 2 will be advanced hepatocellular carcinoma subjects with FGF19 IHC+. In case of being 
within the statistically pre-defined assessment range, additional subjects may be enrolled for further 
evaluation (see Protocol 4.1 for details). FGF19 expression will be determined at central laboratory by 
immunohistochemistry (IHC) with the inclusion criteria of FGF19 IHC+ defined as ≥ 1%. 
In Phase Ib and Phase II, archived or fresh tumor samples must be provided for FGF19 and PD-L1 
IHC test which will be employed at central laboratory. 
The tumors shall be evaluated in accordance with RECIST v1.1. During the 1st year of the treatment, 
subjects will receive CT/MRI examination every 9 weeks (every 3 cycles). After 1 year of treatment, 
CT/MRI examinations shall be carried out once every 12 weeks (The investigator may increase the 
frequency of tumor evaluations where clinically indicated). 
The data from subjects on anti-tumor activity, safety, tolerability, PK profile and host immunogenicity 
will be reviewed from the day of first administration of study drugs up to 90 days after the last 
administration or up to two-year treatment period of combination regimen 
 
. 


21 
 
● 
Dose Escalation Process: 
 
Planned number of subjects: 
Phase Ib: Approximately 12 subjects will be enrolled 
Phase II: Approximately 40 subjects will be enrolled 
Dose limiting toxicity (DLT) 
definition: 
Definition of DLT: All toxicity or adverse events (AEs) are graded 
according to NCI-CTCAE 5.0. Any AE occurring during C1 (21 
days) that is not clearly caused by something other than 
investigational drug: 
Hematological toxicity: 
● 
Grade 4 neutropenia that lasts for ＞7 days; 
● 
Grade ≥3 febrile neutropenia (ANC<1,000/mm3, with a single 
temperature of ≥38.3°C or a sustained temperature of ≥38°C 
for more than one hour); 
● 
Grade 3 neutropenia with infection; 


22 
● 
Grade 3 thrombocytopenia with clinically significantly 
bleeding; 
● 
Grade 4 thrombocytopenia; 
● 
Grade ≥4 anemia 
Non-hematological toxicity: 
● 
Grade ≥4 toxicity; 
● 
Grade 3 toxicity that fails to be resolved to ≤Grade 2, with the 
exception of diarrhea, nausea and vomiting; 
● 
Grade ≥3 immune-related adverse event (irAE); 
● 
Any Grade 3 tumor flare reaction (local pain, irritation or rash 
at known or suspected tumor focus) that lasts for 7 days or 
above; 
● 
Grade 3 or Grade 4 non-hematological laboratory 
abnormalities, if meet any of the followings: 
– need medical intervention 
– require hospitalization 
– last for >7 days 
and other toxicity of any grade that requires premature termination 
of the study as determined by the investigator and the sponsor 
through discussion. 
Definition of MTD: Based on BOIN design, MTD is the highest 
dose level at which 30% of the subjects experience DLT within 21 
days (Cycle 1) among which at least 6 subjects are available for 
DLT evaluation. The RP2D will be determined by SMC based on 
comprehensive 
data 
of 
safety 
and 
tolerability, 
PK, 
pharmacodynamics, and preliminary anti-tumor efficacy obtained 
during the dose escalation phase. The RP2D will not exceed the 
MTD and will be determined at a dose escalation meeting. 
Study Population: 
Inclusion Criteria: 
To meet the conditions for participation in this clinical study, 
subjects must: 
1. Voluntarily participate in the clinical study. Fully 
understand and get informed of this study and sign the 
Informed Consent Form (ICF). 
2. 
≥18 years of age on day of signing the informed consent. 
3. 
Unresectable locally advanced or metastatic hepatocellular 
carcinoma as confirmed by histology or cytology. 
4. 
Stage B or C based on Barcelona Clinic Liver Cancer 
(BCLC) staging system; In case of Stage B, subject must be 


23 
ineligible for surgery and/or local therapy, or has 
progressed after surgery and/or local therapy or refuses 
surgery and/or local treatment. 
5. 
For Phase Ib, subject has failed after or is unsuitable for the 
standard systemic therapy against HCC. For Phase II, 
subject has not previously received systemic therapy 
[systemic 
therapies 
mainly 
include: 
chemotherapy, 
molecular target drugs (e.g. tyrosine kinase inhibitors, 
TKI), immunotherapy (e.g. anti PD-1/PD-L1, CTLA-4 
etc.), biological therapy (e.g. tumor vaccine), cytokines, 
etc.)]. 
6. At least one measurable lesion as evaluable by RECIST 
version1.1, Target lesions within the field of prior efficacy 
irradiation or in the area of local treatment (intervention or 
ablation therapy) are considered measurable in case of 
confirmation of progression. 
7. 
Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) score of 0-1 point. 
8. 
A-level Child-Pugh score. 
9. 
Expected survival≥3 months. 
10. For Phase Ib and II, 9 formalin fixed-paraffin embedded and 
unstained tumor tissue slides should be provided for FGF19 
IHC and PD-L1 analysis in the central laboratory. 
 
Patients to be enrolled in the FGF19 IHC + arm in the Phase 
II study must be FGF19 IHC +; 
 
Patients to be enrolled in the FGF19 IHC - arm in the Phase 
II study must be FGF19 IHC – (whether this arm will be 
initiated or not will be decided based on Phase Ib data) 
11. Clinical laboratory screening criteria:  
  Absolute neutrophil count (ANC)≥1.5 × 
109/L  
 Platelet count≥ 75 × 109/L 
 Hemoglobin≥90 g/L 
 Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) ≤ 5 × ULN 
 Total bilirubin ≤ 2 ×ULN 
 International normalized ratio (INR) or prothrombin time 
(PT) ≤ 1.5 ×ULN (INR ≤ 1.5 × ULN and PT ≤ 1.5 × ULN, if 
both available) 
 Serum creatinine ≤ 1.5 ×ULN or creatinine clearance 
(CL)≥60 mL/min (Cockcroft-Gault Formula) 
Female: CrCl=(140-age) × weight (Kg) × 0.85  
72× serum creatinine (mg/dL) 
Male: CrCl=(140-age) × weight (Kg) × 1.00 
2× serum creatinine (mg/dL) 
12. For subjects with hepatitis C virus (HCV) infection, treatment 
with locally approved and available anti-HCV therapy is 


24 
required if HCV RNA is detected. 
13. For subjects with hepatitis B virus (HBV) infection, HBV 
DNA ≤ 2,000 IU/ml at Screening. 
 
Subject with HBV DNA (+), treatment with HBV antiviral 
therapy (as per the local standard of care) is required at least 
14 days prior to the initiation of study. 
 
Subject with HBsAg (+) and/or HBcAb (+), based on 
investigator assessment, HBV antiviral therapy may be 
applied if needed. 
14. For female subjects of childbearing potential, serum pregnancy 
test must be negative within 7 days prior to randomization. 
Except for female subjects who have been recorded as 
surgically sterilized or who are postmenopausal, female 
subjects of childbearing potential or male subjects and their 
partners must agree to use effective contraception from the 
signature of the informed consent form (ICF) until at least 6 
months after the last dose of study drug. Appendix 6: 
Effective Contraceptive Methods 
Exclusion Criteria: 
Subjects who meet any of the following criteria will not be eligible 
to participate in the study: 
1. Portal vein tumor thrombosis in the main trunk or 
contralateral first branch (VP4), involvement of the inferior 
vena cava or the heart as revealed by imaging at baseline. 
2. Prior or current history of hepatic encephalopathy. 
3. History of liver surgery and/or local treatment for HCC 
(intervention, ablation therapy, absolute alcohol injection, etc.) 
or radiotherapy, etc. within 4 weeks prior to first dose. 
4. Active or documented gastrointestinal bleeding within 6 
months (e.g. esophageal or gastric varices, ulcer bleeding). 
5. Presence of ascites detected by physical examination or clinical 
symptoms caused by ascites during the screening period, or 
ascites that need for special treatment, such as repeated 
drainage, or intraperitoneal drug infusion, etc. (Note: subjects 
with a small amount of ascites that can only be detected by 
imaging may be enrolled). Presence of uncontrolled pleural 
effusion or pericardial effusion (with clinical symptoms, 
requiring repeated drainage, or intrapleural or pericardial drug 
infusion, etc.) during the screening period. 
6. Presence of meningeal metastasis or central nervous system 
(CNS) metastatic lesions. 
7. According to the New York Heart Association (NYHA) 
Classification, subject has clinically significant, uncontrolled 
cardiovascular disease, including Grade III or IV congestive 
heart failure; myocardial infarction or unstable angina 
(within 6 months), uncontrolled hypertension (systolic blood 
pressure≥150 mmHg and diastolic blood pressure≥100 


25 
mmHg) or clinically significant uncontrolled arrhythmias, 
including bradycardia that may result in prolonged QT (e.g. 
Grade II or III heart block). Left ventricular ejection fraction 
(LVEF)<50%. QTc interval >480 msec (corrected using 
Fridericia’s formula). 
8. Subjects who have current interstitial lung disease or 
noninfectious pneumonitis, and prior history of interstitial 
lung disease or noninfectious pneumonitis that may affect 
the assessment or management of study drug-related 
pulmonary 
toxicity. 
Presence 
of 
active 
tuberculosis 
infection. 
9. Any serious acute, chronic infections that require systemic 
antimicrobial, antifungal or antiviral therapy at screening, 
excluding viral hepatitis. 
10. Malabsorption syndrome or inability to take the study drug 
orally for other reasons. 
11. Had primary malignancies other than HCC within 5 years. 
The following prior malignancies were excluded: completely 
excised skin basal cells and squamous cell carcinoma, local 
prostate cancer responsive to treatment, and carcinoma in 
situ with complete resection at any site. 
12. Subject has had major surgery within 4 weeks prior to first 
dose (procedures such as central venous cannulation, biopsy, 
and feeding tube placement are not considered as major 
surgery). 
13. Previously received FGFR4 inhibitor treatment. 
14. Blood transfusion, use of hematopoietic stimulating factors 
[including G-CSF (granulocyte colony stimulating factor), 
GM- CSF (granulocyte-macrophage colony stimulating 
factor), EPO (erythropoietin) and TPO (thrombopoietin)] 
and human albumin preparations within 14 days prior to first 
dose. 
15. Requiring corticosteroids (dose equivalent to > 10 mg/day of 
Prednisone) or other immunosuppressive drugs within 14 
days prior to first dose for systemic therapy. 
Note: For the absence of active autoimmune disease, it is 
allowed to use inhaled or topical steroids or adrenal hormone 
replacement therapy with equivalent dose of ≤10 mg/day 
prednisone. Short-term (≤ 7 days) use of corticosteroids for 
prophylaxis (e.g., contrast allergy) or for the treatment of 
non- autoimmune diseases (e.g., delayed hypersensitivity 
reactions due to contact allergens) is permitted. For subjects 
requiring hormone therapy, the dose administration should 
be done at least two days before and after the injection of 
CS1001. 
16. Use of traditional Chinese medicine (elemene, Kanglaite, 
Cinobufacin, Xiaoaiping, Huaier granule, Ganfule, Jinlong 
capsule, Aidi, etc.) with anti-liver cancer indication within 
14 days prior to the first dose. 
17. Subject has received potent CYP3A4 inhibitors and/or 
inducers within 2 weeks prior to first dose. See Appendix 8: 
Strong Inhibitors and Inducers of CYP3A4. 
18. Concurrent HBV and HCV infection (History of HCV 
infection, but subjects with HCV RNA(-) can be considered 


26 
as not being infected with HCV). 
19. Subjects with human immunodeficiency virus (HIV) 
infection. 
20. Pregnant or lactating women. 
21. Subjects 
with 
a 
history 
of 
hypersensitivity 
or 
hypersensitivity to any of the components of the 
investigational drug. 
22. Any previous or current clinically significant diseases, 
medical conditions, history of surgery, signs, or abnormal 
laboratory parameters that, in the opinion of the 
investigator, may increase the risks associated with study 
participation and study drug administration, or affect the 
subject's ability to receive study drug and reliability of 
study results; other circumstances that in the opinion of the 
investigator would preclude participation in the study. 
23. Subjects who are unwilling or unable to follow the study 
procedures as defined. Subjects with no or limited 
disposing capacity and with psychiatric disorders that 
may affect study compliance. 
24. With the exception of alopecia, all toxicities from prior 
anticancer therapies and other therapies did not recover 
to ≤ Grade 1 (per CTCAE v5.0) prior to the first dose of 
study drug. 
25. Subjects who have received prior allogeneic stem cell or 
solid organ transplantation. 
Definition of end of study: 
All subjects completed the treatment period, EOT visit, disease 
progression follow-up and survival follow-up or the Sponsor 
terminated the study (whichever occurred first). 
Test product, dose and mode of 
administration: 
BLU-554 capsule 100 mg will be taken by oral administration once 
daily. 
CS1001 injection 600 mg/20 ml/Bottle will be given via 
intravenous infusion on the first day of each treatment 
cycle, once every 21 days (3 weeks). 
Planned trial and treatment 
duration per subject: 
No more than 35 cycles (24 months) of study treatment followed 
by a 90-day safety follow-up. 


27 
Statistical methods: 
Analysis Populations 
Safety analysis set: consists of all subjects receiving at least one 
dose of investigational product. 
Efficacy analysis set: consists of all subjects with measurable 
baseline disease who received at least one dose of investigational 
product. It will be the primary analysis set for efficacy in this study. 
Note: Subjects who were screened but never started treatment will 
be listed, but not included in any efficacy analysis set. Therefore, 
these subjects will not be included in any of the summary tables. 
Dose-determining set: consists of all subjects from the safety 
analysis set who, in Cycle 1, meet the minimum exposure criterion 
and complete the follow-up on Cycle 1 Day 21 or discontinue the 
treatment due to DLT. 
A subject is considered to have met the minimum exposure criterion 
if in Cycle 1 the subject has received ≥75% of the treatment (not 
necessarily consecutively). Subjects who do not meet these 
minimum safety evaluation requirements are considered to be 
ineligible for the dose-determining set. Determination of the MTD 
uses subjects eligible for the dose-determining set. 
Pharmacokinetic analysis set: consists of all subjects who received 
at least one dose of investigational product and had at least one 
post-baseline pharmacokinetic assessment. 
Immunogenicity analysis set: consists of all subjects receiving at 
least one dose of investigational product and having available ADA 
data. 
Biomarker analysis set: consists of all subjects receiving at least 
one dose of investigational product and having available biomarker 
data. 
All analysis sets will be determined before the database is locked. 
Primary Analysis Method 
Safety: 
Safety assessments will include adverse events, vital signs, physical 
examination, electrocardiogram (ECG), echocardiography and 
laboratory tests. The incidence of DLT for each dose group will be 
assessed. All treatment-emergent adverse events (TEAEs) in each 
dose group are summarized by system organ classification and 
preferred terms. 
The relationship of the incidence and severity of all TEAEs to the 
investigational drug will be summarized. 
Descriptive summaries of laboratory tests and vital signs for each 
dose group will be made separately. Abnormal findings of 
laboratory tests, vital signs, ECG, echocardiograms will be listed. 
Efficacy: 
Efficacy assessments will be conducted according to RECIST v1.1, 
including ORR, PFS, DCR and DOR. The efficacy endpoint is the 
ORR assessed by the investigator and ORR for the subjects in each 


28 
dose group and overall ORR will be summarized. OS and PFS will 
be expressed by a Kaplan-Meier curve. 
Sample Size Determination 
According to efficacy result of BLU-554-1101 study (data cut-off 
date: 16 Jun 2018), ORR was 17% (11/63) for FGF19 IHC+ 
subjects (1st line and above) and 0 (0/38) for FGF19 IHC- subjects. 
ORR of PD-1/PD-L1 monotherapy was reported around 10~20% 
for 1st line and 2nd line HCC subjects. Based on the data above, 
BLU-554 in combination with CS1001 is targeting 40% ORR for 
1st line and 2nd line FGF19 IHC+ subjects and 30% ORR for 1st 
line and 2nd line FGF19 IHC- subjects. Combining all subjects 
treated at RP2D in Phase Ib and Phase II, gating criteria in Bayesian 
framework are developed as the following: 
Gating based on 25 FGF19 IHC+ subjects 
• 
A non-informative ORR prior is assumed at Beta (0.45, 0.55). 
• 
Timing - when all 25 subjects finish at least two post-baseline 
tumor assessments 
• 
Go - 12 responses or more, corresponding ORR 48%, the 
probability of combo ORR > 40% is 0.788. 
• 
No go - 8 (32%) responses or fewer, the probability of combo 
ORR<40% is 0.797. 
• 
Evaluate - 9 (36%) to 11 (44%) responses, evaluate other 
efficacy endpoints (DOR, DCR etc.) and safety. 
Gating based on 40 FGF19 IHC+ subjects (if enrichment of 15 
FGF19 IHC+ subjects as decided) 
• 
A non-informative ORR prior is assumed at Beta (0.45, 0.55). 
• 
Timing - when all 40 subjects finish at least two post-baseline 
tumor assessments 
• 
Go - 18 responses or more, corresponding ORR 45%, the 
probability of combo ORR > 40% is 0.737. 
• 
No go - 14 (35%) responses or fewer, the probability of combo 
ORR<40% is 0.744. 
• 
Evaluate - 15 (37.5%) to 17 (42.5%) responses, evaluate other 
efficacy endpoints (DOR, DCR, etc.) and safety. 
Gating based on FGF19 IHC - subjects treated at RP2D in Phase 
Ib 
• 
A non-informative ORR prior is assumed at Beta (0.2, 0.8). 
• 
Timing - only conducted if at least 6 FGF19 IHC- subjects are 
treated at RP2D in Phase Ib, when they finish at least two post- 


29 
baseline tumor assessments 
• 
No go - 0 response, the probability of combo ORR<30% is 
greater than 0.99, Phase II will only include the FGF IHC+ 
cohort 
• 
Evaluate - 1 response or more, the cohort of FGF IHC- 
subjects will be included in Phase II 
Gating based on 15 FGF19 IHC- subjects 
• 
A non-informative ORR prior is assumed at Beta (0.2, 0.8). 
• 
Timing - when all 15 subjects finish at least two post-baseline 
tumor assessments 
• 
Go - 6 responses or more, corresponding ORR 40%, the 
probability of combo ORR > 30% is 0.757. If the final 
decision for FGF19 IHC+ subjects is “go” (Gating based on 15 or 40 
FGF19 IHC+ subjects, as above said), FGF19 IHC- subjects may also 
be included in the target population of future development. 
• 
No go - 3 (20%) responses or fewer, the probability of combo 
ORR<30% is 0.845. Future development will not include 
FGF19 IHC- subjects in the target population. 
• 
Evaluate - 4 (26.7%) to 5 (33.3%) responses, evaluate other 
efficacy endpoints (DOR, DCR, etc.) and safety. 
The sample sizes of 25 or 40 FGF19 IHC+ subjects and 15 FGF19 
IHC- subjects are selected to have reasonably high probability of 
ORR exceeding the target when the go criteria are met or ORR 
being lower than the mono therapies when no-go criteria are met. 
The go and no-go criteria are set up to guide future development of 
the combination. They are not binding decision-making rules. 
If the actual numbers of evaluable subjects are different from those 
planned above, the same method will be used to calculate the 
posteriori probability that ORR will reach the predefined target for 
reference in subsequent development. 


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APPENDIX 2： SCHEDULE OF ACTIVITIES 
 
Table 2:Study Assessments and Procedures Schedule in Dose Escalation Part (Phase Ib) 
Phase Iba 
Screenin 
g 
Treatment (21d for each cycle) 
Follow-up 
Cycle 1 
Cycle 2 
≥Cyc 
le 3 
EOT 
visit b 
Safety follow-up c 
Survival 
follow-
up 
c 
1 
2 
3 
Days 
-28 to -1 
1 
2 
8 
15 
1 
15 
1 
0-7 
days 
post 
EOT 
date 
30 days 
post last 
dose 
60 days 
post last 
dose 
90 days 
post last 
dose 
Every 12 
weeks 
post last 
dose 
Time Window 
±2  
±2  
±4  
±4  
±4  
±7  
±7  
±7  
±7  
±7  
Informed Consent d 
X 
Inclusion/Exclusion Criteria 
X 
X 
Demographics 
X 
Medical History e 
X 
X 
Physical Examination f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy 
Test g 
X 
X h 
X 
X 
12-lead ECG i 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram j 
X 
As clinically indicated 
X 
Tumor Imaging k 
X 
Within 1 year: every 9 weeks ± 7 days (end of every 3 dose cycles), after 1 year: every 12 weeks ± 7 days; or based on 
the clinical needs. 
Blood test l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry, CK-MB l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, HBV, HCV m 
X 
X 
X 
X 
AFP m 
X 
X 
X 
Coagulation l 
X 
X 
X 
X 
X 
X 
Routine Urine Test 
X 
X 
X 
X 
X 
X 


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Thyroid Function n 
X 
X 
X 
X 
X 
X 
Tumor Sample 
X o 
CS1001 Administration p 
X 
X 
X 
BLU-554 Administration q 
X 
PK blood sample r 
X 
Immunogenicity Blood 
Sample r 
X 
Subsequent anti-tumor 
therapy s 
 
X 
X 
X 
X 
AE Monitoring 
X 
SAE Monitoring t 
X 
Concomitant Medications 
X 
Survival Status u 
X 
Abbreviations: AFP, Alpha-Fetoprotein; CT, computed tomography; CK-MB, creatine kinase-MB; ECOG, Eastern Cooperative Oncology Group; HBV, Hepatitis B 
Virus; HCV, Hepatitis C Virus; HIV, Human Immunodeficiency Virus; PK, pharmacokinetics. 
a. 
All visits should be performed as noted in Table 2. Additional safety tests (e.g., blood test, ECG) may be performed whenever clinically indicated, at the 
Investigator’s discretion. Unless otherwise indicated, all tests and procedures must be performed predose at each visit. Whenever a test result is questionable, it 
should be repeated immediately. Re-screening is permitted for one time, but need to decide by medical monitor and sponsor assessment. 
b. 
The date of the End of Treatment (EOT) visit is defined as the date on which the investigator decided to stop dosing. The EOT visit should be performed 0-7 
days post the EOT date. If the EOT visit and a treatment visit occur within 7 days, no tests are required for repeated items. If the EOT visit occurs within the 
safety follow-up window, no tests are required for repeated items. If an alternate treatment is started within 7 days of the EOT date, the EOT visit should be 
conducted prior to the first dose of alternate therapy. The last administration date is defined as the later last administration date of the two study drugs. It 
should be noted that the date on which the investigator decided to stop dosing may not coincide with the date of last dose. 
c. 
Safety visits: For subjects who have completed treatment, a safety visit should be conducted on the 30th day (±7 days), 60 days (±7 days), and 90 days (± 7 days) 
post the last dose; the safety follow-up at 90 day post the last dose can be conducted at the same day as that for the first survival follow-up. Survival follow-up: 
subjects will be contacted by telephone or in person every 12 weeks from the last dose of study drug to collect survival status, subsequent anti-tumor therapy, 
and study drug-related SAEs until the death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs first. 
d. 
Consent for the study may be obtained from the subjects by written. 
e. 
A complete medical history will be obtaining at the Screening visit. Only disease-related symptoms and changes from the previous visit need to be collected on 
C1D1. 
f. 
A complete physical examination will be performed at the Screening visit. Subsequent physical examinations will be disease- and AE-focused. 
g. 
To be performed for women with childbearing potential within 7 days of C1D1. A serum pregnancy test should be performed at Screening; thereafter, a serum 
or urine pregnancy test should be performed on every odd cycle (e.g., C3, C5). 
h. 
To be performed on D1 (±4 days) of every odd cycle starting with C3. 
i. 
ECGs (12-lead) exams will be performed after at least a 10 minute rest in the supine position. ECGs will be performed at Screening and during treatment, at 
EOT, and at Safety Follow-Up. In case of PK sampling, ECG should be performed for 3 consecutive times with an interval of 5 minutes each time in Cycle 1, 2 


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and 4. Refer to Table 4 and Table 5 for specific time. For other treatment cycles ECG should be performed at predose of any Cycle Day 1 dosing. For C1D2, 
ECG should be collected at predose. Frequency of ECGs may be increased if clinically indicated. 
j. 
To be performed as clinically indicated. 
k. 
Imaging assessment of tumors: Tumor assessment is conducted according to the standard RECIST v1.1. See the specific assessment standards in Appendix 2. 
The imaging assessment method of tumors may adopt CT or MRI as decided by the investigator, however, the assessment method, machine and technical 
parameters should remain consistent in the entire study period; if there is no contraindication, a contrast medium should be used. The imaging results will be 
interpreted by the investigator or radiologist of each site. In case a tumor assessment has been conducted within 28d before initial administration and by the 
same method and machine in the same hospital, the result can be adopted as baseline tumor assessment. Baseline tumor assessment should cover chest, abdomen, 
pelvic cavity and any other site suspected of tumor lesion (such as brain, bone lesions). Subjects with bone metastases during screening should be followed up 
using CT/MRI/X-ray at subsequent visits. Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days prior to the first dose (baseline 
assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter until (1) disease progression, (2) initiation of a new anti-tumor 
therapy, (3) withdrawal of informed consent, (4) loss of follow-up, (5) death, and (6) termination of the study, whichever occurs first. In case medication is 
discontinued permanently for a subject due to the reasons other than those above said (such as AEs), the tumor assessment will still be conducted as scheduled. 
The investigator can schedule additional imaging examination based on the subject's clinical condition. If an unscheduled tumor assessment is carried out and the 
disease has not progressed, subsequent tumor assessments should also be performed as scheduled. The confirmatory assessment must be completed 4 weeks after 
the efficacy is assessed as complete response (CR) or partial response (PR). If the investigator suspects that the progression of disease is pseudoprogression, then 
progression of disease must be confirmed in the imaging examination four weeks later or at the next scheduled imaging assessment time point (note: the  time 
point of the next imaging examination may not be later than 9 weeks after the initial confirmation of progression of disease). For a subject whose treatment is 
stopped before any clearly- disease progression, imaging examination results should be obtained as far as possible to conduct tumor efficacy assessment. In case 
a subject discontinues study treatment due to disease progression (excluding pseudoprogression), it will be unnecessary to repeat the step of imaging 
assessment in the last visit. If the subject has completed the imaging assessment of the tumor within 28 days prior to the EOT visit or safety visit, it is not 
required to repeat such examinations at the two visits. 
l. 
If the Screening visit tests are performed within 7 days of C1D1, clinical laboratory tests do not need to be repeated on C1D1 (i.e. there is a -7-day window for 
C1D1 labs). When laboratory tests (including blood test, blood biochemistry, myocardial enzyme, coagulation function, urinalysis, and thyroid function, if 
applicable) and study drug administration are scheduled to be conducted on the same day (e.g., Day 1 [D1] of each treatment cycle), the test results should be 
available before the administration can be scheduled. Except for the first dose, laboratory tests at each dosing visit should be completed within 3 days prior to 
dosing. If the subject has received relevant laboratory tests within the first 7 days of the EOT visit or safety visit 1, there is no need to repeat such tests at these 
two visits. 
m. 
Screening visit will be performed at the local laboratory, which includes HCV antibody, HBsAg, HIV antibodies. Subjects with HBsAg positive will further 
assess HBV DNA test, subject with HCV antibody positive will further assess HCV RNA test. Subjects with HBsAg positive need to be retested for HBV 
DNA every 12 weeks until safety follow-up 1; subjects with HCV antibody positive need to be retested for HCV RNA every 12 weeks until safety follow-
up 1; APF test will be done every 12 weeks until the EOT visit. 
n. 
Thyroid function examination covers free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) analysis, conducted respectively 
in the screening period, dosing in the first and second administration cycle, dosing every two subsequent administration cycles, EOT and in the safety follow-
up visit. If the thyroid function test at screening is performed within 7 days prior to the first dose (C1D1), it does not need to be repeated before the first dose 
(i.e., there is a -7-day window for the thyroid function test on C1D1). When thyroid function tests and study drug administration are scheduled to be conducted 
on the same day (eg, on Day 1 [D1] of the respective treatment cycle for thyroid function tests), the test results should be available before the administration 


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can be scheduled. Except for the first dose, the specified thyroid function tests performed at each dosing visit should be completed within 3 days prior to dosing. 
If subjects have completed the thyroid function examination within 7 days prior to the end of treatment visit or safety visit 1, there is no need to repeat such at 
these two visits. 
o. 
The tumor tissue used for FGF19 and PD-L1 IHC test will be sampled at screening and be analyzed at central laboratory. 
p. 
CS1001 will be given on D1 of each 21-day cycle. Each infusion should be completed over 60-120 minutes. The recommended infusion time for PK blood 
sample collection is 90 minutes, as shown in table 4 and table 5. 
q. 
BLU-554 will be administered qd in the morning with no food intake from 2 hours before until 1 hour after study drug administration. On study visit days when 
PK samples are collected, subjects will take their BLU-554 dose at the site. When the 2 study drugs are administered on the same day, BLU-554 should be 
administered before CS1001 infusion completion. After BLU-554 is administered, the subject should be given with CS1001 through intravenous infusion as 
soon as possible. 
r. 
Blood samples for PK and immunogenicity assessment refer to Table 4 and Table 5. 
s. 
Subsequent anti-tumor treatment: Information on subsequent (after the end of study treatment) anti-tumor therapies will be collected, including the name of all 
components of the treatment and the start and end dates of administration. 
t. 
If the investigator learns of any SAE (including death) in a subject after the subject has completed safety follow-up or has withdrawn from the study, and there is a 
reasonable cause to believe that the event is possibly related to the study drug, the investigator should notify the sponsor's pharmacovigilance team or 
representative. 
u. 
Survival status: Subjects will be contacted by telephone or in person every 12 weeks from the last dose of study drug to collect survival status, subsequent anti-
tumor therapy, and study drug-related SAEs until death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs first. 


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Table 3:Study Assessments and Procedures Schedule in Expansion Part (Phase II) 
Phase I1a 
Screening 
Treatment (21d for each cycle) 
Follow-up 
Cycle 1 
Cycle 
2 
≥Cycle 
3 
EOT visit b 
Safety follow-up c 
Survival 
follow-
up 
c 
1 
2 
3 
Days 
-28 to -1 
1 
2 
15 
1 
1 
0-7 days 
post EOT 
date 
30 days 
post last 
dose 
60 days 
post last 
dose 
90 days 
post last 
dose 
Every 12 
weeks 
post last 
dose 
Time Window 
±2  
±4  
±4  
±7  
±7  
±7  
±7  
±7  
Informed Consent d 
X 
Inclusion/exclusion Criteria 
X 
X 
Demographics 
X 
Medical History e 
X 
X 
Physical Examination f 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
Serum or Urine Pregnancy Test 
g 
X 
X h 
X 
X 
12-lead ECG i 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram j 
X 
As clinically indicated 
X 
Tumor Imaging k 
X 
Within 1 year: every 9 weeks ± 7 days (end of every 3 dose cycles), after 1 year: every 12 weeks ± 7 days; or based 
on the clinical needs. 
Blood testl 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry, CK-MB l 
X 
X 
X 
X 
X 
X 
X 
HIV, HBV, HCV m 
X 
X 
X 
X 
AFPm 
X 
X 
X 
Coagulation l 
X 
X 
X 
X 
X 
X 
Routine Urine Test 
X 
X 
X 
Thyroid Function n 
X 
X 
X 
X 
X 
X 
Tumor Sample 
X o 


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CS1001 Administration p 
X 
X 
X 
BLU-554 Administration q 
X 
PK Blood Sample r 
X 
Immunogenicity Blood Sample 
r 
X 
Subsequent anti-tumor therapy s 
 
X 
X 
X 
X 
AE Monitoring t 
X 
SAE Monitoring 
X 
Concomitant Medications 
X 
Survival Status u 
X 
Abbreviations: AFP, Alpha-Fetoprotein; CT, computed tomography; CK-MB, creatine kinase-MB; ECOG, Eastern Cooperative Oncology Group; HBV, Hepatitis B 
Virus; HCV, Hepatitis C Virus; HIV, Human Immunodeficiency Virus; PK, pharmacokinetics. 
a. 
All visits should be performed as noted in Table 3. Additional safety tests (e.g., blood test, ECG) may be performed whenever clinically indicated, at the 
Investigator’s discretion. Unless otherwise indicated, all tests and procedures must be performed predose at each visit. Whenever a test result is questionable, 
it should be repeated immediately. Re-screening is permitted for one time, but need to decide by medical monitor and sponsor assessment. Repeated 
screening is allowed for once and central laboratory-confirmed FGF19 IHC results obtained at screening # 1 may be used in the assessment of FGF19 IHC 
status at repeated screening without recollecting tumor samples for testing. It is recommended that the screening of FGF19 IHC status be performed first and 
then clinical screening continue when FGF19 IHC screening results are acceptable.  
b. 
The date of the End of Treatment (EOT) visit is defined as the date on which the investigator decided to stop dosing. The EOT visit should be performed 0-7 
days after the EOT date. If the EOT visit and a treatment visit occur within 7 days, no tests are required for repeated items. If the EOT visit occurs within the 
safety follow-up window, no tests are required for repeated items. If an alternate treatment is started within 7 days of the EOT date, the EOT visit should be 
conducted prior to the first dose of alternate therapy. The last administration date is defined as the later last administration date of the two study drugs. It 
should be noted that the date on which the investigator decided to stop dosing may not coincide with the date of last dose. 
c. 
Safety visits: For subjects who have completed treatment, a safety visit should be conducted on the 30th day (±7 days), 60 days (±7 days), and 90 days (± 7 days) 
post the last dose; the safety follow-up at 90 day post the last dose can be conducted at the same day as that for the first survival follow-up. Survival follow-up: 
Subjects will be contacted by telephone or in person every 12 weeks from the last dose of study drug to collect survival status, subsequent anti-tumor therapy, 
and study drug-related SAEs until death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs first. 
d. 
Consent may be obtained from the subjects by written. 
e. 
A complete medical history will be obtaining at the Screening visit. Only disease-related symptoms and changes from the previous visit need to be collected 
on C1D1. 
f. 
A complete physical examination will be performed at the Screening visit. Subsequent physical examinations will be disease- and AE-focused. 
g. 
To be performed for women of childbearing potential within 7 days of C1D1. A serum pregnancy test should be performed at Screening; thereafter, a serum or 
urine pregnancy test should be performed on every odd cycle (e.g., C3, C5). 
h. 
To be performed on D1 (±4 days) of every odd cycle starting with C3. 
i. 
ECGs (12-lead) exams will be performed after at least a 10 minutes rest in the supine position. ECGs will be performed at Screening and during treatment, at 


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EOT, and at Safety Follow-Up. In case of PK sampling, ECG test should be perfomed for 3 consecutive times with an interval of 5 minutes each time in Cycle 1, 
2 and 4. Refer to Table 4 and Table 5 for specific time.For other treatment cycles ECG should be performed at predose of any Cycle Day 1 dosing. For C1D2, 
ECG should be collected at predose. Frequency of ECGs may be increased if clinically indicated. 
j. 
To be performed as clinically indicated. 
k. 
Imaging assessment of tumors: Tumor assessment is conducted according to the standard RECIST v1.1. See the specific assessment standards in Appendix 2. The 
imaging assessment method of tumors may adopt CT or MRI as decided by the investigator, however, the assessment method, machine and technical parameters 
should remain consistent in the entire study period; if there is no contraindication, a contrast medium should be used. The imaging results will be interpreted by the 
investigator or radiologist of each site. In case a tumor assessment has been conducted within 28d before initial administration and by thesame method and machine 
in the same hospital, the result can be adopted as baseline tumor assessment. Baseline tumor assessment should cover head, chest, abdomen, pelvic cavity and any 
other site suspected of tumor lesion (such as brain, bone lesions). Subjects with bone metastases during screening should be followed up using CT/MRI/X- ray at 
subsequent visits. Subjects who have no brain metastases confirmed by imaging at screening will not be required to undergo regular brain imaging at subsequent 
visits, which may be scheduled by the investigator as clinically indicated. Imaging (CT or MRI) assessments per RECIST v1.1 will be performed within 28 days 
prior to the first dose (baseline assessment), every 9 weeks during the first year of the study, and every 12 weeks thereafter until (1) the disease progression, (2) 
initiation of a new anti-tumor therapy, (3) withdrawal of informed consent, (4) loss of follow-up, (5) death, and (6) the termination of the study, whichever occurs 
first. In case medication is discontinued permanently for a subject due to the reasons other than those above said (such as AEs), the tumor assessment will still be 
conducted as scheduled. The investigator can schedule additional imaging examination based on the subject's clinical condition. If an unscheduled tumor 
assessment is carried out and the subject has not progressed, subsequent tumor assessments should also be performed as scheduled. The confirmatory assessment 
must be completed 4 weeks after the efficacy is assessed as complete response (CR) or partial response (PR). If the investigator suspects that the progression of 
disease is pseudoprogression, then progression of disease must be confirmed in the imaging examination four weeks later or at the next scheduled imaging 
assessment time point (note: the time point of the next imaging examination may not be later than 9 weeks after the initial confirmation of progression of disease). 
For a subject whose treatment is stopped before any clearly- disease progression, imaging examination results should be obtained as far as possible to conduct 
tumor efficacy assessment. In case a subject discontinues study treatment due to the progression of disease (excluding pseudoprogression), it will be unnecessary 
to repeat the step of imaging assessment in the last visit. If the subject has completed the imaging assessment of the tumor within 28 days prior to the EOT visit or 
safety visit, it is not required to repeat such examinations at the two visits. 
l. 
If the Screening visit tests are performed within 7 days of C1D1, clinical laboratory tests do not need to be repeated on C1D1 (i.e. there is a -7-day window for 
C1D1 labs). When laboratory tests (including blood test, blood biochemistry, myocardial enzyme, coagulation function, urinalysis, and thyroid function, if 
applicable) and study drug administration are scheduled to be conducted on the same day (e.g., Day 1 [D1] of each treatment cycle), the test results should be 
available before the administration can be scheduled. Except for the first dose, laboratory tests at each dosing visit should be completed within 3 days prior to 
dosing. If the subject has received relevant laboratory tests within the first seven days of the EOT visit or safety visit 1, there is no need to repeat such tests at 
these two visits. 
m. 
Screening visit will be performed at the local laboratory, which includes HCV antibody, HBsAg and HIV antibodies. Subjects with HBsAg positive will further 
assess HBV DNA test, subject with HCV antibody positive will further assess HCV RNA test. Subjects with HBsAg positive need to be retested for HBV DNA 
every 12 weeks until safety follow-up 1; subjects with HCV antibody positive need to be retested for HCV RNA every 12 weeks until safety follow-up 1; 
AFP test is required at baseline, and will be done every 12 weeks until the EOT visit.. 
n. 
Thyroid function examination covers free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) analysis, conducted respectively 
in the screening period, dosing in the first and second administration cycle, dosing every two subsequent administration cycles, EOT and in the safety follow-
up visit. If the thyroid function test at screening is performed within 7 days prior to the first dose (C1D1), it does not need to be repeated before the first dose 
(i.e., there is a -7-day window for the thyroid function test on C1D1). When thyroid function tests and study drug administration are scheduled to be conducted 


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on the same day (eg, on Day 1 [D1] of the respective treatment cycle for thyroid function tests), the test results should be available before the administration 
can be scheduled. Except for the first dose, the specified thyroid function tests performed at each dosing visit should be completed within 3 days prior to dosing. 
If subjects have completed the thyroid function examination within 7 days prior to the end of treatment visit or safety visit, there is no need to repeat such at 
these two visits. 
o. 
The tumor issue used for FGF19 and PD-L1 IHC test will be sampled at screening and be analyzed at central laboratory. 
p. 
CS1001 will be given on D1 of each 21-day cycle. Each infusion at Cycle 1 should be completed over 60-120 minutes. The recommended infusion time for PK 
blood sample collection is 90 minutes, as shown in table 4 and table 5. 
q. 
BLU-554 will be administered qd in the morning with no food intake from 2 hours before until 1 hour after study drug administration. On study visit days when 
PK samples are collected, subjects will take their BLU-554 dose at the site. When the 2 study drugs are administered on the same day, BLU-554 should be 
administered before CS1001 infusion completion. After BLU-554 is administered, the subject should be given with CS1001 through intravenous infusion as 
soon as possible. 
r. 
Blood samples for PK and immunogenicity assessment refer to Table 4 and Table 5. 
s. 
Subsequent anti-tumor treatment: Information on subsequent (after the end of study treatment) anti-tumor therapies will be collected, including the name of all 
components of the treatment and the start and end dates of administration. 
t. 
If the investigator learns of any SAE (including the death) in a subject after the subject has completed safety follow-up or has withdrawn from the study, and there 
is a reasonable cause to believe that the event is possibly related to the study drug, the investigator should notify the sponsor's pharmacovigilance team or 
representative. 
u. 
Survival status: Subjects will be contacted by telephone or in person every 12 weeks from the last dose of study drug to collect survival status, subsequent anti-
tumor therapy, and study drug-related SAEs until death, loss of follow-up, withdrawal from the study, or study termination, whichever occurs first. 


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Table 4: Schedule for PK and Immunogenicity Blood Sampling by Study Drugs in Phase Ib 
BLU-554a 
CS1001a 
ECGa, e 
Day 
Time 
Time window 
PK 
Samplin 
g 
Time 
Time window 
PK 
Samplin 
g 
ADA 
Sampling of 
CS1001 
Cycle 1 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 dosing 
b 
  
CS1001 dosingb 
30 min 
± 5 min 
X 
1h 
± 5 min 
X 
2hc, e 
± 10 min 
X 
EOI+30 minc, e 
± 15 min 
X 
X 
4h 
± 15 min 
X 
6h 
± 15 min 
X 
7.5h 
  
EOI+6h 
± 30 min 
X 
8h 
± 30 min 
X 
D2 
24hd 
± 1h 
X 
EOI+22.5hd 
± 1h 
X 
X 
D8 
168h 
  
EOI+168 h 
± 1 day 
X 
D15 
336h 
  
EOI+336h 
± 1 day 
X 
Cycle 2 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
  
CS1001 dosingb 
30 min 
± 5 min 
X 
1h 
± 5 min 
X 
2h 
± 10 min 
X 
X 
4h 
± 15 min 
X 
6h 
± 15 min 
8h 
± 30 min 
X 
D2 
24hd 
± 1h 
X 


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BLU-554a 
CS1001a 
ECGa, e 
Day 
Time 
Time window 
PK 
Sampling 
Time 
Time 
window 
PK 
Sampling 
ADA 
Sampling of 
CS1001 
Cycle 4 
D1 
 
0 (Predose 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
CS1001 dosingb 
 
EOI+30 min 
± 15 min 
X 
X 
EOI+6h 
± 30 min 
X 
D2 
EOI+22.5hd 
± 1 h 
X 
D8 
EOI+168 h 
± 1 d 
X 
D15 
EOI+336h 
± 1 d 
X 
Cycle 5 
D1 
0 (Predose) 
30 min prior 
to 
dosing 
X 
X 
C7, C10、 
C13 and 
C16, and 
every 8 
cycles 
afterwards 
D1 
0 (Predose) 
 
 
30 min prior 
to 
dosing 
X 
X 
Abbreviations: EOI, end of infusion; ADA, anti-drug antibody; PK, pharmacokinetics 
a. It is important that PK sampling occurs as close as possible to the scheduled time. PK and immunogenicity sampling and ECG collection should be 
performed on the same day. Detailed sequential procedures are: 1) Scheduled triplicate ECG with an interval of at least 5 mins; 2) Vital sign measurements; 3) 
PK blood sampling; and 4) Any other tests and assessment required by the study. 
b. After BLU-554 is administered, the subject should be intravenously infused with CS1001 as soon as possible. For PK blood sampling, the recommended 
infusion time of CS1001 is 90 minutes. 
c. Collect two samples at one time point with BLU-554 blood sample be collected firstly and then CS1001 blood sample. 
d. The 24h PK sample of BLU-554 and the EOI+22.5h PK sample of CS1001 must be collected prior to dosing on the same day. 
e. Cycle 1 Day 1: "2 hours post BLU-554 dosing" ECG collection is allowed at 1 - 4 h post BLU-554 dosing; "end of CS1001 infusion + 30 min" ECG collection is 
allowed from the time after the completion of CS1001 infusion to 2.5 h post the completion of CS1001 infusion. If the ECG collection windows for these two time 
points on C1D1 do not overlap, i.e. two sets of ECG data will be collected. 


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Table 5:Schedule for PK and Immunogenicity Blood Sampling by Study Drugs in Phase II 
BLU-554a 
CS1001a 
ECGa, e 
Day 
Time 
Time 
window 
PK sampling 
Time 
Time window 
PK 
sampling 
ADA sampling 
of CS1001 
Cycle 1 
D1 
0 (Predose) 
30 min 
prior to 
dosing 
X 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
CS1001 dosingb 
2hc, e 
±10 min 
X 
EOI+30 minc, e 
± 15 min 
X 
X 
D2 
24hd 
± 1h 
X 
EOI+22.5hd 
± 1h 
X 
X 
Cycle 2 
D1 
0 (Predose) 
30 min 
prior to 
dosing 
X 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
CS1001 dosingb 
30 min 
± 5 min 
X 
1h 
± 5 min 
X 
2h 
± 10 min 
X 
X 
4h 
± 15 min 
X 
6h 
± 15 min 
X 
8h 
± 30 min 
X 
D2 
24hd 
± 1h 
X 
Cycle 4 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
X 
BLU-554 
dosingb 
CS1001 dosingb 
EOI+30 min 
± 15 min 
X 
X 
EOI+6h 
± 30 min 
X 
D2 
EOI+22.5hd 
± 1 h 
X 
D8 
EOI+168 h 
± 1 d 
X 
D15 
EOI+336h 
± 1 d 
X 


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BLU-554a 
CS1001a 
ECGa, e 
Day 
Time 
Time 
window 
PK sampling 
Time 
Time window 
PK 
sampling 
ADA sampling 
of CS1001 
Cycle 5 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
C7, C10、 
C13 and 
C16, and 
every 8 
cycles 
afterwards 
D1 
0 (Predose) 
30 min prior to 
dosing 
X 
X 
Abbreviations: EOI, end of infusion; ADA, anti-drug antibody; PK, pharmacokinetics 
a. It is important that PK sampling occurs as close as possible to the scheduled time. PK and immunogenicity sampling and ECG collection should be 
performed on the same day. Detailed sequential procedures are: 1) Scheduled triplicate ECG with an interval of at least 5 mins; 2) Vital sign 
measurements; 3) PK blood sampling; and 4) Any other tests and assessment required by the study. 
b. After BLU-554 is administered, the subject should be intravenously infused with CS1001 as soon as possible. For PK blood sampling, the 
recommended infusion time of CS1001 is 90 minutes. 
c. Collect two samples at one time point with BLU-554 blood sample be collected firstly and then CS1001 blood sample. 
d. The 24h PK sample of BLU-554 and the EOI+22.5h PK sample of CS1001 must be collected prior to dosing on the same day. 
e. Cycle 1 Day 1: "2 hours post BLU-554 dosing" ECG collection is allowed at 1 - 4 h post BLU-554 dosing; "end of CS1001 infusion + 30 min" ECG 
collection is allowed from the time after the completion of CS1001 infusion to 2.5 h after the completion of CS1001 infusion. If the ECG collection windows 
for these two time points on C1D1 do not overlap, i.e. two sets of ECG data will be collected. 
 
 


 
42 
 
Appendix 1 Processing of Missing Dates 
Missing dates in combined medications should be imputed as follows: 
For the start date, if only the day is missing, the date is defaulted to be the first day of the 
corresponding month, and if both the month and the day are missing, the date should be 
imputed as January 01. For the end date, if only the day is missing, the date is defaulted 
to be the last day of the corresponding month, and if both the month and the day are 
missing, the date should be imputed as December 31. The imputed start date should be 
earlier than the end date.  
Missing dates for adverse events (AEs) should be imputed as follows: 
1)  If the AE end date is missing  
 
If the year and month are known, the last day of the known month should be used for 
imputation. 
 
If only the year is known, “December 31” should be used for imputation. 
 
For AEs leading to death, the AE end date should be the date of death or the imputed 
end date, whichever is earlier. 
 
Dates in other situations are considered as missing. 
2) If the AE start date is missing  
 
If the year and month are known and earlier than the year and month of the first dose 
of the investigational drug, the last day of the known month should be used for 
imputation. 
 
If the year and month are known and equal to the year and month of the first dose of 
the investigational drug, the AE start date should be equal to the date of the first dose of 
the investigational drug (date refers to “XX month XX day”). 
 
If the year and month are known and later than the year and month of the first dose 
of the investigational drug, the first day of the known month should be used for 
imputation. 
 
If the year and month are known and the year is earlier than the year of the first dose 
of the investigational drug, “December 31” should be used for imputation. 
 
If only the year is known and equal to the year of the first dose of the investigational 
drug, the AE start date should be equal to the date of the first dose of the investigational 
drug (date refers to “XX month XX day”). 
 
If only the year is known and later than the year of the first dose of the 
investigational drug, “January 01” should be used for imputation. 


 
43 
 
 
If the year, month, and day are all missing, the date of the first dose of the 
investigational drug should be used as the corresponding start date. 
 
If the imputed start date is later than the end date, the end date should be used as the 
corresponding start date. 
 
Dates in other situations are considered as missing. 
If the date of death is incomplete: 
 
In the safety analysis, the death record needs to be included, and the missing date of 
death will not be imputed. 
 
In the efficacy analyses, if the year and month of the date of death are known, the 
first day of the month should be used for imputation. Otherwise, the date of death will not 
be imputed, and the death record will be censored for the calculation of time-event 
indicators (such as OS).