clinical trial protocol
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A Phase I Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Profiles and Efficacy of Oral BB102 Tablets in Patients with Advanced Solid Tumors Protocol No.: BB102-ST-I-02 Version: **Version 1.0**
Date: **Jul 14, 2022**
Sponsor: BroadenBio Co., Ltd.  
Contract Research Organization: **To be determined**
clinical trial protocol
confidentiality statement

All information contained in this protocol is the property of the sponsor and/or the contract research organization (CRO). Therefore, it is only provided to investigators, sub-investigators, the Ethics Committee, regulatory authorities and other related medical institutions for the purpose of review. Without a prior written permission of the sponsor and/or CRO, except offering necessary explanation during signing an informed consent form (ICF) with subjects who may participate in this study, disclosure of any information to a third party unrelated to this study is strictly prohibited.
clinical trial protocol
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Conduct this study in strict accordance with the protocol, *Good Clinical Practice* (GCP) and applicable laws and regulations.  
Keep all materials provided by the sponsor according to the confidentiality requirements. It must be indicated that these materials are confidential when they are required to be submitted to the Institutional Review Board (IRB) or Ethics Committee (EC).
clinical trial protocol
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| Responsible                      | Person               |     |
|----------------------------------|----------------------|-----|
| of the Sponsor                   | Position             |     |
| Signature                        | Date                 |     |
| Company Name                     | BroadenBio Co., Ltd. |     |
| Contact Address                  | Postal Code          |     |
| Telephone Statistician           | Position             |     |
| Signature                        | Date                 |     |
| Company Name Contact Address     | Postal Code          |     |
| Telephone Principal Investigator | Title                | and |
| Position                         |                      |     |
| Signature                        | Date                 |     |
| Clinical                         | Trial                |     |
| Institution Contact Address      | Postal Code          |     |
| Telephone                        |                      |     |  
| Sponsor Company Name                              | BroadenBio Co., Ltd.   |        |         |         |          |     |             |        |
|---------------------------------------------------|------------------------|--------|---------|---------|----------|-----|-------------|--------|
| Project Leader                                    | Position               |        |         |         |          |     |             |        |
| Room 602, 6th Floor, Unit 1, Building 7, Yard 88, |                        |        |         |         |          |     |             |        |
| Contact Address                                   | Kechuang               | 6th    | Street, | Beijing | Economic | and | Postal Code | 100176 |
| Technological Development Zone, Beijing           |                        |        |         |         |          |     |             |        |
| Telephone                                         | Mobile                 |        |         |         |          |     |             |        |
| Fax                                               | None                   | E-mail |         |         |          |     |             |        |
| Company Name Medical Expert                       | Position               |        |         |         |          |     |             |        |
| Contact Address                                   | Postal Code            |        |         |         |          |     |             |        |
| Telephone                                         | Mobile                 |        |         |         |          |     |             |        |
| Fax                                               | E-mail                 |        |         |         |          |     |             |        |
clinical trial protocol
contract research organization

| Company Name Project Leader   | Position    |
|-------------------------------|-------------|
| Contact Address               | Postal Code |
| Telephone                     | Mobile      |
| Fax                           | E-mail      |
clinical trial protocol
data management

| Company Name Project Leader   | Position    |
|-------------------------------|-------------|
| Contact Address               | Postal Code |
| Telephone                     | Mobile      |
| Fax                           | E-mail      |  
| Statistical Analysis Institution Company Name Project Leader   | Position    |
|----------------------------------------------------------------|-------------|
| Contact Address                                                | Postal Code |
| Telephone                                                      | Mobile      |
| Fax                                                            | E-mail      |
clinical trial protocol
pk sample testing facility

| Company Name Project Leader   | Position    |
|-------------------------------|-------------|
| Contact Address               | Postal Code |
| Telephone                     | Mobile      |
| Fax                           | E-mail      |
clinical trial protocol
biomarker sample testing facility

| Company Name Project Leader   | Position    |
|-------------------------------|-------------|
| Contact Address               | Postal Code |
| Telephone                     | Mobile      |
| Fax                           | E-mail      |  
| Table of Content                                                                                                                          |                                                                                                                                                      |
|-------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|
| CLINICAL TRIAL PROTOCOL                                                                                                                   |                                                                                                                                                      |
| PROTOCOL SIGNATURE PAGE                                                                                                                   |                                                                                                                                                      |
| TABLE OF CONTENT .                                                                                                                        |                                                                                                                                                      |
| ABBREVIATIONS                                                                                                                             |                                                                                                                                                      |
| PROTOCOL SYNOPSIS                                                                                                                         |                                                                                                                                                      |
| STUDY FLOW CHART.......................................................................................................................40 |                                                                                                                                                      |
| 1.                                                                                                                                        | STUDY BACKGROUND .................................................................................................................49                 |
| 1.1                                                                                                                                       | D DISEASE I NTRODUCTION ......................................................................................................49                     |
| 1.2                                                                                                                                       | M M ECHANISM OF A CTION OF FGFR4 I NHIBITORS .................................................................49                                     |
| 1.3                                                                                                                                       | OVERVIEW OF CLINICAL TRIALS OF SIMILAR DRUGS ..............................................................50                                        |
| 1.4                                                                                                                                       | BB102 Introduction .                                                                                                                                 |
| 1.5                                                                                                                                       | SUMMARY OF NONCLINICAL STUDIES OF BB102 ...........................................................................56                                |
| 1.5.1                                                                                                                                     | Pharmacology .                                                                                                                                       |
| 1.5.2                                                                                                                                     | (Nonclinical) PK ................................................................................................................60                  |
| 1.5.3                                                                                                                                     | Toxicology .....................................................................................................................64                   |
| 1.6 OVERVIEW OF CLINICAL TRIALS OF BB102 ........................................................................69                       |                                                                                                                                                      |
| 1.7                                                                                                                                       | R R ISK - BENEFIT A SSESSMENT ..............................................................................................................69       |
| 2.                                                                                                                                        | STUDY OBJECTIVES .                                                                                                                                   |
| 2.1                                                                                                                                       | D DOSE E SCALATION T RIAL ........................................................................................................................73 |
| 2.2                                                                                                                                       | E E XPANSION T RIAL                                                                                                                                  |
| 3.                                                                                                                                        | SELECTION AND WITHDRAWAL OF SUBJECTS ...............................................................74                                               |
| 3.1                                                                                                                                       | INCLUSION CRITERIA ...........................................................................................................................74     |
| 3.2                                                                                                                                       | E E XCLUSION C RITERIA                                                                                                                               |
| 3.3                                                                                                                                       | WITHDRAWAL OF SUBJECTS ..........................................................................................................................78  |
| 3.4                                                                                                                                       | R R ESCREENING .                                                                                                                                     |
| 4.                                                                                                                                        | OVERALL STUDY DESIGN ..............................................................................................................80                |
| 4.1                                                                                                                                       | S TUDY T YPE /D ESIGN ..........................................................................................................................80   |
| 4.1.1                                                                                                                                     | Dose escalation trial (6 fasted dose escalation groups and 1 fed dose                                                                                |
| escalation group)                                                                                                                         |                                                                                                                                                      |
| Expansion trial (expansion groups) ..........................................................................86                           |                                                                                                                                                      |
| 4.1.2                                                                                                                                     |                                                                                                                                                      |
| 4.2                                                                                                                                       | RANDOMIZATION AND BLINDING .................................................................................................86                       |
| 4.2.1                                                                                                                                     | Screening number ..............................................................................................................87                    |
| 4.2.2                                                                                                                                     | Randomization method ...................................................................................................87                           |
| 4.2.3                                                                                                                                     | Blinding                                                                                                                                             |
| 4.2.4                                                                                                                                     | Blind code preservation, unblinding and unblinding procedures .................87                                                                    |
| 4.3                                                                                                                                       | STUDY PROCEDURES .............................................................................................................................87     |
| 4.3.1                                                                                                                                     | Screening period/baseline (D-28 to D-1)                                                                                                              |
| 4.3.2                                                                                                                                     | Single-dose phase (for dose escalation trial only) .............................................91                                                   |
| 4.3.3                                                                                                                                     | MMULTIPLE-dose phase ....................................................................................................94                          |
| 4.3.4                                                                                                                                     | End of study treatment visit (EOT; within 7 days after the last dose) ........103                                                                    |
| 4.3.5                                                                                                                                     | Follow-up period........................................................................................................................105          |
| 4.3.6                                                                                                                                     | Unscheduled visit...........................................................................................................107                      |
| 4.4 SAMPLE COLLECTION AND TESTING .....................................................................................107                |                                                                                                                                                      |
| 4.4.1                                                                                                                                     | PK samples.......................................................................................................................107                 |
| 4.4.2                                                                                                                                     | Samples for metabolite identification ......................................................................109                                      |  
| 4.4.3                                                                                                                                   | Detection of biomarkers:                                                                                                                             |    |
|-----------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|----|
| 4.4.4                                                                                                                                   | Other biological samples............................................................................................................110              |    |
| 4.5                                                                                                                                     | INTERIM ANALYSIS .                                                                                                                                   |    |
| Early Closure of the Study Site/Study Suspension/Early Termination of                                                                   |                                                                                                                                                      |    |
| 4.6                                                                                                                                     |                                                                                                                                                      |    |
| THE STUDY                                                                                                                               |                                                                                                                                                      |    |
| 4.7                                                                                                                                     | D D EFINITION OF S TUDY D ATA C OLLECTION C UT - OFF .                                                                                               |    |
| NUMBER OF STUDY SITES                                                                                                                   |                                                                                                                                                      |    |
| 4.8                                                                                                                                     |                                                                                                                                                      |    |
| 4.9                                                                                                                                     | S S TUDY D URATION .                                                                                                                                 |    |
| s.                                                                                                                                      | STUDY MEDICATION .                                                                                                                                   |    |
| 5.1                                                                                                                                     | DRUG NAME, DOSAGE FORM AND OTHER BASIC INFORMATION                                                                                                   |    |
| 5.1.1                                                                                                                                   | Investigational product (BB102 tablets) .....................................................................112                                     |    |
| 5.1.2                                                                                                                                   | Control drug .                                                                                                                                       |    |
| 5.2                                                                                                                                     | M METHOD OF A DMINISTRATION                                                                                                                          |    |
| 5.3                                                                                                                                     | S S TORAGE C ONDITIONS .                                                                                                                             |    |
| 5.4                                                                                                                                     | D DRUG PACKAGING AND LABELING                                                                                                                        |    |
| D DRUG MANAGEMENT                                                                                                                       |                                                                                                                                                      |    |
| 5.5                                                                                                                                     |                                                                                                                                                      |    |
| 6.                                                                                                                                      | TREATMENT OF SUBJECTS                                                                                                                                |    |
| 6.1                                                                                                                                     | INVESTIGATIONAL TREATMENT                                                                                                                            |    |
| 6.1.1                                                                                                                                   | Dosing schedule (treatment time) ...........................................................................................16                       |    |
| 6.1.2                                                                                                                                   | Dose interruption, resumption, adjustment and permanent discontinuation                                                                              |    |
| during the dosing period .                                                                                                              |                                                                                                                                                      |    |
| 6.1.3                                                                                                                                   | Medication error and overdose ..............................................................................121                                      |    |
| 6.1.4                                                                                                                                   | Treatment of missed doses ...........................................................................................122                             |    |
| 6.2                                                                                                                                     | CONCOMITANT MEDICATIONS .........................................................................................................122                 |    |
| 6.3 Compliance of Subjects .........................................................................................................125 |                                                                                                                                                      |    |
| 7.                                                                                                                                      | STUDY ENDPOINTS .................................................................................................................................127 |    |
| 7.1                                                                                                                                     | D DOSE E SCALATION T RIAL ...............................................................................................................127         |    |
| 7.2                                                                                                                                     | E E XPANSION T RIAL                                                                                                                                  |    |
| SAFETY EVALUATION                                                                                                                       |                                                                                                                                                      |    |
| 8.                                                                                                                                      | 8.1                                                                                                                                                  | AE |
| 8.1.1                                                                                                                                   | Definition of AE                                                                                                                                     |    |
| 8.1.2                                                                                                                                   | Collection and reporting process of AEs ..............................................................130                                            |    |
| 8.1.3                                                                                                                                   | Evaluation of severity ..............................................................................................131                             |    |
| 8.1.4                                                                                                                                   | Evaluation of causal relationship ...........................................................................131                                     |    |
| Study drug-related actions .........................................................................................132                 |                                                                                                                                                      |    |
| 8.1.5                                                                                                                                   |                                                                                                                                                      |    |
| 8.1.6                                                                                                                                   | OUtcome of AEs .........................................................................................................................133          |    |
| 8.2                                                                                                                                     | ADR                                                                                                                                                  |    |
| 8.3                                                                                                                                     | SAE                                                                                                                                                  |    |
| 8.3.1                                                                                                                                   | Definition of SAE ..................................................................................................................133              |    |
| 8.3.2                                                                                                                                   | Collection and reporting of SAEs .................................................................................135                                |    |
| 8.5                                                                                                                                     | A A DVERSE E VENTS OF S PECIAL I NTEREST (AESIS) ..............................................................135                                   |    |
| 8.6                                                                                                                                     | S SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) .....................136                                                                   |    |
| 8.7                                                                                                                                     | PREGNANCY                                                                                                                                            |    |
| 9.                                                                                                                                      | DATA MANAGEMENT ........................................................................................................................138          |    |
| COMPLETION AND TRANSFER OF SOURCE DATA AND ECRF ...........................................138                                          |                                                                                                                                                      |    |
| 9.1                                                                                                                                     |                                                                                                                                                      |    |
| 9.2                                                                                                                                     | DATABASE DESIGN                                                                                                                                      |    |  
| 9.3                                                                                                                                                            | D DATA E NTRY                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------|
| 9.4                                                                                                                                                            | DATA VERIFICATION                                                                                                                         |
| 9.5                                                                                                                                                            | MMEDICAL CODING                                                                                                                           |
| 9.6 D ATABASE L OCKING AND U NLOCKING .....................................................................................139                                 |                                                                                                                                           |
| 9.7                                                                                                                                                            | BLINDING VERIFICATION AND UNBLINDING                                                                                                      |
| 10.                                                                                                                                                            | STATISTICAL ANALYSIS ..........................................................................................................141        |
| 10.1 S AMPLE S IZE ...................................................................................................................................141      |                                                                                                                                           |
| 10.2 S TATISTICAL A NALYSIS S ET ...................................................................................................141                        |                                                                                                                                           |
| 10.3 GENERAL PRINCIPLES FOR STATISTICS .................................................................................141                                    |                                                                                                                                           |
| 10.4 S TATISTICAL M ETHODS ........................................................................................................142                         |                                                                                                                                           |
| 10.4.1 Subject disposition analysis .................................................................................142                                       |                                                                                                                                           |
| 10.4.2 Analysis of demographics and baseline characteristics ..................................142                                                             |                                                                                                                                           |
| 10.4.3 Analysis of compliance and concomitant medications .................................142                                                                 |                                                                                                                                           |
| 10.4.4 Safety analysis ...........................................................................................................142                          |                                                                                                                                           |
| 10.4.5  DLT analysis ..................................................................................................................143                     |                                                                                                                                           |
| 10.4.6 PK parameters analysis ..........................................................................................143                                    |                                                                                                                                           |
| 10.4.7 Analysis of food effect                                                                                                                                 |                                                                                                                                           |
| 10.4.8 Efficacy analyses ......................................................................................................144                             |                                                                                                                                           |
| 10.4.9  Biomarker analysis                                                                                                                                     |                                                                                                                                           |
| 10.4.10                                                                                                                                                        |                                                                                                                                           |
| analysis                                                                                                                                                       |                                                                                                                                           |
| 10.4.11Metabolite analysis ..................................................................................................145                               |                                                                                                                                           |
| 10.4.12                                                                                                                                                        |                                                                                                                                           |
| analysis                                                                                                                                                       |                                                                                                                                           |
| 10.4.13                                                                                                                                                        |                                                                                                                                           |
| analysis                                                                                                                                                       |                                                                                                                                           |
| 1.                                                                                                                                                             | TRIAL MANAGEMENT .....................................................................................................................146 |
| 1.1 S TATEMENT .                                                                                                                                               |                                                                                                                                           |
| 1.2 ETHICAL CONSIDERATIONS .........................................................................................................146                        |                                                                                                                                           |
| 1.3 S OURCE D ATA V ERIFICATION .......................................................................................................146                     |                                                                                                                                           |
| 1.4 QUALITY ASSURANCE                                                                                                                                          |                                                                                                                                           |
| 1.4.1 Requirements for Sponsor.....................................................................................147                                         |                                                                                                                                           |
| 1.4.2 Requirements for Investigators ..............................................................................148                                         |                                                                                                                                           |
| 1.4.3 Statistical analysis                                                                                                                                     |                                                                                                                                           |
| 1.5 I NFORMED C ONSENT .....................................................................................................................148                |                                                                                                                                           |
| 1.6 T RIAL P ROTOCOL R EVISION R ULES  ...........................................................................................149                          |                                                                                                                                           |
| 1.7 ECRF ..................................................................................................................................................149 |                                                                                                                                           |
| 1.8 M ONITORING .....................................................................................................................................150       |                                                                                                                                           |
| 1.9 Confidentiality and Privacy of Subjects .................................................................150                                               |                                                                                                                                           |
| 1.10 .                                                                                                                                                         |                                                                                                                                           |
| 0                                                                                                                                                              | 1.10.1Protocol deviations.................................................................................................150             |
| 1.10.2Personnel training ...................................................................................................151                                |                                                                                                                                           |
| 1.10.3Curriculum vitae of clinical investigator ........................................................151                                                    |                                                                                                                                           |
| 1.10.4Qualification certificates of clinical laboratories and range of normal values                                                                           |                                                                                                                                           |
| 151                                                                                                                                                            |                                                                                                                                           |  
| 11.10.5Agreement of clinical study protocol 151 11.10.6Insurance 151   |                                                        |
|------------------------------------------------------------------------|--------------------------------------------------------|
| 12.                                                                    | INTELLECTUAL PROPERTY RIGHTS AND PAPER PUBLICATION 152 |
| 13.                                                                    | CLINICAL DATA ARCHIVING 154                            |
| 14.                                                                    | REFERENCES 155                                         |
| 15.                                                                    | APPENDIX 157                                           |
clinical trial protocol
list of tables

| Table 1 Study status of FGFR4 inhibitors 50 Table 2 Basic information of BB102 tablets 112 Table 3 Criteria for evaluation of causal relationship between AE and study drug 131 Table 4 Time point response: patients with target (+/- non-target) disease 165 Table 5 Time point response: patients with non-target disease only 166 Table 6 Best overall response when confirmation of CR and PR required 167   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
clinical trial protocol
list of figures

| Figure 1 The modified 3+3 escalation design in dose escalation trial 83 Figure 2 The accelerated escalation diagram in dose escalation trial 83 Figure 3 The 3+3 escalation diagram in dose escalation trial 84   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Abbreviations           |                                                                                                      |
|-------------------------|------------------------------------------------------------------------------------------------------|
| Abbreviations and terms | Interpretation                                                                                       |
| ABEOS                   | Absolute eosinophil count                                                                            |
| ABLYMP                  | Absolute lymphocyte count                                                                            |
| ABMONO                  | Absolute monocyte count                                                                              |
| ABRETIC                 | Absolute reticulocyte count                                                                          |
| ADR                     | Adverse drug reaction                                                                                |
| AE                      | Adverse event                                                                                        |
| AESI                    | Adverse event of special interest                                                                    |
| AFP                     | Alphafetoprotein                                                                                     |
| ALB                     | Albumin                                                                                              |
| ALP                     | Alkaline phosphatase                                                                                 |
| ALT                     | Alanine aminotransferase                                                                             |
| ANC                     | Absolute neutrophil count                                                                            |
| AST                     | Aspartate aminotransferase                                                                           |
| AUC                     | Area under the plasma concentration-time curve                                                       |
| AUCss                   | Area under the plasma concentration-time curve during a dosing interval at  steady state             |
| AUC0-inf                | Area under the plasma concentration-time curve from time 0 to infinity                               |
| AUC0-t or AUClast       | Area under the drug concentration-time curve from 0 to the time point of  quantifiable concentration |
| BCRP                    | Breast cancer resistance protein                                                                     |
| BID                     | Twice daily                                                                                          |
| BMI                     | Body mass index                                                                                      |
| BS                      | Biomarker analysis set                                                                               |
| CA125                   | Carbohydrate antigen 125                                                                             |
| CA15-3                  | Carcinoma antigen 15-3                                                                               |
| CA242                   | Carbohydrate antigen 242                                                                             |
| CEA                     | Carcinoembryonic antigen                                                                             |
| c-Fos                   | Immediate-early gene                                                                                 |
| CK                      | Creatine kinase                                                                                      |
| CKI                     | Creatine kinase isozyme                                                                              |
| CLz/F                   | Apparent clearance                                                                                   |
| Cmax                    | Peak concentration                                                                                   |
| CR                      | Complete response                                                                                    |
| CRO                     | Contract Research Organization                                                                       |
| Css, av                 | Mean plasma concentration at steady state                                                            |
| Css, max                | Peak concentration at steady state                                                                   |
| Css, min                | Trough concentration at steady state                                                                 |
| CT                      | Computed tomography                                                                                  |  
| Abbreviations and terms   | Interpretation                                |
|---------------------------|-----------------------------------------------|
| CTCAE                     | Common terminology criteria for adverse event |
| CTGF                      | Connective tissue growth factor               |
| CYFRA21-1                 | Cytokeratin 19                                |
| DCR                       | Disease control rate                          |
| DF                        | Fluctuation coefficient at steady state       |
| DLT                       | Dose-limiting toxicity                        |
| DM                        | Data Manager                                  |
| DOR                       | Duration of response                          |
| DS                        | DLT set                                       |
| ECOG                      | Eastern Cooperative Oncology Group            |
| eCRF                      | Electronic case report form                   |
| EDC                       | Electronic data capture                       |
| Egr-1                     | Early growth response gene-1                  |
| EMT                       | Epithelial-mesenchymal transition             |
| EOT                       | End of treatment visit                        |
| FGFR                      | Fibroblast growth factor receptor             |
| FGFR1                     | Fibroblast growth factor receptor 1           |
| FGFR2                     | Fibroblast growth factor receptor 2           |
| FGFR3                     | Fibroblast growth factor receptor 3           |
| FGFR4                     | Fibroblast growth factor receptor 4           |
| FGF19                     | Fibroblast growth factor 19                   |
| GCP                       | Good Clinical Practice                        |
| GGT                       | γ-glutamyltransferase                         |
| GLO                       | Globulin                                      |
| GLU                       | Fasting plasma glucose                        |
| GSK3β                     | Glycogen synthase kinase-3β                   |
| Hb                        | Hemoglobin                                    |
| HBsAg                     | Hepatitis B surface antigen                   |
| HBV                       | Hepatitis B virus                             |
| HCC                       | Hepatocellular carcinoma                      |
| HCG                       | Human chorionic gonadotropin                  |
| HCT                       | Haematocrit                                   |
| HCV                       | Hepatitis C virus                             |
| HCV-Ab                    | Hepatitis C virus antibody                    |
| HDL                       | High density lipoprotein cholesterol          |
| HIV-Ab                    | Human immunodeficiency virus antibody         |
| HNSTD                     | Highest non-severely toxic dose               |
| ICC                       | Intrahepatic cholangiocarcinoma               |
| ICF                       | Informed Consent Form                         |  
| Abbreviations and terms   | Interpretation                                                     |
|---------------------------|--------------------------------------------------------------------|
| ICH                       | International Conference on Harmonization                          |
| IC50                      | Half maximal inhibitory concentration                              |
| IHC+                      | Immunohistochemistry positive                                      |
| IL-6                      | Interleukin-6                                                      |
| Kel                       | Elimination rate constant                                          |
| LDH                       | Lactate dehydrogenase                                              |
| LDL                       | Low density lipoprotein cholesterol                                |
| LVEF                      | Left ventricular ejection fraction                                 |
| MCHC                      | Mean corpuscular hemoglobin concentration                          |
| mDOR                      | Median duration of response                                        |
| MedDRA                    | Medical Dictionary for Regulatory Activities                       |
| MEK-ERK                   | Mitogen extracellular kinase/extracellular signal-regulated kinase |
| mPFS                      | Median progression-free survival                                   |
| MRI                       | Magnetic resonance imaging                                         |
| MRSD                      | Maximum recommended starting dose                                  |
| MRT                       | Mean residence time                                                |
| MTD                       | Maximum tolerated dose                                             |
| NOAEL                     | No observed adverse effect level                                   |
| ORR                       | Objective response rate                                            |
| OS                        | Overall survival                                                   |
| PFS                       | Progression-free survival                                          |
| P-gp                      | P-glycoprotein                                                     |
| PI3K/AKT                  | Phosphatidylinositol 3 kinase/protein kinase B                     |
| PK                        | Pharmacokinetics                                                   |
| PKS                       | PK set                                                             |
| PLT                       | Platelet                                                           |
| PR                        | Partial response                                                   |
| PSA                       | Prostatic specific antigen                                         |
| QD                        | Once daily                                                         |
| QTcF                      | QT interval corrected by Fridericia                                |
| Rac                       | Accumulation ratio                                                 |
| RBC                       | Red blood cell                                                     |
| RP2D                      | Recommended phase Ⅱ dose                                           |
| SAE                       | Serious adverse event                                              |
| SD                        | Stable disease                                                     |
| SMC                       | Safety Monitoring Committee                                        |
| SOP                       | Standard operating procedure                                       |
| SS                        | Safety set                                                         |
| STD10                     | Severely toxic dose to 10% of animals                              |  
| Abbreviations and terms   | Interpretation                                |
|---------------------------|-----------------------------------------------|
| SUSAR                     | Suspected unexpected serious adverse reaction |
| TBIL                      | Total bilirubin                               |
| T/C                       | Treatment/control ratio                       |
| TG                        | Triglyceride                                  |
| TGF-β                     | Transforming growth factor beta               |
| TGI                       | Tumor growth inhibition                       |
| TKI                       | Tyrosine kinase inhibitor                     |
| tlag                      | Lag time                                      |
| Tmax                      | Time to maximum plasma concentration          |
| T1/2                      | Half-life                                     |
| ULN                       | Upper limit of normal                         |
| Vz/F                      | Apparent volume of distribution               |
| WBC                       | White blood cell                              |
| WHO                       | World Health Organization                     |
| 95% CI                    | 95% confidence interval                       |  
| Protocol Synopsis   |                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
|---------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Protocol No.        | BB102-ST-I-02                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Protocol Title      | A Phase I Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Profiles and  Efficacy of Oral BB102 Tablets in Patients with Advanced Solid Tumors                                                                                                                                                                                                                                                                                         |
| Version No.         | Version 1.0                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| Date                | Jul 14, 2022                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Sponsor             | BroadenBio Co., Ltd.                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Trial Phase         | Phase I                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Study               | Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that selectively                                                                                                                                                                                                                                                                                                                                                                 |
| Background          | binds to fibroblast growth factor 19 (FGF19) for dimerization and autophosphorylation.  By activating the signaling pathways such as phosphatidylinositol 3‑kinase/protein kinase  B (PI3K/AKT), mitogen-activated extracellular signal-regulated kinase/extracellular  signal-regulated kinase (MEK-ERK), and glycogen synthase kinase-3β/β-catenin  (GSK3β/β-catenin), FGFR4 promotes tumor cell proliferation, promotes epithelialmesenchymal transition (EMT), and inhibits tumor cell apoptosis. Studies have found that,  overexpression of FGF19 and its receptor FGFR4 may upregulate early growth response  gene-1 (Egr-1), immediate early gene (c-Fos), interleukin-6 (IL-6), and connective tissue  growth factor (CTGF) to induce proliferation of liver cancer cells. Meanwhile, it promotes  EMT of liver cancer by activating GSK3β/β-catenin signaling pathway and promotes the  invasion and metastasis of liver cancer by activating transforming growth factor β (TGFβ). The abnormal signaling pathway of FGF19-FGFR4 complex has been confirmed to be  an oncogenic driver of hepatocellular carcinoma (HCC). Besides, FGF19 overexpression  is one of the mechanisms for sorafenib resistance. Therefore, FGFR4 is considered as a  new potential treatment target for liver cancer. A variety of small molecule FGFR4  inhibitors (e.g., BLU-554, FGF401) with different selectivity and binding patterns have  been developed, and the related clinical trials have been started (all ongoing) for the  treatment of HCC and other solid tumors with abnormal FGFR4 signal transduction. BB102 is a small molecule FGFR4 inhibitor independently discovered and developed by  the sponsor. It is an innovative drug/molecular, characterized by an explicit mechanism of  action, a high selectivity, high activities in vitro and in vivo (a variety of liver cancer,  rhabdomyosarcoma, and breast cancer xenograft models), and good safety.                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| Indications         | Dose escalation trial: advanced solid tumors Expansion trial: FGF19 or FGFR4 positive advanced primary HCC or other advanced  solid tumors                                                                                                                                                                                                                                                                                                                 |
| Trial               | Dose escalation trial                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Objectives          | Primary objectives: - To evaluate the safety and tolerability of different doses of BB102 tablets  monotherapy (fasted or fed) in patients with advanced solid tumors. - To explore the maximum tolerated dose (MTD) by observing the dose-limiting  toxicity (DLT) of BB102 tablets monotherapy (fasted or fed) within the specified dose  range, so as to provide rationale for determining the recommended phase II dose  (RP2D). Secondary objectives: |  
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | To investigate the pharmacokinetic (PK) profiles of BB102 tablets monotherapy  (fasted) administered as single and multiple oral doses in patients with advanced solid  tumors.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | To preliminarily investigate the effect of food on the PK profiles of BB102 tablets  monotherapy administered as single and multiple oral doses in patients with advanced  solid tumors.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | To preliminarily investigate the efficacy of BB102 tablets monotherapy (fasted or fed)  in patients with advanced solid tumors.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | To investigate the relationship between biomarker and efficacy and to preliminarily  infer the correlation.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | To explore the correlation between plasma concentration of study drug and Fridericia  method corrected QT interval (QTcF) (C-QTcF analysis).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | To identify the metabolites of BB102 in patients with advanced solid tumors.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| Expansion trial Primary objective: - To evaluate the efficacy of BB102 tablets monotherapy (fasted) in patients with  FGF19 or FGFR4 positive advanced primary HCC or other advanced solid tumors. Secondary objectives: - To investigate the PK profiles of BB102 tablets monotherapy (fasted) in patients with  FGF19 or FGFR4 positive advanced primary HCC or other advanced solid tumors. - To investigate the safety of BB102 tablets monotherapy (fasted) in patients with  FGF19 or FGFR4 positive advanced primary HCC or other advanced solid tumors. - To investigate the relationship between biomarker and efficacy and to preliminarily  infer the correlation. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Study Design                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | This study consists of a dose escalation trial and an expansion trial, both of which are  designed as multi-center and open-label trials. This study aims to investigate the safety,  tolerability, PK profiles and efficacy of BB102 tablets monotherapy (fasted or fed) orally  administered at different doses in patients with advanced solid tumors and to evaluate the  effect of food on the PK profiles. 1. Dose escalation trial (6 fasted dose escalation groups and 1 fed dose escalation  group) 1.1 Selection of starting dose and escalation doses According to the International Conference on Harmonisation of Technical Requirements  for Registration of Pharmaceuticals for Human Use (ICH)-S9 "Guideline on Nonclinical  Evaluation for Anticancer Pharmaceuticals", a common approach for many small  molecules anticancer drugs is to set a starting dose at 1/10 the severely toxic dose to 10%  of the animals (STD10) in rodents of repeat-dose toxicity study; if the non-rodent is the  most appropriate species, then 1/6 the highest non-severely toxic dose (HNSTD) is  considered an appropriate starting dose. According to the CDE "Technical Guidelines for  Clinical Trials of Anticancer Drugs" and "Considerations for Starting Dose Calculation  for Phase I Clinical Trial of New Anticancer Pharmaceuticals", in view of the ethical  factors in tumor patients, 1/3 to 1/5 the no observed adverse effect level (NOAEL) is most  commonly adopted for small molecule targeted anticancer pharmaceuticals. The |  
corresponding human doses are calculated using the body surface area method based on the above parameters and nonclinical effective starting dose. The female rat is the most sensitive species, and the corresponding maximum recommended starting dose (MRSD) is 107.4 mg/day based on the above parameters of nonclinical toxicology; the human equivalent dose calculated based on the nonclinical effective starting dose is 53.6 mg/day. With comprehensive consideration of the starting doses, escalation doses and RP2D of similar drugs as well as the strengths (10 mg, 50 mg) of BB102 tablets, this study plans to adopt 50 mg as the starting dose.  
With a reference to the MTD of repeat-dose toxicity study, MTD and RP2D in the first-inhuman study of similar drugs as well as the strengths (10 mg, 50 mg) of BB102 tablets, this study plans to adopt 420 mg as the maximum dose. Based on the modified Fibonacci method, the proposed fasted escalation doses are 50 mg once daily (QD), 100 mg QD, 160 mg QD, 240 mg QD, 320 mg QD and 420 mg QD. Taking into account the human dose corresponding to the nonclinical effective starting dose (53.6 mg/day), the accelerated escalation (enrolling 1 subject only) of 50 mg enables quick escalation to the effective dose under the premise of guaranteeing the safety of subjects and subsequently avoids excessive exposure of subjects to ineffective doses.  
In addition, according to the action mechanism of FGFR4 inhibitors, inhibition of FGF19/FGFR4 signaling pathway will upregulate CYP7A1 expression (CYP7A1 is associated with metabolism of bile acid) and subsequently cause an increase in bile acid secretion; bile acid secretion also increases after meal. Dose escalation trial of the similar drug FGF401 (NCT02325739) set up separate fed dose escalation groups. Therefore, in order to investigate the effect of food on the safety and tolerability (primary), PK profiles (secondary) of BB102 tablets monotherapy, in this study, an appropriate dose will be selected as the fed dose escalation group according to the previously obtained clinical trial data of BB102 tablets. Rationale for the selection of starting dose and escalation doses is detailed in Sections 4.1.1.1 and 4.1.1.2 of the main text.
clinical trial protocol
1.2 escalation method

This study adopts a modified 3+3 escalation design, including accelerated escalation and 3+3 escalation, with 6 fasted dose groups (50 mg QD, 100 mg QD, 160 mg QD, 240 mg QD, 320 mg QD and 420 mg QD) and 1 fed dose group. Note: Before the start of the dose escalation trial, the dosage of the fed dose group cannot be determined temporarily, and an appropriate dose will be selected subsequently by the safety monitoring committee (SMC) according to the previously obtained clinical trial data of BB102 tablets; the trial of the fed dose group can be synchronized with the dose escalation process of the fasted dose groups, and the trial of the fed dose group can also be started after the dose escalation of the fasted dose groups is completed, but the trial of the fed dose group must only be initiated after the equivalent dose is demonstrated to be safe under the fasted condition. The starting dose group (50 mg QD group) is the accelerated escalation group; other dose groups are 3+3 escalation groups. See the figure below. All subjects enrolled will firstly receive a single dose for safety observation and PK study, and then undergo a 5-day washout period. Later, subjects will receive multiple-dosing to continue the safety observation and PK study. Multiple-dosing is tentatively scheduled as: once daily in 21-  
  
In order to avoid excessive exposure of subjects to ineffective doses, the accelerated escalation group (50 mg QD group) is planned to enroll 1 subject. The method for judging dose escalation is shown in the figure below. During the DLT observation period (defined as the period from a single dose to the end of Cycle 1 of multiple-dosing), if there is no DLT or grade ≥3 drug-related toxicity [defined as an adverse event (AE) definitely/possibly related to the study drug], the enrollment of the next dose group will be started; if any DLT
or grade ≥3 drug-related toxicity occurs, the group will be converted to the 3+3 escalation mode.  
  
is shown in the figure below. For each dose group, if none of the 3 subjects experiences DLT, the trial will proceed to the next dose group. If ≥2 out of the 3 subjects experience DLT, the dose escalation will be discontinued. If 1 of the 3 subjects experiences DLT, 3 additional subjects should be enrolled into this dose group (if none of the 3 newly enrolled subjects experiences DLT, the trial will proceed to the next dose group; If ≥1 of the 3 newly enrolled subjects experience DLT, dose escalation will be discontinued).
clinical trial protocol
the 3+3 escalation diagram in

The second and third subjects in the 3+3 escalation groups should only be enrolled after the first subject is observed for at least 5 days after dosing (enrolled on or after C1D1 of the first subject). If the previous subject experiences DLT, the sponsor and the investigator need to cautiously judge whether to enroll the next subject based on the safety data; if subsequent subjects have already been enrolled, the enrolled subjects should continue the study treatment (unless these subjects meet the criteria for study treatment discontinuation),
with his/her safety data closely monitored.  
SMC will decide whether to perform dose escalation or reduction and determine whether to and how to adjust the escalation doses based on the safety, tolerability and/or PK data obtained during the DLT observation period of a certain dose group. Based on the safety, tolerability, PK and efficacy data of a certain group, if the investigator believes that it is necessary to expand the number of subjects of this dose group to further observe the safety and efficacy and obtain PK data, the number of subjects of this dose group may be increased to 4-12 after reaching a consensus with the sponsor through discussion. To ensure the safety of subjects, the washout time after single-dosing, dosing frequency, cycle setting, and time points of PK sample collection in the subsequent study as well as the design of subsequent escalation doses (e.g., adding dose groups of 520 mg QD and 600 mg QD) may be timely adjusted based on the previously obtained safety, tolerability, PK
parameters [e.g., half-life (T1/2), drug accumulation after multiple-dosing] and other previously obtained clinical trial data of BB102 tablets.  
MTD is defined as the highest dose level in which DLT occurs in ≤1/6 of the total subjects during the DLT observation period. If MTD is not reached after administration of the maximum dose level shown above, the SMC will decide whether to increase dose groups based on the nonclinical data and the efficacy doses and PK parameters of domestic and foreign similar drugs observed in human.
clinical trial protocol
1.3 definition of a dlt

DLT observation period is defined as the period from a single dose to the end of Cycle 1 of multiple-dosing.  
DLT is defined as an AE definitely/possibly related to the study drug occurring in the DLT
observation period [AEs will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0] which meets any of the following criteria:
clinical trial protocol
(1) hematologic toxicity

1) Grade 4 neutrophil count decreased for >3 days.  
2) Grade 3 febrile neutropenia: absolute neutrophil count (ANC) <1.0×109/L with single temperature ≥38.3oC (101℉) or persistent temperature ≥38oC (100.4℉) for more than 1 hour. 3) Grade 4 Platelet (PLT) count decreased.  
4) Grade 3 PLT count decreased with bleeding. 5) Grade 4 anemia.  
6) Other grade 3 hematologic toxicities which do not recover to grade ≤2 after 7 days of symptomatic supportive treatment.
clinical trial protocol
(2) non-hematologic toxicity

1) Grade ≥4 non-hematologic toxicity. Note: Toxicities with no safety risk at the discretion of the investigator are excepted, such as grade 4 γ-glutamyltransferase (GGT) increased and alkaline phosphatase (ALP) increased.  
2) Grade 3 non-hematologic toxicity (including but not limited to hepatobiliary disorders). Note: Toxicities with no safety risk at the discretion of the investigator (such as grade 3 nausea, vomiting, diarrhea, asthenia, constipation, loss of appetite, mucositis, GGT
increased, ALP increased) are not defined as DLT, but they will be defined as DLT when the toxicities do not recover to grade ≤2 within 7 days under the circumstance of symptomatic supportive treatment are permitted.  
(3) **Other conditions** 1) The grade is elevated from baseline with clinically significant and/or unacceptable toxicity, which is judged as a DLT by the SMC.  
2) Drug discontinuation lasting 7 days or more due to drug-related toxicity. 3) The dose received by the subject during the DLT observation period is less than 75% of the scheduled dose due to toxicities attributable to study drug, and the investigator believes that it should be considered as a DLT.
clinical trial protocol
1.4 dlt evaluable subjects

If the dose received by a subject during the DLT observation period is less than 75% of the scheduled dose for reasons other than toxicities attributable to study drug, this subject should not be included into the final DLT analysis of this dose group or the overall groups.  
If the above situation occurs in any subject, the corresponding dose group needs to enroll one more subject for replacement to ensure the minimum required number of DLT
evaluable subjects.
clinical trial protocol
2. expansion trial (expansion groups)

Based on the safety, tolerability, PK and efficacy data obtained in previous trials, 1 to 3 appropriate doses (e.g., 100 mg QD, 160 mg QD, and 240 mg QD) will be selected for the expansion trial.  
The expansion trial can be initiated when the above doses are demonstrated to have a favorable safety in the dose escalation trial (i.e., the number of subjects experiencing DLT  
| in the group is ≤1/6 of total subjects of the group), without waiting for the completion of  the entire dose escalation trial. Each expansion group will enroll 12 subjects to investigate the efficacy, safety and PK  profiles of BB102 tablets. During the expansion trial, AEs meeting the definition of DLT  will be regarded as AEs of special interest for safety assessment, thereby enriching the  safety assessment data. 3. Collection and analysis of PK samples During the single-dosing period of the dose escalation trial, the PK blood sampling  time points are as follows: within 0.5 h (0 h) before single-dosing on D1 and 1 h (±3 min),  2 h (±3 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min), 24 h (±1 h; D2),  48 h (±1 h; D3), 72 h (±2 h; D4) and 96 h (±2 h; D5) after dosing. During the multiple-dosing period of the dose escalation trial, the PK blood sampling  time points are as follows: within 0.5 h pre-dose on C1D1, within 0.5 h pre-dose on C1D8,  within 0.5 h pre-dose on C1D15, within 0.5 h pre-dose and 1 h (±3 min), 2 h (±3 min), 4 h  (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min) and 24 h (±30 min; collected  before dosing on C2D1) post-dose on C1D21. During the expansion trial, the PK blood sampling time points are as follows: within  0.5 h pre-dose on C1D1, within 0.5 h pre-dose on C1D8, within 0.5 h pre-dose on C1D15,  within 0.5 h pre-dose and 1 h (±3 min), 2 h (±3 min), 4 h (±10 min), 6 h (±10 min), 8 h  (±10 min), 10 h (±10 min), and 24 h (±30 min; collected before dosing on C2D1) post-dose  on C1D21. The PK blood sampling time points of the subsequent study may be adjusted based on the  previously obtained clinical trial data of BB102 tablets. If there is dose interruption or missed dose(s) of BB102 tablets within 3 days before a PK  sample collection time point, the investigator should discuss its impact on the PK sampling  schedule with the sponsor and clinical pharmacologist as soon as possible within 24 hours  of awareness, thereby determining whether to continue PK blood sampling as planned and  how to adjust the PK blood sampling time points. The date and time of each dosing and  each blood sampling should be recorded. Concentration of BB102 (and its main metabolites, if applicable) in the PK samples will  be quantitatively measured using the methodologically validated high-performance liquid  chromatography- mass spectrometry/ mass spectrometry (HPLC-MS/MS) method. 4. Identification of metabolites Blood samples will be collected for identification of metabolites only at a high dose group  (e.g., 160 mg QD, 240 mg QD, 320 mg QD or 420 mg) during the single-dosing period of  the dose escalation trial. Blood sampling time points: within 0.5 h (0 h) before single-dosing on D1 and 1 h (±3  min), 2 h (±3 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 10 h (±10 min), 24 h (±1  h; D2), 48 h (±1 h; D3), 72 h (±2 h; D4) and 96 h (±2 h; D5) after dosing. 5. Interim analysis No interim analysis will be performed in this study.   |                                                                                                                                               |
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| Total Number                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | This trial plans to enroll 31-78 subjects in total.                                                                                           |
| of Subjects                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | It is expected that the dose escalation trial will enroll 19-42 subjects. It is expected that the expansion trial will enroll 12-36 subjects. |  
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| Study Sites Study            | Approximately 24 months                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                   |
| Duration Selection  Criteria | of                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                   |
| Subjects                     | Inclusion criteria: Patients must meet all of the following criteria before being enrolled in the study: (1) 18-78 years of age (inclusive) in dose escalation trial and ≥18 years of age in  expansion trial at the time of signing the informed consent form (ICF), male or female. (2) For the dose escalation trial, histologically, cytologically confirmed or clinically  confirmed advanced solid tumors patients who without available standard treatment, failed  in standard treatment or cannot tolerate standard treatment (primary HCC patients are  preferred; primary HCC patients should have a liver function score of ≤9 points as assessed  according to the Child-Pugh classification criteria). Note: Only primary liver cancer can  be clinically diagnosed, and other tumors need to be confirmed by histology or cytology. For the expansion trial, histologically or cytologically confirmed FGF19 or FGFR4  positive advanced primary HCC (primary HCC patients should have a liver function score  of ≤9 points as assessed according to the Child-Pugh classification criteria) or other  advanced solid tumors patients who without available standard treatment, failed in standard  treatment or cannot tolerate standard treatment. Note: FGF19 or FGFR4 positivity includes  but is not limited to FGF19 amplification, FGF19 overexpression, elevation of serum  FGF19 protein level, FGFR4 amplification, FGFR4 overexpression and FGFR4 activating  mutation. At the discretion of the investigator, the patient's previous positive test results  for FGF19 or FGFR4 can be accepted (patients must agree to provide previous positive test  results for FGF19 or FGFR4). Newly reported FGF19 or FGFR4 positive test results from  a central laboratory based on tumor tissue and/or blood samples are also acceptable  (patients must agree to provide tumor tissue samples and/or blood samples for FGF19 or  FGFR4 positive testing. If there are special circumstances such as the tissue is difficult to  obtain or the risk of obtaining biopsy is high, etc., the investigator can communicate with  the sponsor to discuss whether it can be exempted. Tumor tissue: During screening period,  tumor tissue samples from patients in the past 2 years or fresh tumor tissue samples can be  collected; the samples can be collected from the primary lesion or metastatic lesions.  Blood: A fresh blood sample 5 mL can be collected during the screening period). (3) For the dose escalation trial, at least one evaluable tumor lesion according to the  Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix I). For the expansion trial, at least one measurable tumor lesion according to RECIST v1.1. (4) Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1  (Appendix II). (5) Life expectancy of ≥3 months. (6) With good organ function, including: ➢ Liver function: total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN), alanine  aminotransferase (ALT) ≤3×ULN, and aspartate aminotransferase (AST) ≤3×ULN  (for patients with liver cancer or liver metastases, the criteria will be TBIL ≤3×ULN,  ALT ≤5×ULN, and AST ≤5×ULN); |                                                   |  
➢ Renal function: blood creatinine ≤1.5×ULN and creatinine clearance rate ≥50 mL/min
(calculated based on Cockcroft-Gault formula);
➢ Hematology (no blood transfusion or hematopoietic stimulating factor therapy within 14 days of blood sampling for hematology): PLT ≥100×109/L (for patients with liver cancer, the criteria will be PLT ≥85×109/L), ANC ≥1.5×109/L, and hemoglobin (Hb)
≥90 g/L (90 mg/mL);
➢ Coagulation function: activated partial thromboplastin time ≤1.5×ULN and international normalized ratio ≤1.5×ULN.  
(7) For female patients of childbearing potential, the pregnancy test result within 7 days before the first dose is negative and promise to use adequate and effective methods of contraception or abstinence from the start of screening period to 6 months after the last dose of study treatment; male patients who promise to use adequate and effective methods of contraception or abstinence from the start of screening period to 6 months after the last dose of study treatment. The definition of female with childbearing potential and contraceptive requirements are detailed in Appendix III.  
(8) Voluntarily participate in this clinical study, understand the content of the ICF and sign it voluntarily, with good compliance.